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79087151 Fitzpatrick Dermatology

79087151 Fitzpatrick Dermatology

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Fitzpctrick's uermatology ln Ceneral Medlclne SFvFhTh Ful Tl 0h kLA0S w0LFF, N0, F80P liolessoi ol Deinatology Chaiinan lneiitus Depaitnent ol Deinatology íeuical Univeisity ol Vienna Vienna, Austiia L0w£LL A. 60L0SN|Th, N0 liolessoi ol Deinatology Univeisity ol Noith Caiolina School ol íeuicine Chapel Hill, Noith Caiolina Dean lneiitus Univeisity ol Rochestei School ol íeuicine anu Dentistiy Rochestei, Nev Yoil ST£Ph£h |. kATI, N0, Ph0 Diiectoi, National lnstitute ol Aithiitis anu íusculosleletal anu Slin Diseases National lnstitutes ol Health Bethesua, íaiylanu 8A88A8A A. 6|L0h8£ST, N0 liolessoi anu Chaii ol Deinatology Depaitnent ol Deinatology Boston Univeisity School ol íeuicine Boston, íassachusetts ANY S. PALL£8, N0 Waltei [. Hanlin liolessoi anu Chaii ol Deinatology liolessoi ol leuiatiics leinheig School ol íeuicine Noithvestein Univeisity Chicago, lllinois 0AV|0 J. L£FF£LL, N0 liolessoi ol Deinatology anu Suigeiy Chiel, Section ol Deinatologic Suigeiy anu Cutaneous Cncology Depaitnent ol Deinatology Yale Univeisity School ol íeuicine Nev Haven, Connecticut Fitzpctrick's uermatology ln Ceneral Medlclne SFvFhTh Ful Tl 0h Ful T0kS kLA05 W0Lff, M0, fRCP L0WfLL A. 00L05MI1R, M0 51fPRfh I. kA1Z, M0, PR0 ßARßARA A. 0ILCRRf51, M0 AM¥ 5. PALLfR, M0 0AvI0 |. LffffLL, M0 hew ¥ork Chlcago San Franclsco Llsbon London Madrld Mexlco Clty Mllan hew uelhl San }uan Seoul Slngapore Sydney Toronto Copyright © 2008 by The McGraw-Hill Companies, Inc. All rights reserved. ManuIactured in the United States oI America. Except as permitted under the United States Copyright Act oI 1976, no part oI this publication may be reproduced or distributed in any Iorm or by any means, or stored in a database or retrieval system, without the prior written permission oI the publisher. 0-07-154448-8 The material in this eBook also appears in the print version oI this title: 0-07-146690-8. All trademarks are trademarks oI their respective owners. Rather than put a trademark symbol aIter every occurrence oI a trademarked name, we use names in an editorial Iashion only, and to the beneIit oI the trademark owner, with no intention oI inIringement oI the trademark. Where such designations appear in this book, they have been printed with initial caps. McGraw-Hill eBooks are available at special quantity discounts to use as premiums and sales promotions, or Ior use in corporate training programs. Eor more inIorma- tion, please contact George Hoare, Special Sales, at george_hoare¸mcgraw-hill.com or (212) 904-4069. 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FrofessIoaaI Want to learn more? v 'c'' .^¯' ´' ¯his Seventh luition ol lit:¡atri.k´s Dcrmato|og, in Ccncra| /cdi.inc is ueuicateu to the nenoiy ol tvo innovatois in the helu, vhose visionaiy appioach to ueinatology is iehecteu thioughout: ¯honas B. litzpatiicl, íD, lhD anu livin í. lieeuheig, íD Di. litzpatiicl (u. 2OOo) vas Wigglesvoith liolessoi ol Deinatology lneiitus at Haivaiu íeuical School, anu the lounuei ol DlCí as vell as its luitoi-in-Chiel loi the hist loui euitions. Di. lieeuheig (u. 2OO6) vas the Ceoige íillei íaclee liolessoi ol Deinatology, Nev Yoil Univeisity íeuical Centei, anu the luitoi-in-Chiel loi the hlth anu sixth euitions anu leu the hool to nev heights. Copyright ? 2008 by The McGraw-Hill Companies, Inc. Click here for terms of use. This page intentionally left blank v|| .´'¯c'¯' Contiihutois. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvii lielace . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxxiii Aclnovleugnents . . . . . . . . . . . . . . . . . . . . . . . . . . . xxxv Vo|0me 0oe PART 1 1 lhTR0DU0Tl0h SECTION 1. Gonoral Considorations. . . . . . . . . . . . o 1 ¯he lpiueniology anu Buiuen ol Slin Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . o /artin A. \cinsto.k. /D. lhD. and /ar,-/argarct Chrcn. /D 2 lviuence-Baseu Deinatology . . . . . . . . . . . . . . . . 8 /i.hac| 3ig|,. /D. Rosamaria Corona. D:.. /D. and /o,scs ::k|o. /D. /lH. DrlH 3 luhlic Health in Deinatology . . . . . . . . . . . . . . . 18 H,vc| C. \i||iams. /:.. lhD. lRCl. :incad langan. /RCl. and Carstcn l|ohr. /RClCH SECTION 2: Approach to Dormatologic Diagnosis . . . . . . . . . . . . . . . . . . . . . . 2o 4 Stiuctuie ol Slin Lesions anu lunuanentals ol Clinical Diagnosis . . . . . . . . . . 2o Amit Carg. /D. ^ikki A. lcvin. /D. lhD. and jcjjrc, D. 3crnhard. /D 5 Diagnostic lioceuuies anu Devices. . . . . . . . . . . 4O A|on :.o¡c. /D. and A||an C. Ha|¡crn. /D 6 Basic lathologic Reactions ol the Slin . . . . . . . . 4o /artin C. /ihm. jr.. /D. A|du|-Chani li||i. /D. lACl. and l|aus \o|jj. /D. lRCl SECTION 3: Ovorviov of Biology, Dovolopmont, and Structuro of Skin . . . . . . . . . . . 5¯ 7 Developnent anu Stiuctuie ol Slin . . . . . . . . . . 5¯ David H. Chu. /D. lhD ß Cenetics in Relation to the Slin. . . . . . . . . . . . . . ¯o john A. /.Crath. /D. and \. H. lrvin /.lcan. /D 9 Basic Science Appioaches to the lathophysiology ol Slin Disease . . . . . . . . . . . . 8¯ lau| R. 3crgstrcsscr. /D PART 2 98 Dl80RDER8 PRE8EhTlh0 lh 8Klh AhD NU00U8 NENBRAhE8 SECTION 4. Inüammatory Disordors Basod on T-Coll Roactivity and Dysrogulation . . . . . . . . º5 10 lnnate anu Auaptive lnnunity in the Slin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . º5 Ro|crt l. /od|in. /D. jcnn, lim. /D. lhD. Dictcr /aurcr. /D. Christinc 3angcrt. /D. and Ccorg :ting|. /D 11 Cytolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 ljor R. \i||iams. /D. lhD. 3cn¡amin l. Ri.h. lhD. and Thomas :. lu¡¡cr. /D 12 Chenolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12¯ :am T. Hvang. /D. lhD 13 Alleigic Contact Deinatitis. . . . . . . . . . . . . . . . 1o5 David l. Cohcn. /D. /lH. and :haron l. ja.o|. /D 14 Atopic Deinatitis (Atopic lczena) . . . . . . . . . 146 Dona|d Y. /. lcung. /D. lhD. lavrcn.c l. li.hcnµc|d. /D. and /ark 3ogunicvi.:. /D 15 Nunnulai lczena anu Lichen Sinplex Chionicus/liuiigo Nouulaiis . . . . . . . 158 :usan 3urgin. /D 16 Vesiculai lalnoplantai lczena. . . . . . . . . . . . . 162 Davcn ^. Doshi. /D. and A|cxa 3. lim|a||. /D. /lH 17 Autosensitization Deinatitis . . . . . . . . . . . . . . 16¯ Dona|d V. 3c|sito. /D 1ß lsoiiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16º johann l. Cud¡onsson. /D. lhD. and jamcs T. l|dcr. /D 19 lsoiiatic Aithiitis . . . . . . . . . . . . . . . . . . . . . . . . 1º4 Ro|crt \in.hcstcr. /D For more information about this title, click here v||| 20 Reactive Aithiitis . . . . . . . . . . . . . . . . . . . . . . . .2O¯ Andrcv lcat. /D 21 lustulai liuptions ol lalns anu Soles . . . . . . . . 215 !|ri.h /rovict:. /D 22 Sehoiiheic Deinatitis . . . . . . . . . . . . . . . . . . . . .21º Ccrd l|cvig. /D. and Thomas janscn. /D 23 lxloliative Deinatitis . . . . . . . . . . . . . . . . . . . . .225 janc /argarct Crant-lc|s. /D. /cgan l. 3crnstcin. /D. and /arti j. Rothc. /D 24 lityiiasis Ruhia lilaiis. . . . . . . . . . . . . . . . . . . . .2o2 Danic|a 3ru.h-Ccrhar:. /D. and Thomas Ru:i.ka. /D 25 laiapsoiiasis anu lityiiasis Lichenoiues . . . . . . . . . . . . . . . . . . . . .2o6 Car, :. \ood. /D. Chung-Hong Hu. /D. and Andrca l. Carrctt. /D 26 Lichen llanus. . . . . . . . . . . . . . . . . . . . . . . . . . . .244 /ark R. littc|kov. /D. and /a:cn :. Daoud. /D 27 Lichen Nitiuus . . . . . . . . . . . . . . . . . . . . . . . . . . .255 /ark R. littc|kov. /D. and /a:cn :. Daoud. /D 2ß Cialt-Veisus-Host Disease . . . . . . . . . . . . . . . . . 258 /ist, T. :har¡. /D. and Thomas D. Horn. /D 29 Slin Disease in Acute anu Chionic lnnunosuppiession. . . . . . . . . . . . . . . 26¯ l,nda lau|s. /D. and Andrcv 3|auvc|t. /D SECTION 5. Inüammatory Disoasos Basod on Noutrophils and Eosinophils. . . . . . . . .2¯º 30 Regulation ol the liouuction anu Activation ol Neutiophils anu losinophils . . . . . . . . . . . . . . . . . . . . . . . . . .2¯º :tcvcn /. Ho||and. /D. jamcs lovc|css. /D. and lisa A. 3c.k. /D 31 Acute lehiile Neutiophilic Deinatosis (Sveet Synuione). . . . . . . . . . . . . .28º lhi|i¡ R. Cohcn. /D. Hcr|crt Honigsmann. /D. and Ra:c||c lur:ro.k. /D. lACl 32 lyoueina Cangienosun . . . . . . . . . . . . . . . . . .2º6 lrank C. lovc||. /D. and 3ridgct C. Ha.kctt. /RCll 33 Cianulona laciale. . . . . . . . . . . . . . . . . . . . . . . .oO2 Darius R. /chrcgan. /D. and David A. /chrcgan. /D 34 Suh-Coineal lustulai Deinatosis (Sneuuon-Willinson Disease). . . . . . . . . . . . . . . oO5 lran: Trautingcr. /D. and Hcr|crt Honigsmann. /D 35 losinophils in Cutaneous Diseases . . . . . . . . . . oO¯ lristin /. lcijcrman. /D. and /argot :. lctcrs. /D SECTION 6. Inüammatory Disoasos Basod on Abnormal Humoral Roactivity and Othor Inüammatory Disoasos . . . . . . . . . . . . o1º 36 Hunoial lnnunity anu Conplenent . . . . . . . o1º lc|a A. lcc. /D 37 Uiticaiia anu Angioeuena . . . . . . . . . . . . . . . . . ooO A||cn l. la¡|an. /D 3ß liythena íultiloine. . . . . . . . . . . . . . . . . . . . . o4o jcan-C|audc Rou¡cau. /D 39 lpiueinal Neciolysis (Stevens-[ohnson Synuione anu ¯oxic lpiueinal Neciolysis) . . . . . . . . . . . . o4º l. Va|c,ric-A||anorc. /D. and jcan-C|audc Rou¡cau. /D 40 Cutaneous Reactions to Diugs. . . . . . . . . . . . . . o55 ^ci| H. :hcar. /D. :andra R. lnov|cs. 3:.lhm. and lori :ha¡iro. /D 41 lityiiasis Rosea . . . . . . . . . . . . . . . . . . . . . . . . . . o62 Andrcv 3|auvc|t. /D 42 liythena Annulaie Centiilugun anu Cthei liguiate liythenas . . . . . . . . . . . . . . o66 \a|tcr H. C. 3urgdorj. /D 43 Cianulona Annulaie . . . . . . . . . . . . . . . . . . . . . o6º ju|ic :. lrcndivi||c. /D. /RCll. lRClC SECTION 7. Disordors of Epidormal Difforontiation and Koratinization . . . . . . . . . . . . o¯5 44 lpiueinal Ciovth anu Dilleientiation. . . . . . . o¯5 :tan|c, j. /i||cr. /D. Tung-Ticn :un. /D. and licrrc A. Cou|om|c. lhD 45 Slin as an Cigan ol liotection. . . . . . . . . . . . . . o8o lhrhardt lroks.h. /D. lhD. and jcns-/i.hac| jcnscn. /D 46 liiitant Contact Deinatitis. . . . . . . . . . . . . . . . . oº5 Antoinc Amado. /D. jamcs :. Ta,|or. /D. and A¡ra :ood. /D 47 ¯he lchthyoses . . . . . . . . . . . . . . . . . . . . . . . . . . 4O1 lhi|i¡ l|c.kman. /D. and john j. DiCiovanna. /D 4ß lnheiiteu leiatoueinas ol lalns anu Soles . . . . . . . . . . . . . . . . . . . . . . . 424 David l. lc|sc||. /D. and lrcnc /. lcigh. /D 49 Acantholytic Disoiueis ol the Slin: Daiiei-White Disease, Acioleiatosis Veiiuciloinis, Ciovei Disease, anu Hailey-Hailey Disease . . . . . . . . . . . . . . . . . 4o2 A|ain Hovnanian. /D. lhD 50 loioleiatosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . 442 Crainnc /. ·´Rcgan. /RCll. and A|an D. lrvinc. /D. lRCll. /RCl |x SECTION 8. Disordors of Epidormal and Dormal-Epidormal Cohosion and Vosicular and Bullous Disordors . . . . . . . . . . . . . . 44¯ 51 lpiueinal anu lpiueinal-Deinal Cohesion . . . . . . . . . . . . . . . 44¯ lccna 3ru.kncr-Tudcrman. /D. and john R. :tan|c,. /D 52 lenphigus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45º john R. :tan|c,. /D 53 laianeoplastic lenphigus . . . . . . . . . . . . . . . . . 468 Crant j. Anha|t. /D. and Car|os H. ^ousari. /D 54 Bullous lenphigoiu . . . . . . . . . . . . . . . . . . . . . . 4¯5 john R. :tan|c,. /D 55 Cicatiicial lenphigoiu . . . . . . . . . . . . . . . . . . . . 481 lim 3. Yan.c,. /D 56 Lineai lnnunoglohulin A Deinatosis anu Chionic Bullous Disease ol Chiluhoou . . . . . . . . . . . . . . . . . . . . . 485 Caro|inc l. Rao. /D. and Russc|| l. Ha|| lll. /D 57 lenphigoiu Cestationis (Heipes Cestationis) . . . . . . . . . . . . . . . . . . . . . . 4ºO jcjj l. :horni.k. /D. /HA 5ß lpiueinolysis Bullosa Acguisita . . . . . . . . . . . . 4º4 David T. \ood|c,. /D. and /ci Chcn. lhD 59 Deinatitis Heipetiloinis . . . . . . . . . . . . . . . . . . 5OO Russc|| l. Ha|| lll. /D. and :tc¡hcn l. lat:. /D. lhD 60 lnheiiteu lpiueinolysis Bullosa. . . . . . . . . . . . . 5O5 /. lctcr /arinkovi.h. /D. and lugcnc A. 3aucr. /D SECTION º. Disordors of tho Dormal Connoctivo Tissuo . . . . . . . . . . . . . . . . . . . 51¯ 61 Collagen, llastic liheis, anu lxtiacellulai íatiix ol the Deinis. . . . . . . . . . . 51¯ jouni !itto. /D. lhD. /on-li Chu. lhD. Ri.hard Ca||o. /D. lhD. and Arthur Z. liscn. /D 62 íoiphea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54o Vin.cnt la|anga. /D. lACl. and Christina l. li||oran. /D 63 Lichen Scleiosus . . . . . . . . . . . . . . . . . . . . . . . . . 546 !|ri.h R. Hcnggc. /D 64 Deinal Hypeitiophies . . . . . . . . . . . . . . . . . . . . 55O /and, Harting. /D. /. john Hi.ks. /D. DD:. lhD. and /oisc l. lcv,. /D 65 Anetoueina anu Cthei Atiophic Disoiueis ol the Slin. . . . . . . . . . . . . . 55¯ Cathcrinc /aari. /D. and ju|ic lovc||. /D 66 Constiicting Banus (Ainhun anu lseuuoainhun). . . . . . . . . . . . . . . 562 Ro|crt T. 3rodc||. /D. and :tc¡hcn l. Hc|ms. /D 67 Acguiieu leiloiating Disoiueis . . . . . . . . . . . . . 564 /ark lc|voh|. /D SECTION 10. Disordors of Subcutanoous Tissuo. . . . . . . . . . . . . . . . . . . . . . 56º 6ß lanniculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56º luis Rcqucna. /D. lvaristo :an.hc: Yus. /D. and Hcin: lut:ncr. /D 69 Lipouystiophy . . . . . . . . . . . . . . . . . . . . . . . . . . 585 /crcdith l. :hccd,. /D. and :arah A. /,crs. /D SECTION 11. Disordors of Molanocytos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5º1 70 Biology ol íelanocytes . . . . . . . . . . . . . . . . . . . 5º1 Hcc-Young lark. lhD. /arin,a long¡ud¡unth. /D. jin lcc. /D. /3A. and /ina Yaar. /D 71 Alhinisn anu Cthei Cenetic Disoiueis ol lignentation . . . . . . . . . . . . . . . . . 6O8 Thomas j. Horn,ak. /D. lhD 72 Vitiligo. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616 Rc|at /. Ha|dcr. /D. and :uma,ah j. Ta|iajcrro. /D 73 Hyponelanoses anu Hypeinelanoses . . . . . . . 622 Hi|dc la¡ccrc. /D. 3ar|ara 3oonc. /D. :oµc Dc :.hc¡¡cr. /D. lvc|icn Vcrhacghc. /D. latia ·ngcnac. /D. lhD. ^an¡a Van Ccc|. /D. lhD. jo lam|crt. /D. lhD. licvc 3ro.hc:. /D. lhD. and jcan-/aric ^ac,acrt. /D. lhD SECTION 12. Disordors of tho Oral and Gonital Intogumont . . . . . . . . . . . . . . . . . 641 74 Biology anu lathology ol the Cial Cavity. . . . . . . . . . . . . . . . . . . . . . . . 641 Cinat \intcrmc,cr /irovski. D/D. /D. and lva Rav|ings larkcr. /D 75 Diseases anu Disoiueis ol the íale Cenitalia . . . . . . . . . . . . . . . . . . . . . 654 Christo¡hcr 3arr, 3unkcr. /A. /D. lRCl 76 Diseases anu Disoiueis ol the lenale Cenitalia . . . . . . . . . . . . . . . . . . . 6¯5 Ro.hc||c R. Torgcrson. /D. lhD. and li||, ldvards. /D PART 8 o8o Dl80RDER8 0F THE 8Klh APPEhDA0E8 SECTION 13. Disordors of tho Sobacoous Glands . . . . . . . . . . . . . . . . . . . . . 68¯ 77 Biology ol Sehaceous Clanus. . . . . . . . . . . . . . . 68¯ Amanda /. ^c|son. lhD. and Dianc /. Thi|outot. /D x 7ß Acne Vulgaiis anu Acneiloin liuptions. . . . . . . . . . . . . . . . . . . . . .6ºO Andrca l. Zacng|cin. /D. lmm, /. Cra|cr. /D. Dianc /. Thi|outot. /D. and john :. :trauss. /D 79 Rosacea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .¯Oo /i.hc||c T. lc||c. /D ß0 leiioial Deinatitis . . . . . . . . . . . . . . . . . . . . . . .¯Oº :arah l. Cham|in. /D. and lcs|ic l. lav|c,. /D SECTION 14. Disordors of tho Eccrino and Apocrino Glands . . . . . . . . . . . . . . . . . ¯1o ß1 Biology ol lcciine, Apociine, anu Apoecciine Sveat Clanus . . . . . . . . . . . . . .¯1o Thcodora /. /auro. /D. and lovc|| A. Co|dsmith. /D ß2 Disoiueis ol the lcciine Sveat Clanus anu Sveating . . . . . . . . . . . . . . . .¯2O Ro|crt D. lca|c,. /D. and lcn:o :ato. /D. lhD ß3 Disoiueis ol the Apociine Sveat Clanus. . . . . . ¯o1 /arni C. \iscman. /D. lRClC SECTION 15. Disordors of tho Hair and Nails . . . . . . . . . . . . . . . . . . . . . . . . . . .¯oº ß4 Biology ol Haii lollicles . . . . . . . . . . . . . . . . . . .¯oº Ccorgc Cotsarc|is. /D. and V|adimir 3ot.hkarcv. /D. lhD ß5 leiatosis lilaiis anu Cthei lnhannatoiy lolliculai leiatotic Synuiones. . . . . . . . . . . . . .¯4º /aurccn Rogcrs. /D ß6 Haii Ciovth Disoiueis. . . . . . . . . . . . . . . . . . . .¯5o Ra|j laus. /D. l|isc A. ·|scn. /D. and Andrcv C. /csscngcr. /D ß7 Biology ol Nails anu Nail Disoiueis. . . . . . . . . . ¯¯8 Antonc||a Tosti. /D. and 3ian.a /aria lira..ini. /D PART 4 /9o Dl80RDER8 DUE T0 THE EhVlR0hNEhT SECTION 16: Disordors Duo to Ultraviolot Radiation . . . . . . . . . . . . . . . . . . . . . .¯º¯ ßß lunuanentals ol Cutaneous lhotohiology anu lhotoinnunology . . . . . . . . ¯º¯ lrcnc l. lo.hcvar. lhD. Char|cs R. Ta,|or. /D. and jcan lrutmann. /D ß9 Acute anu Chionic lllects ol Ultiaviolet Rauiation on the Slin. . . . . . . . . . . .8Oº Anton, R. Young. lhD. and :usan l. \a|kcr. lhD 90 Ahnoinal Responses to Ultiaviolet Rauiation: luiopathic, liohahly lnnunologic, anu lhoto-lxaceihateu. . . . . . . . 816 john l. /. Havk. /D. and jamcs lcrguson. /D 91 Ahnoinal Responses to Ultiaviolet Rauiation: lhotosensitivity lnuuceu hy lxogenous Agents. . . . . . . . . . . . . . 828 Hcnr, \. lim. /D SECTION 17. Skin Changos Duo to Othor Physical and Chomical Factors. . . . . . . . . . 8o5 92 ¯heinoiegulation. . . . . . . . . . . . . . . . . . . . . . . . 8o5 Dcan l. lc||ogg. jr.. /D. lhD 93 Colu ln|uiies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844 Ccra|d l. licrard. /D. lhD. lrcdcriquc Hcnr,. /D. and C|audinc licrard-lran.himont. /D. lhD 94 ¯heinal ln|uiies . . . . . . . . . . . . . . . . . . . . . . . . . 852 Ro|crt l. :hcridan. /D 95 Rauiohiology anu Rauiation lllects. . . . . . . . . . 858 lrcdcri.k D. /a|kinson. /D. and Rcnato C. lani::on. /D 96 Slin liohlens in Anputees anu Cstonates . . . 862 Ca|um C. l,on. lRCl. /3 3Chir. and /i.hac| H. 3c.k. lCRl. /3 Ch3 97 Coins anu Calluses . . . . . . . . . . . . . . . . . . . . . . . 8¯1 Thomas /. Dclauro. Dl/. and ^i.o|c /. Dclauro. Dl/ 9ß Spoits Deinatology . . . . . . . . . . . . . . . . . . . . . . 8¯o Dirk /. l|ston. /D 99 Decuhitus (liessuie) Ulceis . . . . . . . . . . . . . . . . 8¯8 Tania j. lhi||i¡s. /D. and li|ian /. ·do. /D 100 Bouy Ait . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 886 Annc laumann. /3 Ch3. /RCl PART o 898 hEUR00UTAhE0U8 AhD P8Y0H00UTAhE0U8 A8PE0T8 0F 8Klh Dl8EA8E SECTION 18. Nourocutanoous and Psychocutanoous Skin Disoaso . . . . . . . . . . . 8º5 101 Neuiohiology ol the Slin. . . . . . . . . . . . . . . . . . 8º5 /artin :tcinhojj. /D. lhD. and Thomas A. lugcr. /D 102 lathophysiology anu Clinical Aspects ol liuiitus . . . . . . . . . . . . . . . . . . . . . . . ºO2 Ci| Yosi¡ovit.h. /D. Acr|,n C. Davn. /D. /3A. and /a|.o|m \. Crcavcs. /D. lhD. lRCl 103 lsychocutaneous Diseases . . . . . . . . . . . . . . . . . º12 Andrca :ando:. /D. Thomas locnig. /D. Danic| lusnir. /D. and lran.is.o A. Tausk. /D 104 Cutaneous íanilestations ol Diug Ahuse . . . . . º21 /iguc| R. :an.hc:. /D 105 Slin Signs ol lhysical Ahuse . . . . . . . . . . . . . . . º2¯ Hovard lridc. /D x| PART o 988 8Klh 0HAh0E8 A0R088 THE 8PAh 0F llFE SECTION 1º. From Birth to Old Ago. . . . . . . . . . ºo5 106 Neonatal, leuiatiic, anu Auolescent Deinatology . . . . . . . . . . . . . . . . . . ºo5 /ar, \u Chang. /D. and :cth j. ·r|ov. /D. lhD 107 Slin Changes anu Diseases in liegnancy. . . . . . . . . . . . . . . . . . . . . º55 ju|ic l. larcn. /D. and /iriam lc|t: lomcran:. /D 10ß Aging ol Slin. . . . . . . . . . . . . . . . . . . . . . . . . . . . º6o /ina Yaar. /D. and 3ar|ara A. Ci|.hrcst. /D PART / 9/o hE0PlA8lA SECTION 20. Carcinogonosis. . . . . . . . . . . . . . . . . º¯¯ 109 Cenone lnstahility, DNA Repaii, anu Cancei. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . º¯¯ lcnncth H. lracmcr. /D. and Thomas /. Rungcr. /D 110 Caicinogenesis: Chenical . . . . . . . . . . . . . . . . . º86 Andr:c¡ A. D|ugos:. /D. and :tuart H. Yus¡a. /D 111 Cncogenes, ¯unoi Suppiessoi Cenes, anu Viial Caicinogenesis . . . . . . . . . . . . ºº5 ^i.o|c 3assct-:cguin. /D. Cc|cstc lc||c. /D. Char|ottc lro|,. /D. and A|an :torc,. /D 112 Caicinogenesis: Ultiaviolet Rauiation . . . . . . . . ººº Doug|as l. 3rash. lhD. Timoth, Hcjjcrnan. lhD. and lau| ^ghicm. /D. lhD SECTION 21. Epidormal and Appondagoal Tumors . . . . . . . . . . . . . . . . . . . . . . . 1OO¯ 113 lpithelial liecanceious Lesions . . . . . . . . . . . . 1OO¯ lar,nnc ·. Dun.an. /D. john l. Ccissc. /D. and David j. lcjjc||. /D 114 Sguanous Cell Caicinona . . . . . . . . . . . . . . . . 1O28 Doug|as Crossman. /D. lhD. and David j. lcjjc||. /D 115 Basal Cell Caicinona . . . . . . . . . . . . . . . . . . . . 1Oo6 john A. Caru..i. /D. and David j. lcjjc||. /D 116 Basal Cell Nevus Synuione . . . . . . . . . . . . . . . 1O42 Anthon, l. ·ro. /D. lhD 117 leiatoacanthona . . . . . . . . . . . . . . . . . . . . . . . 1O4º lorcn:o Ccrroni. /D. and Hc|mut lcr|. /D 11ß Benign lpithelial ¯unois, Hanaitonas, anu Hypeiplasias . . . . . . . . . . . . 1O54 Va|cn.ia D. Thomas. /D. ^ci| A. :vanson. /D. and lcn l. lcc. /D 119 Appenuage ¯unois anu Hanaitonas ol the Slin . . . . . . . . . . . . . . . . . 1O68 R. :tan Ta,|or. /D. jcnnijcr 3. lcronc. /D. :tcvcn laddu. /D. and Hc|mut lcr|. /D 120 íeilel Cell Caicinona . . . . . . . . . . . . . . . . . . 1O8¯ lau| ^ghicm. /D. lhD. and ^ata|ia jaimcs. /D 121 íannaiy anu lxtianannaiy laget Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 1Oº4 lsaa. /. ^cuhaus. /D. and Ro, C. Crckin. /D SECTION 22. Molanocytic Tumors . . . . . . . . . . 1Oºº 122 Benign Neoplasias anu Hypeiplasias ol íelanocytes. . . . . . . . . . . . . . 1Oºº jamcs /. Cri.hnik. /D. lhD. Arthur R. Rhodcs. /D. /lH. and Arthur j. :o|cr. /D 123 Atypical íelanocytic Nevi . . . . . . . . . . . . . . . 1122 /argarct A. Tu.kcr. /D 124 Cutaneous íelanona . . . . . . . . . . . . . . . . . . . 11o4 :andra C. lack. /D. Arthur j. :o|cr. /D. Hcnsin Tsao. /D. lhD. /artin C. /ihm. jr.. /D. and Timoth, /. johnson. /D SECTION 23. Tumors and Hyporplasias of tho Dormis and Subcutanoous Fat . . . . . . . . . 115º 125 íalignant lihious ¯unois ol the Deinis . . . . . . . . . . . . . . . . . . . 115º jcnnijcr Z. Coo¡cr. /D. and /ar. D. 3rovn. /D 126 Vasculai ¯unois . . . . . . . . . . . . . . . . . . . . . . . . 1164 Tara /i||cr. /D. and l|ona j. lricdcn. /D 127 Neoplasias anu Hypeiplasias ol íusculai anu Neuial Ciigin . . . . . . . . . . . . 11¯2 lu.i|c l. \hitc. /D. Ross /. lcv,. /D. and /urad A|am. /D 12ß laposi Saicona . . . . . . . . . . . . . . . . . . . . . . . . 118o lrvin Ts.ha.h|cr. /D 129 Neoplasns ol Suhcutaneous lat . . . . . . . . . . . 11ºO Thomas 3rcnn. /D. lhD Vo|0me Two PART 8 1199 THE 8Klh lh 8Y8TENl0 Dl8EA8E SECTION 24. Skin in Nutritional, Motabolic, and Horitablo Disoaso . . . . . . . . . . . . 12O1 130 Cutaneous Changes in Nutiitional Disease. . . . . . . . . . . . . . . . . . . . . . 12O1 /c|inda jcn. /D. lara ^. :hah. /D. lhD. lAAl. and A||crt C. Yan. /D x|| 131 Cutaneous Changes in liiois ol Anino Aciu íetaholisn . . . . . . . . . . . . . . . 121º lctcr H. ltin. /D. and lovc|| A. Co|dsmith. /D 132 ¯he loiphyiias . . . . . . . . . . . . . . . . . . . . . . . . .1228 David R. 3i.kcrs. /D. and jorgc lrank. /D 133 Anyloiuosis anu the Slin. . . . . . . . . . . . . . . . .125¯ Hc|cn j. la.hmann. /D. and lhi|i¡ ^. Havkins. /D 134 Systenic Autoinhannatoiy Diseases . . . . . . .1265 john C. R,an. /3. /RCll. and Danic| l. lastncr. /D 135 Xanthonatoses anu Lipopiotein Disoiueis . . . . 12¯2 lu.i|c l. \hitc. /D 136 lahiy Disease . . . . . . . . . . . . . . . . . . . . . . . . . .1281 /argarita /. larra|dc. /D. and lau|a C. luna. /D 137 Lipoiu lioteinosis . . . . . . . . . . . . . . . . . . . . . . .1288 jonathan A. D,cr. /D 13ß Cutaneous íineialization anu Cssihcation . . . . . . . . . . . . . . . . . . . . . . . . .12ºo john :. \a|sh. /D. and janct A. lair|c,. /D 139 Heiitahle Disoiueis ol Connective ¯issue vith Slin Changes . . . . . . . . . . . . . . . .12º¯ /ario l. la.outurc. /D. and Am, :. la||cr. /D 140 Heieuitaiy Disoiueis ol Cenone lnstahility anu DNA Repaii . . . . . . . . . . . . . . . 1o11 Thomas /. Rungcr. /D. john j. DiCiovanna. /D. and lcnncth H. lracmcr. /D 141 ¯uheious Scleiosis Conplex . . . . . . . . . . . . . .1o25 Thomas ^. Dar|ing. /D. lhD 142 ¯he Neuiohhionatoses . . . . . . . . . . . . . . . . . .1oo1 Ro|crt listcrni.k. /D. and joc| Charrov. /D 143 lctoueinal Dysplasias . . . . . . . . . . . . . . . . . . .1ooº Virginia l. :,|crt. /D 144 Cenetic lnnunouehciency Diseases . . . . . . . .1o48 Am, :. la||cr. /D. and /c|issa A|rams. /D SECTION 25. Skin Manifostations of Bono Marrov and Blood Disordors . . . . . . . . 1o¯o 145 Henatologic Diseases. . . . . . . . . . . . . . . . . . . .1o¯o 3ina A. Rashid. /D. l|i:a|cth 3ahar Houshmand. /D. and /i.hac| l. Hcjjcrnan. /D 146 Cutaneous Lynphona . . . . . . . . . . . . . . . . . . .1o86 Cha|id Assaj. /D. and \o|jram :tcrr,. /D 147 lnhannatoiy Diseases ¯hat Sinulate Lynphonas: Cutaneous lseuuolynphonas. . . . . . . . . . . . . .14O2 Car, :. \ood. /D 14ß Langeihans Cell Histiocytosis . . . . . . . . . . . . . 1414 Ruggcro Ca¡uto. /D. and Car|o Cc|mctti. /D 149 NonLangeihans Cell Histiocytosis. . . . . . . . . 1424 Car|o Cc|mctti. /D. and Ruggcro Ca¡uto. /D 150 Biology ol íast Cells anu the íastocytosis Synuiones . . . . . . . . . . . . . . 14o4 /c|od, C. Cartcr. /D. and Dcan D. /ct.a|jc. /D SECTION 26. Skin Manifostations of Intornal Organ Disordors. . . . . . . . . . . . . . . . . 1445 151 ¯he Slin anu Disoiueis ol the Alinentaiy ¯iact, the Hepatohiliaiy Systen, liuney, anu Caiuiopulnonaiy Systen . . . . . . 1445 Craham A. johnston. /3 Ch3. lRCl. and Ro|in A. C. Craham-3rovn. /D 152 Diahetes íellitus anu Cthei lnuociine Diseases . . . . . . . . . . . . . . . . 1461 Andrca A. la|us. /D. And, j. Chicn. /D. lhD. and john l. ·|crud. /D 153 Saicoiuosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1484 Ri.hard /. /ar.hc||. /D. 3ru.c Thicrs. /D. and /ar. A. judson. /D 154 Cutaneous íanilestations ol lnteinal íalignant Disease: Cutaneous laianeoplastic Synuiones. . . . . . . 14ºo Christinc A. Dc\itt. /D. lu.inda :. 3ucs.hcr. /D. and :tc¡hcn l. :tonc. /D SECTION 27. Tho Skin in Vascular and Connoctivo Tissuo and Othor Autoimmuno Disordors. . . . . . . . . . . . . . . 15Oº 155 íechanisns ol Autoinnune Disease. . . . . . . 15Oº lnsoo lang. /D. and joc Crajt. /D 156 Lupus liythenatosus . . . . . . . . . . . . . . . . . . . . 1515 /c|issa l. Costncr. /D. and Ri.hard D. :onthcimcr. /D 157 Deinatonyositis . . . . . . . . . . . . . . . . . . . . . . . 15o6 Ri.hard D. :onthcimcr. /D. and /c|issa l. Costncr. /D 15ß Scleioueina (Systenic Scleiosis) . . . . . . . . . . . 155o Christo¡hcr l. Dcnton. /D. and Caro| /. 3|a.k. /D 159 Scleieuena anu Scleionyxeuena . . . . . . . . . . 1562 Rogcr H. \ccnig. /D. /lH. and /ark R. littc|kov. /D 160 Relapsing lolychonuiitis . . . . . . . . . . . . . . . . . 156¯ Cami||c lran.cs. /D 161 Rheunatoiu Aithiitis, Rheunatic levei, anu Cout . . . . . . . . . . . . . . . 156º Christina l. Havcrsto.k. /D. /:. and josc¡h l. jori::o. /D x||| 162 S|ogien Synuione. . . . . . . . . . . . . . . . . . . . . . . 15¯¯ :tamatina Danic|idcs. /D. and Ca|or l||ci. /D SECTION 28. Tho Skin in Inüammatory and Othor Vascular Disordors . . . . . . . . . . . . . . . . . . . 1585 163 lnuotheliun in lnhannation anu Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . 1585 lctcr lct:c||aucr. /D. lisan :. lcng. /D. and jordan :. lo|cr. /D 164 Cutaneous Neciotizing Venulitis . . . . . . . . . . . 15ºº ^i.ho|as A. :otcr. /D. and josc l. Dia:-lcrc:. /D 165 Systenic Neciotizing Vasculitis . . . . . . . . . . . . 16O6 Carmcn l. Cota. /D. and 3rian l. /andc||. /D. lhD. lACR 166 liythena llevatun Diutinun . . . . . . . . . . . . . 1616 ^ncka l. Comjcrc. /D. and lavrcn.c l. Ci|son. /D 167 Auanantiaues-Behçet Disease . . . . . . . . . . . . . 162O Christos C. Zou|ou|is. /D. lhD 16ß lavasali Synuione . . . . . . . . . . . . . . . . . . . . . 1626 Dona|d Y. /. lcung. /D. lhD. H. Cod, /cissncr. /D. and Annc \. lu.k,. /D 169 lignenteu luipuiic Deinatoses . . . . . . . . . . . 16oo Thcrcsa :.hrocdcr-Dcvcrc. /D 170 Ciyoglohulinenia anu Ciyohhiinogenenia . . . . . . . . . . . . . . . . . . . . . 16o¯ /i|an j. Anadkat. /D. l,nn A. Cornc|ius. /D. and Thomas j. lav|c,. /D 171 Raynauu lhenonenon . . . . . . . . . . . . . . . . . . . 164o john H. l|i¡¡c|. /D 172 íalignant Atiophic lapulosis (Degos Disease). . . . . . . . . . . . . . . . . . . . . . . . . 1648 Dan li¡skcr. /D. lhD. and jcan-Hi|airc :aurat. /D 173 Vasculai íalloinations . . . . . . . . . . . . . . . . . . 1651 laurcn.c /. 3oon. /D. lhD. and /iikka Vikku|a. /D. lhD 174 Cutaneous Changes in leiipheial Vasculai Aiteiial Disease . . . . . . . . 166¯ /andcc¡ Dhad|,. /D. lACC. :tcvcn /. Dcan. D·. lACl. and Ro|crt T. l|crhardt. /D 175 Cutaneous Changes in Venous anu Lynphatic lnsulhciency. . . . . . . . . . . . . . . 16¯º C|audc :. 3urton. /D. Craig ^. 3urkhart. /D. and lovc|| A. Co|dsmith. /D PART 9 1o8/ Dl8EA8E DUE T0 Nl0R0BlAl A0EhT8, lhFE8TATl0h8, BlTE8, AhD 8Tlh08 SECTION 2º: Bactorial Disoaso. . . . . . . . . . . . . . 168º 176 Ceneial Consiueiations ol Bacteiial Diseases. . . . . . . . . . . . . . . . . . . . . 168º Timoth, C. 3crgcr. /D 177 Supeihcial Cutaneous lnlections anu lyoueinas . . . . . . . . . . . . . . . . . . . . . . . . . 16º4 ^oah Crajt. /D. lhD. lctcr l. lcc. /D. lhD. /atthcv T. Zi¡o|i. /D. Arno|d ^. \cin|crg. /D. /orton ^. :vart:. /D. and Ri.hard A||cn johnson. /D 17ß Cian-lositive lnlections Associateu vith ¯oxin liouuction . . . . . . . . . . . . . . . . . . . 1¯1O jcjjrc, 3. Travcrs. /D. lhD. and ^i.o /ousdi.as. /D 179 Solt-¯issue lnlections: liysipelas, Cellulitis, Cangienous Cellulitis, anu íyoneciosis . . . . . . . . . . . . . . . . . . . . . . . 1¯2O Arturo :aavcdra. /D. lhD. Arno|d ^. \cin|crg. /D. /orton ^. :vart:. /D. and Ri.hard A||cn johnson. /D 1ß0 Cian-Negative Coccal anu Bacillaiy lnlections . . . . . . . . . . . . . . . . . . 1¯o1 /orton ^. :vart:. /D 1ß1 ¯he Slin in lnlective lnuocaiuitis, Sepsis, Septic Shocl, anu Disseninateu lntiavasculai Coagulation . . . . 1¯44 laura lor| lcrris. /D. lhD. and josc¡h C. lng|ish lll. /D 1ß2 Baitonellosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 1¯4º Timoth, C. 3crgcr. /D. and lran.is.o C. 3ravo. /D 1ß3 íiscellaneous Bacteiial lnlections vith Cutaneous íanilestations . . . . . . . . . . . 1¯55 :.ott A. ^orton. /D. /lH 1ß4 ¯uheiculosis anu lnlections vith Atypical íycohacteiia . . . . . . . . . . . . . . 1¯68 Ccrhard Ta¡¡cincr. /D 1ß5 Actinonycosis, Nocaiuiosis, anu Actinonycetona. . . . . . . . . . . . . . . . . . . . 1¯¯8 lran.is.o C. 3ravo. /D. Ro|crto Arcnas. /D. and Danic| As: :iga||. /D 1ß6 Lepiosy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1¯86 Thomas H. Rca. /D. and Ro|crt l. /od|in. /D 1ß7 Lyne Boiieliosis . . . . . . . . . . . . . . . . . . . . . . . . 1¯º¯ /ccra /aha|ingam. /D. lhD. lRClath. jag 3havan. /D. Annc-/aric Chomat. /D. and lindcn Hu. /D x|v SECTION 30. Fungal Disoasos . . . . . . . . . . . . . . .18O¯ 1ßß Supeihcial lungal lnlection: Deinatophytosis, Cnychonycosis, ¯inea Nigia, lieuia . . . . . . . . . . . . . . . . . . . . . . 18O¯ :hannon Vcrma. /D. and /i.hac| l. Hcjjcrnan. /D 1ß9 Yeast lnlections: Canuiuiasis anu ¯inea (lityiiasis) Veisicoloi . . . . . . . . . . . .1822 /atthcv l. janik. /D. and /i.hac| l. Hcjjcrnan. /D 190 Deep lungal lnlections . . . . . . . . . . . . . . . . . . .18o1 Rodcri.k j. Ha,. /D SECTION 31. Viral and Rickottsial Disoasos. . . . . . . . . . . . . . . . . . . . . . . . .1845 191 Viial Diseases: Ceneial Consiueiations . . . . . .1845 Ammar /. Ahmcd. /D. Vandana l. /adkan. /D. ^ata|ic /cndo:a. /D. :tc¡hcn l. T,ring. /D. lhD. /3A and Doug|as R. lov,. /D 192 lxanthenatous Viial Diseases . . . . . . . . . . . . .1851 lcah 3c|a:arian. /D. /a,ra l. lorcn:o. /D. ^i.o|c C. la.c. /D. :usan /. :vccnc,. /D. and larcn /. \iss. /D 193 Heipes Sinplex . . . . . . . . . . . . . . . . . . . . . . . . .18¯o Adriana R. /arqucs. /D. and :tc¡hcn l. :traus. /D 194 Vaiicella anu Heipes Zostei . . . . . . . . . . . . . . .1885 :tc¡hcn l. :traus. /D. /i.hac| ^. ·xman. /D. and lcnncth l. :.hmadcr. /D 195 loxviius lnlections . . . . . . . . . . . . . . . . . . . . . .18ºº \,nnis Tom. /D. and :hci|a la||on lricd|andcr. /D 196 Waits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1º14 l||iot j. Andro¡h,. /D. and Doug|as R. lov,. /D 197 Hunan Retioviial Disease: Hunan ¯-Lynphotiopic Viiuses . . . . . . . . . . .1º2o lrvin Ts.ha.h|cr. /D 19ß Cutaneous íanilestations ol Hunan lnnunouehciency Viius Disease . . . .1º2¯ Arturo :aavcdra. /D. lhD. and Ri.hard A||cn johnson. /D 199 ¯he Riclettsioses, lhilichioses, anu Anaplasnoses. . . . . . . . . . . . . . . . . . . . . . . 1º4O Ana|isa V. Ha|¡crn. /D. justin j. Crccn. /D. and \arrcn R. Hc,mann. /D SECTION 32. Soxually Transmittod Disoasos . . . . . . . . . . . . . . . . . . . . . . . 1º55 200 Syphilis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1º55 /iguc| R. :an.hc:. /D 201 lnuenic (Non-Veneieal) ¯ieponenatoses . . . . 1º¯¯ /iguc| R. :an.hc:. /D 202 Chancioiu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1º8o :tc¡han lautcns.h|agcr. /D 203 Lynphogianulona Veneieun . . . . . . . . . . . . . 1º8¯ :amcr H. Chosn. /D. and Ama| l. lur|an. /D 204 Cianulona lnguinale . . . . . . . . . . . . . . . . . . . . 1ººO A|du|-Chani li||i. /D. lACl. and /,rna l|-:harccj. /D 205 Conoiihea anu Cthei Veneieal Diseases . . . . 1ººo Anna|c||c l. Car.ia. 3:. Vandana l. /adkan. /D. and :tc¡hcn l. T,ring. /D. lhD. /3A SECTION 33. Infostations, Bitos, and Stings . . . . 2OO1 206 Leishnaniasis anu Cthei liotozoan lnlections. . . . . . . . . . . . . . . . . . . . . 2OO1 :amcr H. Chosn. /D. and Ama| l. lur|an. /D 207 Helninthic lnlections . . . . . . . . . . . . . . . . . . . . 2O11 /ar, l|i:a|cth \i|son. /D. and lri. Caumcs. /D 20ß Scahies, Cthei íites, anu leuiculosis . . . . . . . 2O2º :tc¡hcn l. :tonc. /D. jonathan ^. Co|djar|. /D. and Ro.k, l. 3a.c|icri. /D 209 Bites anu Stings ol ¯eiiestiial anu Aguatic Lile . . . . . . . . . . . . . . . 2Oo¯ jcnnijcr :. Da|,. /D. and /ark jordan :.harj. /D 210 Aithiopou Bites anu Stings . . . . . . . . . . . . . . . 2O54 Christo¡hcr j. :tccn. /D. and Ro|crt A. :.hvart:. /D. /lH PART 10 20oo 000UPATl0hAl 8Klh Dl8EA8E8 AhD 8Klh Dl8EA8E8 DUE T0 Bl0l00l0 wARFARE SECTION 34. Occupational Skin Disoasos . . . . . . . . . . . . . . . . . . . . . . . . . . . 2O6¯ 211 Cccupational Slin Diseases Due to liiitants anu Alleigens . . . . . . . . . . . . . 2O6¯ jamcs :. Ta,|or. /D. A¡ra :ood. /D. and Antoinc Amado. /D 212 Cccupational Noneczenatous Slin Diseases Due to Biologic, lhysical, anu Chenical Agents . . . . . . . . . . . . 2O¯4 A¡ra :ood. /D. and jamcs :. Ta,|or. /D SECTION 35. Tho Skin in Biotorrorism and Biologic Warfaro . . . . . . . . . . . 2O81 213 Cutaneous íanilestations ol Biologic, Chenical, anu Rauiologic ¯eiioiisn Attacls . . . . . . . . . . . . . . . . . . . . . . . 2O81 :.ott A. ^orton. /D. /lH xv PART 11 2089 THERAPEUTl08 SECTION 36. Topical Thorapy . . . . . . . . . . . . . . 2Oº1 214 liinciples ol ¯opical ¯heiapy. . . . . . . . . . . . . . 2Oº1 lcndra C. 3crgstrom. /D. and 3ru.c l. :tro|cr. /D 215 lhainacolinetics anu ¯opical Applications ol Diugs . . . . . . . . . . . . . . . . . . . . 2Oº¯ Hans :.hacjcr. /D. Thomas l. Rcdc|mcicr. /D. Ccrhard j. ^oh,nck. /D. and jurgcn ladcmann. /D 216 ¯opical Coiticosteioius. . . . . . . . . . . . . . . . . . . 21O2 lsa|c| C. Va|cn.ia. /D. and lran.is.o A. lcrdc|. /D 217 ¯opical Retinoius. . . . . . . . . . . . . . . . . . . . . . . . 21O6 :cvon lang. /D. and john j. Voorhccs. /D 21ß ¯opical Antihiotics . . . . . . . . . . . . . . . . . . . . . . 211o /ark \. 3onncr. /D. lau| /. 3cnson. /D. and \i||iam D. jamcs. /D. lhD 219 ¯opical Antilungal Agents . . . . . . . . . . . . . . . . 2116 \hitnc, A. High. /D. and jamcs l. lit:¡atri.k. /D 220 ¯opical anu lntialesional Cytotoxic Agents . . . . . . . . . . . . . . . . . . . . . . . 2122 /cgan /. /oorc. /D. and 3ru.c l. :tro|cr. /D 221 ¯opical lnnunonouulatois . . . . . . . . . . . . . . . 2125 Ro|crt :id|ur,. /D. and jon /. Haniµn. /D 222 Cthei ¯opical íeuications. . . . . . . . . . . . . . . . 21oO Craig ^. 3urkhart. /D. and lcnncth A. lat:. /D 223 lhotopiotection anu Sun liotective Agents . . . . 21o¯ Hcnr, \. lim. /D 224 Special Consiueiations loi ¯opical ¯heiapy ol lthnic Slin . . . . . . . . . . . . 2142 Roo¡a| V. lundu. /D SECTION 37. Systomic Thorapy . . . . . . . . . . . . . 214¯ 225 Systenic Clucocoiticoius . . . . . . . . . . . . . . . . . 214¯ Vi.toria l. \crth. /D 226 Dapsone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2154 joni C. :ago. /D. and Russc|| l. Ha|| lll. /D 227 Aninoguinolines. . . . . . . . . . . . . . . . . . . . . . . . 215¯ jcjjrc, R. laDu.a. /D. lhD. and Anthon, A. Cas¡ari. /D 22ß Cytotoxic anu Antinetaholic Agents . . . . . . . 216o \hitnc, A. High. /D. and jamcs l. lit:¡atri.k. /D 229 Retinoius . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2181 Andcrs Vah|quist. /D. lhD. :tc¡hanc lucn:|i. /D. and jcan-Hi|airc :aurat. /D 230 Antihistanines . . . . . . . . . . . . . . . . . . . . . . . . . 2186 :usan l. lim|. /D. and Ro|crt A. \ood. /D 231 Antihiotics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21º4 Christo¡hcr C. Cas|arrc. D·. :tcvcn l. :.hmitt. /D. and lcnncth j. Tomc.ki. /D 232 Antiviial Diugs . . . . . . . . . . . . . . . . . . . . . . . . . 22Oo Christinc /. Ha,. /D. and Ri.hard C. Rci.hman. /D 233 Cial Antilungal Agents . . . . . . . . . . . . . . . . . . 2211 /argarct :. lcc-3c||antoni. /D. lhD. and ^c||ic lonnikov. /D 234 lnnunosuppiessive anu lnnunonouulatoiy Diugs . . . . . . . . . . . . . . . 221¯ Car|os H. ^ousari. /D. and Crant j. Anha|t. /D 235 lnnunohiologicals, Cytolines, anu Ciovth lactois in Deinatology . . . . . . . 222o :tc¡hcn Ri.hardson. /D. and joc| Cc|jand. /D 236 Anti-Angiogenic Agents . . . . . . . . . . . . . . . . . . 22o1 la|¡ana Rcdd,. 3:. and ja.k Ar|iscr. /D 237 Diug lnteiactions . . . . . . . . . . . . . . . . . . . . . . . 22o6 :tc¡hcn l. \o|vcrton. /D SECTION 38. Physical Troatmonts. . . . . . . . . . . 224o 23ß ¯heiapeutic lhotoneuicine: lhototheiapy . . . . . . . . . . . . . . . . . . . . . . . . . . 224o jcan lrutmann. /D. and Akimi.hi /orita. /D. lhD 239 lhotochenotheiapy anu lhotouynanic ¯heiapy . . . . . . . . . . . . . . . . . . 224º Hcr|crt Honigsmann. /D. Ro|j-/arkus ::cimics. /D. and Ro|crt lno||cr. /D 240 Laseis anu llashlanps in Deinatology. . . . . . . . . . . . . . . . . . . . . . . . . 226o lcrnanda H. :akamoto. /D. Tomi \a||. /D. /athcv /. Avram. /D. and R. Rox Andcrson. /D 241 Rauiotheiapy . . . . . . . . . . . . . . . . . . . . . . . . . . 22¯º Rcnato lani::on. /D SECTION 3º. Complomontary and Altornativo Dormatology . . . . . . . . . . . . . . . 2285 242 Conplenentaiy anu Alteinative íeuicine in Deinatology . . . . . . . . . . . . . . . . 2285 A|an Dattncr. /D xv| SECTION 40. Surgory in Dormatology . . . . . . .228º 243 Deinatologic Suigeiy: lntiouuction to Anatony anu Appioach. . . . . . . . . . . . . . . . 228º :umaira Z. Aasi. /D. and 3rcnt lcnnington. /D 244 lxcisional Suigeiy anu Repaii, lncluuing llaps anu Cialts . . . . . . . . . . . . . . . . 2oO2 junc l. Ro|inson. /D 245 íohs íiciogiaphic Suigeiy. . . . . . . . . . . . . . .2o15 lcn l. lcc. /D. Va|cn.ia D. Thomas. /D. and ^ci| A. :vanson. /D 246 Nail Suigeiy. . . . . . . . . . . . . . . . . . . . . . . . . . . .2o2O Ro|crt 3aran. /D 247 Ciyosuigeiy anu llectiosuigeiy. . . . . . . . . . . .2ooO justin j. Vu¡cvi.h. /D. and lconard H. Co|d|crg. /D 24ß Suigical Conplications . . . . . . . . . . . . . . . . . . .2oo6 Ri.hard 3cnnctt. /D 249 Wounu Repaii: íechanisns anu liactical Consiueiations . . . . . . . . . . . . . . 2o42 Vin.cnt la|anga. /D. lACl. and :atori lvamoto. /D. lhD 250 ¯ieatnent loi Vaiicose anu ¯elangiectatic Leg Veins . . . . . . . . . . . . . . . . . . 2o4º Ro|crt A. \ciss. /D. and /argarct A. \ciss. /D SECTION 41. Cosmotic Dormatology . . . . . . . . 2o5¯ 251 Cosnetics anu Slin Caie in Deinatology . . . . . . . . . . . . . . . . . . . . . . . . . 2o5¯ lcs|ic 3aumann. /D 252 Slin Resuilacing: Ahlative Laseis, Chenical leels, anu Deinahiasion. . . . . . . . . 2o64 l|i:a|cth l. Tan:i. /D. and Tina :. A|stcr. /D 253 Cosnetic Applications ol Non-Ahlative Laseis anu Cthei Light Devices . . . . . . . . . . . . 2o¯2 Annc /. Cha¡as. /D. and Ro, C. Ccroncmus. /D 254 Liposuction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2o¯8 Aimcc l. lconard. /D. and C. \i||iam Hankc. /D. /lH. lACl 255 Solt-¯issue Augnentation . . . . . . . . . . . . . . . . 2o8O lisa /. Donojrio. /D 256 Botulinun ¯oxin. . . . . . . . . . . . . . . . . . . . . . . . 2o88 Ri.hard C. C|ogau. /D 257 Haii ¯iansplantation anu Alopecia Reuuction . . . . . . . . . . . . . . . . . . 2oº4 \a|tcr l. !ngcr. /D. lRCl(C;. lACl. Ro|in H. !ngcr. /D. and /ark !ngcr. /D lnuex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . l-1 xv|| .´'¯'' cU¯´'' S0ma|ra I. Aas|, N0 Assistant liolessoi, Depaitnent ol Deinatology Yale Univeisity School ol íeuicine Nev Haven, Connecticut Ne||ssa Abrams, N0 Depaitnents ol Deinatology anu leuiatiics Noithvestein Univeisity Chicago, lllinois Ammar N. Ahmed, N0 Depaitnent ol Deinatology Bayloi College ol íeuicine Houston, ¯exas N0rad A|am, N0 Chiel, Section ol Cutaneous anu Aesthetic Suigeiy Associate liolessoi, Depaitnents ol Deinatology anu Ctolaiyngology Heau 8 Necl Suigeiy leinheig School ol íeuicine Noithvestein Univeisity Chicago, lllinois L. Va|eyr|e-A||aoore, N0 Depaitnent ol Deinatology Henii íonuoi Hospital Univeisity ol laiis laiis, liance T|oa S. A|ster, N0 Clinical liolessoi, Depaitnent ol Deinatology [ohns Hoplins íeuical Centei Baltinoie, íaiylanu Ceoigetovn Univeisity íeuical Centei Washington lnstitute ol Deinatological Lasei Suigeiy Washington, D.C. Aoto|oe Amado, N0 Contact Deinatitis lellov Depaitnent ol Deinatology ¯he Clevelanu Clinic lounuation Clevelanu, Chio N||ao J. Aoadkat, N0 Division ol Deinatology Depaitnent ol íeuicine Washington Univeisity School ol íeuicine St. Louis, íissouii 8. 8ox Aodersoo, N0 liolessoi ol Deinatology Haivaiu íeuical School Wellnan Centei loi lhotoneuicine íassachusetts Ceneial Hospital Boston, íassachusetts £|||ot J. Aodrophy, N0 Baihaia anu Nathan Cieenheig Chaii in Bioneuical Reseaich Univeisity ol íassachusetts íeuical School Woicestei, íassachusetts 6raot J. Aoha|t, N0 Consultant, Depaitnent ol Deinatology [ohns Hoplins lnstitutes ol íeuicine Baltinoie, íaiylanu Jack Arb|ser, N0 Depaitnent ol Deinatology lnoiy Univeisity Atlanta, Ceoigia 8oberto Areoas, N0 Depaitnent ol Deinatology íycology Section Di. íanuel Cea Conzalez Ceneial Hospital íexico City, íexico 0ha||d AssaI, N0 Associate liolessoi, Depaitnent ol Deinatology anu Alleigy Chaiite-Univeisitatsneuiczin, Beilin Slin Cancei Centei, Chaiite Univeisity ol íeuicine Beilin, Ceinany Nathew N. Avram, N0 Diiectoi, íCH Deinatology Lasei anu Cosnetics Centei íassachusetts Ceneial Hospital liolessoi, Depaitnent ol Deinatology Haivaiu íeuical School Boston, íassachusetts 8ocky £. 8ace||er|, N0 Division ol Deinatology Depaitnent ol lnteinal íeuicine Southein lllinois Univeisity School ol íeuicine Spiinghelu, lllinois 0hr|st|oe 8aogert, N0 Depaitnent ol Deinatology íeuical Univeisity ol Vienna Vienna, Austiia 8obert 8arao, N0 Nail Disease Centie Cannes, liance h|co|e 8asset-Ség0|o, N0 Seivice ue Deinatologie Hopital Saint-Louis laiis, liance £0geoe A. 8a0er, N0 Lucy Beclei liolessoi in íeuicine lneiitus Stanloiu Univeisity School ol íeuicine Stanloiu, Caliloinia Les||e 8a0maoo, N0 liolessoi, Depaitnent ol Deinatology Diiectoi, Univeisity ol íiani Cosnetic Centei Univeisity ol íiani íillei School ol íeuicine íiani, lloiiua *1his conLriluLor´s vorl as auLhor vas per- lorned ouLside Lhe scope ol his enploy- nenL as a U.S. governnenL enployee. 1his vorl represenLs his personal and proles- sional vievs and noL necessarily Lhose ol Lhe U.S. governnenL. 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Click here for terms of use. xv||| L|sa A. 8eck, N0 Associate liolessoi, Depaitnent ol Deinatology Univeisity ol Rochestei School ol íeuicine Rochestei, Nev Yoil N|chae| h. 8eck, F80P, N8 0h8 Consultant Deinatologist anu Honoiaiy Clinical Lectuiei Univeisity ol íanchestei School ol íeuicine Hope Hospital íanchestei, lnglanu Leah 8e|azar|ao, N0 Resiuent, Depaitnent ol Deinatology Univeisity ol íassachusetts íeuical School Woicestei, íassachusetts 0ooa|d V. 8e|s|to, N0 Clinical liolessoi ol íeuicine (Deinatology) Univeisity ol íissouii, lansas City lansas City, íissouii 8|chard 8eooett, N0 Clinical liolessoi, Depaitnent ol Deinatology Univeisity ol Southein Caliloinia Clinical liolessoi, Depaitnent ol íeuicine Univeisity ol Caliloinia at Los Angeles Los Angeles, Caliloinia Pa0| N. 8eosoo, N0 ¯iiCities Slin 8 Cancei [ohnson City, ¯ennessee T|mothy 6. 8erger, N0 liolessoi ol Clinical Deinatology Depaitnent ol Deinatology Univeisity ol Caliloinia, San liancisco San liancisco, Caliloinia Pa0| 8. 8ergstresser, N0 [anes N. Cillian Chaii, Depaitnent ol Deinatology Univeisity ol ¯exas Southvestein íeuical Centei Dallas, ¯exas keodra 6. 8ergstrom, N0 Resiuent lhysician, ¯he Ronalu C. leielnan Depaitnent ol Deinatology Nev Yoil Univeisity íeuical Centei Nev Yoil, Nev Yoil JeIIrey 0. 8erohard, N0 liolessoi ol íeuicine Division ol Deinatology Univeisity ol íassachusetts íeuical School Univeisity ol íassachusetts íenoiial Health Caie Woicestei, íassachusetts Negao L. 8eroste|o, N0 lntein, ít. Sinai Hospital Nev Yoil, Nev Yoil Jag 8hawao, N0 liolessoi ol Deinatology anu lathology Heau, Deinatopathology Section Depaitnent ol Deinatology Boston Univeisity School ol íeuicine Boston, íassachusetts 0av|d 8. 8|ckers, N0 Cail ¯iunan Nelson liolessoi anu Chaii Depaitnent ol Deinatology Colunhia Univeisity Nev Yoil, Nev Yoil N|chae| 8|gby, N0 Associate liolessoi, Deinatology Haivaiu íeuical School Depaitnent ol Deinatology Beth lsiael Deaconess íeuical Centei Boston, íassachusetts 0aro| N. 8|ack, N0 liolessoi ol Rheunatology Centie loi Rheunatology Royal liee anu Univeisity College íeuical School Hanpsteau Canpus Lonuon, lnglanu Aodrew 8|a0ve|t, N0 liolessoi, Depaitnent ol Deinatology anu Depaitnent ol íoleculai íiciohiology anu lnnunology Ciegon Health 8 Science Univeisity loitlanu, Ciegon Nark 8og0o|ew|cz, N0 Depaitnent ol leuiatiics National [evish íeuical anu Reseaich Centei Univeisity ol Coloiauo School ol íeuicine Denvei, Coloiauo Nark w. 8oooer, N0 Ceoigia Deinatology Wainei Rohins, Ceoigia La0reoce N. 8ooo, N0, Ph0 Centei loi Vasculai Anonalies, Division ol llastic Suigeiy Clinigues Univeisitaiies St. Luc Biussels, Belgiun 8arbara 8oooe, N0 Depaitnent ol Deinatology Univeisity Hospital Chent Chent, Belgiun V|ad|m|r 8otchkarev, N0, Ph0 Associate Reseaich liolessoi Depaitnents ol Deinatology, lathology anu Lahoiatoiy íeuicine Boston Univeisity School ol íeuicine Boston, íassachusetts 0o0g|as £. 8rash, Ph0 liolessoi, Depaitnent ol ¯heiapeutic Rauiology Yale Univeisity School ol íeuicine Nev Haven, Connecticut Fraoc|sco 6. 8ravo, N0 Associate liolessoi ol Deinatology anu lathology Univeisiuau leiuana Cayetano Heieuia Lina, leiu Thomas 8reoo, N0, Ph0 Consultant Deinatopathologist, Depaitnent ol lathology Westein Ceneial Hospital ¯he Univeisity ol luinhuigh luinhuigh, Scotlanu Univeisity ol íanchestei Salloiu, Uniteu linguon L|eve 8rochez, N0, Ph0 liolessoi, Depaitnent ol Deinatology Univeisity Hospital Chent Chent, Belgiun 8obert T. 8rode||, N0 liolessoi ol lnteinal íeuicine Deinatology Section Clinical liolessoi, Deinatopathology in lathology Noitheastein Chio Univeisities College ol íeuicine Associate Clinical liolessoi ol Deinatology Case Westein Reseive School ol íeuicine Waiien, Chio Narc 0. 8rowo, N0 liolessoi, Depaitnent ol Deinatology Diiectoi, Division ol Deinatologic Suigeiy, Cncology, anu íohs Suigeiy Univeisity ol Rochestei School ol íeuicine Stiong íenoiial Hospital Rochestei, Nev Yoil 0ao|e|a 8r0ch-6erharz, N0 liolessoi, Depaitnent ol Deinatology Heiniich-Heine Univeisity Univeisity Hospital ol Duesseluoil Duesseluoil, Ceinany x|x Leeoa 8r0ckoer-T0dermao, N0 liolessoi anu Chaii, Depaitnent ol Deinatology Univeisity ol lieihuig lieihuig, Ceinany L0c|oda S. 80escher, N0 Associate liolessoi, Division ol Deinatology Depaitnent ol lnteinal íeuicine Southein lllinois Univeisity School ol íeuicine Spiinghelu, lllinois 0hr|stopher 8arry 80oker, NA, N0, F80P liolessoi ol Deinatology anu Consultant Deinatologist lnpeiial College School ol íeuicine Chelsea 8 Westninstei anu Royal íaisuen Hospitals Lonuon, Uniteu linguon wa|ter h. 0. 80rgdorI, N0 Clinical Lectuiei Depaitnent ol Deinatology Luuvig íaxinilian Univeisity íunich, Ceinany S0sao 80rg|o, N0 lnstiuctoi, Depaitnent ol Deinatology Beth lsiael Deaconess íeuical Centei Haivaiu íeuical School Boston, íassachusetts 0ra|g h. 80rkhart, N0 Depaitnent ol Deinatology Univeisity ol Noith Caiolina Chapel Hill, Noith Caiolina 0|a0de S. 80rtoo, N0 Depaitnent ol Deinatology Dule Univeisity íeuical Centei Duihan, Noith Caiolina 80ggero 0ap0to, N0 liolessoi ol Deinatology lnstitute ol Deinatological Sciences íilan, ltaly (u. 2OO¯) Ne|ody 0. 0arter, N0 Au|unct laculty National lnstitute ol Alleigy anu lnlectious Diseases National lnstitutes ol Health Bethesua, íaiylanu Joho A. 0ar0cc|, N0 Chiel, íohs íiciogiaphic anu Deinatologic Suigeiy Weill íeuical College ol Coinell Univeisity Nev Yoil lieshyteiian Hospital Nev Yoil, Nev Yoil £r|c 0a0mes, N0 liolessoi ol lnlectious anu ¯iopical Diseases Univeisity lieiie et íaiie Cuiie Depaitnent ol lnlectious anu ¯iopical Diseases Hopital litié-Salpêtiieie laiis, liance Loreozo 0erroo|, N0 liolessoi, Depaitnent ol Deinatology íeuical Univeisity ol Ciaz Ciaz, Austiia Sarah L. 0ham||o, N0 Associate liolessoi, Division ol Deinatology Chiluien`s íenoiial Hospital Noithvestein Univeisity Chicago, lllinois Nary w0 0haog, N0 Chiel, leuiatiic Deinatology Connecticut Chiluien`s íeuical Centei Associate liolessoi ol Deinatology 8 leuiatiics Univeisity ol Connecticut School ol íeuicine Haitloiu, Connecticut Aooe N. 0hapas, N0 Clinical Assistant liolessoi, ¯he Ronalu C. leielnan Depaitnent ol Deinatology Lasei anu Slin Suigeiy Centei ol Nev Yoil Nev Yoil Univeisity íeuical Centei Nev Yoil, Nev Yoil Joe| 0harrow, N0 Associate liolessoi, Depaitnent ol leuiatiics leinheig School ol íeuicine Noithvestein Univeisity Heau, Division ol Cenetics Chiluien`s íenoiial Hospital Chicago, lllinois Ne| 0heo, Ph0 Depaitnent ol Deinatology lecl School ol íeuicine Univeisity ol Southein Caliloinia Los Angeles, Caliloinia Aody J. 0h|eo, N0, Ph0 Acting Assistant liolessoi, Division ol Deinatology Univeisity ol Washington Seattle, Washington Aooe-Nar|e 0homat, N0 lellov in lnlectious Diseases ¯ults-Nev lnglanu íeuical Centei Boston, íassachusetts Nary-Nargaret 0hreo, N0 liolessoi in Resiuence Depaitnent ol Deinatology Univeisity ol Caliloinia, San liancisco Stall Deinatologist Veteians Allaiis íeuical Centei San liancisco, Caliloinia 0av|d h. 0h0, N0, Ph0 lnstiuctoi, ¯he Ronalu C. leielnan Depaitnent ol Deinatology Nev Yoil Univeisity School ol íeuicine Nev Yoil, Nev Yoil Noo-L| 0h0, Ph0 liolessoi anu Vice Chaii ol Reseaich Depaitnent ol Deinatology anu Cutaneous Biology [elleison íeuical College [elleison lnstitute ol íoleculai íeuicine ¯honas [elleison Univeisity lhilauelphia, lennsylvania 0av|d £. 0oheo, N0, NPh Associate liolessoi, ¯he Ronalu C. leielnan Depaitnent ol Deinatology ¯he Nev Yoil Univeisity School ol íeuicine Nev Yoil, Nev Yoil Ph|||p 8. 0oheo, N0 Clinical Associate liolessoi, Depaitnent ol Deinatology Univeisity ol ¯exas-Houston íeuical School Houston, ¯exas hoeka |. 0omIere, N0 Assistant liolessoi íayo Clinic College ol íeuicine Consultant in Deinatology íayo Clinic Rochestei, íinnesota Jeoo|Ier I. 0ooper, N0 Assistant liolessoi, Depaitnent ol Deinatology Univeisity ol íaiylanu School ol íeuicine Baltinoie, íaiylanu Lyoo A. 0oroe||0s, N0 Associate liolessoi anu Chiel, Division ol Deinatology Washington Univeisity St. Louis, íissouii 8osamar|a 0orooa, 0Sc, N0 lstituto Deinopatico uell`lnnacolata Divisione ui lnnunoueinatologia Rone, ltaly xx Ne||ssa |. 0ostoer, N0 Assistant liolessoi, Depaitnent ol Deinatology Univeisity ol ¯exas Southvestein íeuical School at Dallas Dallas, ¯exas 6eorge 0otsare||s, N0 Associate liolessoi, Depaitnent ol Deinatology Univeisity ol lennsylvania íeuical Centei lhilauelphia, lennsylvania P|erre A. 0o0|ombe, Ph0 liolessoi, Depaitnents ol Biological Chenistiy anu Deinatology Diiectoi, Ciauuate liogian in Cellulai anu íoleculai íeuicine [ohns Hoplins Univeisity School ol íeuicine Baltinoie, íaiylanu Joe 0raIt, N0 Section ol lnnunohiology Depaitnent ol lnteinal íeuicine Yale Univeisity Nev Haven, Connecticut hoah 0raIt, N0, Ph0 Associate liogian Diiectoi, Division ol Deinatology Haihoi UCLA íeuical Centei Los Angeles, Caliloinia Jeoo|Ier S. 0a|y, N0 Depaitnent ol íeuicine Division ol lnlectious Diseases anu lnnunology Univeisity ol íassachusetts íeuical School Woicestei, íassachusetts Stamat|oa 0ao|e||des, N0 S|ogien`s Synuione Clinic Cene ¯heiapy anu ¯heiapeutics Bianch National lnstitute ol Dental anu Cianiolacial Reseaich National lnstitutes ol Health Bethesua, íaiylanu Nazeo S. 0ao0d, N0 loit íyeis Deinatology loit íyeis, lloiiua Thomas h. 0ar||og, N0, Ph0 Associate liolessoi, Depaitnent ol Deinatology Uniloineu Seivices Univeisity ol the Health Sciences Bethesua, íaiylanu A|ao 0attoer, N0 Nev Rochelle, Nev Yoil Aer|yo 6. 0awo, N0, N8A Depaitnent ol Deinatology Wale loiest Univeisity School ol íeuicine Winston-Salen, Noith Caiolina Steveo N. 0eao, 00, FA0P Division ol Caiuiovasculai íeuicine Chio State Univeisity Colunhus, Chio h|co|e N. 0eLa0ro, 0PN Nev Yoil College ol louiatiic íeuicine Nev Yoil, Nev Yoil Thomas N. 0eLa0ro, 0PN liolessoi Nev Yoil College ol louiatiic íeuicine Nev Yoil, Nev Yoil 0hr|stopher P. 0eotoo, N0 liolessoi ol lxpeiinental Rheunatology Centie loi Rheunatology Royal liee anu Univeisity College íeuical School Hanpsteau Canpus Lonuon, lnglanu Sohe 0e Schepper, N0 Depaitnent ol Deinatology Univeisity Hospital Chent Chent, Belgiun 0hr|st|oe A. 0ew|tt, N0 Division ol Deinatology Depaitnent ol lnteinal íeuicine Southein lllinois Univeisity School ol íeuicine Spiinghelu, lllinois Naodeep 0had|y, N0, FA00 Section ol Caiuiovasculai íeuicine Boston Univeisity School ol íeuicine Boston, íassachusetts Jose L. 0|az-Perez, N0 Ciuces Univeisity Hospital llaza Ciuces Bilhao, Spain Joho J. 0|6|ovaooa, N0 liolessoi, Division ol Deinatology Diiectoi, Division ol Deinatophainacology Biovn Univeisity íeuical School Rhoue lslanu Hospital lioviuence, Rhoue lslanu Aodrzej A. 0|0gosz, N0 liolessoi, Depaitnent ol Deinatology Conpiehensive Cancei Centei Univeisity ol íichigan Ann Aihoi, íichigan L|sa N. 0oooIr|o, N0 Assistant Clinical liolessoi Depaitnent ol Deinatology Yale Univeisity School ol íeuicine Nev Haven, Connecticut 0aveo h. 0osh|, N0 Depaitnent ol Deinatology Haivaiu íeuical School Boston, íassachusetts karyooe 0. 00ocao, N0 St. Helena, Caliloinia Jooathao A. 0yer, N0 Assistant liolessoi, Depaitnent ol Deinatology Univeisity ol íissouii-Colunhia Colunhia, íissouii 8obert T. £berhardt, N0 Division ol Caiuiovasculai íeuicine Boston Univeisity íeuical Centei Boston, íassachusetts L|bby £dwards, N0 Chiel, Division ol Deinatology Caiolinas íeuical Centei Chailotte, Noith Caiolina Clinical Associate liolessoi Depaitnent ol Deinatology Univeisity ol Noith Caiolina Chapel Hill, Noith Caiolina Lawreoce F. £|cheohe|d, N0 Chiel, Division ol leuiatiic anu Auolescent Deinatology Chiluien`s Hospital anu Depaitnents ol leuiatiics anu íeuicine (Deinatology) Univeisity ol Caliloinia San Diego San Diego, Caliloinia Arth0r I. £|seo, N0 Winlieu anu lnna Shovnan liolessoi, Division ol Deinatology Depaitnent ol íeuicine Washington Univeisity íeuical Centei St. Louis, íissouii James T. £|der, N0 liolessoi, Depaitnent ol Deinatology Univeisity ol íichigan Ann Aihoi Veteians Allaiis Hospital Ann Aihoi, íichigan Nyroa £|-ShareeI, N0 Depaitnent ol Deinatology Aneiican Univeisity ol Beiiut íeuical Centei Beiiut, Lehanon 0|rk N. £|stoo, N0 Depaitnent ol Deinatology Ceisingei íeuical Centei Danville, lennsylvania xx| Joseph 0. £og||sh |||, N0 Associate liolessoi, Depaitnent ol Deinatology Univeisity ol littshuigh littshuigh, lennsylvania Jaoet A. Fa|r|ey, N0 liolessoi, Depaitnent ol Deinatology íeuical College ol Wisconsin íilvaulee, Wisconsin V|oceot Fa|aoga, N0, FA0P Depaitnent ol Deinatology anu Slin Suigeiy Rogei Willians íeuical Centei lioviuence, Rhoue lslanu Depaitnent ol Deinatology anu Biochenistiy Boston Univeisity Boston, íassachusetts 8obert 0. Fea|ey, N0 Assistant liolessoi, Depaitnent ol Neuiology íayo Clinic íeuical School Rochestei, íinnesota James Ferg0soo, N0 lhotohiology Unit Ninevells Hospital Dunuee, Scotlanu La0ra korb Ferr|s, N0, Ph0 Assistant liolessoi, Depaitnent ol Deinatology Univeisity ol littshuigh littshuigh, lennsylvania James £. F|tzpatr|ck, N0 liolessoi, Deinatology 8 Deinatopathology Univeisity ol Coloiauo Health Sciences Centei Denvei, Coloiauo, Deinatopathology Consultants, Anschutz Cancei Centei Depaitnent ol Deinatology Auioia, Coloiauo Ph|||p F|eckmao, N0 liolessoi, Division ol Deinatology Univeisity ol Washington Seattle, Washington 0arsteo F|ohr, N80P0h Centei ol lviuence-Baseu Deinatology Nottinghan Univeisity Hospitals NHS ¯iust Nottinghan, Uniteu linguon 0am|||e Fraoces, N0 Univeisité laiis Vl Seivice ue Deinatologie-Alleigologie Hopital ¯enon laiis, liance Jorge Fraoks, N0 Depaitnent ol Deinatology íaastiicht Univeisity Centei loi íoleculai Deinatology (íUCíD) íaastiicht, ¯he Netheilanus ||ooa J. Fr|edeo, N0 liolessoi, Depaitnent ol Deinatology Univeisity ol Caliloinia, San liancisco San liancisco, Caliloinia She||a Fa||oo Fr|ed|aoder, N0 Clinical liolessoi ol leuiatiics anu íeuicine Univeisity ol Caliloinia San Diego School ol íeuicine Chiluien`s Hospital, San Diego San Diego, Caliloinia 8|chard 6a||o, N0, Ph0 Chiel, Auult Deinatology Associate Clinical liolessoi, leuiatiics anu íeuicine Depaitnent ol íeuicine Univeisity ol Caliloinia, San Diego La [olla, Caliloinia Aooabe||e L. 6arc|a, 8S Univeisity ol ¯exas Health Science Centei Houston, ¯exas Am|t 6arg, N0 Assistant liolessoi ol íeuicine Division ol Deinatology Univeisity ol íassachusetts íeuical School Univeisity ol íassachusetts íenoiial Health Caie Woicestei, íassachusetts Aodrea L. 6arrett, N0 Depaitnent ol Deinatology Univeisity ol Wisconsin íauison, Wisconsin 0hr|stopher 0. 6asbarre, 00 Senioi Resiuent in Deinatology ¯he Clevelanu Clinic lounuation Clevelanu, Chio Aothooy A. 6aspar|, N0 Depaitnent ol Deinatology ¯he Clevelanu Clinic lounuation Clevelanu, Chio Joho k. 6e|sse, N0 Associate Clinical liolessoi Depaitnents ol Deinatology anu lathology Univeisity ol Caliloinia, San liancisco San liancisco, Caliloinia Joe| 6e|Iaod, N0 Assistant liolessoi, Depaitnent ol Deinatology Univeisity ol lennsylvania lhilauelphia, lennsylvania 0ar|o 6e|mett|, N0 liolessoi ol Deinatology lnstitute ol Deinatological Sciences íilan, ltaly 8oy 6. 6erooem0s, N0 Clinical liolessoi, ¯he Ronalu C. leielnan Depaitnent ol Deinatology Nev Yoil Univeisity íeuical Centei Lasei anu Slin Suigeiy Centei ol Nev Yoil Nev Yoil, Nev Yoil Samer h. 6hoso, N0 Assistant liolessoi, Depaitnent ol Deinatology Aneiican Univeisity ol Beiiut íeuical Centei Beiiut, Lehanon Lawreoce £. 6|bsoo, N0 liolessoi ol Deinatology íayo Clinic College ol íeuicine Consultant in Deinatology íayo Clinic Rochestei, íinnesota 8arbara A. 6||chrest, N0 liolessoi anu Chaii ol Deinatology Depaitnent ol Deinatology Boston Univeisity School ol íeuicine Boston, íassachusetts 8|chard 6. 6|oga0, N0 Clinical liolessoi ol Deinatology Univeisity ol Caliloinia, San liancisco San liancisco, Caliloinia 8aphae|a 6o|dbach-Naosky, N0 National lnstitute ol Aithiitis anu íusculosleletal anu Slin Disease National lnstitutes ol Health Bethesua, íaiylanu Leooard h. 6o|dberg, N0 DeinSuigeiy Associates, l.A. Houston, ¯exas Jooathao h. 6o|dIarb, N0 Division ol Deinatology Depaitnent ol lnteinal íeuicine Southein lllinois Univeisity School ol íeuicine Spiinghelu, lllinois xx|| Lowe|| A. 6o|dsm|th, N0 liolessoi ol Deinatology Univeisity ol Noith Caiolina School ol íeuicine Chapel Hill, Noith Caiolina Dean lneiitus Univeisity ol Rochestei School ol íeuicine anu Dentistiy Rochestei, Nev Yoil 0armeo £. 6ota, N0 Stall, Depaitnent ol Rheunatology Centei loi Vasculitis Caie anu Reseaich ¯he Clevelanu Clinic lounuation Clevelanu, Chio £mmy N. 6raber, N0 Chiel Resiuent, Depaitnent ol Deinatology ¯he lennsylvania State Univeisity College ol íeuicine Heishey, lennsylvania 8ob|o A. 0. 6raham-8rowo, N0 Consultant Deinatologist Honoiaiy Senioi Lectuiei, Depaitnent ol Deinatology Leicestei Royal lnhinaiy Leicestei, lnglanu Jaoe Nargaret 6raot-ke|s, N0 liolessoi anu Chaii Depaitnent ol Deinatology Univeisity ol Connecticut Health Centei lainington, Connecticut Na|co|m w. 6reaves, N0, Ph0, F80P lneiitus liolessoi ol Deinatology National Slin Centie Singapoie J0st|o J. 6reeo, N0 Depaitnent ol Deinatology Univeisity ol íeuicine anu Dentistiy ol Nev [eiseyRoheit Woou [ohnson íeuical School at Canuen Canuen, Nev [eisey 8oy 0. 6rek|o, N0 Clinical liolessoi ol Deinatology Deinatologic Suigeiy Unit Univeisity ol Caliloinia, San liancisco San liancisco, Caliloinia James N. 6r|cho|k, N0, Ph0 Associate liolessoi, Depaitnent ol Deinatology Dule Univeisity íeuical Centei Duihan, Noith Caiolina 0o0g|as 6rossmao, N0, Ph0 Associate liolessoi Depaitnents ol Deinatology anu Cncological Sciences Huntsnan Cancei lnstitute Univeisity ol Utah Salt Lale City, Utah Johaoo £. 60djoossoo, N0, Ph0 lellov, Depaitnent ol Deinatology Univeisity ol íichigan Ann Aihoi, íichigan 8r|dget 0. hackett, N80P| Regional Centie ol Deinatology íatei íiseiicoiuiae Hospital Duhlin, lielanu 8ebat N. ha|der, N0 liolessoi anu Chaii, Depaitnent ol Deinatology Hovaiu Univeisity Hospital Washington, D.C. 80sse|| P. ha|| |||, N0 [. Lanai Callavay liolessoi ol Deinatology Chiel, Division ol Deinatology Dule Univeisity íeuical Centei Duihan, Noith Caiolina A||ao 0. ha|pero, N0 Deinatology Acauenic Clhces íenoiial Sloan-letteiing Cancei Centei Nev Yoil, Nev Yoil Aoa||sa V. ha|pero, N0 Depaitnent ol Deinatology Univeisity ol íeuicine anu Dentistiy ol Nev [eiseyRoheit Woou [ohnson íeuical School Coopei Univeisity Hospital Canuen, Nev [eisey 0. w||||am haoke, N0, NPh, FA0P Lasei anu Slin Suigeiy Centei ol lnuiana Cainel, lnuiana Joo N. hao|ho, N0 liolessoi, Depaitnent ol Deinatology Ciegon Health anu Sciences Univeisity loitlanu, Ciegon Naody hart|og, N0 Resiuent, Depaitnent ol Deinatology Bayloi College ol íeuicine Houston, ¯exas 0hr|st|oa L. haverstock, N0, NS Resiuent, Depaitnent ol Deinatology Wale loiest Univeisity íeuical Centei Winston-Salen, Noith Caiolina Joho L. N. hawk, N0 Chaii, lhotohiology Unit St. [ohn`s lnstitute ol Deinatology St. ¯honas` Hospital ling`s College Lonuon Lonuon, lnglanu Ph|||p h. hawk|os, N0 National Anyloiuosis Centie, Depaitnent ol íeuicine Royal liee Hospital Lonuon, lnglanu 0hr|st|oe N. hay, N0 lnlectious Diseases Division Univeisity ol Rochestei íeuical Centei Rochestei, Nev Yoil 8oder|ck J. hay, N0 laculty ol íeuicine anu Health Cueen`s Univeisity Bellast Bellast, Noithein lielanu N|chae| P. heIIeroao, N0 Associate liolessoi anu Chiel, Division ol Deinatology Wiight State Univeisity Boonsholt School ol íeuicine Dayton, Chio T|mothy heIIeroao, Ph0 Depaitnent ol íeuical Cncology Dana laihei Cancei lnstitute Haivaiu íeuical School Boston, íassachusetts Stepheo £. he|ms, N0 Associate liolessoi ol lnteinal íeuicine, Deinatology Section Noitheastein Chio Univeisity College ol íeuicine Case Westein Reseive College ol íeuicine Waiien, Chio 0|r|ch 8. heogge, N0 liolessoi, Depaitnent ol Deinatology Heiniich-Heine Univeisity Univeisity Hospital ol Duesseluoil Duesseluoil, Ceinany Frédér|g0e heory, N0 Deinatopathology Seivice Univeisity Hospital ol Liege Liege, Belgiun warreo 8. heymaoo, N0 Depaitnent ol Deinatology Univeisity ol íeuicine anu Dentistiy ol Nev [eiseyRoheit Woou [ohnson íeuical School at Canuen Canuen, Nev [eisey xx||| N. Joho h|cks, N0, 00S, Ph0 liolessoi, Depaitnent ol lathology Diiectoi ol Anatonic lathology ¯exas Chiluien`s Hospital Bayloi College ol íeuicine Houston, ¯exas wh|toey A. h|gh, N0 Assistant liolessoi, Deinatology 8 Deinatopathology Univeisity ol Coloiauo Health Sciences Centei Denvei, Coloiauo Steveo N. ho||aod, N0 Chiel, Lahoiatoiy ol Clinical lnlectious Diseases National lnstitutes ol Health Bethesua, íaiylanu herbert höo|gsmaoo, N0 liolessoi anu Chaii, Depaitnent ol Deinatology íeuical Univeisity ol Vienna Vienna, Austiia Thomas 0. horo, N0 liolessoi anu Chaii, Depaitnent ol Deinatology Univeisity ol Ailansas loi íeuical Sciences Little Rocl, Ailansas *Thomas J. horoyak, N0, Ph0 lnvestigatoi, Deinatology Bianch Centei loi Cancei Reseaich National Cancei lnstitute National lnstitutes ol Health Bethesua, íaiylanu £||zabeth 8ahar ho0shmaod, N0 Associate liolessoi anu Chiel, Division ol Deinatology Wiight State Univeisity Boonsholt School ol íeuicine Dayton, Chio A|a|o hovoao|ao, N0, Ph0 liolessoi, Depaitnent ol íeuical Cenetics Univeisity laul Sahatiei luipan Hospital ¯oulouse, liance 0h0og-hoog h0, N0 Depaitnent ol Deinatology Univeisity ol Wisconsin íauison, Wisconsin L|odeo h0, N0 Division ol Ceogiaphic íeuicine anu lnlectious Disease ¯ults Nev lnglanu íeuical Centei Boston, íassachusetts *Sam T. hwaog, N0, Ph0 Senioi lnvestigatoi Deinatology Bianch Centei loi Cancei Reseaich, National Cancei lnstitute National lnstitutes ol Health Bethesua, íaiylanu 6abor |||e|, N0 S|ogien`s Synuione Clinic Cene ¯heiapy anu ¯heiapeutics Bianch National lnstitute ol Dental anu Cianiolacial Reseaich National lnstitutes ol Health Bethesua, íaiylanu A|ao 0. |rv|oe, N0, F80P|, N80P Consultant laeuiatiic Deinatologist Cui Lauy`s Hospital loi Sicl Chiluien Duhlin, lielanu Peter h. |t|o, N0 liolessoi anu Heau, Depaitnent ol Deinatology Univeisity Hospital Basel Basel, Svitzeilanu Sator| |wamoto, N0, Ph0 Depaitnent ol Deinatology anu Biochenistiy Boston Univeisity Boston, íassachusetts Sharoo £. Jacob, N0 Assistant liolessoi, Depaitnent ol Deinatology anu Cutaneous Suigeiy Univeisity ol íiani íillei íeuical School íiani, lloiiua hata||a Ja|mes, N0 Resiuent in Deinatology Univeisiuau lontihcia Bolivaiiana íeuellin, Colonhia w||||am 0. James, N0, Ph0 Depaitnent ol Deinatology Univeisity ol lennsylvania lhilauelphia, lennsylvania Natthew P. Jao|k, N0 Depaitnent ol Deinatology Wiight State Univeisity anu Boonsholt School ol íeuicine Dayton, Chio Thomas Jaoseo, N0 liolessoi, Depaitnent ol Deinatology, Veneieology, anu Alleigology Univeisity ol lssen lssen, Ceinany Ne||oda Jeo, N0 Resiuent, Depaitnent ol leuiatiics Section ol leuiatiic Deinatology Chiluien`s Hospital ol lhilauelphia lhilauelphia, lennsylvania Jeos-N|chae| Jeoseo, N0 liolessoi, Depaitnent ol Deinatology Univeisity ol liel Univeisity Hospitals ol liel liel, Ceinany 8|chard A||eo Johosoo, N0 lnstiuctoi in Deinatology Haivaiu íeuical School Clinical Associate in Deinatology íassachusetts Ceneial Hospital Boston, íassachusetts T|mothy N. Johosoo, N0 Depaitnent ol Deinatology Univeisity ol íichigan Ann Aihoi, íichigan 6raham A. Johostoo, N8 0h8, F80P Consultant Deinatologist, Depaitnent ol Deinatology Leicestei Royal lnhinaiy Leicestei, lnglanu Joseph L. Jor|zzo, N0 loinei (lounuing) Chaii, Depaitnent ol Deinatology Wale loiest Univeisity íeuical Centei Winston-Salen, Noith Caiolina Narc A. J0dsoo, N0 liolessoi, Division ol lulnonaiy anu Ciitical Caie íeuicine íeuical Univeisity ol South Caiolina Chaileston, South Caiolina Steveo kadd0, N0 Depaitnent ol Deinatology íeuical Univeisity ol Ciaz Ciaz, Austiia Aodrea A. ka|0s, N0 Acting Assistant liolessoi, Division ol Deinatology Univeisity ol Washington Seattle, Washington |osoo kaog, N0 Associate liolessoi, Section ol Rheunatology Depaitnent ol íeuicine Yale Univeisity School ol íeuicine Nev Haven, Connecticut Sewoo kaog, N0 liolessoi, Depaitnent ol Deinatology Univeisity ol íichigan Ann Aihoi, íichigan xx|v A||eo P. kap|ao, N0 National Alleigy Asthna anu Uiticaiia Centeis ol Chaileston Chaileston, South Caiolina J0||e k. kareo, N0 Resiuent, ¯he Ronalu C. leielnan Depaitnent ol Deinatology Nev Yoil Univeisity School ol íeuicine Nev Yoil, Nev Yoil 0ao|e| L. kastoer, N0 Chiel, Cenetics anu Cenonics Bianch National lnstitute ol Aithiitis anu íusculosleletal anu Slin Disease National lnstitutes ol Health Bethesua, íaiylanu keooeth A. katz, N0 Depaitnent ol Deinatology Univeisity ol lennsylvania lhilauelphia, lennsylvania *Stepheo |. katz, N0, Ph0 Diiectoi, National lnstitute ol Aithiitis anu íusculosleletal anu Slin Diseases National lnstitutes ol Health Bethesua, íaiylanu Lyoda ka0|s, N0 Assistant liolessoi, Depaitnent ol Deinatology Ciegon Health anu Science Univeisity loitlanu, Ciegon Aodrew keat, N0 Consultant lhysician Noithvicl lail Hospital Haiiov, íiuulesex, lnglanu 0eao L. ke||ogg, Jr., N0, Ph0 Associate liolessoi, Division ol Ceiiatiics anu Ceiontology Depaitnent ol íeuicine Univeisity ol ¯exas Health Science Centei at San Antonio, ¯exas San Antonio, ¯exas 0av|d P. ke|se||, N0 ¯he Royal Lonuon Hospital Lonuon, lnglanu Fraoc|sco A. kerde|, N0 Voluntaiy laculty Depaitnent ol Deinatology anu Cutaneous Suigeiy Univeisity ol íiani íillei School ol íeuicine íiani, lloiiua he|m0t ker|, N0 liolessoi anu Chaiinan, Depaitnent ol Deinatology íeuical Univeisity ol Ciaz Ciaz, Austiia Abd0|-6hao| k|bb|, N0, FA0P liolessoi anu Chaii, Depaitnent ol Deinatology Aneiican Univeisity ol Beiiut íeuical Centei Beiiut, Lehanon 0hr|st|oa £. k|||orao, N0 Depaitnent ol Deinatology anu Slin Suigeiy Rogei Willians íeuical Centei lioviuence, Rhoue lslanu Jeooy k|m, N0, Ph0 Assistant Clinical liolessoi, Division ol Deinatology Daviu Cellen School ol íeuicine Univeisity ol Caliloinia at Los Angeles Los Angeles, Caliloinia A|exa 8. k|mba||, N0, NPh Depaitnent ol Deinatology Haivaiu íeuical School Boston, íassachusetts Joho h. k||ppe|, N0 Aithiitis lounuation Atlanta, Ceoigia 8obert koob|er, N0 Associate liolessoi ol Deinatology Depaitnent ol Deinatology Division ol Special 8 lnviionnental Deinatology íeuical Univeisity ol Vienna Vienna, Austiia Saodra 8. koow|es, 8ScPhm Division ol Deinatology Sunnyhiool Health Sciences Centei Univeisity ol ¯oionto ¯oionto, Cntaiio, Canaua |reoe £. kochevar, Ph0 liolessoi, Depaitnent ol Deinatology Haivaiu Univeisity School ol íeuicine Wellnan Centei loi lhotoneuicine íassachusetts Ceneial Hospital Boston, íassachusetts Thomas koeo|g, N0 Associate Dean loi Stuuent Allaiis Assistant liolessoi ol lsychiatiy anu Behavioial Sciences ¯he [ohns Hoplins Univeisity School ol íeuicine Baltinoie, íaiylanu he|||e kooo|kov, N0 Depaitnent ol Deinatology Boston Veteians Allaiis íeuical Centei Boston, íassachusetts keooeth h. kraemer, N0 Reseaichei National lnstitutes ol Health Centei loi Cancei Reseaich Bethesua, íaiylanu Jeao kr0tmaoo, N0 liolessoi ol Deinatology anu lnviionnental íeuicine Diiectoi, lnstitut lui Unveltneuizinische loischung (lUl) at the Heiniich-Heine-Univeisity Dusseluoil, Ceinany Stéphaoe k0eoz||, N0 Uppsala, Sveuen 8oopa| V. k0od0, N0 Assistant liolessoi ol Deinatology Noithvestein Univeisity Diiectoi, Noithvestein Centei loi lthnic Slin leinheig School ol íeuicine Noithvestein Univeisity Chicago, lllinois Thomas S. k0pper, N0 Diiectoi, Haivaiu Slin Disease Reseaich Centei Haivaiu lnstitute ol íeuicine Biighan anu Wonen`s Hospital Boston, íassachusetts Ama| k. k0rbao, N0 Depaitnent ol Deinatology Boston Univeisity School ol íeuicine Boston, íassachusetts 8aze||e k0rzrock, N0, FA0P Diiectoi, lhase Cne liogian Division ol Cancei íeuicine Univeisity ol ¯exas í.D. Anueison Cancei Centei Houston, ¯exas 0ao|e| k0so|r, N0 Diiectoi ol the íulticultuial lsychotheiapy ¯iaining anu Reseaich lnstitute liogian Diiectoi La lanilia Chiluien`s Day ¯ieatnent Hayvaiu, Caliloinia he|oz k0tzoer, N0 Deinatopathologische Ceneinschaltspiaxis liieuiichshalen, Ceinany he|eo J. Lachmaoo, N0 National Anyloiuosis Centie Depaitnent ol íeuicine Royal liee anu Univeisity College íeuical School Lonuon, lnglanu xxv Nar|o £. Laco0t0re, N0 Assistant liolessoi, Depaitnent ol Deinatology leinheig School ol íeuicine Noithvestein Univeisity Chicago, lllinois J0rgeo Lademaoo, N0 Deinatology Depaitnent Chaiite Hospital/Hunholut Univeisity Beilin Beilin, Ceinany JeIIrey 8. La00ca, N0, Ph0 lingei Lales Deinatology Auhuin, Nev Yoil Jo Lambert, N0, Ph0 liolessoi, Depaitnent ol Deinatology Univeisity Hospital Chent Chent, Belgiun S|oéad Laogao, N80P Centei ol lviuence-Baseu Deinatology Nottinghan Univeisity Hospitals NHS ¯iust Nottinghan, Uniteu linguon h||de Lapeere, N0 Depaitnent ol Deinatology Univeisity Hospital Chent Chent, Belgiun Nargar|ta N. Larra|de, N0 leuiatiic Deinatology Depaitnent Hospital Ranos íe|ia Chiel ol Deinatology Depaitnent Hospital Alenán Buenos Aiies, Aigentina Aooe La0maoo, N8 0h8, N80P Associate liolessoi, Depaitnent ol Deinatology leinheig School ol íeuicine Noithvestein Univeisity Chicago, lllinois Stephao La0teosch|ager, N0 Heau, Cutpatient Clinic ol Deinatology anu Veneieology ¯iienli Hospital anu Univeisity ol Zuiich Zuiich, Svitzeilanu Les||e P. Law|ey, N0 leuiatiic Deinatology lellov Division ol Deinatology Chiluien`s íenoiial Hospital Noithvestein Univeisity Chicago, lllinois Thomas J. Law|ey, N0 Depaitnent ol Deinatology lnoiy Univeisity School ol íeuicine Atlanta, Ceoigia 0e|este Lebbé, N0 Seivice ue Deinatologie Hopital Saint-Louis laiis, liance Nark Lebwoh|, N0 liolessoi anu Chaiinan, Depaitnent ol Deinatology íount Sinai School ol íeuicine Nev Yoil, Nev Yoil J|o Lee, N0, N8A Resiuent, Depaitnent ol Deinatology Boston Univeisity Boston, íassachusetts keo k. Lee, N0 Associate liolessoi, Depaitnent ol Deinatology Diiectoi ol Deinatologic Suigeiy Ciegon Health anu Science Univeisity loitlanu, Ciegon Le|a A. Lee, N0 liolessoi ol Deinatology anu íeuicine Univeisity ol Coloiauo School ol íeuicine Chiel ol Deinatology Denvei Health íeuical Centei Denvei, Coloiauo Peter k. Lee, N0, Ph0 Assistant liolessoi, Depaitnent ol Deinatology Univeisity ol íinnesota íinneapolis, íinnesota Nargaret S. Lee-8e||aotoo|, N0, Ph0 Depaitnent ol Deinatology Boston Univeisity anu ¯ultsNev lnglanu íeuical Centei Boston, íassachusetts 0av|d J. LeIIe||, N0 liolessoi ol Deinatology anu Suigeiy Chiel, Section ol Deinatologic Suigeiy anu Cutaneous Cncology Depaitnent ol Deinatology Yale Univeisity School ol íeuicine Nev Haven, Connecticut kr|st|o N. Le|Iermao, N0 liolessoi, Depaitnent ol Deinatology Univeisity ol Utah Health Sciences Centei Salt Lale City, Utah |reoe N. Le|gh, N0 Centie loi Cutaneous Reseaich St. Baitholonev`s 8 the Royal Lonuon School ol íeuicine Cueen íaiy 8 Westhelu College Lonuon, lnglanu A|mee L. Leooard, N0 Nev lnglanu Deinatology anu Lasei Centei Spiinghelu, íassachusetts 0ooa|d Y. N. Le0og, N0, Ph0 Heau, Division ol leuiatiic Alleigy anu lnnunology National [evish íeuical anu Reseaich Centei Univeisity ol Coloiauo íeuical School Denvei, Coloiauo h|kk| A. Lev|o, N0, Ph0 Assistant liolessoi ol íeuicine Division ol Deinatology Univeisity ol íassachusetts íeuical School Univeisity ol íassachusetts íenoiial Health Caie Woicestei, íassachusetts No|se L. Levy, N0 liolessoi, Depaitnents ol leuiatiics anu Deinatology Bayloi College ol íeuicine Chiel, Deinatology Seivice ¯exas Chiluien`s Hospital Houston, ¯exas 8oss N. Levy, N0 Chiel Resiuent, Depaitnent ol Deinatology leinheig School ol íeuicine Noithvestein Univeisity Chicago, lllinois heory w. L|m, N0 Chaiinan, Depaitnent ol Deinatology Heniy loiu Hospital Detioit, íichigan S0sao L. L|mb, N0 [ohns Hoplins Univeisity School ol íeuicine Baltinoie, íaiylanu 0ao L|psker, N0, Ph0 Clinigue Deinatologigue Hopitaux Univeisitaiies Stiashouig Ceuex, liance 8obert L|stero|ck, N0 liolessoi, Depaitnent ol leuiatiics leinheig School ol íeuicine Noithvestein Univeisity Divisions ol Ceneial Acauenic leuiatiics ¯he Chiluien`s íenoiial Hospital Chicago, lllinois xxv| Nayra £. Loreozo, N0 Resiuent, Depaitnent ol Deinatology Univeisity ol íassachusetts íeuical School Woicestei, íassachusetts James Love|ess, N0 Deinatology Resiuent Depaitnent ol Deinatology [ohns Hoplins íeuical lnstitutions Baltinoie, íaiylanu 0o0g|as 8. Lowy, N0 Heau, Signaling anu Cncogenesis Section Lahoiatoiy Chiel, Lahoiatoiy ol Cellulai Cncology National Cancei lnstitute National lnstitutes ol Health Bethesua, íaiylanu Aooe w. L0cky, N0 Deinatology Reseaich Associates, lnc. Cincinnati, Chio Thomas A. L0ger, N0 liolessoi anu Chaiinan, Depaitnent ol Deinatology Univeisity ol íunstei íunstei, Ceinany Pa0|a 0. L0oa, N0 Deinatology Depaitnent Chuiiuca-Visca Hospital Buenos Aiies, Aigentina 0a|0m 0. Lyoo, F80P, N8 80h|r Consultant Deinatologist anu Honoiaiy Clinical ¯utoi Hull anu Yoil íeuical School Yoil Hospital Yoil, Uniteu linguon 0ather|oe Naar|, N0 Depaitnent ol Deinatology Univeisity ol íontieal íontieal, Cuehec, Canaua Vaodaoa k. Nadkao, N0 Clinical Reseaich lellov Centei loi Clinical Stuuies Univeisity ol ¯exas Health Science Centei Houston, ¯exas Neera Naha||ogam, N0, Ph0, F80Path Associate liolessoi anu Diiectoi, Deinatopathology Division ol Deinatology Univeisity ol íassachusetts íeuical School Univeisity ol íassachusetts íenoiial Health Caie Woicestei, íassachusetts Freder|ck 0. Na|k|osoo, N0 Depaitnent ol Deinatology Univeisity Hospital Centie Hospitaliei Univeisitaiie Vauuois Lausanne, Svitzeilanu 8r|ao F. Naode||, N0, Ph0, FA08 Vice Chaiinan, Division ol íeuicine Stall, Depaitnent ol Rheunatology Centei loi Vasculitis Caie anu Reseaich ¯he Clevelanu Clinic lounuation Clevelanu, Chio 8|chard N. Narche||, N0 Assistant liolessoi, Depaitnent ol Deinatology íeuical Univeisity ol South Caiolina Chaileston, South Caiolina N. Peter Nar|okov|ch, N0 Associate liolessoi, Depaitnent ol Deinatology liogian in lpithelial Biology Stanloiu Univeisity School ol íeuicine Stanloiu, Caliloinia Adr|aoa 8. Narg0es, N0 Lahoiatoiy ol Clinical lnlectious Diseases National lnstitute ol Alleigy anu lnlectious Diseases National lnstitutes ol Health Bethesua, íaiylanu 0|eter Na0rer, N0 liolessoi Depaitnent ol Deinatology íeuical Univeisity ol Vienna Vienna, Austiia Theodora N. Na0ro, N0 Associate liolessoi, Depaitnent ol Deinatology Univeisity ol Caliloinia, San liancisco San liancisco Veteians Hospital San liancisco, Caliloinia Joho A. Nc6rath, N0 liolessoi, Division ol Slin Sciences lings College Lonuon St. [ohn`s lnstitute ol Deinatology St. ¯honas` Hospital Lonuon, lnglanu w. h. |rw|o NcLeao, N0 Wellcone ¯iust Senioi Reseaich lellov liolessoi anu Heau, Hunan Cenetics Reseaich Diiectoi, lpithelial Cenetics Cioup Hunan Cenetics Unit Division ol lathology anu Neuioscience Ninevells Hospital, Univeisity ol Dunuee Dunuee, Scotlanu 0ar|0s 8. Nehregao, N0 Assistant liolessoi ol Deinatology Wayne State Univeisity Detioit, íichigan Diiectoi ol Deinatopathology linlus Deinatopathology Lahoiatoiy, l.C. íonioe, íichigan 0av|d A. Nehregao, N0 Assistant liolessoi ol Deinatology Wayne State Univeisity Detioit, íichigan Diiectoi ol Deinatopathology linlus Deinatopathology Lahoiatoiy, l.C. íonioe, íichigan h. 0ody Ne|ssoer, N0 liolessoi, Depaitnent ol leuiatiics ¯ults Nev lnglanu íeuical Centei Boston, íassachusetts hata||e Neodoza, N0 Centei loi Clinical Stuuies Houston, ¯exas Aodrew 6. Nesseoger, N0 Honoiaiy Senioi Clinical Lectuiei Univeisity ol Shelhelu Shelhelu, lnglanu, U.l. 0eao 0. Netca|Ie, N0 Chiel, Lahoiatoiy ol Alleigic Diseases National lnstitute ol Alleigy anu lnlectious Diseases National lnstitutes ol Health Bethesua, íaiylanu Nart|o 0. N|hm, Jr., N0 Clinical liolessoi ol lathology Senioi Deinatopathologist Haivaiu íeuical School íassachusetts Ceneial Hospital Boston, íassachusetts Stao|ey J. N|||er, N0 Associate liolessoi, Deinatology anu CtolaiyngologyHeau anu Necl Suigeiy [ohns Hoplins Hospital Baltinoie, íaiylanu Tara N|||er, N0 Deinatology Resiuent Univeisity ol Caliloinia, San liancisco San liancisco, Caliloinia xxv|| 6|oat w|otermeyer N|rowsk|, 0N0, N0 Associate liolessoi, Depaitnent ol Deinatology leinheig School ol íeuicine Noithvestein Univeisity Chicago, lllinois Au|unct Associate liolessoi Depaitnent ol Cial lathology, íeuicine, Rauiology lnuiana Univeisity School ol Dentistiy lnuianapolis, lnuiana 8obert L. Nod||o, N0 llein liolessoi anu Chiel, Depaitnent ol Deinatology liolessoi ol íiciohiology, lnnunology, anu íoleculai Cenetics Daviu Cellen School ol íeuicine Univeisity ol Caliloinia, Los Angeles Los Angeles, Caliloinia Negao N. Noore, N0 ¯he Ronalu C. leielnan Depaitnent ol Deinatology Nev Yoil Univeisity School ol íeuicine Nev Yoil, Nev Yoil Ak|m|ch| Nor|ta, N0, Ph0 liolessoi anu Chaiinan, Depaitnent ol Ceiiatiic anu lnviionnental Deinatology Nagoya City Univeisity Ciauuate School ol íeuical Sciences Nagoya, [apan h|co No0sd|cas, N0 Depaitnents ol Deinatology, leuiatiics, lhainacology anu ¯oxicology lnuiana Univeisity School ol íeuicine lnuianapolis, lnuiana 0|r|ch Nrow|etz, N0 liolessoi Depaitnent ol Deinatology Univeisity ol liel liel, Ceinany Sarah A. Nyers, N0 Division ol Deinatology Dule Univeisity íeuical Centei Duihan, Noith Caiolina Jeao-Nar|e haeyaert, N0, Ph0 liolessoi, Depaitnent ol Deinatology Univeisity Hospital Chent Chent, Belgiun Amaoda N. he|soo, Ph0 lostuoctoial Scholai, Depaitnent ol Deinatology ¯he [ale Cittlen Cancei Reseaich lounuation ¯he lennsylvania State Univeisity College ol íeuicine Heishey, lennsylvania |saac N. he0ha0s, N0 Assistant liolessoi ol Clinical Deinatology Depaitnent ol Deinatology Univeisity ol Caliloinia, San liancisco San liancisco, Caliloinia Pa0| hgh|em, N0, Ph0 Assistant liolessoi, Division ol Deinatology Alhliate lnvestigatoi, lieu Hutchinson Cancei Reseaich Centei Seattle, Washington 6erhard J. hohyoek, N0 Depaitnent ol Deinatology Chaiite Hospital/Hunholut Univeisity Beilin Beilin, Ceinany Scott A. hortoo, N0, NPh liolessoi, Depaitnent ol Deinatology Uniloineu Seivices Univeisity ol the Health Sciences Bethesua, íaiylanu 0ar|os h. ho0sar|, N0 Deinpath Diagnostics South lloiiua lonpano Beach, lloiiua L|||ao N. 0do, N0 Depaitnent ol Deinatology ol Santo Anaio Univeisity Cuo Clinics ol Deinatology Sao laulo, Biazil Joho £. 0|er0d, N0 Ceoige l. Culanu liolessoi Depaitnent ol íeuicine Heau, Division ol Deinatology Univeisity ol Washington Seattle, Washington £||se A. 0|seo, N0 liolessoi ol íeuicine Divisions ol Deinatology anu Cncology Dule Univeisity íeuical Centei Duihan, Noith Caiolina kat|a 0ogeoae, N0, Ph0 liolessoi, Depaitnent ol Deinatology Univeisity Hospital Chent Chent, Belgiun 6ra|ooe N. 0'8egao, N80P| Cui Lauy`s Chiluien`s Hospital Duhlin, lielanu Seth J. 0r|ow, N0, Ph0 Chaiinan, ¯he Ronalu C. leielnan Depaitnent ol Deinatology Sanuel Weinheig liolessoi ol Deinatology, leuiatiics, anu Cell Biology Nev Yoil Univeisity School ol íeuicine Nev Yoil, Nev Yoil Aothooy £. 0ro, N0, Ph0 Associate liolessoi, Depaitnent ol Deinatology liogian in lpithelial Biology Stanloiu Univeisity, School ol íeuicine Stanloiu, Caliloinia N|chae| h. 0xmao, N0 liolessoi ol íeuicine anu lathology Univeisity ol Caliloinia at San Diego Stall lhysician (lnlectious Diseases) San Diego Veteians Allaiis Healthcaie Systen San Diego, Caliloinia h|co|e 0. Pace, N0 leuiatiic Deinatology lellov Daitnouth-Hitchcocl íeuical Centei Lehanon, Nev Hanpshiie Saodra 0. Paek, N0 Chiel Resiuent, Depaitnent ol Deinatology Univeisity ol íichigan Ann Aihoi, íichigan Amy S. Pa||er, N0 Waltei [. Hanlin liolessoi anu Chaii ol Deinatology liolessoi ol leuiatiics leinheig School ol íeuicine Noithvestein Univeisity Chicago, lllinois 8eoato 6. Pao|zzoo, N0 liolessoi anu Chaiinan, Depaitnent ol Deinatology Univeisity Hospital Centie Hospitaliei Univeisitaiie Vauuois Univeisity ol Lausanne Lausanne, Svitzeilanu hee-Yo0og Park, Ph0 Associate Reseaich liolessoi, Depaitnent ol Deinatology Boston Univeisity School ol íeuicine Boston, íassachusetts £va 8aw||ogs Parker, N0 Assistant liolessoi, Division ol Deinatology Loyola Univeisity íeuical Centei íayvoou, lllinois 8a|I Pa0s, N0 liolessoi anu Heau, lxpeiinental Deinatology Univeisity Hospital Schlesvig-Holstein Canpus Luehecl Univeisity ol Luehecl Luehecl, Ceinany xxv||| N|che||e T. Pe||e, N0 Assistant Clinical liolessoi, Division ol Deinatology Univeisity ol Caliloinia, San Diego San Diego, Caliloinia L|sao S. Peog, N0 lnteiuepaitnental liogian in Vasculai Biology anu ¯iansplantation Yale Univeisity School ol íeuicine Nev Haven, Connecticut 8reot Peoo|ogtoo, N0 Depaitnent ol Deinatology Yale Univeisity School ol íeuicine Nev Haven, Connecticut Jeoo|Ier 8. Perooe, N0 Assistant liolessoi, Depaitnent ol Deinatology Univeisity ol ¯exas Southvestein íeuical School Dallas, ¯exas Nargot S. Peters, N0 Rochestei, íinnesota Peter Petze|ba0er, N0 liolessoi, Depaitnent ol Deinatology íeuical Univeisity ol Vienna Vienna, Austiia Tao|a J. Ph||||ps, N0 liolessoi, Depaitnent ol Deinatology Boston Univeisity School ol íeuicine Boston, íassachusetts 6éra|d £. P|érard, N0, Ph0 Chiel, Deinatopathology Seivice Depaitnent ol Deinatology Univeisity Hospital ol Liege Liege, Belgiun 0|a0d|oe P|érard-Fraoch|moot, N0, Ph0 Lahoiatoiy Chiel, Deinatopathology Seivice Univeisity Hospital ol Liege Liege, Belgiun 8|aoca Nar|a P|racc|o|, N0 Depaitnent ol Deinatology Univeisity ol Bologna Bologna, ltaly Nark 8. P|tte|kow, N0 Consultant, Depaitnent ol Deinatology íayo Clinic liolessoi, Depaitnents ol Deinatology, Biochenistiy, anu íoleculai Biology íayo Clinic College ol íeuicine Rochestei, íinnesota 6erd P|ew|g, N0 liolessoi, Depaitnent ol Deinatology Luuvig-íaxinilian-Univeisity ol íunich íunich, Ceinany Jordao S. Pober, N0 lnteiuepaitnental liogian in Vasculai Biology anu ¯iansplantation Yale Univeisity School ol íeuicine Nev Haven, Connecticut N|r|am ke|tz Pomeraoz, N0 Assistant liolessoi, ¯he Ronalu C. leielnan Depaitnent ol Deinatology Nev Yoil Univeisity School ol íeuicine Nev Yoil, Nev Yoil Nar|oya Poogp0dp0oth, N0 Depaitnent ol Deinatology Boston Univeisity School ol íeuicine Boston, íassachusetts Fraok 0. Powe||, N0 Univeisity College Duhlin Consultant Deinatologist íatei liivate Hospital Duhlin, lielanu J0||e Powe||, N0 liolessoi, Depaitnent ol leuiatiics Univeisity ol íontieal íontieal, Cuehec, Canaua J0||e S. Preod|v|||e, N0, N80P|, F80P0 Clinical liolessoi in leuiatiics Univeisity ol Biitish Colunhia Heau, Division ol leuiatiic Deinatology Biitish Colunhia Chiluien`s Hospital Vancouvei, Biitish Colunhia, Canaua howard Pr|de, N0 Depaitnent ol Deinatology Ceisingei íeuical Centei Danville, lennsylvania 0har|otte Proby, N0 Centie loi Cutaneaous Reseaich Baits anu the Lonuon Cueen íaiy`s School ol íeuicine anu Dentistiy Univeisity ol Lonuon Lonuon, lnglanu £hrhardt Proksch, N0, Ph0 liolessoi, Depaitnent ol Deinatology Univeisity ol liel Univeisity Hospitals ol liel liel, Ceinany 0aro||oe L. 8ao, N0 Dule Univeisity Health Systen Chapel Hill, Noith Caiolina 8|oa A. 8ash|d, N0 Division ol Deinatology Wiight State Univeisity Boonsholt School ol íeuicine Dayton, Chio Thomas h. 8ea, N0 lneiitus liolessoi ol Deinatology lecl School ol íeuicine Univeisity ol Southein Caliloinia Chiel, Hansen`s Disease Clinic Los Angeles, Caliloinia ka|paoa 8eddy, 8S lellov, Depaitnent ol Deinatology ¯he Chio State Univeisity College ol íeuicine Atlanta, Ceoigia Thomas £. 8ede|me|er, N0 Deinatology Depaitnent Chaiite Hospital/Hunholut Univeisity Beilin Beilin, Ceinany 8|chard 0. 8e|chmao, N0 lnlectious Diseases Division School ol íeuicine anu Dentistiy Univeisity ol Rochestei Rochestei, Nev Yoil L0|s 8eg0eoa, N0 Depaitnent ol Deinatology lunuacion [inénez Diaz Univeisiuau Autonona íauiiu, Spain Arth0r 8. 8hodes, N0, NPh liolessoi ol Deinatology Rush íeuical College Senioi Attenuing lhysician Rush Univeisity íeuical Centei Chicago, lllinois 8eojam|o £. 8|ch, Ph0 Haivaiu School ol íeuicine Biighan anu Wonen`s Hospital Boston, íassachusetts Stepheo 8|chardsoo, N0 lnstiuctoi, Depaitnent ol Deinatology Univeisity ol lennsylvania Health Systen lhilauelphia, lennsylvania J0oe k. 8ob|osoo, N0 liolessoi ol Clinical Deinatology leinheig School ol íeuicine Noithvestein Univeisity Chicago, lllinois Na0reeo 8ogers, N0 Honoiaiy Consultant Deinatologist ¯he Chiluien`s Hospital at Westneau Syuney, Austialia xx|x Nart| J. 8othe, N0 Associate liolessoi, Depaitnent ol Deinatology Univeisity ol Connecticut Health Centei lainington, Connecticut Jeao-0|a0de 8o0jea0, N0 Depaitnent ol Deinatology Hopital Henii íonuoi Univeisité laiis Xll Ciéteil laiis, liance Thomas N. 80oger, N0 liolessoi, Depaitnent ol Deinatology Boston Univeisity School ol íeuicine Boston, íassachusetts Thomas 80z|cka, N0 liolessoi anu Chaiinan, Depaitnent ol Deinatology Heiniich-Heine Univeisity Luuvig-íaxinilian-Univeisity ol íunich íunich, Ceinany Joho 6. 8yao, N8, N80P| Cenetics anu Cenonics Bianch National lnstitute ol Aithiitis anu íusculosleletal anu Slin Diseases National lnstitutes ol Health Bethesua, íaiylanu Art0ro Saavedra, N0, Ph0 lnstiuctoi in íeuicine Haivaiu íeuical School Stall in Deinatology, Deinatopathology, anu lnteinal íeuicine Biighan anu Wonen`s Hospital Boston, íassachusetts Joo| 6. Sago, N0 Division ol Deinatology Depaitnent ol íeuicine Dule Univeisity íeuical Centei Duihan, Noith Caiolina Feroaoda h. Sakamoto, N0 Depaitnent ol Deinatology íassachusetts Ceneial Hospital Haivaiu íeuical School Boston, íassachusetts N|g0e| 8. Saochez, N0 Associate liolessoi, Depaitnent ol Deinatology Nev Yoil Univeisity íeuical Centei Nev Yoil, Nev Yoil Aodrea Saodoz, N0 Clinical Senioi lnstiuctoi in lsychiatiy, Chilu anu Auolescent lsychiatiy, anu leuiatiics Univeisity ol Rochestei School ol íeuicine anu Dentistiy Rochestei, Nev Yoil keozo Sato, N0, Ph0 liolessoi ol Deinatology Hunan Cene ¯heiapy Reseaich lnstitute lova Health Systen Des íoines, lova Jeao-h||a|re Sa0rat, N0 liolessoi anu Chaiinan Depaitnent ol Deinatology Hopital Cantonal Univeisitaiie Ceneve, Svitzeilanu haos SchaeIer, N0 liolessoi ol Biochenistiy Depaitnent ol Deinatology Chaiite Hospital/Hunholut Univeisity Beilin Beilin, Ceinany Nark Jordao ScharI, N0 Depaitnent ol Deinatology Univeisity ol íassachusetts íeuical School Univeisity ol íassachusetts íenoiial Health Caie Woicestei, íassachusetts keooeth £. Schmader, N0 Associate liolessoi ol íeuicine- Ceiiatiics Vice Chiel, Division ol Ceiiatiics Duihan Veteians Allaiis íeuical Centei CRlCC Dule Univeisity íeuical Centeis Duihan, Noith Caiolina Steveo k. Schm|tt, N0 Stall lhysician, Depaitnent ol lnlectious Diseases ¯he Clevelanu Clinic lounuation Clevelanu, Chio Theresa Schroeder-0evere, N0 Assistant liolessoi, Depaitnent ol Deinatology Ciegon Health anu Science Univeisity loitlanu, Ciegon 8obert A. Schwartz, N0, NPh Depaitnent ol Deinatology Univeisity ol íeuicine anu Dentistiy ol Nev [eisey Nevail, Nev [eisey A|oo Scope, N0 Deinatology Seivice íenoiial Sloan-letteiing Cancei Centei Nev Yoil, Nev Yoil kara h. Shah, N0, Ph0, FAAP lellov, Depaitnent ol leuiatiics anu Deinatology Chiluien`s Hospital ol lhilauelphia ¯he Univeisity ol lennsylvania School ol íeuicine lhilauelphia, lennsylvania Lor| Shap|ro, N0 Assistant liolessoi, Division ol Deinatology Sunnyhiool Health Sciences Centei Univeisity ol ¯oionto ¯oionto, Cntaiio, Canaua N|sty T. Sharp, N0 Depaitnent ol Deinatology Univeisity ol Ailansas loi íeuical Sciences Little Rocl, Ailansas he|| h. Shear, N0 liolessoi anu Heau, Division ol Deinatology Sunnyhiool Health Sciences Centei Univeisity ol ¯oionto ¯oionto, Cntaiio, Canaua Nered|th P. Sheedy, N0 Resiuent, Division ol Deinatology Dule Univeisity íeuical Centei Duihan, Noith Caiolina 8obert L. Sher|dao, N0 Chiel, Buin Suigeiy Seivice Shiinei`s Hospital loi Chiluien Co-Diiectoi, Sunnei Reustone Auult Buin Centei íassachusetts Ceneial Hospital Boston, íassachusetts JeII k. Shoro|ck, N0, NhA liivate liactice Cioton, Connecticut 8obert S|db0ry, N0 Assistant liolessoi Depaitnents ol leuiatiics anu lnnunology Chiluien`s Hospital Boston Haivaiu íeuical School Boston, íassachusetts 0ao|e| Asz S|ga||, N0 Depaitnent ol Deinatology íycology Section Di. íanuel Cea Conzalez Ceneial Hospital íexico City, íexico xxx Arth0r J. Sober, N0 liolessoi ol Deinatology Haivaiu íeuical School Associate Chiel ol Deinatology íassachusetts Ceneial Hospital Boston, íassachusetts 8|chard 0. Soothe|mer, N0 liolessoi anu Vice-Chaiinan Depaitnent ol Deinatology Richaiu anu Auelaiu lleischalei Chaii in Deinatology Reseaich Univeisity ol Cllahona Health Sciences Centei Cllahona City, Cllahona Apra Sood, N0 Resiuent, Depaitnent ol Deinatology ¯he Clevelanu Clinic lounuation Clevelanu, Chio h|cho|as A. Soter, N0 liolessoi, Depaitnent ol Deinatology Nev Yoil Univeisity School ol íeuicine Nev Yoil, Nev Yoil Joho 8. Stao|ey, N0 íilton B. Haitzell liolessoi anu Chaii Depaitnent ol Deinatology Univeisity ol lennsylvania School ol íeuicine lhilauelphia, lennsylvania 0hr|stopher J. Steeo, N0 Depaitnent ol Deinatology Univeisity ol íeuicine anu Dentistiy ol Nev [eisey Nevail, Nev [eisey Nart|o Ste|ohoII, N0, Ph0 liolessoi, Depaitnent ol Deinatology Boltznann lnstitute loi lnnunohiology ol the Slin Univeisity ol íunstei íunstei, Ceinany wo|Iram Sterry, N0 liolessoi anu Chaii, Depaitnent ol Deinatology anu Alleigy Chaiite Univeisity ol íeuicine Beilin, Ceinany 6eorg St|og|, N0 liolessoi ol Deinatology Heau, Division ol lnnunology, Alleigy, anu lnlectious Diseases (DlAD) íeuical Univeisity ol Vienna Vienna Ceneial Hospital Vienna, Austiia Stepheo P. Stooe, N0 liolessoi, Division ol Deinatology Depaitnent ol lnteinal íeuicine Southein lllinois Univeisity School ol íeuicine Spiinghelu, lllinois A|ao Storey, N0 Centie loi Cutaneaous Reseaich Baits anu the Lonuon Cueen íaiy`s School ol íeuicine anu Dentistiy Univeisity ol Lonuon Lonuon, lnglanu Stepheo £. Stra0s, N0 Chiel, Lahoiatoiy ol Clinical lnvestigation National lnstitute ol Alleigy anu lnlectious Diseases Diiectoi, National Centei loi Conplenentaiy anu Alteinative íeuicine National lnstitutes ol Health Bethesua, íaiylanu (u. 2OO¯) Joho S. Stra0ss, N0 Depaitnent ol Deinatology ¯he lennsylvania State Univeisity College ol íeuicine Heishey, lennsylvania 8r0ce £. Strober, N0 Assistant liolessoi, ¯he Ronalu C. leielnan Depaitnent ol Deinatology Nev Yoil Univeisity íeuical Centei Nev Yoil, Nev Yoil T0og-T|eo S0o, N0 Ruuoll L. Baei liolessoi ol Deinatology liolessoi, Cell Biology, lhainacology anu Uiology Nev Yoil Univeisity íeuical School Nev Yoil, Nev Yoil he|| A. Swaosoo, N0 liolessoi anu Chaii, Depaitnent ol Deinatology Ciegon Health anu Science Univeisity loitlanu, Ciegon Nortoo h. Swartz, N0 liolessoi ol íeuicine Haivaiu íeuical School íassachusetts Ceneial Hospital Boston, íassachusetts S0sao N. Sweeoey, N0 Assistant liolessoi ol íeuicine anu leuiatiics Division ol Deinatology Univeisity ol íassachusetts íeuical School Univeisity ol íassachusetts íenoiial Health Caie Woicestei, íassachusetts V|rg|o|a P. Sybert, N0 Clinical liolessoi, Division ol íeuical Cenetics Depaitnent ol íeuicine Univeisity ol Washington School ol íeuicine Stall lhysician, Deinatology Cioup Health leinanente Seattle, Washington 8o|I-Nark0s Sze|m|es, N0 Associate liolessoi, Depaitnent ol Deinatology Univeisity ol Regenshuig Regenshuig, Ceinany Noyses Szk|o, N0, NPh, 0rPh liolessoi, Chionic Disease lnnunology [ohns Hoplins Univeisity School ol Hygiene anu luhlic Health Baltinoie, íaiylanu S0mayah J. Ta||aIerro, N0 Depaitnent ol Deinatology Hovaiu Univeisity College ol íeuicine Washington, D.C. £||zabeth L. Taoz|, N0 Clinical lnstiuctoi, Depaitnent ol Deinatology [ohns Hoplins íeuical Centei Baltinoie, íaiylanu Washington lnstitute ol Deinatologic Lasei Suigeiy Washington, D.C. 6erhard Tappe|oer, N0 Associate liolessoi Depaitnent ol Deinatology íeuical Univeisity ol Vienna Vienna, Austiia Fraoc|sco A. Ta0sk, N0 liolessoi, Depaitnents ol Deinatology anu lsychiatiy Univeisity ol Rochestei School ol íeuicine Rochestei, Nev Yoil 0har|es 8. Tay|or, N0 Depaitnent ol Deinatology íassachusetts Ceneial Hospital Haivaiu íeuical School Boston, íassachusetts James S. Tay|or, N0 Heau, Section ol lnuustiial Deinatology Depaitnent ol Deinatology ¯he Clevelanu Clinic lounuation Clevelanu, Chio xxx| 8. Stao Tay|or, N0 liolessoi, Depaitnent ol Deinatology Univeisity ol ¯exas Southvestein íeuical Centei Dallas, ¯exas 0|aoe N. Th|bo0tot, N0 Vice-Chaii, Reseaich Allaiis, Depaitnent ol Deinatology [ale Cittlen Cancei Reseaich lounuation ¯he lennsylvania State Univeisity College ol íeuicine Heishey, lennsylvania 8r0ce Th|ers, N0 liolessoi anu Chaii, Depaitnent ol Deinatology íeuical Univeisity ol South Caiolina Chaileston, South Caiolina Va|eoc|a 0. Thomas, N0 Assistant liolessoi, Depaitnent ol Deinatology Section ol Deinatologic Suigeiy 8 Cutaneous Cncology Yale Univeisity School ol íeuicine Nev Haven, Connecticut wyoo|s Tom, N0 Chiel Resiuent, Depaitnent ol Deinatology Saint Louis Univeisity St. Louis, íissouii keooeth J. Tomeck|, N0 Stall lhysician, Depaitnent ol Deinatology ¯he Clevelanu Clinic lounuation Clevelanu, Chio 8oche||e 8. Torgersoo, N0, Ph0 Assistant liolessoi, Depaitnent ol Deinatology íayo Clinic College ol íeuicine Rochestei, íinnesota Aotooe||a Tost|, N0 liolessoi, Depaitnent ol Deinatology Univeisity ol Bologna Bologna, ltaly Fraoz Tra0t|oger, N0 liolessoi, Division ol Deinatology State Hospital ol St. lolten St. lolten, Austiia JeIIrey 8. Travers, N0, Ph0 lanpen-Noiins lnvestigatoi anu Chaii ol Deinatology liolessoi, Depaitnents ol Deinatology, leuiatiics, lhainacology anu ¯oxicology lnuiana Univeisity School ol íeuicine lnuianapolis, lnuiana heos|o Tsao, N0, Ph0 Associate liolessoi, Depaitnent ol Deinatology Haivaiu íeuical School Wellnan Centei loi lhotoneuicine íassachusetts Ceneial Hospital Boston, íassachusetts £rw|o Tschach|er, N0 liolessoi, Depaitnent ol Deinatology anu Veneieology íeuical Univeisity ol Vienna Vienna, Austiia Nargaret A. T0cker, N0 Diiectoi, Hunan Cenetics liogian Division ol Cancei lpiueniology anu Cenetics National Cancei lnstitute National lnstitutes ol Health Bethesua, íaiylanu Stepheo k. Tyr|og, N0, Ph0, N8A liolessoi ol Deinatology, íiciohiology/ íoleculai Cenetics, anu lnteinal íeuicine Diiectoi, Centei loi Clinical Stuuies Univeisity ol ¯exas Health Science Centei Houston, ¯exas Jo0o| 0|tto, N0, Ph0 liolessoi anu Chaii, Depaitnent ol Deinatology anu Cutaneous Biology ¯honas [elleison Univeisity lhilauelphia, lennsylvania Nark 0oger, N0 Depaitnent ol Deinatology ít. Sinai íeuical School Nev Yoil, Nev Yoil 8ob|o h. 0oger, N0 Clinical lnstiuctoi, Depaitnent ol Deinatology ít. Sinai íeuical School Nev Yoil, Nev Yoil wa|ter P. 0oger, N0, F80P(0), FA0P Clinical liolessoi, Depaitnent ol Deinatology ít. Sinai íeuical School Nev Yoil, Nev Yoil Au|unct liolessoi, Deinatology [ohns Hoplins School ol íeuicine Baltinoie, íaiylanu Aoders Vah|g0|st, N0, Ph0 Depaitnent ol íeuical Sciences Uppsala Univeisity Hospital Uppsala, Sveuen |sabe| 0. Va|eoc|a, N0 Assistant liolessoi Depaitnent ol Deinatology anu Cutaneous Suigeiy Univeisity ol íiani íillei School ol íeuicine íiani, lloiiua L. Va|eyr|e-A||aoore, N0 Depaitnent ol Deinatology Henii íonuoi Hospital Univeisité laiis laiis, liance haoja Vao 6ee|, N0, Ph0 liolessoi, Depaitnent ol Deinatology Univeisity Hospital Chent Chent, Belgiun £ve||eo Verhaeghe, N0 Depaitnent ol Deinatology Univeisity Hospital Chent Chent, Belgiun Shaoooo Verma, N0 Resiuent, Depaitnent ol Deinatology Wiight State Univeisity Dayton, Chio N||kka V|kk0|a, N0, Ph0 íaitie ue Recheiches uu l.N.R.S., Hunan íoleculai Cenetics Chiistian ue Duve lnstitute 8 Univeisity ol Louvain íeuical School Biussels, Belgiun Joho J. Voorhees, N0 Duncan 8 llla loth Distinguisheu liolessoi Chaii, Depaitnent ol Deinatology Univeisity ol íichigan Ann Aihoi, íichigan J0st|o J. V0jev|ch, N0 DeinSuigeiy Associates, l.A. Houston, ¯exas S0sao L. wa|ker, Ph0 St. [ohn`s lnstitute ol Deinatology Division ol Cenetics anu íoleculai íeuicine ling`s College Lonuon School ol íeuicine Cuy`s, ling`s College anu St. ¯honas` Hospitals Univeisity ol Lonuon Lonuon, lnglanu Tom| wa||, N0 Depaitnent ol Deinatology íassachusetts Ceneial Hospital Haivaiu íeuical School Boston, íassachusetts xxx|| Joho S. wa|sh, N0 Assistant liolessoi, Depaitnent ol Deinatology íayo íeuical School Consultant in Deinatology anu Deinatopathology íayo Clinic [aclsonville, lloiiua 8oger h. weeo|g, N0, NPh Assistant liolessoi, Depaitnent ol Deinatology íayo Clinic School ol íeuicine Rochestei, íinnesota Aroo|d h. we|oberg, N0 liolessoi ol íeuicine íassachusetts Ceneial Hospital Haivaiu íeuical School Boston, íassachusetts Nart|o A. we|ostock, N0, Ph0 Diiectoi, Division ol Deinatoepiueniology Biovn Univeisity Chiel ol Deinatology Veteians Allaiis íeuical Centei lioviuence, Rhoue lslanu Nargaret A. we|ss, N0 Depaitnent ol Deinatology [ohns Hoplins Univeisity School ol íeuicine Baltinoie, íaiylanu 8obert A. we|ss, N0 Depaitnent ol Deinatology [ohns Hoplins Univeisity School ol íeuicine Baltinoie, íaiylanu V|ctor|a P. werth, N0 liolessoi, Depaitnent ol Deinatology Univeisity ol lennsylvania lhilauelphia Veteians Allaiis íeuical Centei lhilauelphia, lennsylvania L0c||e £. wh|te, N0 Assistant liolessoi, Depaitnent ol Deinatology leinheig School ol íeuicine Noithvestein Univeisity Chicago, lllinois hywe| 0. w||||ams, NSc, Ph0, F80P liolessoi ol Deinatoepiueniology Centei ol lviuence-Baseu Deinatology Nottinghan Univeisity Hospitals NHS ¯iust Nottinghan, Uniteu linguon |Ior 8. w||||ams, N0, Ph0 Depaitnent ol lathology lnoiy Univeisity Atlanta, Ceoigia Nary £||zabeth w||soo, N0 Associate Clinical liolessoi ol íeuicine Haivaiu íeuical School Associate liolessoi ol lopulation anu lnteinational Health Haivaiu School ol luhlic Health Boston, íassachusetts 8obert w|ochester, N0 liolessoi, Depaitnent ol leuiatiics Colunhia lieshyteiian íeuical Centei Colunhia Univeisity College ol lhysicians anu Suigeons Nev Yoil, Nev Yoil Naro| 0. w|semao, N0, F80P0 Univeisity ol íanitoha Cancei Caie íanitoha Winnepeg, Canaua kareo N. w|ss, N0 liolessoi ol íeuicine anu leuiatiics Division ol Deinatology Univeisity ol íassachusetts íeuical School Univeisity ol íassachusetts íenoiial Health Caie Woicestei, íassachusetts k|a0s wo|II, N0, F80P liolessoi ol Deinatology Chaiinan lneiitus Depaitnent ol Deinatology íeuical Univeisity ol Vienna Vienna, Austiia Stepheo £. wo|vertoo, N0 liolessoi ol Clinical Deinatology Vice Chaii ol Clinical Allaiis lnuiana Univeisity lnuianapolis, lnuiana 6ary S. wood, N0 liolessoi anu Chaii, Depaitnent ol Deinatology Univeisity ol Wisconsin íauison, Wisconsin 8obert A. wood, N0 liolessoi, leuiatiic Alleigy anu lnnunology Division ol lnnunology 8 Alleigy [ohns Hoplins Univeisity School ol íeuicine Baltinoie, íaiylanu 0av|d T. wood|ey, N0 liolessoi anu Chaii, Depaitnent ol Deinatology lecl School ol íeuicine Univeisity ol Southein Caliloinia Los Angeles, Caliloinia N|oa Yaar, N0 liolessoi, Depaitnent ol Deinatology Boston Univeisity School ol íeuicine Boston, íassachusetts A|bert 0. Yao, N0 Assistant liolessoi Diiectoi, leuiatiic Deinatology Chiluien`s Hospital ol lhilauelphia ¯he Univeisity ol lennsylvania lhilauelphia, lennsylvania k|m 8. Yaocey, N0 liolessoi anu Chaiinan, Depaitnent ol Deinatology Univeisity ol ¯exas Southvestein íeuical Centei at Dallas Dallas, ¯exas 6|| Yos|pov|tch, N0 liolessoi, Depaitnent ol Deinatology, anu Neuiohiology 8 Anatony Wale loiest íeuical Centei Winston-Salen, Noith Caiolina Aotooy 8. Yo0og, Ph0 Deputy Heau, St. [ohn`s lnstitute ol Deinatology Division ol Cenetics anu íoleculai íeuicine ling`s College Lonuon School ol íeuicine Cuy`s, ling`s College, anu St. ¯honas` Hospitals Univeisity ol Lonuon Lonuon, lnglanu £var|sto Sáochez Y0s, N0 Depaitnent ol Deinatology Hospital Clinico San Cailos Ciuuau Univeisitaiia íauiiu, Spain St0art h. Y0spa, N0 Chiel, Lahoiatoiy ol Cancei Biology anu Cenetics Centei loi Cancei Reseaich National Cancei lnstitute National lnstitutes ol Health Bethesua, íaiylanu Aodrea L. Iaeog|e|o, N0 Depaitnent ol Deinatology ¯he lennsylvania State Univeisity College ol íeuicine Heishey, lennsylvania Natthew T. I|po||, N0 Deinatology Associates ol Concoiu Concoiu, íassachusetts 0hr|stos 0. Io0bo0||s, N0, Ph0 liolessoi anu Diiectoi Depaitnents ol Deinatology anu lnnunology Dessau íeuical Centei Dessau, Ceinany xxx||| ''c'^.c We aie piouu to piesent this Seventh lui- tion ol lit:¡atri.k´s Dcrmato|og, in Ccncra| /cdi.inc (DlCí), vhich has heen ieoiga- nizeu anu suhstantially ieviitten to ie- hect the cuiient state ol the science, piac- tice, anu ait ol ueinatology. íoie than 5O peicent ol the text anu hguies ol oui 25¯ chapteis aie nev to this euition, as aie 5O peicent ol the authois. lntegiation ol the hasic anu clinical science ienains the DlCí signatuie, anu the oiganiza- tion ol the hool is intenueu to pionote unueistanuing ol the slin as an auaptive oigan that changes thioughout the lile span. Clinical uisease chapteis aie nov gioupeu vithin sections hy pathogenic anu causative nechanisn, anu each sec- tion is intiouuceu hy the ielevant hasic science chapteis. ¯o achieve the goal ol naling the text tiuly encyclopeuic anu ieauily accessihle to ieaueis at all levels ol expeitise, theie aie nov tvo veisions ol the hool, a con- cise piinteu veision anu an on-line vei- sion. ¯hioughout the text, vhen auui- tional on-line content is availahle, the lolloving icon is piesent in the text to aleit the ieauei: ¯o save space in piint, the na|oiity ol ieleiences aie avail- ahle on-line only. ¯he on-line euition anu the on-line ieleiences can he lounu at vvv.uign¯.con. Without saciihcing its locus on the slin as integial to anu iehec- tive ol oveiall health, the nev euition pioviues incieaseu enphasis on theiapy, ueinatologic suigeiy, anu cosnetic uei- natology. ¯he on-line euition pioviues auuitional uetaileu text loi lull anu ex- haustive coveiage ol each suh|ect, nany auuitional inages, chaits, anu algoiithns, anu conpiehensive up-to-uate liteiatuie ieleiences. ¯he layout ol DlCí has also changeu. Reaueis vill nov hnu an °At a Clance` oveiviev at the heginning ol each chaptei, algoiithns loi uiagnosis anu theiapy to expeuite uecision nal- ing, hoxes on uilleiential uiagnosis, anu a vealth ol uiagians, chaits, anu auui- tional nev inages to enhance unuei- stanuing ol the text. íany noie auui- tional inages can he lounu in the electionic veision. ¯he nev leatuies anu inpioveu as- pects ol DlCí shovcase the vealth ol the contiihuting authois` lnovl- euge. We have enueavoieu to integiate that lnovleuge into a single conpie- hensive anu consistent ieleience that vill seive the euucational anu ielei- ence neeus ol the entiie ueinatology connunity. We hope that you vill hnu this goal achieveu anu use DlCí loi this puipose loi nany yeais to cone. llaus Wolll Lovell A. Colusnith Stephen l. latz Baihaia A. Cilchiest Any S. lallei Daviu [. Lellell Copyright ? 2008 by The McGraw-Hill Companies, Inc. Click here for terms of use. This page intentionally left blank xxxv ^.''´.'c'.Vc'¯' We aie veiy giatelul to the contiihuting authois vho voileu closely vith us anu one anothei unuei gieat tine constiaints to naintain the excellent stanuaius ol DlCí in a iauically nev loinat. We aie also inuehteu to oui lanilies loi theii un- ueistanuing anu suppoit, as vell as the tine vith us they gave up uuiing the ue- velopnent ol the nev euition. Suppoit stall at oui institutions vho helpeu us vith this euitionRenate losna, [acy Beinal, anu Ciace Caniieueseive spe- cial iecognition loi theii extiaoiuinaiy level ol assistance vith nanusciipts thioughout the piocess ol ieviev anu puhlication. ¯he vihiancy ol the nev uia- gians, algoiithns, anu chaits is the voil ol Susan Cilheit, Cíl, to vhon ve aie giatelul loi hei uiligent elloits uone vithin a veiy uilhcult scheuule. linally, ve vish to aclnovleuge the excellent guiuance anu haiu voil ol the ícCiav- Hill tean, especially Anne í. Syuoi, Roheit lancotti, Sheiii Soulliance, Chaiissa Balei, Ainen Cvsepyan, levin íoian, Helen laii, anu Alexa Blonuell. llaus Wolll Lovell A. Colusnith Stephen l. latz Baihaia A. Cilchiest Any S. lallei Daviu [. Lellell Copyright ? 2008 by The McGraw-Hill Companies, Inc. Click here for terms of use. This page intentionally left blank 1 ' ^ ' ¯ |r||cduc||cr Copyright ? 2008 by The McGraw-Hill Companies, Inc. Click here for terms of use. 3 ' c .¯ ' ´' 1 0E\ERA| C0\S|DERAT|0\S C H A P T E R 1 The £p|dem|o|ogy aod 80rdeo oI Sk|o 0|sease |a|||r A. we|rº|cc| |a|]-|a|ça|e| C||er Scientists in health-ielateu helus locus on phenonena at uilleient levels. loi lahoia- toiy scientists, the locus is at the nolecu- lai, cellulai, oi oigan systen level, loi clin- ical scientists, the locus is on the patient, anu loi puhlic health piactitioneis, the lo- cus is on the population. lpiueniology is the hasic science ol puhlic health. lpiueniology has nany suhuivisions anu ollshoots. Clten the c¡idcmio|og, oj a discasc in a clinical ieviev ieleis piinaiily to its lieguency anu uistiihution in the population anu estinates ol its noihiuity anu noitality. ¯hese uata aie ueiiveu hy uesciiptive epiueniology. Case-contiol, cohoit, anu cioss-sectional stuuies nay seel to iuentily iisl lactois anu causes ol uisease anu loin the coie ol analytical ep- iueniology. lvaluations ol puhlic health inteiventions (expeiinental epiueniol- ogy) constitute the thiiu na|oi hianch ol classic epiueniology. ¯he hasic piinciples ol epiueniology have lounu hioau appli- cation in nany aieas, incluuing unuei- stanuing the puhlic health inplications ol natuially occuiiing anu synthetic con- pounus (noleculai epiueniology), the conplex inteiactions ol genetic anu envi- ionnental lactois in uisease (genetic epi- ueniology), the loinulation ol hettei ui- agnostic anu tieatnent stiategies loi patients haseu on availahle eviuence (clin- ical epiueniology), anu the stiuctuiing ol health caie ueliveiy loi hettei outcones anu gieatei elhciency (health seivices ie- seaich). ¯he ieauei is ieleiieu to othei souices loi a noie uetaileu uiscussion ol vaiious topics in ueinatoepiueniology. 1o T\PES 0| EP|DE||0|00|C STUD|ES ¯hiee ol the nany types ol epiuenio- logic stuuies aie nentioneu heie hecause ol theii pioninence in epiueniologic ie- seaich. ¯he ianuonizeu, contiolleu tiial is a paiticulaily iigoious type ol stuuy ap- piopiiate to the evaluation ol puhlic health inteiventions. ln geneial, the intei- vention is peiloineu on a ianuon san- ple ol the stuuy population, anu the en- tiie stuuy population is then ohseiveu loi the occuiience ol the outcone in gues- tion. ¯he ianuon assignnent ol inteiven- tion allovs the noie iigoious application ol nany statistical technigues anu ie- uuces the potential loi hias. llinination ol hiases peinits these stuuies to evaluate the elhcacy anu inpact ol an inteivention noie accuiately than tiials that uo not as- sign the inteivention ianuonly. Stan- uaius loi iepoiting have heen puhlisheu 4 (http://vvv.consoit-statenent.oig, last accesseu [une 2º, 2OO6) anu auopteu hy leauing ueinatology |ouinals to in- piove assessnent ol theii valiuity anu theii use in suhseguent systenatic ievievs 5 (see Chap. 2). When evaluating iisl lactois loi uis- ease, it is lieguently inpossihle to as- sign the iisl lactoi ianuonly. Hence, inleience is haseu on ohseivational stuuies. ln classical cohoit stuuies, a gioup vith exposuie to the iisl lactoi anu a gioup vithout aie chosen anu oh- seiveu ovei tine. Cccuiiences ol the stuuy outcone aie counteu anu con- paieu hetveen gioups. Although noie vulneiahle to hias than ianuonizeu tii- als, cohoit stuuies, in vhich exposuie to the iisl lactoi is lnovn vell heloie the stuuy outcone is lnovahle, avoiu po- tentially seiious hiases. ln a cohoit stuuy, the inciuence ol the stuuy out- cone can he neasuieu uiiectly in each gioup, anu the ielative iisl can he neas- uieu uiiectly as the iatio ol the inci- uence hetveen the tvo gioups. Cohoit stuuies olten aie guite expen- sive to conuuct hecause they ieguiie lol- loving a laige population ovei tine anu nay he inpossihle il the outcone heing stuuieu is unconnon. Hence, ohseiva- tional stuuies olten use the case-contiol appioach, in vhich cases vith the out- cone heing stuuieu anu appiopiiate con- tiols aie investigateu to ueteinine theii past exposuie to the iisl lactoi. Relative iisls geneially can he estinateu hy this appioach, although inciuence ol the uis- oiuei cannot. Reaueis aie ieleiieu to stanuaiu texts loi noie uetail iegaiuing epiueniologic stuuy uesigns. 6 Case- contiol anu cohoit stuuy nethous in uei- natology also have heen ievieveu. ¯º B|AS A\D C0\|0U\D|\0 ¯he piohlen vith inleience lion ohsei- vational stuuies is that one nay he leu to uiav eiioneous conclusions. ln paiticu- lai, an association that is lounu hetveen an exposuie anu a uisease nay he an ai- tilact uue to one oi noie ol the nany loins ol hias oi conlounuing. liopei in- leience iegaiuing cause anu ellect ie- guiies unueistanuing these possihle aiti- lacts anu theii potential inpacts. 1O Selection hias occuis vhen lactois that leau to selection ol the stuuy population allect the lilelihoou ol the outcones oi exposuies evaluateu. loi exanple, a case- contiol stuuy ol cutaneous lynphona nay ieciuit its cases lion souices that typically incluue a high piopoition ol ie- leiieu patients. ll contiols aie ieciuiteu lion a local clinic population, theii socio- ||rea| |eº|cr. (|||uº||a||cr |] 0|er H|r|/, |S. De|ra|c|cç] |e/|ccr P|cjec|. \|H-\|A|S Ccr- ||ac| \c. \01-AR-1-22oo., Copyright ? 2008 by The McGraw-Hill Companies, Inc. Click here for terms of use. 4 econonic status anu location ol iesiuence nay he suhstantially uilleient lion those ol the cases sinply uue to the nethou ol ieciuitnent. Unuei these ciicunstances, an association ol cutaneous lynphona vith occupation nay he noteu. lt then hecones inpoitant to note that the oh- seiveu association nay he uue not to a caicinogenic chenical in the voilplace hut iathei to the nethou hy vhich cases anu contiols veie selecteu. Sinilaily, il one veie conuucting a cohoit stuuy ol the ellect ol hieast-leeuing on the iisl ol atopic ueinatitis, it voulu he inpoitant to select hieast-leu anu hottle-leu inlants lion sinilai enviionnents. lnloination hias occuis vhen the as- sessnent ol exposuie oi outcone nay uillei hetveen the gioups heing con- paieu. leople vho veie exposeu to a puhlicizeu enviionnental toxin nay he noie lilely to seel caie loi ninoi synp- tons oi signs (anu hence he noie lilely to he uiagnoseu anu tieateu) than those vho veie not so exposeu, even il the ex- posuie hau no hiologic ellect. Sinilaily, people vho aie uiagnoseu vith a uisease nay he noie lilely to iecall past expo- suies than healthy contiols. Conlounuing occuis vhen an ohseiveu association (oi lacl theieol) hetveen ex- posuie anu uisease is uue to the inhuence ol a thiiu lactoi on hoth the exposuie anu the uisease. loi exanple, people vho use sunscieens nay have noie intense sun exposuie than those vho uo not, anu in- tense sun exposuie is one cause ol nela- nona. Hence, ohseivational stuuies nay nistalenly concluue that sunscieen use is a cause ol nelanona vhen the ohseiveu association is uue to sunscieen use seiv- ing as an inuicatoi ol a lilestyle involving intense sun exposuie. CAUSA| |\|ERE\CE ley issues in the puhlic health aiena ol- ten nust iely on ohseivational uata loi inleiiing cause anu ellect, in these situa- tions, the valiuity anu geneializahility ol the inuiviuual stuuies anu ol the totality ol the eviuence nust he caielully exan- ineu. ¯he lolloving ciiteiia geneially aie applieu loi causal inleience vhen an association is lounu. Although they aie uesciiheu loi inleiiing causality he- tveen an exposuie anu a uisease, they aie noie geneially applicahle to epiue- niologic causal inleience. T|re Se(uerce ¯he exposuie nust pieceue the uisease. ¯his concept is sinple anu ohvious in the ahstiact hut sonetines uilhcult to estahlish in piactice hecause the onset ol uisease nay pieceue the uiagnosis ol uisease hy yeais, anu the tining ol ex- posuie is olten not vell uehneu. Ccrº|º|erc] cr Rep||ca||cr Replication ol the ohseiveu association is ley anu pioviues the stiongest evi- uence il the ieplications aie nany anu uiveise anu vith consistent iesults. ¯he uiveisity ol the ieplications ieleis to vaiieu contexts as vell as to stuuy ue- signs vith uilleient potential veal- nesses anu stiengths. S||erç|| c| Aººcc|a||cr ¯iue causal ielationships nay he stiong (i.e., high ielative iisl) oi veal, hut aiti- lactual associations aie unlilely to have a high ielative iisl. ll the association he- tveen lactois x anu , is uue to the associ- ation ol hoth vith conlounuing vaiiahle :, the nagnituue ol the association hetveen x anu , alvays vill he less than the nag- nituue ol the association ol eithei vith :. 0|aded Aººcc|a||cr Also uesciiheu as |io|ogi. gradicnt, this cii- teiion ieleis to an association ol the ue- giee ol exposuie vith occuiience ol uis- ease, in auuition to an oveiall association ol piesence ol exposuie vith uisease. ¯his uose-iesponse ielation nay tale nany loins, as uegiee ol exposuie nay, loi exanple, ielei to intensity, uuiation, lieguency, oi latency ol exposuie. Cc|e|erce Cohcrcn.c ieleis to plausihility haseu on eviuence othei than the existence ol an association hetveen this exposuie anu this uisease in epiueniologic stuuies. Coheience vith existing epiueniologic lnovleuge ol the uisease in guestion (e.g., othei iisl lactois loi the uisease anu population tienus in its occuiience) anu othei uisoiueis (incluuing hut not liniteu to ielateu uisoiueis) suppoits in- leience. Coheience vith existing lnovl- euge lion othei helus, paiticulaily those ielevant to pathogenesis, is ciiti- cally inpoitant vhen those helus aie vell uevelopeu. lt nay involve uiiect linls, vhich aie pieleiieu, oi analogy. [ust as ohseivations in the lahoiatoiy as- sune gieatei signihcance vhen theii ielevance is suppoiteu hy epiueniologic uata, the ieveise is egually tiue. E/pe||rer| lxpeiinental suppoit is ciitical vhen leasihle. As noteu in ¯ypes ol lpiueni- ologic Stuuies, the stiongest inleiences ueiive lion iesults ol ianuonizeu tiials, although othei expeiinental uesigns anu guasi-expeiinental uesigns nay contiihute uselul eviuence. íoie uetaileu uiscussions ol these is- sues aie availahle. 11,12 |\VEST|0AT|0\ 0| D|SEASE 0UTBREA|S Although outhieals ol uisease vaiy tie- nenuously, use ol a stanuaiu liane- voil loi investigation is inpoitant to auuiess the puhlic health issues elh- ciently (see Chap. o). ¯he Centeis loi Disease Contiol anu lievention has out- lineu this lianevoil as a seiies ol 1O steps, vhich aie uesciiheu in noie ue- tail at http://vvv.cuc.gov. 1. lrc¡aration. Beloie initiating helu- voil, haclgiounu inloination on the uisease nust he gatheieu, anu appio- piiate inteiinstitutional anu inteipei- sonal contacts shoulu he naue. 2. Conµrm thc out|rcak. luhlicity, popula- tion changes, oi othei ciicunstances nay leau to an inaccuiate peiception that noie cases than expecteu have occuiieu. Hence, local oi iegional uata shoulu he sought to conhin the existence ol an incieaseu lieguency ol uisease. o. Conµrm thc diagnosis. Synptons anu signs ol peisons allecteu shoulu he ueteinineu anu lahoiatoiy hnuings conhineu, peihaps vith the assis- tance ol ieleience lahoiatoiies. 4. lsta||ish a .asc dcµnition. and µnd .ascs. Caielul epiueniologic investi- gation vill involve piecise anu sin- ple case uehnitions that can he applieu in the helu. llloits to hnu anu count auuitional cases heyonu those iepoiteu initially is ley to uehning the scope ol the outhieal. 5. lsta||ish thc dcs.ri¡tivc c¡idcmio|og,. ¯he cases can nov he chaiacteiizeu in teins ol timc, incluuing uevelop- nent ol an epiuenic cuive that uesciihes the changes in nagnituue ol the outhieal, ¡|a.c, incluuing nap- ping the uistiihution ol cases, anu ¡cr- son, the uenogiaphic anu potential exposuie chaiacteiistics ol cases. 6. Dcvc|o¡ h,¡othcscs. Cn the hasis ol the uata gatheieu in steps 1 thiough 5 anu the input ol othei inuiviuuals, plausi- hle hypotheses ahout causality can he uevelopeu loi luithei evaluation. 5 ¯. Condu.t ana|,ti.a| c¡idcmio|ogi. invcsti- gations. ll the uata gatheieu uo not yet cleaily piove a hypothesis, cohoit anu case-contiol investiga- tions can he conuucteu to veiily oi uispiove the hypotheses. 8. Rcvisc h,¡othcscs and o|tain additiona| cvidcn.c as nccdcd. Steps 6 anu ¯ aie iepeateu, each huiluing on piioi itei- ations, to estahlish the causal chain ol events. º. lm¡|cmcnt .ontro| mcasurcs. As soon as the causal chain ol events is unuei- stoou, pievention anu contiol nea- suies aie initiateu. 1O. Communi.atc rcsu|ts. An outhieal inves- tigation is not conplete until the iesults have heen appiopiiately connuni- cateu to the ielevant connunities. DESCR|PT|0\S 0| D|SEASE |\ P0PU|AT|0\S. |EASURES 0| D|SEASE BURDE\ No single nunhei can conpletely ue- sciihe the huiuen ol slin uisease hecause that huiuen has nany uinensions anu hecause the tein skin discasc itsell is iathei anhiguous. íany uisoiueis vith suhstantial noihiuity oi noitality, such as nelanona oi lupus eiythenatosus, al- lect nultiple oigan systens. ¯he uegiee ol slin involvenent nay vaiy viuely lion patient to patient anu vithin the sane patient lion tine to tine. Diseases not typically tieateu hy ueinatologists, such as theinal huins, olten aie excluueu lion estinates ol the huiuen ol slin uis- ease even though they piinaiily involve the slin. ln auuition, sone uiseases tieateu nost olten hy ueinatologists nay he classiheu in a uilleient categoiy hy lunuing agencies oi otheis |e.g., nela- nona is classiheu as an oncologic uisoi- uei as opposeu to a uisease ol the slin hy the National lnstitutes ol Health anu hy the lntcrnationa| C|assiµ.ation oj Discascs, (http://vvv.vho.int/classihcations/apps/ icu/icu1Oonline/, accesseu [une 2º, 2OO6) even though it alnost alvays aiises in the slin]. Cigan systens aie inteiielateu, anu the oveilap is sulhciently gieat that any uehnition ol slin uisease is necessai- ily aihitiaiy, anu any glohal estinate ol the puhlic health huiuen ol these uis- eases is theieloie open to challenge. ¯yp- ical neasuies ol uisease huiuen aie uis- cusseu in the lolloving sections. |c||a|||] íoitality is a ciitical neasuie ol uisease inpact. Death ceitihcation is univeisal in the Uniteu States, anu the lntcrna- tiona| C|assiµ.ation oj Discascs coue ol the unueilying cause ol each ueath is ie- coiueu. loi the yeai 2OO2, theie veie 14,º68 ueaths iepoiteu as uue to °slin uisease` in the Uniteu States, ol vhich nost veie uue to nelanona (¯ahle 1-1). Auuitional na|oi causes incluueu othei slin canceis (piinaiily leiatinocyte cai- cinonas), inlections ol the slin, anu slin ulceis (piinaiily uecuhitus ulceis). Bullous uisoiueis iepiesenteu ahout 1 peicent ol these ueaths. ¯he total nun- hei ol slin uisease ueaths, ol couise, ue- penus ciitically on the uehnition ol slin uisease, as noteu in Desciiptions ol Dis- ease in lopulations: íeasuies ol Dis- ease Buiuen. ln auuition to the total nunhei ol ueaths, noitality typically is expiesseu as an age-au|usteu iate to lacilitate con- paiisons anong populations vith uil- leient age uistiihutions. Statenents ol age-au|usteu iates ol noitality (oi othei iesults stanuaiuizeu hy age) shoulu he acconpanieu hy an inuication ol the stanuaiu useu in the au|ustnent to avoiu potentially nisleauing inleiences. loi exanple, vhen 1ºº8 nelanona noitality iates aie estinateu using the 2OOO U.S. population stanuaiu, the ie- sult is 5O peicent highei than il the 1º4O U.S. stanuaiu population is useu (1.8 vs. 1.2 pei 1OO,OOO pei yeai loi vonen anu 4.1 vs. 2.¯ pei 1OO,OOO pei yeai loi nen). Sinilaily, vhen yeais ol potential lile lost is iepoiteu, the ieauei nust he vaiy ol uilleient uehnitions that nay he applieu. ln one analysis, a uecline in noitality lion nelanona vas noteu hy one uehnition that vas not ohseiveu vith anothei. 1o Caielul analyses ol noitality incluue assessnent ol the valiuity ol the uata. íelanona noitality statistics appeai to he ieasonahly accuiate. 14,15 Hovevei, ueaths lion leiatinocyte caicinonas aie oveiestinateu hy a lactoi ol 2 (nostly uue to the eiioneous inclusion ol nucosal sguanous cell caicinonas ol the heau anu necl iegion), 16,1¯ anu ueaths lion cutaneous lynphona aie unueiestinateu hy ahout 4O peicent. 15 |rc|derce ln.idcn.c ieleis to the nunhei ol nev cases ol a uisoiuei. íoitality is lov loi nost slin uiseases, hence, inciuence nay he a noie uselul neasuie loi the assessnent ol huiuen ol slin uisease. Hovevei, nany leatuies ol slin uis- eases nale theii inciuence uilhcult to neasuie. loi exanple, loi nany slin uisoiueis, theie aie no uiagnostic laho- iatoiy tests, anu, in lact, sone uisoiueis nay evaue physician uiagnosis (e.g., al- leigic ieactions). lnciuence loi iepoit- ahle connunicahle uiseases in the Uniteu States is puhlisheu peiiouically haseu on iepoits to health uepaitnents, although unuei-iepoiting ol slin uis- eases uue to lailuie to piesent loi neui- cal caie oi to nisuiagnosis is a concein (¯ahle 1-2). lnciuences ol nelanona anu cutaneous lynphona have heen puh- lisheu haseu on uata lion a systen ol nationviue cancei iegistiies, yet unuei- iepoiting ienains a potential concein vith these uata. 18,1º Special suiveys have heen conuucteu to estinate inci- uence ol othei uisoiueis, such as leiati- nocyte caicinonas, although a systen ol sentinel iegistiies voulu he ieguiieu loi nationviue assessnent. 2O loi sone uiseases unlilely to evaue neuical ue- tection uue to theii seveiity, such as toxic epiueinal neciolysis, elloits to es- tinate inciuence have net vith consiu- eiahle success. 21,22 Specihc contexts that peinit noie accuiate inciuence esti- nates incluue the voilplace, loi exan- ple, vheie occupational slin uisease is a pievalent piohlen. 2o Cc|c|| Pa||e|rº Cohoit patteins ol changes in noitality oi inciuence typically aie ohseiveu vhen exposuies ueteinineu in chilu- hoou pieuict lieguency ol uisease thioughout the lile span. A classic ex- anple is nelanona noitality, loi vhich sun exposuie in chiluhoou is an inpoi- tant ueteininant. A hiith cohoit is ue- hneu as the gioup ol inuiviuuals hoin Ik8L£ 1-1 Sk|n 0|saasa 0aaths, Un|tad Statas, 2002 0|SFASF 0FATHS (h} Carce|º 11,081 |e|arcra /o14 0er||a| 101/ |]rp|cra 109 0||e| carce|º 2891 a (p||ra|||] |aºa| ard º(uarcuº ce|| ca|c|rcra, U|ce|º 1o/1 Bac|e||a| |r|ec||crº 1288 Bu||cuº d|ºc|de|º 1o4 0||e| cauºeº 819 Tota| 14,9o8 a we eº||ra|e ||a| app|c/|ra|e|] cre-|a|| c| ||eºe a|e r|ºc|aºº||ed º(uarcuº ce|| ca|c|rcraº a||º|rç ||cr ruccºa| ºu||aceº |r ||e |ead ard rec|. 1o Adap|ed ||cr |||p.//Wcrde|.cdc.çc./rc|||CD10J. ||r| (.e|||ed Jure 18, 200o,. 6 vithin a uehneu (e.g., 1O-yeai) peiiou. íelanona noitality geneially incieases as a povei lunction ol age vithin a hiith cohoit. Until iecent uecaues, each successive hiith cohoit hau highei iisl than its pieuecessoi, hence, the cuives ol noitality veisus age veie shilteu up- vaiu. ¯hus the cioss-sectional ielation- ship ol noitality veisus age anu the in- ciease in noitality iisl uuiing nost ol the tventieth centuiy lolloveu a co- hoit pattein. loi nany countiies in the past seveial uecaues a uecline in nela- nona noitality has heen ohseiveu in youngei age gioups uespite an inciease in oluei age gioups, suggesting a lovei haseline in these noitality-veisus-age cuives loi iecent cohoits anu hence a lilely lutuie uecline in oveiall nela- nona noitality. P|e.a|erce lrcva|cn.c ieleis to the piopoition ol the population allecteu hy a uisoiuei. Be- cause nany slin uiseases aie nonlethal yet chionic, pievalence is a paiticulaily inpoitant neasuie ol lieguency in uei- natology. lopulation-haseu uata on pievalence ol slin uisease loi the Uniteu States veie ohtaineu in the hist Health anu Nutiition lxanination Sui- vey, vhich vas conuucteu in the eaily 1º¯Os. 24 Despite its linitations, this stuuy vas notahle hecause the sanple vas iepiesentative ol the geneial U.S. population, the nunhei suiveyeu vas laige (ovei 2O,OOO), anu the entiie sui- veyeu population vas exanineu hy physicians (piinaiily ueinatology iesi- uents), so the iesulting estinates veie not uepenuent on patients` ahility oi in- clination to seel neuical caie. lnueeu, one ol the hnuings ol the suivey vas that neaily one-thiiu ol those exanineu hau one oi noie slin conuitions |uugeu to he signihcant enough to neiit a visit to a physician. ¯he nost connon conuitions anu theii age- anu genuei- specihc pievalences aie inuicateu in ¯a- hle 1-o anu lig. 1-1. A sinilai suivey in the Uniteu linguon ol ovei 2OOO Lon- uoneis in 1º¯5 noteu that alnost one- guaitei ol auults hau a slin conuition seiious enough to vaiiant neuical caie. 25 Cthei elloits have locuseu on ohtaining pievalence estinates ol spe- cihc conuitions vith special suiveys. 26,2¯ |||e||re R|º| Liletine iisls loi ceitain uisoiueis aie guoteu connonly, although theii valiu- ity can he guestioneu. Liletine iisl can he neasuieu only in ietiospect, anu even then it iehects conpeting causes ol noitality in auuition to inciuence. lt is connonly guoteu loi uisoiueis such as cutaneous nalignancies that aie chang- ing suhstantially in inciuence, yet those changes aie lieguently ignoieu in its cal- culation, anu, in any case, pio|ections ol lutuie changes aie guite speculative anu nay he nisleauing. 28 \ur|e| c| P|]º|c|ar V|º||º Nunhei ol physician visits loi a conui- tion is one piactical neasuie ol its lie- guency that nay iehect its inciuence, pievalence, anu seveiity, as vell as ac- cess to health caie. ¯ahle 1-4 lists lie- guencies ol ueinatologist anu othei physician outpatient visits loi sone ol the nost connon slin conuitions. A Ik8L£ 1-2 haw 0asas of Sa|actad 8aportab|a 0|saasas |n tha Un|tad Statas 1940 1950 19ö0 1970 1980 1990 2000 2005 Ac(u||ed |rrurcde|c|erc] º]rd|cre - - - - - 41,o9o 40,/o8 80,oo8 Ar|||a/ /o 49 28 2 1 0 1 - Ccrçer||a| |u|e||a - - - // o0 11 9 1 Ccrçer||a| º]p||||º - - - - - 88oo o29 2/8 D|p|||e||a 1o,o8o o/9o 918 48o 8 4 1 - 0crc|||ea 1/o,841 28o,/4o 2o8,988 o00,0/2 1,004,029 o90,1o9 8o8,99o 814,8/0 Harºer d|ºeaºe - 44 o4 129 228 198 91 89 |]re d|ºeaºe - - - - - - 1/,/80 21,804 |eaº|eº 291,1o2 819,124 441,/08 4/,8o1 18,o0o 2/,/8o 8o o2 a P|açue 1 8 2 18 18 2 o / Rcc|] |cur|a|r ºpc||ed |e.e| 4o/ 4o4 204 880 11o8 oo1 49o 1848 S]p||||º (p||ra|] ard ºeccrda|], - 28,989 1o,14o 21,982 2/,204 o0,228 o9/9 8020 Tc/|c º|cc| º]rd|cre - - - - - 822 18o 9o Tu|e|cu|cº|º | 102,984 c 121,/42 c oo,494 8/,18/ 2/,/49 2o,/01 1o,8// 11,o4/ U.S. pcpu|a||cr (r||||crº, 182 1o1 1/9 208 22/ 249 281 29o - = da|a rc| a.a||a||e. a ||||]-cre |rd|çercuº caºeº. | Repc|||rç c|||e||a c|arçed |r 19/o. c Da|a |rc|ude reW|] |epc||ed ac||.e ard |rac||.e caºeº. Adap|ed W||| pe|r|ºº|cr ||cr we|rº|cc| |A, Bc]|e ||. S|a||º||cº c| |r|e|eº| |c ||e de|ra|c|cç|º|, |r TIc 1car 8cck c| 0crratc!cçy arc 0crratc!cçic 30rçcry, 2006, ed||ed |] T||e|º BH, |arç P0 J|. P|||ade|p||a, E|ºe.|e| |cº|], 200o, p 80. Ik8L£ 1-3 Prava|anca of Sk|n 0ond|t|ons-Un|tad Statas, 1971-1974 a NALF FFNALF 80TH SFXFS º De|ra|c- p|]|cº|º 181 84 81 º Acre (.u|ça||º ard c]º||c, /4 oo /0 º Se|c|||e|c de|ra||||º 80 2o 28 º A|cp|c de|ra||- ||º/ec/era 20 18 19 º Ve||uca .u|ça||º 9 o 8 º |a||çrar| |urc|º o o o º Pºc||aº|º o o o º V|||||çc o 4 o º He|peº º|rp|e/ 4 o 4 a Caºeº pe| 1000 pcpu|a||cr. ||cr S||r ccrd|||crº ard |e|a|ed reed |c| red|ca| ca|e arcrç pe|ºcrº 1-/4 ]ea|º, Ur||ed S|a|eº, 19/1-19/4. ¡ita! Ica!tI 3tat [11|, rc 212, U.S. Depa||rer| c| Hea|||, Educa||cr, ard we||a|e, \c.er|e| 19/8. 7 leatuie ol this neasuie ol uisease lie- guency is its uiiect ielation to expenui- tuies loi caie ol the uisease. 0||e| |eaºu|eº c| |c|||d||]. Ccrcep|ua| |ººueº ¯he conseguences ol slin uisease loi a population nay he uilhcult to ueteinine conpiehensively hecause these conui- tions nost olten uo not allect suivival. 2º luitheinoie, the nost inpoitant gauges ol slin uisease status anu piogiession (i.e., the physical exanination anu pa- tients` iepoits) aie uilhcult to neasuie anu conpile. loi exanple, a patient vith psoiiasis nay have thiclening anu scaling ol the palns (a houily inpaiinent), vhich allects his oi hei lunctioning (e.g., use ol the hanus), activities (iole at voil), anu guality ol lile. íoieovei, the chal- lenges in neasuiing these conplex con- stiucts aie luithei conpounueu hecause people unueistanu anu value these as- pects ol health veiy uilleiently hecause ol age, genuei, cultuial conceptions, oi ac- cess to health caie. ln lact, the neasuie- nent ol nonlatal conseguences ol uisease is the suh|ect ol nuch inteinational sci- entihc anu political attention (http:// vvvo.vho.int/icl/icltenplate.cln, ac- cesseu [uly o, 2OO6). A ciucial point loi slin uiseases is that a patient`s expeiiences ol ellects ol slin uis- ease on his oi hei activities anu vell-heing aie inpoitant loi ueteinining the oveiall conseguences ol that uisease. ¯hese expe- iiences nay not he assesseu vith glohal neasuies that locus on single aspects ol health. loi exanple, slin uiseases that aie visihle anu allect appeaiance nay iesult in social stigna anu noou changes, vhich voulu not he neasuieu vith netiics that aie haseu on uyslunction. oO 0||e| |eaºu|eº c| |c|||d||]. |ººueº |r 0uar|||ca||cr Lile all assays, neasuies ol the nonlatal conseguences ol uiseases nust have cei- tain chaiacteiistics ol accuiacy. o1 loi ex- anple, they nust he rc|ia||c in that the vaiiahility in iesults anong suh|ects vho tiuly uillei shoulu he gieatei than the vaii- ahility vhen a stahle suh|ect is exanineu iepeateuly. ¯he neasuies nust have evi- uence ol va|idit,, vhich ieleis to the extent to vhich an instiunent neasuies vhat it is supposeu to neasuie anu uoes not neasuie sonething else. linally, health outcone neasuies also nust uenonstiate rcs¡onsivcncss, the ahility to uetect clinical change. ln geneial, the accuiacy ol nea- suies ol uisease status anu noihiuity in ueinatology has not heen evaluateu aue- guately. o2 luitheinoie, even vhen a vali- uateu instiunent exists, the clinical signih- cance ol scoies oi changes in scoies olten cannot he |uugeu until the tool is useu viuely anu scoies aie availahle loi nany patients vith uisease ol vaiying seveiity. linally, a signihcant challenge is uevelop- ing a consensus anong ueinatologists ahout the specihc clinical leatuies ol an in- uiviuual uisease that aie inpoitant to in- cluue in such neasuies. loi exanple, cii- teiia loi clinically inpoitant inpiovenent have heen uevelopeu loi sone iheunato- logic conuitions oo that, lile slin uiseases, aie chionic anu aie hest assesseu using clinical iathei than lahoiatoiy ciiteiia. |rpa||rer| ¯he extent to vhich a specihc slin uis- ease uisiupts the slin itsell is ielateu hoth to the peicentage ol houy suilace aiea involveu anu to physical signs ol the eiuption, such as the anount ol in- uuiation anu the uegiee ol scale. Civen the pleonoiphisn ol slin eiuptions anu lesions, nost ueinatologic seveiity-ol- uisease neasuies aie uisease-specihc. Anong the nost stuuieu instiunents to neasuie clinical seveiity ol uisease aie the lsoiiasis Aiea anu Seveiity lnuex (lASl) o4 anu the Seveiity Scoiing ol Atopic Deinatitis (SCCRAD) inuex. o5 With the lASl, seveiity ol uisease is as- sesseu hy |uugnent ol the uegiee ol in- volvenent ol loui houy iegions vith signs ol eiythena, inuuiation, anu ues- F|608£ 1-1 P|e.a|erce |a|eº |c| ||e |cu| |ead|rç |]peº c| º|çr||car| º||r pa||c|cç] arcrç pe|ºcrº 1 |c /4 ]ea|º, |] açe, |r ||e Ur||ed S|a|eº, 19/1-19/4. 800 250 200 150 100 50 0 Age iu ]ears Diseases of seoaceous glauds Dermatoph]toses Tumors 8eoorrheic dermatitis 10 20 80 40 50 O0 70 Ik8L£ 1-4 V|s|ts to hon-Fadara| 0fhca-8asad Phys|c|ans |n tha Un|tad Statas, 2003 a TYPF 0F PHYS|0|Ah 0|A0h0S|S 0F8NAT0L00|ST b 0THF8 ALL PHYS|0|AhS Acre Vu|ça||º 8//2 (12./°, c 4402 (0.o°, Ec/era|cuº de|ra||||º 24o2 (8.2°, oo/o (0./°, 8128 (0.9°, wa||º 1400 (4./°, 1oo/ (0.2°, 29o/ (0.8°, S||r carce| 2108 (/.1°, 14o9 (0.2°, 8oo2 (0.4°, Pºc||aº|º 1100 (8./°, c 12o8 (0.1°, |urça| |r|ec||crº c 2104 (0.2°, 2ooo (0.8°, Ha|| d|ºc|de|º //2 (2.o°, c 1o90 (0.2°, Ac||r|c |e|a|cº|º 2oo8 (8.9°, c 8081 (0.8°, Ber|çr recp|aºr c| ||e º||r 2/91 (9.4°, c 898o (0.4°, A|| d|ºc|de|º 29,801 (100°, 8/o,222 (100°, 90o,028 (100°, a Eº||ra|eº |r ||cuºardº. | Pe|cer|açe c| |c|a| .|º||º |º |r pa|er||eºeº. c ||çu|e dceº rc| ree| º|arda|d c| p|ec|º|cr. Adap|ed W||| pe|r|ºº|cr ||cr we|rº|cc| |A, Bc]|e ||. S|a||º||cº c| |r|e|eº| |c ||e de|ra|c|cç|º|, |r TIc 1car 8cck c| 0crratc!cçy arc 0crratc!cçic 30rçcry, 2006, ed||ed |] T||e|º BH, |arç P0 J|. P|||ade|p||a, E|ºe.|e| |cº|], 200o, p 89. 8 guanation. ¯he SCCRAD inuex con- hines an assessnent ol uisease aiea vith six clinical signs ol uisease inten- sity (scales to neasuie piuiitus anu sleep loss also can he incluueu). ¯hese instiunents shaie ceitain piohlens, loi exanple, estinates ol houy suilace aiea aie olten unieliahle, o6 anu investigatois (anu patients) nay not agiee that the se- lecteu clinical signs iepiesent the inpoi- tant leatuies ol uisease seveiity. o¯ |urc||cr|rç ard 0ua|||] c| |||e Suhstantial piogiess has heen naue in the uevelopnent anu testing ol patients` ie- poits ol the ellects ol theii slin uiseases on theii activities anu guality ol lile. Seveial geneiic instiunents aie availahle to nea- suie slin-ielateu guality ol lile associateu vith ueinatologic uisease ol any soit. o841 Data continue to he accunulateu ahout the peiloinance ol these instiunents (in- cluuing the use ol sophisticateu psycho- netiic nethous 42 anu the inteipietation ol theii scoies. 4o An inpoitant conclusion lion these stuuies is that coiielations he- tveen the guality-ol-lile ellects ol slin uis- eases anu theii clinical seveiity as assesseu hy physicians aie nouest at hest anu nay in lact he guite lov. ¯his hnuing is also typical ol nany nonueinatologic uiseases anu inplies that a conpiehensive assess- nent ol patients vith slin uisease shoulu incluue neasuienent ol clinical seveiity as vell as its ellects on guality ol lile. 44 U||||||eº A utility is a nuneiic neasuie ol the value a patient places on a given health state conpaieu vith othei health states. ln the neasuienent ol utilities, a vaiiety ol pioceuuies aie useu (such as visual an- alog scales anu tine tiaueoll exeicises) to assign a nuneiical value (oi utility) to health states. ¯his value iehects patients` pieleiences loi the health states, in vhich 1.O iepiesents peilect health anu O.O iepiesents ueath. Utilities aie auvan- tageous hecause they peinit the incoipo- iation ol patient pieleiences into neuical caie uecisions. Also, hecause they ue- sciihe inpiovenents in noihiuity vith a single veighteu netiic, utilities aie useu loi the evaluation ol conplex tiaueolls such as the calculation ol cost-ellective- ness, in vhich the costs ol tieatnents aie conpaieu vith the values ol the health states they nale possihle. Utilities aie contioveisial, hovevei, hecause they can he uilhcult to neasuie anu can vaiy viuely anong patients in unpieuictahle vays. An incieasing nunhei ol stuuies exist that loinally neasuie utilities ol patients vith slin uiseases. 45 Ccº|º Costs ol slin uisease uepenu on the pei- spective lion vhich they aie neasuieu, hecause the costs to insuieis anu patients nay he guite uilleient lion the oveiall cost to society. Also, hecause nost slin uiseases aie chionic anu aie caieu loi in the outpatient setting, estination ol hoth theii nonetaiy anu intangihle costs is uilhcult. A iecent stuuy estinateu the oveiall uiiect anu inuiiect cost to payeis, patients, anu society ol 22 slin uis- eases. 46 ln auuition, costs loi inuiviuual slin conuitions have heen calculateu, anu theiapies have heen evaluateu in ielation to theii henehts anu ellectiveness. 4¯,48 0UA||T\ 0| CARE |\ DER|AT0|00\ Health seivices ieseaich uses nany ol the scientihc nethous lion epiueniol- ogy, clinical epiueniology, anu the guan- titative social sciences to stuuy anu in- piove the guality ol health caie. lion the peispective ol health seivices ie- seaich, the piocesses involveu in the pio- vision ol health caie, as vell as the pai- ticulai theiapeutic inteiventions anu patient anu pioviuei chaiacteiistics, aie all potentially inpoitant ueteininants ol the guality ol caie. Deinatologic health seivices ieseaich is still nev, anu nuch attention has locuseu on stuuies ol the ellectiveness ol caie (i.e., outcones ol health caie as it is usually piacticeu). ¯o inloin stanuaiu caie, hovevei, elhcacy ol inteiventions is also inpoitant (i.e., the iesults ol inteiventions inplenenteu in the iuealizeu ciicunstances ol a ian- uonizeu clinical tiial). íany ol the ex- anples citeu eailiei uenonstiate a shaip- eneu locus in ueinatology on accuiate neasuienent ol the clinical encountei. ¯his capacity to neasuie the piogiess ol chionic uiseases anu theii caie vill pei- nit iigoious elloits to evaluate anu in- piove the guality ol that caie. |E\ RE|ERE\CES T|e |u|| |e|e|erce ||º| |c| a|| c|ap|e|º |º a.a||a||e a| WWW.d|çr/.ccr. 1. Baizilai DA et al: Deinatoepiueniol- ogy. j Am A.ad Dcrmato| :55º, guiz 5¯4, 2OO5 2. Willians HC, Stiachan Dl: Thc Cha|- |cngc oj Dcrmatoc¡idcmio|og,. Boca Raton, lloiiua, CRC liess, 1ºº¯ o. Weinstocl íA: Dcrmatoc¡idcmio|og,. lhilauelphia, W.B. Saunueis Conpany, 1ºº5 45. Chen SC et al: A catalog ol ueinatology utilities: A neasuie ol the huiuen ol slin uiseases. j lnvcstig Dcrmato| :,m¡ lro. :16O, 2OO4 46. Bicleis DR et al: ¯he huiuen ol slin uiseases: 2OO4. j Am A.ad Dcrmato| :4ºO, 2OO6 C H A P T E R 2 £v|deoce-8ased 0ermato|ogy ||c|ae| B|ç|] Rcºara||a Cc|cra |c]ºeº S/||c BR|E| H|ST0R\ 0| EV|DE\CE- BASED |ED|C|\E Hunuieus ol ianuonizeu contiolleu clinical tiials veie conuucteu hetveen 1º5O anu the 1º¯Os. Hovevei, theii ie- sults veie not catalogueu oi useu sys- tenatically to inloin neuical uecision naling. ln 1º¯2 Aichie Cochiane, a Biitish epiueniologist anu physician, puhlisheu his iesponse to heing asleu to evaluate the ellectiveness ol the Biitish National Health Seivice in ueliveiing health caie to the population ol the Uniteu linguon. ln his analysis he concluueu that neuical science vas pooi at uistinguishing inteiventions that veie ellective lion those that veie not anu that physicians veie not using availahle eviuence lion clinical ie- seaich to inloin theii uecision naling. 6 See http://vvv.cochiane.oig/cochiane/ aichieco.htn loi noie inloination on Aichie Cochiane. Cioups ol lile-ninueu epiueniolo- gists anu physicians iesponueu to Aichie Cochiane`s challenge hy exanining the nethous hy vhich neuical uecisions anu conclusions veie ieacheu anu pioposeu an alteinative appioach haseu on hnuing, appiaising, anu using availahle uata lion clinical ieseaich involving intact pa- tients. ¯ ln 1º85 Saclett et al. puhlisheu C|ini.a| l¡idcmio|og,: A 3asi. :.icn.c jor C|ini.a| /cdi.inc, vhich uetaileu the ia- tionale anu technigues ol this eviuence- haseu appioach. ¯ ¯hese authois anu oth- eis ieuuceu the iules ol eviuence to a snall suhset ol piinciples that veie eas- 9 iei to teach anu to unueistanu, anu iein- tiouuceu the concept in 1ºº2. 8 ¯hey naneu this technigue cvidcn.c-|ascd mcd- i.inc (lBí). lt vas uehneu as the consci- entious, explicit, anu |uuicious use ol the hest cuiient eviuence in naling uecisions ahout the caie ol inuiviuual patients. 8 Wheieas naling uecisions ahout theiapy has heen the piinaiy locus ol lBí, its piinciples have heen extenueu to uiagno- sis, piognosis, avoiuance ol the hainlul ellects ol inteiventions, ueteinination ol cost ellectiveness, anu econonic analyses. ¯he intiouuction ol lBí vas net vith consiueiahle hostility. lt vas peiceiveu as coolhool neuicine, olu hat, too iestiic- tive, anu an insult to those alieauy tiying to piactice goou neuical caie. ¯he uehni- tion vas solteneu to incluue the integia- tion ol inuepenuent clinical expeitise, hest availahle exteinal clinical eviuence lion systenatic ieseaich, anu the patient`s val- ues anu expectations. 2 ¯he Cochiane Collahoiation vas loineu to sone extent in iesponse to Aichie Cochiane`s challenge to geneiate ciitical sunnaiies, oiganizeu hy spe- cialty oi suhspecialty anu upuateu peii- ouically, ol all ielevant ianuonizeu con- tiolleu tiials. º Cieateu anu naintaineu thiough the collahoiative elloits ol vol- unteeis, the Cochiane Lihiaiy is an in- piessive anu uselul conpenuiun ol sys- tenatic ievievs, ahstiacts ol systenatic ievievs, anu the Cochiane Cential Reg- istei ol Contiolleu ¯iials, a uatahase ol ovei 4¯o,OOO contiolleu clinical tiials (http://vvvo.inteiscience.viley.con/ cgi-hin/nivhone/1O6568¯5o/HCíl). ¯he Cochiane Lihiaiy is the nost con- plete anu hest inuex uatahase ol ian- uonizeu contiolleu clinical tiials anu contiolleu clinical tiials anu is the hest anu nost elhcient place to hnu eviuence ahout theiapy. ¯he acceptance ol lBí in the spe- cialty ol ueinatology has heen slov anu ieluctant. ¯he tein anu piinciples aie unueistoou hy lev anu nisunuei- stoou hy nany. lBí is peiceiveu as an attenpt to cut costs, inpose iigiu stan- uaius ol caie, anu iestiict ueinatolo- gists` lieeuon to exeicise inuiviuual |uugnent. liacticing lBí in ueinatol- ogy is hanpeieu hy the continueu heliel anong ueinatologists that clinical ueci- sions can he guiueu hy an unueistanu- ing ol the pathophysiology ol uisease, logic, tiial anu eiioi, anu nonsystenatic ohseivation. 1,1O lt is hanpeieu also hy a lacl ol sulhcient uata in nany aieas. As vith lBí in geneial, theiapy is olten piinaiily enphasizeu, hovevei, evi- uence-haseu appioaches to uiagnosis anu avoiuance oi evaluation ol hain aie also inpoitant consiueiations. wHAT |S 'THE BEST EV|DE\CE'´ liacticing lBí is pieuicateu on hnuing anu using the hest eviuence. lotential souices ol eviuence incluue lnovleuge iegaiuing the etiology anu pathophysiol- ogy ol uisease, logic, peisonal expeii- ence, the opinions ol colleagues oi ex- peits, texthools, aiticles puhlisheu in |ouinals, anu systenatic ievievs. An in- poitant piinciple ol lBí is that the gual- ity (stiength) ol eviuence is haseu on a hieiaichy. ¯he piecise hieiaichy ol evi- uence uepenus on the type ol guestion heing asleu (¯ahle 2-1). 11 ¯his hieiaichy consists ol iesults ol vell-uesigneu stuu- ies (especially il the stuuies have hnuings ol sinilai nagnituue anu uiiection, anu il theie is statistical honogeneity anong stuuies), iesults ol case seiies, expeit opinion, anu peisonal expeiience, in ue- scenuing oiuei. º,1O ¯he hieiaichy vas cieateu to encouiage the use ol the evi- uence that is nost lilely to he accuiate anu uselul in clinical uecision naling. ¯he oiueiing in this hieiaichy has heen viuely uiscusseu, actively uehateu, anu sonetines hotly contesteu. 12 A systenatic ieviev is an oveiviev that ansveis a specihc clinical guestion, contains a thoiough, unhiaseu seaich ol the ielevant liteiatuie, uses explicit cii- teiia loi assessing stuuies, anu pioviues a stiuctuieu piesentation ol the iesults. A systenatic ieviev that uses guantita- tive nethous to sunnaiize iesults is a neta-analysis. 1o,14 A neta-analysis pio- viues an oh|ective anu guantitative sun- naiy ol eviuence that is anenahle to statistical analysis. 1o íeta-analysis is cieuiteu vith alloving the iecognition ol inpoitant tieatnent ellects hy con- hining the iesults ol snall tiials that in- uiviuually lacleu the povei to uenon- stiate uilleiences anong tieatnents. loi exanple, the henehts ol intiavenous stieptolinase in tieating acute nyocai- uial inlaiction veie iecognizeu hy neans ol a cunulative neta-analysis ol snallei tiials at least a uecaue heloie this tieatnent vas ieconnenueu hy expeits anu heloie it vas uenonstiateu to he elhcacious in laige clinical tii- als. 15,16 íeta-analysis has heen ciiti- cizeu hecause ol the uisciepancies he- tveen the iesults ol neta-analysis anu those ol laige clinical tiials. 161º loi exanple, iesults ol a neta-analysis ol 14 snall stuuies ol the use ol calciun to tieat pieeclanpsia shoveu a heneht to tieatnent, vheieas a laige tiial laileu to shov a tieatnent ellect. 16 ¯he lie- guency ol such uisciepancies ianges lion 1O peicent to 2o peicent. 16 Dis- ciepancies can olten he explaineu hy uilleiences in tieatnent piotocols, het- eiogeneity ol stuuy populations, oi changes that occui ovei tine. 16 luhlication hias is an inpoitant con- cein iegaiuing systenatic ievievs. lt ie- sults vhen lactois othei than the gual- ity ol the stuuy aie alloveu to inhuence its acceptahility loi puhlication. Seveial stuuies have shovn that lactois such as sanple size, uiiection anu statistical sig- nihcance ol hnuings, anu investigatois` peiceptions ol vhethei the hnuings aie °inteiesting` aie ielateu to the lileli- hoou ol puhlication. 2O,21 loi exanple, in a stuuy hy Dicleisin et al., the ieasons given hy investigatois that iesults ol conpleteu stuuies veie not puhlisheu incluueu °negative ie- sults` (28 peicent), °lacl ol inteiest` (12 peicent), anu °sanple size piohlens` (11 peicent). 2O Results ol stuuies vith snall sanples aie less lilely to he puh- lisheu, especially il they have negative iesults. 2O,21 ¯his type ol puhlication hias |eopaiuizes one ol the nain goals ol neta-analysis (i.e., an inciease in povei thiough pooling ol the iesults ol snall stuuies). Cieation ol stuuy iegisteis anu auvance puhlication ol ieseaich uesigns have heen pioposeu as vays to pievent puhlication hias. 22,2o luhlication hias can he uetecteu hy using a sinple EV|DE\CE-BASED |ED|C|\E AT A 0|A\CE E.|derce-|aºed red|c|re (EB|, |º ||e uºe c| ||e |eº| cu||er| e.|derce |r ra|- |rç dec|º|crº a|cu| ||e ca|e c| |rd|.|dua| pa||er|º. EB| |º p|ed|ca|ed cr aº||rç c||r|ca| (ueº||crº, |rd|rç ||e |eº| e.|derce |c arºWe| ||e (ueº||crº, c||||ca||] app|a|º|rç ||e e.|derce, app|]|rç ||e e.|derce |c ||e ||ea|rer| c| ºpec||c pa||er|º, ard ºa.|rç ||e c||||ca||] app|a|ºed e.|derce. T|e EB| app|cac| |º rcº| app|cp||a|e |c| ||e(uer||] erccur|e|ed ccrd|||crº. Reºu||º ||cr We||-deº|çred c||r|ca| º|ud- |eº |r.c|.|rç |r|ac| pa||er|º a|e a| ||e p|r- rac|e c| ||e ||e|a|c|] c| e.|derce uºed |c p|ac||ce e.|derce-|aºed red|c|re. Reccrrerda||crº a|cu| ||ea|rer|, d|aç- rcº|º, ard a.c|darce c| |a|r º|cu|d |a|e |r|c acccur| ||e .a||d||], raçr||ude c| e||ec|, p|ec|º|cr, ard app||ca|||||] c| ||e e.|derce cr W||c| ||e] a|e |aºed. 10 giaphic test (lunnel plot) oi hy seveial othei statistical nethous.` 24,25 ln auui- tion, loi nany uiseases, the stuuies puh- lisheu aie uoninateu hy uiug conpany sponsoieu tiials ol nev, expensive tieat- nents. ¯he neeu loi stuuies to ansvei the clinical guestions ol nost concein to piactitioneis is not auuiesseu hecause souices ol lunuing aie inaueguate. Not all systenatic ievievs anu neta- analyses aie egual. A systenatic ieviev can he only as goou as the clinical tiials that it enconpasses. ¯he ciiteiia loi ciitically appiaising systenatic ievievs anu neta-analyses aie shovn in ¯ahle 2-2. Detaileu explanations ol each ciite- iion aie availahle. 1o,26 ¯he type ol clinical stuuy that consti- tutes hest eviuence is ueteinineu hy the categoiy ol guestion heing asleu. Cues- tions ahout theiapy anu pievention aie hest auuiesseu hy ianuonizeu con- tiolleu tiials. 1o,2628 Cuestions ahout ui- agnosis aie hest auuiesseu hy cohoit stuuies. 1o,26,2º,oO Cohoit stuuies, case- contiol stuuies, anu post-naileting sui- veillance stuuies hest auuiess guestions ahout hain. 1o,26,o1 Ranuonizeu con- tiolleu tiials aie a goou souice ol evi- uence ahout the hainlul ellects ol intei- ventions loi auveise events that occui lieguently hut not loi iaie auveise events. Case iepoits aie olten the hist line ol eviuence iegaiuing iaie auveise events, anu sonetines they aie the only eviuence. íethous loi assessing the guality ol each type ol eviuence aie availahle. 1o,26 With iegaiu to guestions ahout theiapy anu pievention, the ianuonizeu con- tiolleu clinical tiial has hecone the golu stanuaiu loi ueteinining tieatnent elh- cacy. ¯housanus ol ianuonizeu con- tiolleu tiials have heen conuucteu. Stuu- ies have uenonstiateu that lailuie to use ianuonization oi to pioviue aueguate concealnent ol allocation iesulteu in laigei estinates ol tieatnent ellects, causeu pieuoninantly hy a pooiei piog- nosis in nonianuonly selecteu contiol gioups than in ianuonly selecteu contiol gioups. o2 Hovevei, stuuies conpaiing ianuonizeu anu nonianuonizeu clinical tiials ol the sane inteiventions have ieacheu uispaiate anu contioveisial ie- sults. o2o4 Sone lounu that ohseivational stuuies iepoiteu stiongei tieatnent el- lects than ianuonizeu contiolleu tiials. o2 Ctheis lounu that the iesults ol vell- uesigneu ohseivational stuuies (vith ei- thei a cohoit oi a case-contiol uesign) uo not systenatically oveiestinate the nag- nituue ol the ellects ol tieatnent con- paieu vith ianuonizeu contiolleu tiials on the sane topic. oo,o4 lxanining the ue- tails ol the contioveisy leaus to the lol- loving liniteu conclusions. ¯iials using histoiical contiols uo yielu laigei esti- nates ol tieatnent ellects than uo ian- uonizeu contiolleu tiials. Laige, inclu- sive, lully hlinueu ianuonizeu contiolleu tiials aie lilely to pioviue the hest possi- hle eviuence ahout ellectiveness. 12,o5,o6 Although peisonal expeiience is an invaluahle pait ol heconing a conpe- tent physician, the pitlalls ol ielying too heavily on peisonal expeiience have heen viuely uocunenteu. ¯,o¯,o8 Nishett anu Ross extensively ievieveu people`s ahility to uiav inleiences lion peisonal expeiience anu uesciihe seveial ol these pitlalls. oº ¯hese incluue the lolloving: º Cveienphasis on viviu anecuotal occuiiences anu unueienphasis on signihcant statistically stiong eviuence º Bias in iecognizing, ienenheiing, anu iecalling eviuence that suppoits pie-existing lnovleuge stiuctuies (e.g., iueas ahout uisease etiology anu pathogenesis) anu paiallel lailuie to iecognize, ienenhei, anu iecall eviuence that is noie valiu Ik8L£ 2-1 0radas of Fv|danca a,b 08A0F LFVFL 0F FV|0Fh0F THF8APY/HA8N 0|A0h0S|S A 1a S]º|era||c |e.|eW (W||| |crcçere- ||] c , c| RCTº S]º|era||c |e.|eW (W||| |crcçere||], c| |e.e| 1 (ºee cc|urr 2, d|açrcº||c º|ud|eº, c| a CP0 .a||da|ed cr a |eº| ºe|. 1| |rd|.|dua| RCT (W||| ra||cW ccr|- derce |r|e|.a|º, |rdeperder| |||rd ccrpa||ºcr c| ar app|cp||a|e ºpec||ur c| ccrºecu||.e pa||er|º, a|| c| W|cr |a.e |eer e.a|ua|ed |] |c|| ||e d|açrcº||c |eº| ard ||e |e|e|erce º|arda|d. 1c A|| c| rcre d Ve|] ||ç| ºerº|||.||] c| ºpec||c||] B 2a S]º|era||c |e.|eW (W||| |crcçere- ||], c| cc|c|| º|ud|eº S]º|era||c |e.|eW (W||| |crcçere||], c| |e.e| 2 c| |e||e| (ºee cc|urr 2, d|açrcº||c º|ud|eº 2| |rd|.|dua| cc|c|| º|ud] [|rc|ud|rç |cW- (ua|||] RCT (e.ç., < 80° |c||cW-up,| |rdeperder| |||rd ccrpa||ºcr |u| e|||e| |r rcr-ccrºecu||.e pa||er|º c| ccr|red |c a ra|- |cW ºpec||ur c| º|ud] |rd|.|dua|º (c| |c||,, a|| c| W|cr |a.e |eer e.a|ua|ed |] |c|| ||e d|açrcº||c |eº| ard ||e |e|e|erce º|arda|d c| a d|açrcº||c CP0 rc| .a||da|ed |r a |eº| ºe| 2c '0u|ccreº' |eºea|c| e 8a S]º|era||c |e.|eW (W||| |crcçere- ||], c| caºe-ccr||c| º|ud|eº S]º|er|c |e.|eW (W||| |crcçere||], c| 8| (ºee cc|urr 2, ard |e||e| º|ud|eº 8| |rd|.|dua| caºe-ccr||c| º|ud] |rdeperder| |||rd ccrpa||ºcr c| ar app|cp||a|e ºpec||ur, |u| ||e |e|e|erce º|arda|d Waº rc| app||ed |c a|| º|ud] pa||er|º C 4 Caºe ºe||eº (ard pcc|-(ua|||] cc|c|| ard caºe-ccr||c| º|ud|eº, Re|e|erce º|arda|d Waº rc| app||ed |rdeperder||] c| rc| app||ed |||rd|] D o E/pe|| cp|r|cr W|||cu| e/p||c|| c||||ca| app|a|ºa|, c| |aºed cr p|]º|c|cç], |erc| |eºea|c|, c| |cç|ca| deduc||cr CP0 = c||r|ca| p|ac||ce çu|de||re, a º]º|era||ca||] de.e|cped º|a|erer| deº|çred |c |e|p p|ac||||cre|º ard pa||er|º ra|e dec|º|crº a|cu| app|cp||a|e |ea||| ca|e |c| ºpec||c c||r|ca| c||curº|arceº, RCT = |ardcr|/ed ccr||c||ed |||a|. a T|eºe |e.e|º We|e çere|a|ed |r a ºe||eº c| ||e|a||crº arcrç rer|e|º c| ||e \HS RöD Cer||e |c| E.|derce-Baºed |ed|c|re (C|||º Ba||, Da.e Sac|e||, Bc| P|||||pº, B||ar Ha]reº, ard S|a|cr S||auº,. |c| de|a||º ºee |e.e|º c| E.|derce ard 0|adeº c| Reccrrerda||cr, |||p.//WWW.ce|r.re|/|e.e|º_c|_e.|derce.aºp, |a] 2001. | Reccrrerda||crº |aºed cr |||º app|cac| app|] |c 'a.e|açe' pa||er|º ard ra] reed |c |e rcd||ed |r ||ç|| c| ar |rd|.|dua| pa||er|'º ur|(ue ||c|cç] (e.ç., ||º|, |eºpcrº|.ereºº, ard p|e|e|erceº a|cu| ||e ca|e |e c| º|e |ece|.eº. c Icrcçcrcity rearº |ac||rç .a||a||cr |r ||e d||ec||cr ard raçr||ude c| |eºu||º c| |rd|.|dua| º|ud|eº. d /!! cr rcrc rearº |r|e|.er||crº ||a| p|cduced d|ara||c |rc|eaºeº |r ºu|.|.a| c| cu|ccre, ºuc| aº ||e uºe c| º||ep|cr]c|r |c ||ea| |u|e|cu|a| rer|rç|||º. e 0u|ccreº |eºea|c| |rc|udeº ccº|-|ere||, ccº|-e||ec||.ereºº, ard ccº|-u|||||] ara|]º|º. 11 º lailuie to accuiately chaiacteiize pop- ulation uata hecause ol ignoiance ol statistical piinciples, incluuing san- ple size, sanple selection hias, anu iegiession to the nean º lnahility to uetect anu uistinguish statistical association anu causality º leisistence ol heliels in spite ol ovei- vhelning contiaiy eviuence Nishett anu Ross pioviue exanples lion contiolleu clinical ieseaich. Sinple clinical exanples ahounu. lhysicians nay ienenhei patients vhose conui- tion inpioveu, olten assune that pa- tients vho uiu not ietuin loi lollov-up got hettei, anu conveniently loiget the patients vhose conuition uiu not in- piove. A patient tieateu vith a given neuication nay uevelop a seveie lile- thieatening ieaction. Cn the hasis ol this single unuesiiahle expeiience, the physician nay avoiu using that neuica- tion loi nany lutuie patients, although on aveiage it nay he noie elhcacious anu less toxic than the alteinative tieat- nents that the physician chooses. lev physicians leep aueguate, easily ietiiev- ahle iecoius to couily iesults ol tieat- nents vith a paiticulai agent oi tieat- nents ol a paiticulai uisease, anu even levei actually caiiy out analyses. lev physicians nale piovisions loi tiacling those patients vho aie lost to lollov- up. ¯heieloie, statenents naue ahout a physician`s °clinical expeiience` nay he hiaseu. linally, loi nany conuitions, a single physician sees lai too lev pa- tients vith the given uisoiuei to allov ieasonahly hin conclusions to he uiavn ahout the iesponse to tieat- nents. loi exanple, suppose that a physician has tieateu 2O patients vith lichen planus using tietinoin anu lounu that 12 (6O peicent) hau an excellent ie- sponse. ¯he conhuence inteival loi this iesponse iate (i.e., the tiue iesponse iate loi this tieatnent in the laigei popula- tion lion vhich this physician`s sanple vas ohtaineu) ianges lion o6 peicent to 81 peicent. ¯hus the tiue iesponse iate night vell he suhstantially less (oi noie) than the physician concluues lion peisonal expeiience. lxpeit opinion can he valuahle, pai- ticulaily vhen the uisoiuei is a iaie con- uition in vhich the expeit has the nost expeiience oi vhen othei loins ol evi- uence aie not availahle. Hovevei, sev- eial stuuies have uenonstiateu that ex- peit opinion olten lags signihcantly hehinu conclusive eviuence. ¯ lxpeits sullei lion ielying on hench ieseaich, pathophysiology, anu tieatnents haseu on logical ueuuction lion pathophysiol- ogy as vell as lion the sane pitlalls noteu loi ieliance on peisonal expeii- ence. lxpeits shoulu he avaie ol the guality ol the eviuence that exists. lt is viuely helieveu that clinical ueci- sions can he naue on the hasis ol an un- ueistanuing ol the etiology anu patho- physiology ol uisease anu logic. 1,1O ¯his paiauign is piohlenatic hecause the accepteu hypothesis iegaiuing the eti- ology anu pathogenesis ol uisease changes ovei tine. ¯heieloie, the logi- cally ueuuceu tieatnents change ovei tine. loi exanple, in the last 2O yeais, hypotheses ahout the cause ol psoiiasis have shilteu lion a uisoiuei ol leiati- nocyte piolileiation anu honeostasis, to ahnoinal signaling ol cyclic auenosine nonophosphate, to aheiiant aiachi- uonic aciu netaholisn, to aheiiant vi- tanin D netaholisn, to the cuiient lavoiite, ¯-cellneuiateu autoinnune uisease. lach ol these hypotheses spavneu logically ueuuceu tieatnents. ¯he elhcacy ol nany ol these tieat- nents has heen suhstantiateu hy iigoi- ous contiolleu clinical tiials, hut otheis aie useu even in the ahsence ol systen- atically collecteu ohseivations. ¯heie- loie, ve have nany options loi tieating patients vith seveie psoiiasis (e.g., ultia- violet B iauiation, naiiov-hanu ultiavio- let B iauiation, Coecleinan tieatnent, psoialen plus ultiaviolet A iauiation, nethotiexate, cyclospoiin, anu the hio- logics) anu nilu to noueiate psoiiasis (e.g., anthialin, topical coiticosteioius, calcipotiiene, anu tazaiotene) (see Chap. 18). Hovevei, ve lacl a cleai sense ol vhich is hest, in vhat oiuei they shoulu he useu, anu in vhat conhinations. 1O,4O ¯ieatnents haseu on logical ueuuction lion pathophysiology nay have unex- pecteu conseguences. loi exanple, the ohseivation that antiaiihythnic uiugs coulu pievent ahnoinal ventiiculai ue- polaiization altei nyocaiuial inlaiction logically leu to theii use to pievent suu- uen ueath altei nyocaiuial inlaiction. Hovevei, a ianuonizeu contiolleu clin- ical tiial shoveu incieaseu noitality anong patients tieateu vith antiai- ihythnic uiugs than anong those given a placeho. 28,41,42 ¯exthools can he valuahle souices ol eviuence, paiticulaily loi iaie conuitions anu loi conuitions loi vhich the evi- uence uoes not change iapiuly ovei tine. Hovevei, texthools have seveial vell- uocunenteu linitations. ¯hey tenu to ie- hect the hiases anu shoitconings ol the expeits vho viite then. Because ol the vay they aie viitten, piouuceu, anu uis- tiihuteu, nost aie appioxinately 2 yeais out ol uate at the tine ol puhlication. íost texthool chapteis aie naiiative ie- vievs that uo not consiuei the guality ol the eviuence iepoiteu. ¯,1o ||\D|\0 THE BEST EV|DE\CE ¯he ahility to hnu the hest eviuence to ansvei clinical guestions is ciucial loi the piactice ol lBí. linuing eviuence ieguiies access to electionic seaich tools, seaiching slills, anu availahility ol ielevant uata. lviuence ahout theiapy is the easiest to hnu. ¯he nost uselul souices loi locating the hest eviuence ahout tieatnent incluue the lolloving: º ¯he Cochiane Lihiaiy º ¯he ílDLlNl (íeuical Liteiatuie Analysis anu Retiieval Systen Cn- Line) anu líBASl (lxcr¡ta /cdi.a Data|asc) uatahases º liinaiy |ouinals º Seconuaiy |ouinals º lviuence-haseu ueinatology anu lBí hools º ¯he National Cuiueline Cleaiing- house (http://vvv.guiueline.gov/) Ik8L£ 2-2 C||||ca| App|a|ºa| c| a S]º|era||c Re.|eW º A|e ||e |eºu||º c| |||º º]º|era||c |e.|eW .a||d´ º D|d ||e |e.|eW add|eºº a |ccuºed c||r|ca| (ueº||cr´ a º we|e ||e c|||e||a uºed |c ºe|ec| a|||c|eº |c| |rc|uº|cr app|cp||a|e´ a º |º || ur|||e|] ||a| |rpc||ar| |e|e.ar| º|ud- |eº We|e r|ººed´ | º waº ||e .a||d||] c| ||e |rc|uded º|ud|eº app|a|ºed´ | º we|e aººeººrer|º c| º|ud|eº |ep|cduc|||e´ | º we|e ||e |eºu||º º|r||a| ||cr º|ud] |c º|ud]´ | º A|e ||e .a||d |eºu||º c| |||º º]º|era||c |e.|eW |rpc||ar|´ º w|a| a|e ||e c.e|a|| |eºu||º c| ||e |e.|eW´ º HcW p|ec|ºe We|e ||e |eºu||º´ º Car ]cu app|] |||º .a||d, |rpc||ar| e.|- derce |r ca||rç |c| ]cu| pa||er|´ º Car ||e |eºu||º |e app||ed |c ]cu| pa||er|'º ca|e´ º we|e a|| c||r|ca||] |rpc||ar| cu|ccreº ccrº|de|ed´ º A|e ||e |ere||º Wc||| ||e |a|rº ard ccº|º´ a P||ra|] çu|deº. | Seccrda|] çu|deº. ||cr Sac|e|| D e| a|. £viccrcc-8ascc Vccicirc. IcW tc Iracticc arc TcacI £8V. Ed|r|u|ç|, C|u|c|||| ||.|rçº|cre, 199o. 12 º ¯he National lnstitute loi Health anu Clinical lxcellence (http://vvv.nice. oig.ul) ¯he Cochiane Lihiaiy contains the Cochiane Datahase ol Systenatic Re- vievs, the Datahase ol Ahstiacts ol Re- vievs ol lllectiveness, the Cochiane Cential Registei ol Contiolleu ¯iials, anu the Health ¯echnology Assessnent Datahase, anong othei uatahases (http:// vvvo.inteiscience.viley.con/cgi-hin/ nivhone/1O6568¯5o/HCíl). Volun- teeis viite the systenatic ievievs in the Cochiane Lihiaiy accoiuing to stiict guiuelines uevelopeu hy the Cochiane Collahoiation. lssue 1, 2OO¯, ol the Co- chiane Lihiaiy containeu 4655 con- pleteu systenatic ievievs. ¯he nunhei ol ievievs ol ueinatologic topics is steauily incieasing. ¯he Datahase ol Ahstiacts ol Re- vievs ol lllectiveness contains ah- stiacts ol systenatic ievievs puhlisheu in the neuical liteiatuie. lt pioviues ah- stiacts anu hihliogiaphic uetails on 5ºo1 puhlisheu systenatic ievievs. ¯he Da- tahase ol Ahstiacts ol Revievs ol lllec- tiveness is the only uatahase to contain ahstiacts ol systenatic ievievs that have heen assesseu loi guality. lach ah- stiact incluues a sunnaiy ol the ieviev togethei vith a ciitical connentaiy ahout the oveiall guality. ¯he Health ¯echnology Assessnent Datahase con- sists ol conpleteu anu ongoing health technology assessnents (stuuies ol the neuical, social, ethical, anu econonic inplications ol health caie inteiven- tions) lion aiounu the voilu. ¯he ain ol the uatahase is to inpiove the guality anu cost ellectiveness ol health caie. ¯he Cochiane Lihiaiy is the hest souice loi eviuence ahout tieatnent. lt can he easily seaicheu using sinple Boolean conhinations ol seaich teins as vell as noie sophisticateu seaich stiategies. ¯he Cochiane Datahase ol Systenatic Revievs, Datahase ol Ah- stiacts ol Revievs ol lllectiveness, Cential Registei ol Contiolleu ¯iials, anu Health ¯echnology Assessnent Da- tahase can he seaicheu sinultaneously. ¯he Cochiane Lihiaiy is availahle on CD-RCí hy peisonal oi institutional suhsciiption anu on the Woilu Wiue Weh lion Wiley lnteiScience (http:// vvvo.inteiscience.viley.con/cgi-hin/ nivhone/1O6568¯5o/HCíl). Suh- sciiheis to the Cochiane Lihiaiy aie pioviueu vith guaiteily upuates. ¯he Cochiane Lihiaiy is olleieu liee ol chaige in nany countiies hy national piovision anu hy nany neuical schools in the Uniteu States. lt shoulu he avail- ahle at youi neuical lihiaiy. ¯he seconu hest nethou loi hnuing ev- iuence ahout tieatnent anu the nost use- lul souice loi hnuing nost othei types ol hest eviuence in ueinatology is seaiching the ílDLlNl uatahase hy conputei. 44,45 ílDLlNl is the National Lihiaiy ol íeuicine`s hihliogiaphic uatahase covei- ing the helus ol neuicine, nuising, uen- tistiy, veteiinaiy neuicine, the health caie systen, anu the pie-clinical sciences. ¯he ílDLlNl uatahase contains hihlio- giaphic citations anu authoi ahstiacts lion appioxinately 5OOO cuiient hio- neuical |ouinals puhlisheu in the Uniteu States anu 8O loieign countiies. ¯he uata- hase contains appioxinately 15 nillion iecoius uating hacl to the niu-1º5Os. 46 ílDLlNl seaiches have inheient linitations that nale theii ieliahility less than iueal. 45 Specihc seaich stiategies, oi hlteis, have heen uevel- opeu to aiu in hnuing ielevant ielei- ences anu excluuing iiielevant ielei- ences to locate the hest eviuence ahout uiagnosis, theiapy, piognosis, hain, anu pievention. 48 ¯hese hlteis have heen incoipoiateu into the luhíeu Clinical Cueiies seaich engine ol the National Lihiaiy ol íeuicine anu aie availahle at http:// vvv.nchi.nln.nih.gov/entiez/gueiy/ static/clinical.shtnl. 4º ¯he use ol luhíeu Clinical Cueiies (http://vvv.nchi.nln.nih.gov/entiez/ gueiy/static/clinical.shtnl) is the pieleiieu nethou loi seaiching the ílDLlNl uata- hase to locate the hest clinically ielevant eviuence. lt can he useu lieely hy anyone vith lnteinet access. íoie than 2O venuois pioviue ílDLlNl systens on-line anu on CD- RCí. Haynes et al. 5O conpaieu seveial venuois ol ílDLlNl on-line anu on CD-RCí to ueteinine vhich systen vas hest in teins ol locating ielevant aiticles anu excluuing iiielevant aiticles. As assesseu lion conhineu ianlings loi the highest nunhei ol ielevant anu the lovest nunhei ol iiielevant citations ie- tiieveu, Silveillattei ílDLlNl clinical |ouinal suhset on CD-RCí peiloineu hest loi lihiaiian seaiches, vheieas the lapeiChase on-line systen voileu hest loi clinician seaiches. When |uugeu hy cost pei ielevant citation, Dialog`s lnovleuge lnuex peiloineu hest loi hoth lihiaiian anu clinician seaiches. 5O líBASl is lx.cr¡ta /cdi.a`s uata- hase coveiing phainacology anu hio- neuical specialties. 1o líBASl has het- tei coveiage ol luiopean anu non lnglish language souices anu nay he noie up to uate. 1o ¯he oveilap in |oui- nals coveieu hy ílDLlNl anu líBASl is appioxinately o4 peicent (iange, 1O peicent to ¯5 peicent uepenuing on the suh|ect). 51,52 líBASl is availahle on-line thiough the na|oi uatahase venuois |e.g., Data- Stai, Dialog, DlíDl (Deutschen lnstitut lui íeuizinische Dolunentation unu lnloination), Cviu Cnline, anu S¯N]. loi noie inloination, see http://vvv. elseviei.con/vps/hnu/hihliogiaphicua- tahaseuesciiption.cvs_hone/52oo28/ uesciiption=uesciiption. leisonal anu in- stitutional suhsciiptions aie availahle. Stiuctuieu ahstiacts ol aiticles aie puh- lisheu in seconuaiy |ouinals (e.g., the lvi- uence-Baseu Deinatology section ol Ar- .hivcs oj Dcrmato|og,). ¯he aiticles aie stiictly selecteu on the hasis ol nethou- ologic guality anu aie acconpanieu hy connentaiy putting the inloination in clinical peispective. lvidcn.c-3ascd Dcr- mato|og, (Willians H et al., euitois, Cx- loiu, Blaclvell luhlishing Ltu., 2OO2) is a conpenuiun ol °nini` systenatic ie- vievs ol the tieatnent ol slin uiseases. C|ini.a| lvidcn.c is a conpenuiun ol evi- uence on the ellects ol connon clinical inteiventions that is upuateu eveiy 6 nonths. lt is availahle thiough the Anei- ican College ol lhysicians anu the Biitish íeuical Association. lull-text veisions ol nany piinaiy |ouinals aie nov availahle on the lntei- net. Availahle venuois incluue DataStai, Dialog, DlíDl, Cviu Cnline, anu S¯N, anong otheis. ¯he National Cuiueline Cleaiinghouse naintains a uatahase ol guiuelines loi the tieatnent ol uisease viitten hy panels ol expeits lolloving stiict ciiteiia loi eviuence. ¯he uatahase is accessihle thiough the lnteinet (http:// vvv.guiuelines.gov). Cuiient coveiage ol ueinatologic topics is liniteu. ¯he National lnstitute loi Health anu Clinical lxcellence piouuces guiuance on puhlic health, health technologies, anu clinical piactice haseu on the hest availahle eviuence. lt is accessihle on- line at http://vvv.nice.oig.ul. CR|T|CA||\ APPRA|S|\0 THE EV|DE\CE Altei eviuence is lounu, the next step in piacticing lBí is ciitically appiaising the guality ol the eviuence anu ueteinining the nagnituue ol ellects anu the piecision ol the eviuence. ¯he ciiteiia loi ciitically appiaising papeis ahout tieatnent, uiag- nostic tests, anu hainlul ellects ol expo- suies aie shovn in ¯ahles 2-o, 2-4, anu 2-5, iespectively. 1o,26 lapeis that neet 13 these ciiteiia aie noie lilely to pioviue in- loination that is accuiate anu uselul in the caie ol patients. 1o,26 A uetaileu expla- nation ol each ciiteiion 1o,26 anu an exan- ple involving a patient vith a ueinato- logic conplaint aie availahle. 45 Ciitically appiaising eviuence consists ol the thiee steps ol ueteinining vhethei the iesults have each ol the lol- loving chaiacteiistics: º Valiuity (i.e., they aie as unhiaseu as possihle) º Clinical inpoitance º Applicahility to the specihc patient heing seen Deteinining the valiuity ol eviuence centeis on asceitaining vhethei the evi- uence vas piouuceu in a nannei nost lilely to elininate anu avoiu hias. ¯he ciitical guestions to asl to ueteinine the valiuity ol papeis ahout theiapy, ui- agnostic tests, anu hainlul ellects aie shovn at the tops ol ¯ahles 2-o, 2-4, anu 2-5, iespectively. E.|derce A|cu| T|e|ap] ard P|e.er||cr Stuuies ol theiapy shoulu ianuonly as- sign patients to tieatnent gioups (us- ing a tahle ol ianuon nunheis oi pseuuo-ianuon nunheis geneiateu hy conputei) anu ensuie concealeu alloca- tion (e.g., hy using opague envelopes so that the tieating physician cannot guess to vhich tieatnent gioup the patient has heen assigneu). ln auuition, theie shoulu he neaily conplete lollov-up ol all pa- tients enteieu into the stuuy, intention- to-tieat analysis ol iesults, nasling ol investigatois, patients, anu statisticians vheie possihle, egual tieatnent ol gioups, anu sinilaiity hetveen tieat- nent gioups vith iegaiu to the uistiihu- tions ol piognostic vaiiahles. ¯hese ciite- iia iepiesent only a snall suhset ol the leatuies ol a vell-uesigneu anu vell- iepoiteu clinical tiial. o¯ A noie conplete set ol ciiteiia has heen puhlisheu, anu au- heience to these ciiteiia is ieguiieu hy nany ol the leauing neuical |ouinals. 5o lnpoitant teins anu concepts that nust he unueistoou to ueteinine vhethei the iesults ol a papei ahout theiapy aie clinically inpoitant incluue the lolloving: º ¯he nagnituue ol the tieatnent ellect º ¯he piecision ol this value º ¯he uilleience in iesponse iates º lts iecipiocal, the nunhei neeueu to tieat (NN¯) º ¯he conhuence inteival Ik8L£ 2-3 0r|t|ca| Appra|sa| of a Papar About Tharapy A|e ||e |eºu||º c| |||º º|rç|e p|e.er||.e c| ||e|apeu||c |||a| .a||d´ waº ||e aºº|çrrer| c| pa||er|º |c ||ea|rer|º |ardcr|/ed ard Waº ||e |ardcr|/a||cr ||º| ccr- cea|ed´ we|e a|| pa||er|º W|c er|e|ed ||e |||a| acccur|ed |c| a| ||º ccrc|uº|cr ard We|e ||e|| da|a ara|]/ed |r ||e ç|cupº |c W||c| ||e] We|e |ardcr|] aºº|çred´ we|e pa||er|º ard c||r|c|arº |ep| |||rd aº |c W||c| ||ea|rer| Waº |e|rç |ece|.ed´ Aº|de ||cr ||e e/pe||rer|a| ||ea|rer|, We|e ||e ç|cupº ||ea|ed e(ua||]´ we|e ||e ç|cupº º|r||a| a| ||e º|a|| c| ||e |||a|´ A|e ||e .a||d |eºu||º c| |||º |ardcr|/ed |||a| |rpc||ar|´ Ca|cu|a||crº. |r|e|.er||cr Reºpcrºe Ra|e Ccrpa||ºcr (|r|e|.er- ||cr, Reºpcrºe Ra|e D|||e|erce |r Reºpcrºe Ra|eº \ur|e| \eeded |c T|ea| (|RR, (CRR, (DRR, (|RR - CRR, (\\T, (1/DRR, w|a| |º ||e 9o° ccr|derce |r|e|.a| c| ||e d|||e|erce |r |eºpcrºe |a|eº (DRR,´ a w|a| |º ||e 9o° ccr|derce |r|e|.a| c| ||e \\T´ | Car ]cu app|] |||º .a||d, |rpc||ar| e.|derce |r ca||rç |c| ]cu| pa||er|´ Dc ||eºe |eºu||º app|] |c ]cu| pa||er|´ |º ]cu| pa||er| ºc d|||e|er| ||cr ||cºe |r ||e |||a| ||a| ||º |eºu||º car'| |e|p ]cu´ HcW ç|ea| Wcu|d ||e pc|er||a| |ere|| c| ||e|ap] ac|ua||] |e |c| ]cu| |rd|.|dua| pa||er|´ Dc ||e |eç|rer ard ||º ccrºe(uerceº ºa||º|] ]cu| pa||er|'º .a|ueº ard p|e|e|erceº´ Dc ]cu| pa||er| ard ]cu |a.e a c|ea| aººeººrer| c| ]cu| .a|ueº ard p|e|e|erceº´ A|e |||º |eç|rer ard ||º ccrºe(uerceº ccrº|º|er| W||| ||er´ a T|e 9o° ccr|derce |r|e|.a| c| ||e DRR |º ||cr | T|e 9o° ccr|derce |r|e|.a| c| ||e \\T = 1/||r||º cr ||e ccr|derce |r|e|.a| c| ||º DRR. ||cr Sac|e|| D e| a|. £viccrcc-8ascc Vccicirc. IcW tc Iracticc arc TcacI £8V. Ed|r|u|ç|, C|u|c|||| ||.- |rçº|cre, 199o. Ik8L£ 2-4 0r|t|ca| Appra|sa| of a Papar About a 0|agnost|c Tast A|e ||e |eºu||º c| |||º d|açrcº||c º|ud] .a||d´ º waº ||e|e ar |rdeperder|, |||rd ccrpa||ºcr W||| a |e|e|erce (çc|d, º|arda|d c| d|açrcº|º´ º waº ||e d|açrcº||c |eº| e.a|ua|ed |r ar app|cp||a|e ºpec||ur c| pa||er|º (|||e ||cºe |r W|cr || Wcu|d |e uºed |r p|ac||ce,´ º waº ||e |e|e|erce º|arda|d app||ed |eça|d|eºº c| ||e d|açrcº||c |eº| |eºu||´ A|e ||e .a||d |eºu||º c| |||º d|açrcº||c º|ud] |rpc||ar|´ Ca|cu|a||crº. Ta|çe| D|ºc|de| P|eºer| A|ºer| D|açrcº||c Teº| Reºu|| Pcº|||.e a | \eça||.e c d º Serº|||.||] = a/(a + c, º Spec||c||] = d/(| + d, º |||e|||ccd |a||c |c| a pcº|||.e |eº| |eºu|| = [a/(a + c,|/[|/(| + d,| = ºerº|||.||]/(1 - ºpec||c||], º |||e|||ccd |a||c |c| a reça||.e |eº| |eºu|| = [c/(a + c,|/[d/(| + d,| = (1 - ºerº|||.||],/ºpec||c||] Car ]cu app|] |||º .a||d, |rpc||ar| e.|derce a|cu| a d|açrcº||c |eº| |r ca||rç |c| ]cu| pa||er|´ º |º ||e d|açrcº||c |eº| a.a||a||e, a||c|da||e, accu|a|e, ard p|ec|ºe |r ]cu| ºe|||rç´ º Car ]cu çere|a|e a c||r|ca||] ºerº|||e eº||ra|e c| ]cu| pa||er|'º p|e-|eº| p|c|a|||||] (||cr p|ac- ||ce da|a, ||cr pe|ºcra| e/pe||erce, ||cr ||e |epc|| ||ºe||, c| ||cr c||r|ca| ºpecu|a||cr,´ º w||| ||e |eºu|||rç pcº|-|eº| p|c|a||||||eº a||ec| ]cu| raraçerer| ard |e|p ]cu| pa||er|´ (Ccu|d || rc.e ]cu ac|cºº a |eº|-||ea|rer| |||eº|c|d´ wcu|d ]cu| pa||er| |e a W||||rç pa||re| |r ca||]|rç cu| ]cu| |eccrrerda||crº´, º wcu|d ||e ccrºe(uerceº c| ||e |eº| |e|p ]cu| pa||er|´ ||cr Sac|e|| D e| a|. £viccrcc-8ascc Vccicirc. IcW tc Iracticc arc TcacI £8V. Ed|r|u|ç|, C|u|c|||| ||.- |rçº|cre, 199o. DRR 1.9o SE  |c DRR 1.9o SE  +  W|e|e SE (º|arda|d e||c|, I II 1 | RR    \c. |r|e|.er||cr pa||er|º --------------------------------------------------- 0II 1 0II    \c. ccrpa||ºcr pa||er|º --------------------------------------------------- + = 14 ln evaluating a clinical tiial, the physi- cian shoulu lool loi clinical outcone neasuies that aie cleai-cut anu clinically neaninglul to the physician anu his oi hei patients. o¯ loi exanple, in a stuuy ol a systenic tieatnent loi vaits, con- plete uisappeaiance ol vaits is a nean- inglul outcone, vheieas a ueciease in the volune ol vaits is not. Histoiically, tvo piincipal nethous have heen useu to ueteinine patient outcones in uei- natologic clinical tiials. ¯he hist in- volves exanining the patient heloie, uuiing, anu at the conclusion ol tieat- nent anu iepoiting hov the patient ap- peais at the vaiious tine points. ¯he seconu involves ueteinining the uegiee ol inpiovenent uuiing tieatnent. 54 A thiiu nethou, ueteinining the inpact ol theiapy on the guality ol the patient`s lile, is heing incieasingly useu in ueina- tologic tiials. o¯ An exanple ol the hist nethou is connonly encounteieu in theiapeutic tiials ol psoiiasis. A connon piactice is to assign nuneiical values to the anount ol eiythena, the anount ol scaling, the uegiee ol inhltiation, anu the houy sui- lace aiea involveu, anu to loinulate an °inuex` hy calculating a ueiivative ol sone piouuct ol these loui nunheis. 55,56 ¯he oveiall conuition ol the patient can then he iepiesenteu hy this inuex. A connon inuex is the psoiiasis aiea anu seveiity inuex, vhich ianges lion O to ¯2. 55 ¯he na|oi piohlen vith inuices is that they conlounu aiea ol involvenent vith seveiity ol uisease. 54 loi instance, a patient vith thicl plague-type psoiiasis ol the lnees, elhovs, anu scalp nay have the sane inuex as a patient vith uilluse hut nininal psoiiasis ol the tiunl anu ains. Wheieas the loinei conuition is notoiiously uilhcult to tieat, the lattei vill geneially iesponu iapiuly anu easily to nany loins ol theiapy. 54 ¯he seconu piohlen vith inuices is that they lenu an aii ol piecision to the anal- ysis anu piesentation ol uata that is not vaiianteu. 54 loi instance, ¯iling-Ciosse anu Rees uenonstiateu that physicians anu neuical stuuents veie pooi at esti- nating the aiea ol involvenent ol slin uisease, anu theieloie sone ol the con- ponents that nale up inuices nay he in- accuiate. 5¯ linally, calculations ol the neans, uilleiences in neans, anu pei- centages ol change in inuices in iesponse to tieatnent olten uo not convey an ac- cuiate clinical pictuie ol the changes that have occuiieu. 54 ¯he seconu nethou ol assessnent gioups patients accoiuing to theii ue- giee ol inpiovenent. ¯ieatnents aie then conpaieu in teins ol theii ahility to nove patients into categoiies iepie- senting highei uegiees ol inpiovenent. ¯heie aie tvo na|oi piohlens vith this loin ol assessnent. ¯he hist is that the categoiies ol inpiovenent aie olten not vell uehneu. ¯he seconu piohlen is that the categoiies aie not auuitive. 54 ¯hat is, 6O peicent to 8O peicent in- piovenent is olten assuneu to he tvice as goou as 2O peicent to 4O peicent in- piovenent, hut no such nuneiical iela- tionship exists hetveen these suh|ec- tively uehneu categoiies. ¯o he nost uselul, the outcone vaii- ahles to he neasuieu nust he cleaily ue- hneu, nust he as oh|ective as possihle, anu nust have clinical anu hiologic sig- nihcance. o¯,54 ¯he hest inuices anu scales aie the ones that accuiately iehect the state ol the uisease anu the ones vhose valiuity anu ieliahility have heen veiiheu hy pievious voil. o¯,54,58 ¯he uevelopnent ol scales anu inuices loi assessing cutaneous uiseases anu the testing ol theii valiuity, iepiouucihility, anu iesponsiveness have heen inaue- guate. o¯,54,5º ¯heieloie, a lacl ol cleaily uehneu anu uselul outcone vaiiahles ie- nains a na|oi piohlen in inteipieting ueinatologic clinical tiials. Until hettei scales aie uevelopeu, tii- als vith the sinplest anu nost oh|ective outcone vaiiahles aie the hest. ¯hey leau to the least anount ol conlusion anu suppoit the stiongest conclusions. ¯hus, tiials in vhich a conpaiison is naue hetveen ueath anu suivival, ie- cuiience ol uisease anu no iecuiience, oi cuie anu lacl ol cuie aie stuuies vhose outcone vaiiahles aie easily un- ueistoou anu veiiheu. loi tiials in vhich the outcones aie less cleai-cut anu noie suh|ective, a sinple oiuinal scale is piohahly the hest choice. 54 ¯he hest oiuinal scales involve a nininun ol hu- nan |uugnent, have a piecision that is nuch snallei than the uilleiences heing sought, anu aie sulhciently stanuaiu- izeu so that they can he useu hy otheis anu piouuce sinilai iesults. o8 ln auuition to heing cleaily uehneu, outcone vaiiahles shoulu have clinical anu hiologic signihcance. 2¯,28 loi exan- ple, in a theiapeutic tiial ol patients vith seveie acne, tieatnent vas associ- ateu vith a ueciease in lesion count lion a nean ol 4OO to a nean ol o5O. Ik8L£ 2-5 0r|t|ca| Appra|sa| of a Papar About Harm A|e ||e |eºu||º c| |||º |a|r º|ud] .a||d´ º we|e ||e|e c|ea||] de|red ç|cupº c| pa||er|º, º|r||a| |r a|| |rpc||ar| Wa]º c||e| ||ar e/pcºu|e |c ||e ||ea|rer| c| c||e| cauºe´ º we|e ||ea|rer| e/pcºu|eº ard c||r|ca| cu|ccreº reaºu|ed ||e ºare Wa]º |r |c|| ç|cupº´ [|c| |rº|arce, Waº ||e aººeººrer| c| cu|ccreº e|||e| c|jec||.e (e.ç., dea||, c| |||rded |c e/pcºu|e´| º waº ||e |c||cW-up c| º|ud] pa||er|º ccrp|e|e ard |crç ercuç|´ Dc ||e |eºu||º ºa||º|] ºcre 'd|açrcº||c |eº|º |c| cauºa||cr'´ º |º || c|ea| ||a| ||e e/pcºu|e p|eceded ||e crºe| c| ||e cu|ccre´ º |º ||e|e a dcºe-|eºpcrºe ç|ad|er|´ º |º ||e|e pcº|||.e e.|derce ||cr a 'dec|a||erçe-|ec|a||erçe' º|ud]´ º |º ||e aººcc|a||cr ccrº|º|er| ||cr º|ud] |c º|ud]´ º Dceº ||e aººcc|a||cr ra|e ||c|cç|c ºerºe´ A|e ||e .a||d |eºu||º ||cr |||º |a|r º|ud] |rpc||ar|´ Ca|cu|a||crº. Ad.e|ºe 0u|ccre P|eºer| (Caºe, A|ºer| (Ccr||c|, E/pcºed |c ||e T|ea|rer| \eº (cc|c||, a | \c (cc|c||, c d º |r a |ardcr|/ed |||a| c| cc|c|| º|ud], |e|a||.e ||º| = [a/(a + |,|/[c/(c + d,|. º |r a caºe-ccr||c| º|ud], cddº |a||c (c| |e|a||.e cddº, = ad/|c. S|cu|d ||eºe .a||d, pc|er||a||] |rpc||ar| |eºu||º c| a c||||ca| app|a|ºa| a|cu| a |a|r|u| ||ea|rer| c|arçe ||e ||ea|rer| c| ]cu| pa||er|´ º Car ||e º|ud] |eºu||º |e e/||apc|a|ed |c ]cu| pa||er|´ º w|a| a|e ]cu| pa||er|'º ||º|º c| ||e ad.e|ºe cu|ccre´ º w|a| a|e ]cu| pa||er|'º p|e|e|erceº, ccrce|rº, ard e/pec|a||crº ||cr |||º ||ea|rer|´ º w|a| a||e|ra||.e ||ea|rer|º a|e a.a||a||e´ ||cr Sac|e|| D e| a|. £viccrcc-8ascc Vccicirc. IcW tc Iracticc arc TcacI £8V. Ed|r|u|ç|, C|u|c|||| ||.- |rçº|cre, 199o. 15 ¯his nuneiical uilleience nay he ol sta- tistical signihcance, hut it uoes not con- vey the hiologic signihcance ol the change in lesion nunhei. 54 ¯his iesult nay nean that sone patients vith se- veie acne expeiienceu conplete cleai- ance, vheieas in otheis the acne ie- naineu the sane oi got voise. lt coulu also nean that in nost patients the acne got slightly hettei. luitheinoie, uoes an inuiviuual patient lool hettei vhen the lesion nunhei has heen ieuuceu lion 4OO to o5O` ls theie less scaiiing anu levei conplications` ¯o stiengthen clinical tiials anu help valiuate theii conclusions, investigatois shoulu select only a lev outcone vaii- ahles anu shoulu choose then heloie initiation ol the stuuy. íeasuienent ol nany outcone vaiiahles incieases the lilelihoou that spuiious, chance uillei- ences vill he uetecteu. An inellective tieatnent nay he lounu elhcacious vhen testeu using pooily uesigneu outcone assessnent tools. Conveisely, an ellec- tive theiapy nay he lounu inellective vhen an insensitive scale is useu. Special piecautions aie ieconnenueu to iecognize anu ienain sleptical ol suhstitute oi suiiogate enupoints, espe- cially vhen no uilleiences aie uetecteu in clinically inpoitant outcones. 28,6O lx- anples ol such enupoints incluue CD4/ CD8 iatios insteau ol suivival iates in stuuies ol tieatnents loi acguiieu in- nunouehciency synuione, anti-nucleai antihouy levels oi seuinentation iates insteau ol clinical neasuies ol uisease activity in lupus eiythenatosus, anu volune ol vaits insteau ol piopoition ol patients cleaieu ol vaits. ¯he use ol caielully chosen anu valiuateu suiiogate enupoints olten allovs stuuies to pio- viue ansveis to guestions that voulu typically ieguiie nuch laigei oi longei tiials il the taigeteu clinical enupoint veie useu. loi exanple, a vell-uesigneu shoit clinical tiial nay he sulhcient to uenonstiate that a nev uiug ellectively loveis seiun cholesteiol level oi that a given uiug is ellective in contiolling hy- peitension. ln hoth cases, nuch longei anu laigei stuuies voulu he ieguiieu to uenonstiate that the cholesteiol-lovei- ing uiug anu the antihypeitensive uiug ieuuceu noihiuity anu noitality lion atheioscleiotic anu hypeitensive caiuio- vasculai uiseases, iespectively. Suiio- gate enupoints nust coiielate vith clini- cal outcones, hovevei, anu theii valiuity nust have heen uenonstiateu in piioi stuuies. Cnce sounu, clinically ielevant out- cone neasuies aie chosen, the nagni- tuue ol the uilleience hetveen the tieatnent gioups in achieving these neaninglul outcones shoulu he uetei- nineu. ¯he piecision ol the estinate ol the uilleiences anong tieatnents shoulu he assesseu. Uselul neasuies ol the nagnituue ol the tieatnent ellect aie the uilleience in iesponse iate anu its iecipiocal, the NN¯. 1o,26,45 ¯he NN¯ iepiesents the nunhei ol patients one voulu neeu to tieat to achieve one auui- tional cuie. ¯he conhuence inteival pioviues a uselul neasuie ol the piecision ol the tieatnent ellect. 1o,26,45,61,62 ¯he calcula- tion anu inteipietation ol conhuence in- teivals have heen extensively uesciiheu. 6o ln sinple teins, the iepoiteu iesult (lnovn as the ¡oint cstimatc) pioviues the hest estinate ol the tieatnent ellect. Val- ues hecone less anu less lilely as they nove avay lion the iepoiteu iesult vithin the conhuence inteival. 1o,26,45 ¯he conhuence inteival pioviues a iange ol values in vhich the °population` oi tiue iesponse to tieatnent is lilely to lie. lxanples ol the application ol the concepts ol NN¯ anu conhuence intei- val aie given in a papei iuentiheu thiough a seaich ol the Cochiane Li- hiaiy that iepoiteu the iesults ol a ian- uonizeu contiolleu tiial conpaiing the use ol a placeho, acyclovii, pieunisone, anu acyclovii plus pieunisone in the tieatnent ol heipes zostei. 64 At uay oO ol the tiial, 48 ol 52 patents tieateu vith acyclovii expeiienceu total healing con- paieu vith 22 ol 52 patients vho ie- ceiveu a placeho. ¯he iesponse iates loi acyclovii anu placeho veie O.º2 anu O.42, iespectively, anu the uilleience in iesponse iates vas O.5. ¯he NN¯ vas 2 (1/O.5). ¯his iesult neans that loi eveiy tvo patients tieateu vith acyclovii in- steau ol placeho, one auuitional patient voulu shov total healing hy uay oO. ¯he º5 peicent conhuence inteival loi the uilleience in iesponse iates is O.o5 to O.65, anu the º5 peicent conhuence inteival loi the NN¯ is 2 to o. What uoes it actually nean that the conhuence inteival loi the uilleience in iesponse iates in the loiegoing exanple is O.o5 to O.65` ll the investigatois in this stuuy hau the oppoitunity to iepeat the stuuy nany tines using the sane uesign anu pioceuuies, sanpling vaii- ahility voulu pievent ohtaining the sane iesults in each stuuy. Repeateu tii- als veie sinulateu using iesanpling (ie- sanpling is a conputei-intensive nethou that uses the iepoiteu iesults ol a tiial to sinulate the iesults that voulu he oh- taineu il the tiial veie iepeateu a nun- hei ol tines). 45,65 ¯he iesults vhen the tiial vas iepeateu 1O anu 1OOO tines aie shovn in lig. 2-1A anu B, iespectively. A º5 peicent conhuence inteival ol O.o5 to O.65 neans that il the tiial is iepeateu nany tines anu a conhuence inteival is calculateu loi each tiial, the tiue iesult oi iesponse to tieatnent vill he in- cluueu in º5 peicent ol the conhuence inteivals so piouuceu. Alteinatively, il the tiial veie iepeateu nultiple tines, the iesults voulu lie vithin that inteival (O.o5 to O.65) º5 peicent ol the tine. ¯he population oi tiue iesponse to tieatnent vill nost lilely lie neai the niuule ol the conhuence inteival anu vill iaiely he lounu at oi neai the enus ol the inteival. ¯he population oi tiue iesponse to tieatnent has only a 1 in 2O chance ol heing outsiue ol the º5 pei- cent conhuence inteival. Unless a given patient is veiy uilleient lion the pa- tients incluueu in the stuuy, his oi hei iesponse vill nost lilely lie neai the niuule ol the conhuence inteival. ll the º5 peicent conhuence inteival ol the uil- leience in iesponse iates excluues zeio uilleience, one can ie|ect the null hy- pothesis that the tvo tieatnents aie the sane. 26,45,61,62 íisinteipieting tiials that lail to shov statistically signihcant uilleiences anong tieatnents is a connon eiioi in ueina- tologic clinical tiials. lt is inpoitant to ienenhei that °not statistically signih- cant` neans that a uilleience has a iea- sonahly high piohahility ol having heen uue to chance, it uoes not nean that theie is no uilleience oi that tieatnent is necessaiily inellective. o¯ Signihcant uilleiences in tieatnent ellects in con- paiison tiials nay he nisseu il the nun- hei ol suh|ects testeu is snall. loi exan- ple, in a 1º¯8 suivey ol ¯1 puhlisheu tiials vith negative iesults, lieinan et al. lounu that a 25 peicent oi 5O peicent inpiovenent in outcone night have heen nisseu in 5¯ (8O peicent) anu o4 (48 peicent) ol the stuuies, iespec- tively. 66 A lollov-up stuuy conuucteu hy íohei, Dulheig, anu Wells in 1ºº4 inui- cateu that a 25 peicent oi 5O peicent in- piovenent in outcone night have heen nisseu in 84 peicent anu 64 peicent, ie- spectively, ol 1O2 stuuies vith negative iesults. 6¯ ¯he sanple sizes ol nany uei- natologic tiials aie olten inaueguate to uetect clinically inpoitant uilleiences. ¯he acceptance ol a signihcance level ol .O5 as the cutoll loi ie|ecting the null hypothesis is a tiauition haseu on gual- ity contiol stanuaius anu is not an ahso- lute tiuth. At tines (e.g., vhen tieat- nents have suhstantial siue ellects) 16 noie stiingent stanuaius aie ieguiieu, anu paiauoxically, iesults that uo not neet the p = O.O5 stanuaiu sonetines nay he clinically signihcant. loi exan- ple, consiuei a hypothetical tiial ol a nev chenotheiapeutic agent involving oO patients vith netastatic nelanona ianuonly assigneu to tieatnent gioups that piouuceu a 5-yeai suivival iate ol ¯ ol 15 anong patients tieateu vith the nev agent anu o ol 15 anong contiol patients tieateu vith conventional sui- geiy, chenotheiapy, anu iauiation. Wheieas the iesult uoes not achieve sta- tistical signihcance vhen analyzeu hy chi sguaie testing (Yates coiiecteu chi sguaie = 1.o5, p = O.25), the iesult is nonetheless potentially signihcant. ll the theiapy is henehcial anu the estinateu uilleience in iesponse iates is the tiue uilleience in iesponse iates, it nay iesult in the saving ol 24OO lives annually (haseu on ¯2OO ueaths lion nelanona annually anu the inpiovenent in sui- vival in this hypothetical exanple). Be- cause ol the hiologic anu clinical inpoi- tance ol the iesults suggesteu hy the tiial, the tieatnent shoulu he investi- gateu in a stuuy that uses a laigei patient gioup anu has noie povei to uetect a signihcant uilleience il one exists. o¯ ¯he potential heneht ol the tieatnent nay he luithei ievealeu hy the use ol conhuence inteivals. ¯o ueteinine vhethei a tieatnent ellect nay have heen nisseu in a stuuy iepoiting nega- tive (not statistically signihcant) iesults, one shoulu lool at the uppei hounuaiy ol the º5 peicent conhuence inteival. ll this value voulu he clinically inpoitant il it veie the tiue iesponse, then an in- poitant tieatnent ellect nay have heen nisseu in the stuuy. Consiuei oui hypo- thetical nev tieatnent loi netastatic nelanona. ¯he cuie iates loi the nev tieatnent anu the conventional tieat- nent veie 4¯ peicent anu 2O peicent, iespectively, anu the uilleience hetveen then vas thus 2¯ peicent. ¯he º5 pei- cent conhuence inteival loi the uillei- ence in cuie iates vas 1O peicent to 51 peicent. ¯he uppei hounuaiy ol the uil- leience in cuie iates vas 51 peicent. ¯his uilleience voulu cleaily have a sig- nihcant inpact on the tieatnent ol pa- tients vith netastatic nelanona (the NN¯ is 2!), anu theieloie a signihcant tieatnent auvance nay have heen nisseu in this stuuy. Also note that the º5 peicent conhuence inteival ol the uil- leience in cuie iates incluues zeio uil- leience, theieloie, ve cannot concluue vith a high uegiee ol conhuence that the iesponse iates ol the tvo tieatnents aie uilleient. Hovevei, vhen zeio is in- cluueu as one ol the values in the conh- uence inteival, the inleience that the theiapy is not elhcacious lails to con- siuei the lact that the hest estinate ol ellect is the point estinate (e.g., the oh- seiveu uilleience in cuie iates ol 2¯ pei- cent in oui hypothetical exanple). 68 ln othei voius, the values containeu in the conhuence inteival aie not egually lilely anu hecone less anu less lilely as they nove avay lion the point estinate. ¯hus, in the exanple, a uilleience ol 25 peicent (close to the ohseiveu 2¯ pei- cent) is nuch noie lilely than a uillei- ence ol 5 peicent (lai lion the oh- seiveu 2¯ peicent). o¯ E.|derce A|cu| D|açrcº||c Teº|º ¯o he valiu, stuuies ol uiagnostic tests shoulu incluue hlinu conpaiison vith a ciiteiion (golu) stanuaiu, evaluation in an appiopiiate spectiun ol patients, anu consistent application ol the ciite- iion stanuaiu. lev stuuies in ueinatol- ogy neet these ciiteiia. lnpoitant teins anu concepts that nust he unueistoou to ueteinine vhethei the iesults ol a papei exanining a uiag- nostic test aie clinically inpoitant in- cluue the lolloving: º Lilelihoou iatio º lie-test piohahility º lost-test piohahility º ¯hiesholu loi action ¯he lilelihoou iatio is the peicentage ol people vith the given uisease loi vhon the test iesult is positive uiviueu F|608£ 2-1 || ||e ac]c|c.|| |||a| We|e |epea|ed 10 (A, c| 1000 (8, ||reº, ||e |eºu||º |r A ard 8, |e- ºpec||.e|], r|ç|| |e c||a|red. C| = ccr|derce |r|e|.a|. 20 15 10 5 0 0.1 0.2 0.8 0.4 0.5 0.O 0.7 0.8 0.9 Differeuce iu respouse rates 800 200 100 0 0.1 0.2 0.8 0.4 0.5 0.O 0.7 0.8 0.9 Differeuce iu respouse rates 95° 0l A 8 A 8 17 hy the peicentage ol people vho uo not have the uisease loi vhon the test ie- sult is positive. 45 ¯he lilelihoou iatio is tiauitionally taught as the sensitivity ui- viueu hy 1 ninus the specihcity |lileli- hoou iatio = sensitivity/(1 specihcity)] anu pioviues an estination ol hov nuch highei the lilelihoou ol the uis- ease is, given a positive test iesult (post- test piohahility), conpaieu vith the piohahility heloie the test is uone (pie- test piohahility). 1o,26 An iueal test is one that vill alnost alvays yielu positive iesults vhen the uisease is piesent anu negative iesults vhen the uisease is ah- sent. ¯hus, it is one vith a high sensitiv- ity anu specihcity. Such a test vill have a veiy high lilelihoou iatio. loi the lilelihoou iatio to he uselul, one nust have an iuea ol hov lilely it is that the uisease is piesent heloie the test is uone (i.e., the pie-test piohahil- ity) anu a sense ol hov ceitain one neeus to he to concluue that the patient has the uisease anu to act on this inloi- nation (i.e., the thiesholu loi ac- tion). 45,6º ¯he pie-test piohahility is ue- teinineu lion availahle puhlisheu uata oi haseu on physician expeiience anu |uugnent. 26,45 Cnce the pie-test pioha- hility is lnovn oi estinateu anu the lilelihoou iatio is ueteinineu, a nono- gian can he useu to estinate the post- test piohahility (lig. 2-2). 26 ll a nonogian is not availahle, the calculations can he uone nanually, hut conveision ol piohahilities to ouus is ie- guiieu. ¯he ouus ol uisease is uehneu as the piohahility ol uisease uiviueu hy 1 ninus the piohahility |ouus = piohahil- ity/(1 piohahility)]. loi a uehneu gioup ol inuiviuuals oi patients, it can also he calculateu as the iatio ol the nunhei ol those vith uisease to those vithout uis- ease. ¯hus, il the piohahility (piopoi- tion) ol a uisease is O.2O (2O peicent), the ouus ol that uisease aie O.2O/(1 O.2O), oi O.2O/O.8O, oi 1:4. ¯his iesult neans that loi eveiy peison vith the uisease, theie aie loui people vithout the uisease. ¯he post-test ouus aie egual to the pie-test ouus tines the lilelihoou iatio (post-test ouus = pie-test ouus  lilelihoou iatio). 26 ¯he loinula |pioha- hility = ouus/(ouus + 1)] is useu to con- veit ouus hacl to piohahility. Whethei loinally oi inloinally, phy- sicians uevelop thiesholus ol ceitainty at oi ahove vhich they aie conloitahle vith estahlishing a uiagnosis anu acting on the uiagnoses. Action nay tale the loin ol connunicating the uiagnosis oi piognosis to the patient, piesciihing tieatnent, oi ieleiiing the patient. When histoiical anu physical eviuence leaus a clinician to suspect a uiagnosis hut the uegiee ol ceitainty uoes not exceeu the thiesholu loi estahlishing a uiagnosis, a test is peiloineu to iaise the piohahility that the uisease is piesent ahove the cli- nician`s thiesholu loi action. 6º E.|derce A|cu| Ha|r ¯o he valiu, stuuies ahout the hainlul ellects ol exposuies shoulu incluue co- hoits vith conpaiahle gioups ol ex- poseu anu unexposeu inuiviuuals, oi cases anu contiols, oh|ective outcone neasuies, anu aueguate lollov-up. ln auuition, the iesults shoulu nale clini- cal anu hiologic sense. 1o,26 lev ueina- tologic stuuies neet these ciiteiia. lnpoitant teins anu concepts that nust he unueistoou to ueteinine vhethei the iesults ol a papei ahout hainlul ellects ol exposuies aie clini- cally inpoitant incluue the lolloving: º Case-contiol anu cohoit stuuies º Risl iatio º Cuus iatio ln a cohoit stuuy a gioup ol inuiviuu- als vho aie exposeu to an agent is con- paieu vith an appiopiiately selecteu unexposeu contiol gioup anu hoth gioups aie lolloveu until an event ol in- teiest occuis oi loi a pie-speciheu length ol tine. ¯he association hetveen exposuie anu the hainlul outcone is expiesseu as the ielative iisl (see ¯ahle 2-5 loi ielative iisl calculations). A iela- tive iisl ol 1 inplies no association. ll the ielative iisl is gieatei than 1, then the iesult inplies a positive association hetveen exposuie anu the hainlul out- cone. ll it is less than 1, then the inpli- cation is ol an inveise association. Hov- evei, to inlei a causal association iehecteu hy eithei an inciease in iisl (ielative iisl ol noie than 1) oi a piotec- tive ellect (ielative iisl less than 1), one nust evaluate the valiuity anu piecision ol the ielative iisl estinate. ¯he pieci- sion can he ieauily assesseu hy neans ol the º5 peicent conhuence inteival. A conhuence inteival that uoes not in- cluue 1.O uenotes a statistically signih- cant association. Because the nost lilely iesult ol a stuuy is the point esti- nate (i.e., the iepoiteu iesult), the oh- seiveu association (expiesseu hy the point estinate) nay he causal, even il the conhuence inteival incluues 1.O as a iesult ol a snall sanple size. 1o,26 Case-contiol stuuies aie useu vhen the hau outcone is iecognizeu anu the causative agent is not yet uiscoveieu. ¯hey aie also useu vhen theie is a veiy long tine lag hetveen exposuie anu outcone oi vhen the lieguency ol au- veise events is veiy snall. ln a case- contiol stuuy, patients vith a uisease ol inteiest aie conpaieu vith appiopiiately selecteu contiols. ¯he ouus ol exposuie to suspecteu etiologic agents aie ascei- taineu in cases anu in contiols (see ¯ahle 2-5). Recall that the ouus ol an event aie calculateu as the iatio ol the nunhei ol events to the nunhei ol non-events. ¯O lvents aie exposuies to potentially hainlul iisl lactois in case-contiol stuu- ies. ¯he ouus ol exposuie anong cases aie uiviueu hy the ouus ol exposuie anong contiols to ueiive the ouus iatio, vhich is a goou estinate ol the ielative iisl vhen the outcone (e.g., uisease, ueath) is ielatively iaie (i.e., vhen it oc- cuis in levei than 5 peicent ol exposeu suh|ects). ¯he association hetveen ex- F|608£ 2-2 \crcç|ar |c| de|e|r|r|rç ||e pcº|-|eº| p|c|a|||||]. Tc de|e|r|re ||e pcº|-|eº| p|c|a|||||], d|aW a º||a|ç|| ||re |||cuç| ||e p|e- |eº| p|c|a|||||] ard ||e |||e|||ccd |a||c ard |ead ||e pcº|-|eº| p|c|a|||||] cr ||e ||ç||. .1 .2 .5 1 2 5 10 20 80 40 50 O0 70 80 90 95 99 1000 500 200 100 50 20 10 5 2 1 .5 .2 .1 .05 .02 .01 .005 .002 .001 Pretest prooaoilit] likelihood ratio Posttest prooaoilit] 99 95 90 80 70 O0 50 40 80 20 10 5 2 1 .5 .2 .1 18 posuie anu outcone is expiesseu as the ouus iatio in case-contiol stuuies. An ouus iatio ol 1 inplies no association. ll the ouus iatio is highei than 1, then the iesult inplies a positive association he- tveen exposuie anu the hainlul out- cone. ll the ouus iatio is less than 1, then the iesult inplies a piotective el- lect ol the exposuie. 1o,26 As noteu eai- liei, it is inpoitant to evaluate the valiu- ity anu piecision ol the ouus iatio estinate hy exanining the º5 peicent conhuence inteival. loi exanple, suppose a case-contiol stuuy vas peiloineu to stuuy the iela- tionship hetveen linh ueloinity anu exposuie to thaliuoniue. ¯he iesults ol the stuuy inuicateu that patients vith linh ueloinities veie noie lilely than contiols to have heen exposeu to thaliu- oniue in uteio. ¯he ouus iatio loi tha- liuoniue exposuie vas o.5 anu the con- huence inteival vas lion 1.8 to 6.6. ¯hus the ouus that patients vith linh ueloinities veie exposeu to thaliuo- niue in uteio veie o.5 tines the ouus ol thaliuoniue exposuie in contiols. Be- cause the ouus iatio is gieatei than 1 anu its º5 peicent conhuence inteival uoes not incluue 1, the iesult inplies a positive association hetveen thaliuo- niue use anu linh ueloinities not lilely to have heen uue to ianuon eiioi. ¯hese iesults (an ouus iatio ol o.5 anu conhuence inteival ol 1.8 to 6.6) veie actually the hnuings ol a stuuy hy Woll et al., vho stuuieu the ielationship he- tveen sunscieen use anu nelanona in a case-contiol stuuy in Austiia. ¯1 ¯heii ie- sults inuicateu that patients vith nela- nona veie noie lilely than contiols to have useu sunscieen olten. ¯o inlei cau- sality it is inpoitant to assess vhethei the iesults coulu have occuiieu lion hias anu vhethei the iesults aie hiologi- cally plausihle. ¯o auu conlusion to an alieauy uilh- cult aiea, clinical ieseaicheis vill olten iepoit iesults ol neta-analyses, cohoit stuuies, anu ianuonizeu contiolleu tiials using ouus iatios. Cuus iatios aie useu hecause they have stiongei statistical piopeities than othei neasuies. ¯O loi ex- anple, ouus iatios can tale any value he- tveen O anu inhnity, aie synnetiic in a log scale, anu can he useu to nale au- |ustnents loi conlounuing lactois us- ing nultiple iegiession. ¯O Unloitunately, they aie the neasuie ol association least intuitively unueistoou. ll a neta-analy- sis, contiolleu tiial, oi cohoit stuuy is ie- poiteu using ouus iatios, the ielative iisl, uilleience in iesponse iates, oi NN¯ can olten he calculateu il the piinaiy uata aie pioviueu. Alteinatively, these noie ieauily unueistanuahle neasuies can he ueiiveu il the nunhei ol suh|ects in each gioup, ouus iatio, anu oveiall event iate aie pioviueu. APP|\|\0 EV|DE\CE T0 SPEC|||C PAT|E\TS Applying the eviuence to tieatnent ol specihc patients involves ueteinining vhethei the eviuence lion stuuies is ap- plicahle to a given patient. ¯his uecision is haseu on the patient`s conuition anu val- ues. lt involves asling a seiies ol gues- tions that aie specihc to the type ol evi- uence heing consiueieu (see ¯ahles 2-o, 2-4, anu 2-5). When laceu vith the tasl ol ueteinining vhethei the iesults ol a paiticulai stuuy aie applicahle to specihc patients, physicians shoulu ueteinine vhethei theie aie any conpelling ieasons that the iesult shoulu not he applieu. o¯ Applying eviuence to specihc patients al- vays involves physician |uugnent. SAV|\0 THE CR|T|CA| APPRA|SA| 0| THE EV|DE\CE Cnce the physician has naue the elloit to asl a clinical guestion, hnu the hest eviuence, anu ciitically appiaise it, the physician shoulu save the analysis in a place anu loinat that allovs it to he easily ietiievahle loi lutuie use. Woil- sheets loi iecoiuing eviuence lion pa- peis uealing vith uiagnosis, theiapy anu pievention, piognosis, anu hain aie availahle (http://vvv.cehn.utoionto.ca/ teach/nateiials/cavoilsheets.htn). 26 ¯hese voilsheets can he saveu elec- tionically oi hleu physically. |E\ RE|ERE\CES T|e |u|| |e|e|erce ||º| |c| a|| c|ap|e|º |º a.a||a||e a| WWW.d|çr/.ccr. 2. Saclett DL et al: lviuence haseu neui- cine: What it is anu vhat it isn`t. 3/j :¯1, 1ºº6 6. Cochiane A: ljjc.tivcncss and ljµ.icn.,. Lonuon, Royal Society ol íeuicine liess Ltu, 1ººº ¯. Saclett DL et al: C|ini.a| l¡idcmio|og,: A 3asi. :.icn.c jor C|ini.a| /cdi.inc. Bos- ton, Little, Biovn anu Conpany, 1ºº1, p 441 1o. Cieenhalgh ¯: Hov to Rcad a la¡cr: Thc 3asi.s oj lvidcn.c 3ascd /cdi.inc. Lon- uon, Bí[ luhlishing Cioup, 1ºº¯, http:// vvv.health.lihiaiy.ncgill.ca/ehn/ gieenhalgh.htn, accesseu Apiil 2, 2OO¯ 26. Saclett D et al: lvidcn.c-3ascd /cdi.inc: Hov to lra.ti.c and Tca.h l3/. luin- huigh, Chuichill Livingstone, 1ºº6, p 25O o¯. Bighy í, Cauenne A-S: Unueistanuing anu evaluating clinical tiials. j Am A.ad Dcrmato| :555, 1ºº6 oº. Nishett R, Ross L: Human lnjcrcn.c: :tratcgics and :hort.omings oj :o.ia| judg- mcnt. lnglevoou Clills, N[, lientice- Hall, 1º8O, p ooO 4º. luhíeu clinical gueiies using ieseaich nethouology hlteis, http://vvv.nchi. nln.nih.gov/entiez/gueiy/static/clinical. shtnl, accesseu [anuaiy 2OO5 52. Higgins [l¯, Cieen S, eus.: Cochiane hanuhool loi systenatic ievievs ol intei- ventions 4.2.6 |upuateu Septenhei 2OO6], http://vvv.cochiane.oig/iesouices/ hanuhool/hhool.htn, accesseu íaich 2º, 2OO¯ 6o. Caiunei í[, Altnan DC, euitois: :tatis- ti.s vith Conµdcn.c. 2nu eu. Lonuon, Biitish íeuical [ouinal, 2OO5 C H A P T E R 8 P0b||c hea|th |o 0ermato|ogy H]We| C. w||||arº S|read |arçar Ca|º|er ||c|| wHAT |S PUB||C HEA|TH |ED|C|\E A|| AB0UT´ De|r|||cr ¯he Woilu Health Ciganization uehnes health as °a state ol conplete physical, nental anu social vell-heing anu not neiely the ahsence ol uisease oi inhi- nity.` 1 ¯he ley nessage ol this uehni- tion is that health is a holistic neasuie that is inhuenceu hy socioecononic lac- tois anu ineguality. luhlic health is a uiscipline in vhich the level ol locus is on the health ol populations as opposeu to that ol inuiviuuals, as is the case in clinical neuicine. A uselul uehnition ol puhlic health is as lollovs: lu||i. hca|th is thc s.icn.c and thc art oj ¡rcvcnting discasc. ¡ro|onging |ijc. and ¡romoting ¡h,si.a| hca|th and mcnta| hca|th and cjµ.icn., through organi:cd .ommunit, cjjorts 19 tovard a sanitar, cnvironmcnt. thc .ontro| oj .ommunit, injc.tions. thc cdu.ation oj thc individua| in ¡rin.i- ¡|cs oj ¡crsona| h,gicnc. thc organi- :ation oj mcdi.a| and nursing scrvi.c jor thc car|, diagnosis and trcatmcnt oj discasc and thc dcvc|o¡mcnt oj thc so.ia| ma.hincr, to cnsurc to cvcr, individua| in thc .ommunit, a stan- dard oj |iving adcquatc jor thc main- tcnan.c oj hca|th. ` ¯his uehnition aiticulates sone ol the ioles ol puhlic health piactitioneis in iela- tion to society anu health. lt also high- lights the loui ley aieas ol puhlic health action: (1) pieventing uisease anu pionot- ing health, (2) inpioving neuical caie, (o) pionoting health-enhancing hehavioi, anu (4) nouilying the enviionnent. o H|º|c||ca| Pe|ºpec||.eº luhlic health has playeu a ley iole in the pievention anu tieatnent ol ueinatologic uiseases. Cne ol the hist histoiical exan- ples is scuivy. ln 1¯46, [anes Linu uiscov- eieu thiough ohseivation, analysis, anu peiloinance ol a contiolleu tiial that scuivy in sailois vas a uietaiy uisease that coulu he cuieu hy auninistiation ol oi- anges anu lenons 5 (see eligs. o-O.1 anu o-O.2 in on-line euition). Linu`s tieatise pieceueu the uiscoveiy ol vitanin C hy noie than a centuiy. ln 1¯¯5, leicivall lott vas the hist to uesciihe an occupa- tionally inuuceu cancei hy noting that the noitality lion sciotal cancei vas 2OO tines highei in chinney sveeps than in othei voileis. 6 He attiihuteu the excess noitality to tai anu soot exposuie in con- hination vith pooi peisonal hygiene. ¯he hist caicinogenic polycyclic aionatic hy- uiocaihon vas not uiscoveieu until 1ºoo. ln the eaily tventieth centuiy, pellagia vas a na|oi puhlic health piohlen (see elig. o-O.o in on-line euition). ¯heie veie 1OO,OOO ueaths lion the uisease in a 4O- yeai peiiou anu ovei o nillion sulleieis in the Uniteu States at that tine. ln 1º14 Di. [oseph Coluheigei noticeu that innates at the Ceoigia State Sanatoiiun uevelopeu high iates ol pellagia vheieas the nuises anu attenuants uiu not, anu concluueu that the oiigin ol pellagia vas piohahly a uisease causeu hy a uietaiy uehciency. He conhineu his hypothesis vith contiolleu clinical tiials. ¯ ¯he uehcient uietaiy lactoi, niacin, vas uiscoveieu in 1ºo¯. Collectively these exanples illustiate the inpoitance ol puhlic health in the pievention ol uisease. ¯hese exanples also highlight the lact that lnovleuge ol uisease pathophysiology (i.e., necha- nisns) is not alvays a pieieguisite to ueteinining the cause oi iisl lactois loi a uisease anu the potential loi ellective puhlic health inteiventions. H|0H-R|S| A\D |0w-R|S| APPR0ACHES T0 PUB||C HEA|TH ¯iauitionally, ueinatology, lile othei hianches ol specialist neuicine, has con- centiateu on the tieatnent ol those vho have lallen ill oi those vho helieve they aie ill oi at high iisl ol ueveloping uisease. loi instance, ve piesciihe topical coitico- steioius loi those vith atopic ueinatitis anu ve nay give auvice on sun piotection to patients vho pieviously hau a nalig- nant nelanona. We nay see such nela- nona patients on a iegulai hasis in slin cancei lollov-up clinics to nonitoi tieat- nent success anu to he ahle to uetect ie- cuiiences oi nev eaily seconu nelano- nas. Doctois anu patients alile tenu to he highly notivateu vhen such an appioach is useu. ¯he potential henehts seen ohvi- ous, anu although theie nay he siue el- lects associateu vith the piesciiheu tieat- nent, such as slin thinning vith piolongeu use ol topical coiticosteioius, oi a scai lion excision ol a nelanona, nany patients vill accept such iisls, he- cause appiopiiate tieatnent leaus to a sig- nihcant inpiovenent ol synptons anu inpioveu guality ol lile oi suivival. Such an appioach to taclling uisease has olten heen ieleiieu to in the liteiatuie as the high-risk appioach, hecause it locuses on the tieatnent anu uetection ol those at high iisl ol ueveloping uisease anu those vho have alieauy lallen ill. 8 ln contiast to the high-iisl appioach, the ultinate ain ol puhlic health neui- cine anu puhlic health ueinatology is to pievent the uevelopnent ol uisease in the hist place vhenevei possihle, not only hy loiestalling it in those iuentiheu as heing at high iisl (e.g., hecause ol a stiong lan- ily histoiy), hut hy shilting the entiie uis- tiihution ol a ceitain exposuie in a health- iei uiiection loi the vhole population (population stiategy). Such a lov-iisl ap- pioach can he inplenenteu thiough laige-scale puhlic health euucation canpaigns aineu at lunuanentally changing the entiie population`s he- havioi anu l ilestyl e. loi exanpl e, haseu on the uata ol the lianinghan stuuy one can extiapolate that a ieuuc- tion ol eveiyhouy`s hloou piessuie hy 1O nn Hg voulu iesult in an oveiall ieuuction in noitality lion heait uis- ease ol aiounu oO peicent. 8 ln ueina- tology, a goou exanple ol a such a pop- ulation stiategy is attenpts to change the geneial population`s sun exposuie hehavioi to ieuuce exposuie to ultiavi- olet light anu ultinately slin cancei in- ciuence anu noitality thiough puhlic health euucation canpaigns that aie national (e.g., Austialia) oi inteina- tional (e.g., the Woilu Health Cigani- zation`s lN¯lRSUN piogian, http:// vvv.vho.int/uv/inteisunpiogianne/ en/) in scope (lig. o-1). ¯his nales sense paiticulaily in a countiy lile Austialia, he- cause a stiong association hetveen ultia- PUB||C HEA|TH |\ DER|AT0|00\ AT A 0|A\CE Pu|||c |ea||| de|ra|c|cç] |º a|cu| p|c- rc||rç º||r |ea||| ard rc| juº| ||ea||rç º||r d|ºeaºe. Deºp||e º||crç ||º|c||ca| c||ç|rº, rcde|r pu|||c |ea||| de|ra|c|cç] |º º|||| |e|a||.e|] urde|de.e|cped. Dcc|c|º car dc a |c| |c |e|p |rd|.|dua| pa||er|º |u| |a.e |||||e |r1uerce cr ||e |ea||| c| er|||e pcpu|a||crº. Ccr.e|ºe|], ||e |rpac| c| |a|çe pcpu|a- ||cr |ere||º a|e |a|e|] app|ec|a|ed |] |rd|.|dua|º. P|e.er||cr |º c||er rc|e |cç|ca| ||ar ||ea||rç º|c| |rd|.|dua|º W|c ccre |c| red|ca| ca|e. Scre||reº a '|cW-||º|' app|cac| c| |educ- |rç ||º| |c| d|ºeaºeº ºuc| aº re|arcra |r ||e er|||e pcpu|a||cr car ac||e.e rc|e ||ar a '||ç|-||º|' app|cac| c| |a|çe||rç juº| ||cºe W|c |a.e º||r carce| c| W|c a|e a| ||ç| ||º| c| de.e|cp|rç º||r carce|. w|er er|||e pcpu|a||crº a|e ccrº|de|ed, a |||||e ||| c| |a|r a||ec||rç a |c| c| pecp|e car add up |c rc|e ||ar a |c| c| |a|r a||ec||rç a |eW pecp|e |r a|ºc|u|e |e|rº. |cde|r pu|||c |ea||| de|ra|c|cç] |aº |ad ºcre ºucceºº |r |educ||cr c| º||r carce| |rc|derce ard ccr||c| c| |r|ec||cuº d|ºeaºeº. Scre||reº, |cW-|ec|rc|cç] educa||cra| |r|e|.er||crº d||ec|ed a| er|||e ccrrur|- ||eº car |eºu|| |r rc|e |ere|| ||ar ||ç|- |ec|rc|cç] d|uçº |a|çe|ed a| a |eW ||| |rd|.|dua|º. 20 violet iauiation anu nelanocytic anu non- nelanocytic slin cancei is vell estah- lisheu, anu such iisl is uistiihuteu viuely thiough the pieuoninantly laii-slinneu population. Slin cancei is an inpoitant cause ol ueath, anu tieatnents loi all loins ol slin cancei pose an inpoitant huiuen on nany countiies` health caie ie- souices. Sinple neasuies, such as avoiu- ing sun exposuie uuiing peal houis ol ia- uiation anu veaiing suitahle clothing, can pioviue aueguate piotection. ¯he state ol Victoiia, Austialia, has the nost conpie- hensive population-haseu piinaiy pie- vention canpaign against slin cancei in the voilu (SunSnait canpaign, http:// vvv.sunsnait.con.au/), anu it has heen iepoiteu that this piogian`s puhlic in- vestnent vas voithvhile. Not only has it iesulteu in a signihcant ieuuction in slin cancei inciuence anu noitality, hut the ietuins lion savings on slin cancei tieatnents have also exceeueu the oveiall costs ol the SunSnait canpaign. º lt nay seen ohvious that upstiean pievention is noie uesiiahle than tieating sicl inuiviuuals vho cone loi tieatnent uovnstiean altei a long chain ol patho- logic events, sone ol vhich nay he iiie- veisihle. lunuing population pievention stiategies nay he uilhcult, yet the vhole population vill potentially heneht, as long as such inteiventions aie eviuence haseu anu sustainahle. Hovevei, it is geneially noie uilhcult to peisuaue healthy inuiviu- uals to piotect thenselves against pio- longeu sun exposuie than to peisuaue those vho have alieauy hau a nalignant nelanona exciseu. lt is also voith point- ing out that although a puhlic health intei- vention such as vaccination against nea- sles has uianatically ieuuceu the inciuence ol uisease at a population level, it is inpossihle to say vhich inuiviuuals have heen helpeu hy such a population in- teiventiona phenonenon lnovn as the ¡rcvcntion ¡aradox. A population stiategy is not suitahle loi tiying to contiol all slin uiseases at piesent, hecause such a stiategy uepenus on lnovleuge ol nouihahle iisl lactois. ln the nany cases loi vhich exposuies that pieuispose to a paiticulai slin conui- tion aie unlnovn, pievention thiough avoiuance is not possihle, anu the only option availahle is tieatnent ol uisease iathei than piinaiy uisease pievention. A |0T 0| HAR| A||ECT|\0 A |Ew PE0P|E VERSUS A B|T 0| HAR| A||ECT|\0 |A\\ íaling the conceptual |unp lion thinl- ing ahout inuiviuual patients to thinling ahout entiie populations can he chal- lenging loi piacticing ueinatologists, es- pecially hecause such |unps can cone up vith sone suipiising iesults. loi ex- anple, a ueinatologist vith an inteiest in contact ueinatitis night see a case ol seveie hanu ueinatitis in a piintei causeu hy alleigic contact ueinatitis lion a chenical anu then puhlicize such a case in a iespecteu |ouinal. 1O Anothei ueinatologist ieauing such a case iepoit night cone to the conclusion that allei- gic contact ueinatitis is an inpoitant cause ol hanu ueinatitis in piinteis. Yet vhen this ueinatologist visits the voil- place to conuuct a suivey ol all cases ol hanu eczena in piinteis, it hecones ap- paient that tiue alleigic contact ueinati- tis is piohahly guite iaie, anu hy lai the nost connon cause ol hanu eczena is constant lov-giaue exposuie to soap anu vatei lion iepeateu vashing anu liiction lion papei anu uiit. 11 ¯hus, it is possihle that a little hit ol hain allecting a lot ol inuiviuuals can auu up to nuch noie in ahsolute teins (the iealn ol the puhlic health/occupational health physi- cian) than a lot ol hain allecting one oi tvo voileis (the iealn ol the ueinatol- ogist). Anothei vell-lnovn exanple ol such a phenonenon is the ellects ol snoling on ieuuction in caiuiovasculai uisease. lven though the association he- tveen tohacco snoling anu lung cancei (ielative iisl ol 14.O) is nuch stiongei than that hetveen snoling anu caiuio- vasculai uisease (ielative iisl, 1.6), stiat- egies loi snoling cessation save aiounu tvice as nany lives lion caiuiovasculai uisease than lion lung cancei sinply he- cause heait uisease is nuch noie con- non than lung cancei. 12 lion a puhlic health peispective, theieloie, the popu- lation-attiihutahle iisl (the piopoition ol the uisease that nay he attiihutahle to a paiticulai iisl lactoi) is noie inpoitant than othei tiauitional neasuies ol iisl, such as the ielative iisl (vhose nagni- tuue nay tell us sonething ahout the stiength ol a paiticulai association). ln a stuuy ol iisl lactois loi psoiiasis in ltaly, Nalui et al. lounu that snoling ac- counteu loi up to 26 peicent ol all cases. ln inuiviuuals vith psoiiasis vho snoleu vho also hau a lanily histoiy ol psoiiasis, an incieaseu houy nass in- uex night account loi up to 48 peicent ol uisease. 1o ¯he lact that snoling anu ohesity aie nouihahle iisl lactois sug- gests that psoiiasis is pieventahle, at least to sone uegiee, in this population. PUB||C HEA|TH APPR0ACH |\ ACT|0\ |\ DER|AT0|00\ So lai, ve have illustiateu the puhlic health appioach in ueinatology using nainly histoiical exanples. Yet although cuiient ueinatologic ieseaich is still iela- tively uoninateu hy the puisuit ol stuu- ies in vhich the unit ol analysis is at a cellulai oi suh-cellulai level, theie aie sone goou exanples ol puhlic health ueinatology in action. Cne ol the classic stuuies illustiating the puhlic health appioach in action loi inlectious slin uisease vas that con- uucteu hy ¯aplin anu colleagues con- ceining scahies anong luna lnuians on the San Blas Aichipelago. 14 ¯hese is- lanus oll the coast ol lanana veie plagueu hy veiy high iates ol scahies in chiluien in the 1º8Os, vhich leu to nis- eiy anu seconuaiy hacteiial inlections. Despite the use ol the hest tieatnents availahle to conhat the piohlen, the population huiuen ol scahies ienaineu laigely unchangeu. Cnly altei the auop- tion ol a puhlic health appioach in vhich eveiyone in uehneu aieas vas F|608£ 3-1 D|º||||u||cr c| u|||a.|c|e| (UV, |ad|a||cr e/pcºu|e |e|c|e (sc!ic !irc, ard a||e| (casIcc !irc, |rp|erer|a||cr c| a pcpu|a||cr º||a|eç] |c |educe pe|ºcra| UV |ad|a||cr e/pcºu|e. 80 20 0 Persoual UV radiatiou exposure 21 tieateu uiu the pievalence ol scahies lall uianatically lion appioxinately oo peicent to appioxinately 1 peicent. Sinilai uianatic uecieases in scahies pievalence (lion 25 peicent to 1 pei- cent) anu in associateu pyoueina anu possihly post-stieptococcal nephiitis have heen ohseiveu thiough the use ol pop- ulation-haseu tieatnent vith iveinec- tin in the Solonon lslanus. 15 Anothei exanple is the Clohal Alliance to llin- inate Lynphatic lilaiiasis (http:// vvv.hlaiiasis.oig/), an alliance hetveen the Woilu Health Ciganization, ninistiies ol health, anu the piivate sectoi aineu at the voiluviue eiauication ol this uevas- tating uisease. ¯he Clohal Alliance to llininate Lynphatic lilaiiasis canpaign is one ol the nost iapiuly expanuing puhlic health piogians in histoiy anu hau iegu- laily tieateu 25 nillion people in 12 coun- tiies hy 2OOO anu 25O nillion in oº coun- tiies hy 2OO4. lt is not iestiicteu to nass tieatnent vith antihlaiial uiugs hut also incluues puhlic health euucation anu au- vice on slin caie ol lynpheuenatous legs to pievent luithei noihiuity. luhlic health inteiventions aie not ie- stiicteu to auninistiation ol phainaceu- tical uiugs hut can also incluue euuca- tional inteiventions such as the puhlic euucation canpaigns loi ieuucing slin cancei thiough ieuuction in ultiaviolet light exposuie. Cne such successlul pio- gian has heen the intiouuction ol hasic ueinatologic caie in íali thiough the uevelopnent ol a tiaining piogian loi geneial health caie voileis on the nan- agenent ol connon slin uiseases. 16 ¯he piopoition ol patients vith slin uisease vith a cleai uiagnosis anu appiopiiate ui- agnosis incieaseu lion 42 peicent heloie the tiaining to 81 peicent altei it. Al- though such uianatic ellects night he oveiestinateu in a sinple heloie-anu- altei stuuy, the ellects veie sustaineu loi up to 18 nonths altei tiaining. laiauoxi- cally, these inpiovenents in caie veie associateu vith a 25 peicent ieuuction in piesciiption costs, vhich suggests that inappiopiiate enpiiical piesciihing vas a souice ol unnecessaiy expenuituie he- loie the tiaining. Cthei ieseaicheis have also uocunenteu hov scaice lanily in- cone can he vasteu on inappiopiiate tieatnent loi slin uiseases such as pyoueina anu scahies in íexico. 1¯ Ryan has uesciiheu the iole ol euuca- tional clinics in the pievention ol slin canceis as vell as the nanagenent ol eaily lesions in the alhino population ol 1¯O,OOO in ¯anzania. 18 Although nany puhlic health intei- ventions nay not sounu as °high tech` as uiugs taigeteu at specihc hiologic ie- ceptois, they nay he noie ellective anu appiopiiate loi sicl populations. ¯he concept that a little hit ol hain allecting a lot ol people can auu up to noie than a lot ol hain allecting a lev people vas uevelopeu eailiei, hut a sinilai naxin also holus tiue: sonetines a lov-tech- nology henehcial inteivention that can he applieu to a laige population can auu up to lai gieatei heneht in population teins than a high-technology solution that vill heneht only a lev. |UTURE 0| PUB||C HEA|TH |\ DER|AT0|00\ Sone ueinatologists have alieauy con- uucteu a population-haseu neeus assess- nent loi ueinatologic caie, lolloveu hy oiganization ol the appiopiiate seivices at a population level, iathei than |ust vieving the voilu ol slin uisease lion vithin the naiiov conhnes ol a hospi- tal-haseu piactice. ¯heie aie also in- cieasing inteinational collahoiations to tiy to pievent anu ieuuce the huiuen ol slin uiseases at a glohal level thiough health caie planning anu locuseu intei- ventions. ¯hese aie caiiieu out thiough oiganizations such as the lnteinational lounuation loi Deinatology (http:// vvv.ilu.oig/) in con|unction vith the lnteinational League ol Deinatological Societies (http://veh.ilus.oig/). ¯he ln- teinational League ol Deinatological Societies is voiling to inpiove con- nunity ueinatologic piogians in uevel- oping countiies, locusing on hettei uiag- nosis anu cleai eviuence-haseu guiuance loi the nanagenent ol connon ueina- toses. ¯iaining couises have heen estah- lisheu, such as those at the Regional Deinatology ¯iaining Centie in íoshi, ¯anzania (http://vvv.glohal-canpus. oig/iutc) anu shoit couises in Cueiieio, íexico anu íali. Cne ol the ley ains ol these piogians is to euucate at the piinaiy caie level vith the iuea that the tiainees vill then nultiply such lnovl- euge hy tiaining otheis in theii ovn countiies. As Weinstocl points out in Chaptei 1, the huiuen ol slin uiseases is high. íany slin uiseases can alieauy heneht lion a puhlic health appioach. What is neeueu to ieuiess the ielative paucity ol puhlic health ueinatology is to unueistanu the concept that popula- tions aie as inpoitant as inuiviuuals anu to huilu on the soit ol collahoiation chanpioneu hy the lnteinational loun- uation loi Deinatology. |E\ RE|ERE\CES T|e |u|| |e|e|erce ||º| |c| a|| c|ap|e|º |º a.a||a||e a| WWW.d|çr/.ccr. 2. Winslov ClA: ¯he untilleu helu ol puhlic health. /od /cd :18o, 1º2O ¯. Coluheigei [, Wheelei CA, Synuen- stiiclei l: A stuuy ol the uiet ol nonpel- lagious anu pellagious householus. jA/A :º44, 1º18 8. Rose C: Sicl inuiviuuals anu sicl popu- lations. lnt j l¡idcmio| :o2, 1º85 º. Caitei R, íails R, Hill D: Coulu a national slin cancei piinaiy pievention canpaign in Austialia he voithvhile` An econonic peispective. Hca|th lromot lnt :¯o, 1ººº 14. ¯aplin D et al: Connunity contiol ol scahies: A nouel haseu on use ol pei- nethiin ciean. lan.ct :1O16, 1ºº1 16. íahé A et al: lntegiation ol hasic uei- natological caie into piinaiy health caie seivices in íali. 3u|| \or|d Hca|th ·rgan :ºo5, 2OO5 18. Ryan ¯[: Healthy slin loi all. lnt j Dcr- mato| :82º, 1ºº4 This page intentionally left blank 23      2 APPR0ACH T0 DER|AT0|00|C D|A0\0S|S C H A P T E R 4 Str0ct0re oI Sk|o Les|oos aod F0odameota|s oI 0||o|ca| 0|agoos|s Ar|| 0a|ç \|||| A. |e.|r Je|||e] D. Be|r|a|d \hat is most dijµ.u|t oj a||` lt is vhat a¡¡cars most sim¡|c: To scc vith ,our c,cs vhat |ics in jront oj ,our c,cs. Coethe THE ART 0| D|A0\0S|S ¯he uiagnosis anu tieatnent ol uiseases that allect the slin iest on the physi- cian`s ahility to use the lexicon ol uei- natology, to iecognize the hasic anu se- guential lesions ol the slin, anu to iecognize the vaiious patteins in vhich they occui in a vaiiety ol uiseases anu synuiones. ln this chaptei, ve uiscuss a lunuanental appioach to the patient piesenting vith a slin piohlen. We in- tiouuce the technical vocahulaiy ol uei- natologic uesciiption, the °ueinatology lexicon`a set ol teins that uenote types ol slin lesions. lt is inpoitant to lnov anu use this stanuaiu teininol- ogy, as it is the hist step in geneiating a uilleiential uiagnosis. Cnce a lesion has heen uesciiheu as a peaily, hesh- coloieu, telangiectatic, ulceiateu nouule, the expeiienceu physician puts hasal cell caicinona at the top ol the uilleien- tial uiagnosis. lt is also inpoitant to use stanuaiu ueinatologic teininology loi consistency in clinical uocunentation, in ieseaich, anu in connunication vith othei physicians. ¯he piocess ol exanining anu ue- sciihing slin lesions nay he lileneu to that ol vieving a painting. liist, one stanus hacl anu tales in the vhole °canvas,` analogous to vieving the pa- tient lion a lev leet avay at vhich uis- tance an oveiall assessnent ol the pa- tient`s geneial anu cutaneous health nay he naue. Cne nay note such hnu- ings as slin coloi anu tuigoi, piesence ol palloi oi |aunuice, uegiee ol sun uanage, anu the oveiall nunhei anu lo- cation ol lesions. Next, one lools noie closely at the °tiees` oi °nountains` that nale up the lanuscape, analogous to uesciihing anu categoiizing the spe- cihc lesions on the patient. linally, one nay closely exanine the uetails ol the canvas, taling in the textuie anu hiush- stioles, analogous to using nagnihca- tion to see the hoiueis ol a nevus oi conpiessing a lesion to see il it hlanches. [ust as a lnovleugeahle vievei ol ait nay iecognize a voil ol Ceoiges Seuiat hy its tiny, uot-lile hiush stioles, an expeiienceu ohseivei ol the slin can iecognize a nelanona hy its asynnetiy, iiiegulai hoiueis anu nultiple colois. ¯his chaptei ains to in- tiouuce the ieauei to the ait anu science ol ueinatologic uiagnosis. APPR0ACH T0 THE PAT|E\T H|º|c|] Deinatology is a visual specialty, anu sone slin lesions nay he uiagnoseu at a glance. Nonetheless, the histoiy is in- poitant anu in conplex cases, such as the patient vith iash anu levei oi the patient vith geneializeu piuiitus, it nay he ciucial. Deinatologists vaiy in vhethei they pielei to tale a histoiy heloie, uuiing, oi altei peiloining a physical exanination. ln piactice, nany peiloin a hiiel exanination initially, ohtain sone histoiy, then ietuin to a noie locuseu exanination. loi the lolloving ieasons, it is olten uselul to at least hiiehy exanine the pa- tient heloie taling a lengthy histoiy: º Ceitain slin conuitions, such as clas- sic plague-type psoiiasis oi nollus- cun contagiosun, loi exanple, piesent vith such uistinctive noiphologies S||\ |ES|0\S A\D D|A0\0S|S AT A 0|A\CE A pa||er| ard ||c|cuç| app|cac| |c ||e e.a|ua||cr dec|eaºeº ||e ||º| c| ra||rç ar |rcc||ec| d|açrcº|º c| c.e||cc||rç arc||e| d|açrcº|º. |rcW|edçe ard app|cp||a|e uºe c| de|ra|c|cç] |e|r|rc|cç] a|e |urda- rer|a|. Reccçr|||cr c| d|ºeaºe pa||e|rº |e(u||eº |epea|ed pa||er| erccur|e|º. T|e ||º|c|] |º |rd|ºperºa||e |r e|uc|da||rç ccrp|e/ d|açrcºeº. T|e er|||e rucccu|arecuº ºu||ace, aº We|| aº ||e |a|| ard ra||º, º|cu|d |e e/ar|red W|ere.e| |eaºcra||e. |c|p|c|cç|c c|a|ac|e||º||cº de||.ed ||cr ce|| |]pe |r º||r ruº| |e ca|e|u||] ºc|u||r|/ed. D|ºeaºeº |a.e c|a|ac|e||º||c rc|p|c|cç] ard d|º||||u||cr. Ccrrcr p|||a||º |r de|ra|c|cç|c d|açrc- º|º e/|º| ard car |e a.c|ded. Copyright ? 2008 by The McGraw-Hill Companies, Inc. Click here for terms of use. 24 that the uiagnosis nay he inneui- ately ohvious, ienueiing extensive his- toiy taling unnecessaiy. º A patient`s histoiy nay contain °ieu heiiings,` vhich leau the physician avay lion, iathei than tovaiu, the coiiect uiagnosis. lxanination ol the patient heloie taling a histoiy nay yielu a noie conplete anu unhiaseu uilleiential uiagnosis. º ln ceitain situations, such as the eval- uation ol alopecia, initial exanination ol the patient to ueteinine vhat type ol haii loss is piesent allovs the phy- sician to puisue a line ol guestions peitinent to that type ol alopecia. ln taling a histoiy lion a patient pie- senting vith a nev slin conplaint, the physician`s piinaiy goal is to estahlish a uiagnosis, vith a seconuaiy goal ol evaluating the patient as a canuiuate loi theiapy. ln patients vhose uiagnosis is alieauy estahlisheu, the physician`s goals aie to ie-evaluate the oiiginal ui- agnosis, nonitoi uisease piogiess anu conplications, anu nouily tieatnent accoiuingly. ¯ahle 4-1 is a guiue uselul in evaluating a patient vith a iash oi giovth. ¯he tahle is not an algoiithnic Ik8L£ 4-1 Approach to 0armato|og|c 0|agnos|s a º |r|||a| c||r|ca| |rp|eºº|cr. Dceº ||e pa||er| appea| |||´ º Re.|eW c| º]º|erº aº |rd|ca|ed |] c||r|ca| º||ua||cr, W||| pa|||cu|a| a||er||cr |c º]rp|crº |rd|ca||rç a pcºº|||e ccrrec||cr |e|Weer cu|a- recuº º|çrº ard d|ºeaºe c| c||e| c|çar º]º|erº (e.ç., ||eura||c ccr- p|a|r|º. r]a|ç|aº, a||||a|ç|aº, Ra]raud p|ercrercr, º|cca º]rp|crº, º P|]º|ca| e/ar|ra||cr. de|a||ed e/ar|ra||cr c| ||e º||r, |a||, ra||º, ard ruccuº rer||areº º |cu| ca|d|ra| |ea|u|eº º T]pe c| |eº|cr. racu|e, papu|e, rcdu|e, .eº|c|e, e|c. (ºee Ta||e 4-2, º Re.|eW c| º]º|erº |c| ç|cW||º ºuºp|c|cuº |c|, c| aººcc|a|ed W|||, ra||ç- rarc]. pa|||cu|a| a||er||cr |c º]rp|crº c| re|aº|aº|º (We|ç|| |cºº, |e.e|º, c||||º, r|ç|| ºWea|º, |eadac|e, ºWc||er ç|ardº, a|dcr|ra| pa|r, a|rc|ra| º|cc||rç, |cre pa|r, e|c., º S|ape c| |rd|.|dua| |eº|crº. arru|a|, |||º, a|c||c|r, ||rea|, |curd, c.a|, ur||||ca|ed, e|c. º A||arçerer| c| ru|||p|e |eº|crº. |ºc|a|ed, ºca||e|ed, ç|cuped, ||rea|, |e|- pe|||c|r, /cº|e|||c|r, e|c. º |ed|ca||cr ||º|c|]. a||e|ç], a|| p|eºc||p||cr, rcrp|eºc||p||cr, ard 'ccr- p|erer|a|]' red|ca||crº, W||| pa|||cu|a| a||er||cr |c ||cºe ||a| |erpc- |a||] cc||eºpcrd |c ||e crºe| c| ||e e|up||cr º D|º||||u||cr (|e ºu|e |c e/ar|re ºca|p, rcu||, pa|rº, ard ºc|eº, º E/|er| c| |r.c|.erer|. c||curºc|||ed, |eç|cra|, çere|a||/ed, ur|.e|ºa|´ w|a| pe|cer|açe c| ||e |cd] ºu||ace |º |r.c|.ed´ º Paº| red|ca| ||º|c|] º Pa||e|r. º]rre||], e/pcºed a|eaº, º||eº c| p|eººu|e, |r|e||||ç|rcuº a|eaº´ º |||reººeº º C|a|ac|e||º||c |cca||crº. 1e/u|a|, e/|erºc|, |r|e||||ç|rcuº, ç|a||cuº, pa|rº ard ºc|eº, de|ra|cra|, ||ur|, |cWe| e/||er|||eº, e/pcºed a|eaº, e|c.´ º 0pe|a||crº º A|cp|c ||º|c|] (aº||ra, |a] |e.e|, ec/era, º T||ee rajc| c|a|ac|e||º||cº º |ar||] red|ca| ||º|c|], pa|||cu|a||] c| º||r d|ºc|de|º ard c| a|cp] º Cc|c| (ºee Ta||e 4-8, º |ar||] ||º|c|] c| º||r, c| c||e|, carce|º ~ || d|||uºe. |ed, ||cWr, ç|a]-||ue, W|||e, ||ue, c|arçe-]e||cW, e|c., || c||curºc|||ed. |ed, .|c|acecuº, c|arçe, ]e||cW, |||ac, ||.|d, ||cWr, ||ac|, ||ue, ç|a], W|||e, e|c. º Scc|a| ||º|c|] W||| pa|||cu|a| |e|e|erce |c cccupa||cr, |c|||eº, ºur e/pcºu|e, pe| e/pcºu|e, |c|accc ºrc||rç, a|cc|c| ccrºurp||cr, |ec|e- a||cra| d|uçº, ||a.e|, ºe/ua| c||er|a||cr ard e/pcºu|eº ~ Dceº ||e cc|c| ||arc| W||| p|eººu|e (d|aºccp] |eº|,´ º |a|c|a|c|] º|ud|eº ~ wccd'º |arp e/ar|ra||cr c| p|çrer|a|] a||e|a||crº. |º ccr||aº| er|arced´ º Spec|a| p|ccedu|eº aº de|e|r|red |] ||e |rd|.|dua| c||r|ca| º||ua- ||cr (ºee C|ap. o, º Ccrº|º|erc] ard |ee| c| |eº|cr. ºc||, dcuç|], ||r, |a|d, '|r||||a|ed,' d|], rc|º|, rc|||e, |erde|, Wa|r´ º De|ra|cºccp] º Hard |erº c| / |cupe raçr||ca||cr |c| |der|||]|rç ºpec||c |ea|u|eº º Ara|cr|c ccrpcrer|º c| ||e º||r p||ra|||] a||ec|ed. |º ||e p|cceºº ep|de|- ra|, de|ra|, ºu|cu|arecuº, apperdaçea|, c| a ccr||ra||cr c| ||eºe´ º B|cpº] |c| ||º|cpa||c|cç|c ard c||e| ara|]ºeº (e.ç., e|ec||cr r|c|cºccp], |rrurc1uc|eºcerce, ºpec|a| º|a|rº, || |rd|ca|ed º 0ere|a| p|]º|ca| e/ar|ra||cr aº |rd|ca|ed |] ||e c||r|ca| p|eºer|a||cr ard d|||e|er||a| d|açrcº|º, W||| pa|||cu|a| a||er||cr |c .||a| º|çrº, |]rp|adercpa- ||], |epa|creça|], ºp|ercreça|], jc|r|º, e|c. º T|ººue |c |e r|rced |c| |ac|e||a| ard |urça| cu||u|eº º 0|ar º|a|rº c| c|uº|, ºca|e, c| e/uda|eº º Pc|aºº|ur |]d|c/|de p|epa|a||cr |c| ]eaº| c| |urç| º H|º|c|] c| a |aº|. |e] (ueº||crº. º C]|c|cç|c p|epa|a||cr (T/arc| ºrea|, |r .eº|cu|a| ard |u||cuº e|up||crº º w|er d|d || º|a||´ º Dceº || ||c|, |u|r, c| |u||´ º SWa| |c| |ac|e||a|, .||a|, ard |urça| cu||u|eº º w|e|e cr ||e |cd] d|d || º|a||´ º wccd'º |arp e/ar|ra||cr c| u||re |c| pc|p|]||rº ard c| |a|| ard º||r |c| 1uc|eºcerce c| |c| c|arçeº |r p|çrer|a||cr º HcW |aº || ºp|ead (pa||e|r c| ºp|ead,´ º HcW |a.e |rd|.|dua| |eº|crº c|arçed (e.c|u||cr,´ º 0|| rcur| p|epa|a||cr c| ºc|ap|rç |c| ºca||eº r||e º P|c.cca||.e |ac|c|º´ º Pa|c| |eº||rç |c| a||e|ç|c ccr|ac| de|ra||||º º P|e.|cuº ||ea|rer|º ard |eºpcrºe´ º 0ere|a|. |era|c|cç], c|er|º||], u||ra|]º|º, ºe|c|cç|c |eº|º (e.ç., º]p||||º, ar||ruc|ea| ar|||cd],, |raç|rç º|ud|eº, ard c||e|º aº |rd|ca|ed |] ||e p|eºer|a||cr º H|º|c|] c| a ç|cW||. |e] (ueº||crº. º HcW |crç |aº ||e |eº|cr |eer p|eºer|´ º Haº || c|arçed, ç|cWr, ||ed, ||c|ed, c| |a||ed |c |ea|´ º ||ra| d|açrcº|º. |e-e/ar|ra||cr c.e| ||re ard rc|e ||ar cre ||cpº] ra] |e |e(u||ed |c| de|r|||.e d|açrcº|º º 0ere|a| ||º|c|] c| p|eºer| |||reºº aº |rd|ca|ed |] c||r|ca| º||ua||cr, W||| pa|- ||cu|a| a||er||cr |c ccrº|||u||cra| ard p|cd|cra| º]rp|crº º Acu|e |||reºº º]rd|cre (|e.e|, ºWea|º, c||||º, |eadac|e, rauºea, .cr||- |rç, ccuç|, |urr] rcºe, e|c.,´ º C||cr|c |||reºº º]rd|cre (|a||çue, arc|e/|a, We|ç|| |cºº, ra|a|ºe,´ a T||º app|cac| Waº de.e|cped |] T|craº B. |||/pa|||c|, Je|||e] D. Be|r|a|d, ard Ha||e] A. Ha]reº. || |aº |eer rcd||ed |] Ar|| 0a|ç, \|||| |e.|r, ard Je|||e] D. Be|r|a|d. 25 nethou ol aiiiving at a uiagnosis. Rathei, it is neant to pioviue the leainei vith a lunuanental anu geneial ap- pioach to uiagnosing an unlnovn. E/ar|ra||cr c| ||e De|ra|c|cç|c Pa||er| S00P£ 0F Th£ 00NPL£T£ 00TAh£00S £XAN|hAT|0h ¯he conplete cutaneous exanination incluues inspection ol the entiie slin suilace, incluuing olten-ovei- looleu aieas such as the scalp, eyelius, eais, genitals, huttocls, peiineal aiea, anu inteiuigital spaces, the haii, the nails, anu the nucus nenhianes ol the nouth, eyes, anus, anu genitals. ln ioutine clini- cal piactice, not all ol these aieas aie ex- anineu unless theie is a specihc ieason to uo so, such as a histoiy ol nelanona oi a paiticulai localizing conplaint. A0VAhTA6£S T0 P£8F08N|h6 A 00NPL£T£ 00TAh£00S £XAN|hAT|0h Although it is not alvays essential oi piactical to pei- loin a conplete slin exanination, theie aie nany auvantages to uoing so, especially loi nev patients anu chal- lenging cases: º luentihcation ol potentially hainlul lesions (e.g., slin canceis) ol vhich the patient is unavaie, any patient vith a histoiy ol slin cancei oi a chiel conplaint ol a °nev giovth` ueseives a lull slin exanination. º luentihcation ol henign lesions (e.g., sehoiiheic leiatoses, angioleiato- nas) that the patient vas conceineu ahout hut ieluctant to nention, theiehy enahling the physician to pioviue ieassuiance. º linuing hiuuen clues to uiagnosis (e.g., scahies lesions on the penis, psoiiatic plagues on the huttocls, Wiclhan stiiae ol lichen planus on the huccal nucosa, nail pitting in alo- pecia aieata). º Cppoitunity loi patient euucation (e.g., lentigines aie a sign ol sun uanage anu suggest the neeu loi inpioveu sun piotection). º Cppoitunity to convey the physi- cian`s concein ahout the patient`s slin health as a vhole. latients appieciate this anu also iegaiu the physician as thoiough. 8A88|£8S T0 P£8F08N|h6 A 00NPL£T£ Sk|h £XAN|hAT|0h Despite the auvan- tages ol peiloining a lull cutaneous ex- anination, nuneious haiiieis exist that nay pievent the ueinatologist lion peiloining such an evaluation loi eveiy patient. Unueistanuahly, patients nay uecline a lull exanination vhen theii chiel conplaint is ielatively ninoi oi lo- calizeu, such as a vait oi acne. ln othei cases, patients nay expiess iesistance to uisiohing loi a lull exanination uue to enhaiiassnent, especially vhen the physician is ol the opposite genuei. Sonetines the physician is unconloit- ahle peiloining a conplete slin exani- nation vith the concein that a patient nay nisinteipiet the exanination as inpiopei. ln nany instances, tine con- stiaints anu lacl ol peisonnel to seive as chapeiones linit the ahility to peiloin lull slin exanination. |0£AL 00h0|T|0hS F08 Th£ 00NPL£T£ Sk|h £XAN|hAT|0h A conplete slin ex- anination is nost ellective vhen pei- loineu unuei iueal conuitions. lt is nost inpoitant to have excellent lighting, pieleiahly hiight, even light that sinu- lates the solai spectiun. Without goou lighting, suhtle hut inpoitant uetails nay he nisseu. ¯he patient shoulu he lully unuiesseu, veaiing only a govn that is easily noveu asiue, vith a sheet ovei the legs, il uesiieu. Unueiveai, socls, anu shoes shoulu he ienoveu, as shoulu any naleup oi eyeglasses. ¯he exanining tahle shoulu he at a conloit- ahle height, vith a heau that ieclines, an extenuahle lootiest, anu gynecologic stii- iups. ¯he exanining ioon shoulu he at a conloitahle tenpeiatuie loi the lightly uiesseu patient. lt shoulu contain a sinl loi hanu vashing anu uisinlecting hanu loan, as patients aie ieassuieu hy seeing theii physician vash hanus heloie the exanination. ll the patient anu physician aie ol opposite genueis, having a chapei- one in the ioon can nale the exanina- tion noie conloitahle loi hoth. 8£00NN£h0£0 T00LS F08 Th£ 00NPL£T£ Sk|h £XAN|hAT|0h Although the physi- cian`s eyes anu hanus aie the only es- sential tools loi exanination ol the slin, the lolloving aie olten uselul anu highly ieconnenueu: º A nagnilying tool such as a loupe, nagnilying glass, oi ueinatoscope. º A hiight locuseu light such as a hash- light oi penlight to siuelight lesions. º Class sliues oi a hanu nagnihei loi uiascopy. º Alcohol paus to ienove scale oi sui- lace oil. º Cauze paus oi tissues vith vatei loi ienoving naleup. º Cloves to he useu loi exanination vhen scahies oi anothei highly inlec- tious conuition (seconuaiy syphilis) is suspecteu, vhen exanining nucus nenhianes, vulvai anu genital aieas, anu vhen peiloining any pioceuuie. º A iulei loi neasuiing lesions. º Nunhei 15 anu nunhei 11 scalpel hlaues loi sciaping oi incising lesions, iespectively. º A caneia loi photogiaphic uocu- nentation. º A Woou`s lanp (o65 nn) loi high- lighting suhtle pignentaiy changes. T£0hh|00£ 0F Th£ 0£8NAT0L06|0 PhYS|- 0AL £XAN|hAT|0h [ust as theie is no one coiiect vay to peiloin a geneial physi- cal exanination, each physician ap- pioaches the conplete slin exanination vith his oi hei ovn style. A connon thieau to ellective styles ol slin exani- nation is consistency in the oiuei ol ex- anining uilleient houy aieas to ensuie that no aieas aie oveilooleu. Cne ap- pioach to the conplete slin exanina- tion is piesenteu heie. liist, ohseive the patient at a uistance loi geneial inpies- sions (e.g., asynnetiy uue to a stiole, ohesity, palloi, latigue, |aunuice). Next, exanine the patient in a systenatic vay, usually lion heau to toe, uncovei- ing one aiea at a tine to pieseive pa- tient nouesty. íove the patient (e.g., lion sitting to lying) anu the illunina- tion as neeueu loi the hest viev ol each houy aiea. lalpate giovths to uetei- nine vhethei they aie solt, heshy, hin, tenuei, oi huiu-hlleu. Use ol the hanus to stietch the slin is especially uselul in uiagnosis ol hasal cell caicinona, in vhich stietching slin ieveals a °peaily` guality olten not seen on ioutine inspec- tion. A nagnihei voin on the heau leaves hoth hanus liee loi palpation ol lesions. Ceitain lesions, such as poio- leiatosis, aie hest exanineu vith siue lighting that ieveals uepth anu the ue- tails ol hoiueis. Duiing the exanina- tion, patients olten hnu it ieassuiing loi the physician to nane anu uenystily henign lesions as they aie encounteieu. Special exanination technigues loi haii uisoiueis aie uiscusseu in Chap. 86, hut incluue having the patient sit in a chaii so that the entiie scalp is easily ex- anineu, paiting the patient`s haii at the liont anu occiput anu gently tugging on haiis to ueteinine the liaction ol loose (telogen) haiis. lxanination ol the nails is uiscusseu in Chap. 8¯. Altei conpleting the exanination, it is inpoitant to uocunent the slin hnu- ings, incluuing the type ol lesions anu theii locations, eithei uesciiptively oi on a houy nap. Caielul uocunentation is 26 paiticulaily inpoitant loi suspicious le- sions that aie to he hiopsieu, so that the exact location nay he lounu anu uehni- tively tieateu at a latei uate. lnstant oi uigital photogiaphy is a uselul au|unct loi uocunentation. |\TR0DUCT|0\ T0 |0RPH0|00\ Sienens (18º11º6º) viote, °he vho stuuies slin uiseases anu lails to stuuy the lesion hist vill nevei leain ueina- tology.` His statenent ieinloices the notion that the piinaiy slin lesion, oi the evolution theieol, is the essential el- enent on vhich clinical uiagnosis iests. [oseph [aloh lulei von llencl`s (1¯o8 18O¯) anu Roheit Willan`s (1¯5¯1812) voil in uehning hasic noiphologic tei- ninology luithei peinitteu uesciiption anu conpaiison ol lunuanental lesions, theiehy lacilitating chaiacteiization anu iecognition ol slin uisease. ¯o ieau voius, one nust iecognize letteis, to ieau the slin, one nust iecognize the hasic lesions. ¯o unueistanu a paia- giaph, one nust lnov hov voius aie put togethei, to aiiive at a uilleiential uiagnosis, one nust lnov vhat the hasic lesions iepiesent, hov they evolve, anu hov they aie aiiangeu anu uistiihuteu. Vaiiation anu anhiguity in the noi- phologic teins geneially accepteu hy the inteinational ueinatology connu- nity have engenueieu haiiieis to con- nunication anong physicians ol all uis- ciplines, incluuing ueinatologists. ln ueinatologic texthools, the papule, loi exanple, has heen uesciiheu as no gieatei than 1 cn in size, less than O.5 cn, oi ianging lion the size ol a pin- heau to that ol a split pea. ¯hus, in loining a nental inage ol a lesion oi eiuption altei heaiing its noiphologic uesciiption, physicians sonetines ie- nain iiiesolute. ¯he nission ol the Dei- natology Lexicon lio|ect is to cieate a univeisally accepteu anu conpiehensive glossaiy ol noiphologic uesciiptive teins to suppoit ieseaich, neuical in- loinatics, anu patient caie (http:// vvv.DeinatologyLexicon.oig). íoi- phologic uehnitions in this chaptei paiallel anu anplily those ol the Dei- natology Lexicon lio|ect. ln uesciihing noiphologic teins, oui intent is sinple: to pioviue the ieauei vith a puie ap- pieciation ol the °letteis that nale up the alphahet` iathei than uetailing a °helu guiue` loi uiagnoses, vhich aie coveieu in uepth thioughout the text- hool. ¯ahle 4-2 is a sunnaiy ol the le- sions uiscusseu. Ra|ºed |eº|crº PAP0L£ A papule is a soliu, elevateu le- sion less than O.5 cn in size in vhich a signihcant poition pio|ects ahove the plane ol the suiiounuing slin. Chligue lighting vith a hashlight in a uaileneu ioon is sonetines necessaiy to uetect the slight elevation ol enheuueu pap- ules. lapules suinounteu vith scale aie ieleiieu to as papulosguanous lesions. Sessile, peuunculateu, uone-shapeu, hat- toppeu, iough, snooth, hliloin, nan- nillateu, acuninate, anu unhilicateu constitute sone connon shapes anu suilaces ol papules. A clinical exanple is lichen planus (lig. 4-1, see Chap. 26). PLA00£ A plague is a soliu plateau-lile elevation that occupies a ielatively laige suilace aiea in conpaiison vith its height ahove the noinal slin level anu has a uianetei laigei than O.5 cn. ¯he elevation neeu not he signihcant. llagues, vhich nay loin hy extension oi conhu- ence ol papules, aie luithei chaiactei- izeu hy theii size, shape, coloi, anu sui- lace change. A clinical exanple is psoiiasis (lig. 4-2, see Chap. 18). h000L£ Depenuing on the anatonic conponent(s) piinaiily involveu, nou- ules aie ol hve nain types: (1) epiuei- nal, (2) epiueinal-ueinal, (o) ueinal, (4) ueinal-suhueinal, anu (5) suhcuta- neous. Cn the slin, a nouule is a soliu, iounu oi ellipsoiual, palpahle lesion that has a uianetei laigei than O.5 cn. Size, hovevei, is not the na|oi consiueiation in the uehnition ol nouule. Depth ol in- volvenent anu/oi suhstantive palpahil- ity, iathei than uianetei, uilleientiates a nouule lion a laige papule oi plague. Tumor, also sonetines incluueu unuei the heauing ol nouule, is a geneial tein loi any nass, henign oi nalignant. A gumma is, specihcally, the gianulona- tous nouulai lesion ol teitiaiy syphilis. loi cases in vhich noie than one tein nay he applicahle, it is sinply hest to incluue neasuienents anu uesciiptive teins that convey the inpoitant lea- tuies ol the lesion in guestion. Sone au- uitional leatuies ol a nouule that nay help ieveal a uiagnosis incluue vhethei it is vain, haiu, solt, huctuant, nov- ahle, hxeu, oi painlul. Sinilaily, uillei- ent suilaces ol nouules, such as snooth, leiatotic, ulceiateu, oi lungating, also help uiiect uiagnostic consiueiations. A clinical exanple is nouulai hasal cell cai- cinona (lig. 4-o, see Chap. 115). F|608£ 4-1 Papu|e. |u|||p|e, We||-de|red pap- u|eº c| .a|]|rç º|/eº a|e ºeer. ||a| |cpº ard ç||º|er- |rç ºu||ace a|e c|a|ac|e||º||c c| ||c|er p|aruº. F|608£ 4-2 P|a(ue. we||-dera|ca|ed p|r| p|a(ueº W||| a º||.e|] ºca|e |ep|eºer||rç pºc||a- º|º .u|ça||º. Ik8L£ 4-2 Norpho|og|c Las|ons 8A|SF0 0FP8FSSF0 FLAT SU8FA0F 0HAh0F FLU|0 F|LLF0 VAS0ULA8 Papu|e E|cº|cr |acu|e Sca|e Veº|c|e Pu|pu|a P|a(ue U|ce| Pa|c| C|uº| Bu||a Te|arç|ec|aº|a \cdu|e A||cp|] E|]||era E/cc||a||cr Puº|u|e |r|a|c| C]º| Pc||||cde|ra E|]|||cde|ra ||ººu|e |u|urc|e w|ea| S|ruº ||c|er||ca||cr A|ºceºº Sca| S|||ae |e|a|cde|ra Ccredc Bu||cW Eºc|a| Hc|r Sc|e|cº|º Ca|c|rcº|º 27 0YST A cyst is an encapsulateu cavity oi sac lineu vith a tiue epitheliun that contains huiu oi senisoliu nateiial (cells anu cell piouucts such as leiatin). lts spheiical oi oval shape iesults lion the tenuency ol the contents to spieau egually in all uiiections. ll the oveilying slin is stietcheu enough hy the cyst, lol- liculai openings nay he pioninent. Sonetines, the cavity is so supeihcial that it gives the appeaiance ol a vesicle that lacls encapsulation. A nouule oi papule nay he suspecteu ol heing a cyst il, on palpation, it is iesilient, the eye- hall, loi exanple, leels sinilai to a cyst. Depenuing on the natuie ol the con- tents, cysts nay he haiu, uoughy, oi huctuant. A clinical exanple is a cystic hiuiauenona (lig. 4-4, see Chap. 11º). wh£AL A vheal is a svelling ol the slin that is chaiacteiistically evanescent, uis- appeaiing vithin houis. ¯hese lesions, also lnovn as hivcs oi urti.aria, aie the iesult ol euena piouuceu hy the escape ol plasna thiough vessel valls in the uppei poition ol the ueinis. Wheals nay he tiny papules 2 nn to 4 nn in uianetei oi giant plagues neasuiing gieatei than 1O cn. Vaiiahle shapes (iounu, oval, seipiginous, oi annulai) nay he noteu, olten in the sane patient. Boiueis ol a vheal, although shaip, aie not stahle anu in lact nove lion in- volveu to au|acent uninvolveu aieas ovei a peiiou ol houis. Wheals aie pinl to pale ieu in coloi. ¯he haie, oi iing ol pinl eiythena, ol a vheal nay he in- tense il supeihcial vessels aie uilateu. ll the anount ol euena is sulhcient to conpiess supeihcial vessels, vheals nay in lact he vhite in the centei oi aiounu the peiipheiy, piouucing a zone ol palloi. With associateu inhannatoiy uisiuption ol the vessels valls, vheals nay have a ueepei ieu coloi, nay he puipuiic, anu aie noie peisistent. Wheals aie solt to hin uepenuing on the extent ol euena piesent. Angioeuena is a ueepei, euenatous ieaction that occuis in aieas vith veiy loose ueinis anu suhcutaneous tissue such as the lip, eyeliu, oi sciotun. lt nay occui on the hanus anu leet as vell, anu iesult in giotesgue ueloinity. A caielul seaich loi laiyngeal euena shoulu he naue in cases ol angioeuena, as such cases nay iesult in ueath lion aiivay ohstiuction (see Chap. o¯). A clinical exanple is ueinatogiaphisn (lig. 4-5, see Chap. o¯). S0A8 A scai aiises lion piolileiation ol hhious tissue that ieplaces pieviously noinal collagen altei a vounu oi ulcei- ation hieaches the ieticulai ueinis. Scais have a ueepei pinl to ieu coloi eaily on heloie heconing hypo- oi hypeipig- nenteu. ln nost scais, the epiueinis is thinneu anu inpaits a viinlleu appeai- ance at the suilace. Aunexal stiuctuies, such as haii lollicles, noinally piesent in the ueinis aie uestioyeu. Hypeitiophic scais typically tale the loin ol hin pap- ules, plagues, oi nouules. leloiu scais aie also elevateu. Unlile hypeitiophic scais (lig. 4-6, see Chap. 64), leloius exceeu, F|608£ 4-4 C]º|. A ||u|º| cc|c|ed |eº|||er| c]º| |||ed W||| a ruccuº-|||e ra|e||a| cr ||e c|ee| |º a c]º||c ||d|adercra. F|608£ 4-5 w|ea|. A º|a|p|] dera|ca|ed W|ea| W||| a ºu||curd|rç e|]||era|cuº 1a|e cc- cu|||rç W||||r ºeccrdº c| ||e º||r |e|rç º||c|ed. F|608£ 4-6 Sca|. A p|r| ||r |]pe|||cp||c ºca|. F|608£ 4-3 \cdu|e. A rcdu|a| |aºa| ce|| ca|c|rcra W||| We||-de|red, ||r rcdu|e W||| a ºrcc|| ard ç||º|er|rç ºu||ace |||cuç| W||c| |e|arç|ec|aº|a car |e ºeer. 28 vith veh-lile extensions, the aiea ol ini- tial vounuing. Atiophic scais aie thin uepiesseu plagues. 00N£00 A coneuo is a haii lollicle in- lunuihulun that is uilateu anu pluggeu hy leiatin anu lipius. When the pilose- haceous unit is open to the suilace ol the slin vith a visihle leiatinaceous plug, the lesion is ieleiieu to as an o¡cn .omcdo. ¯he hlacl coloi ol the coneuo is uue to the oxiuizeu sehaceous content ol the inlunuihulun (°hlaclheau`). A closeu inlunuihulun in vhich the lollic- ulai opening is unappaient accunulates vhitish leiatin anu is calleu a .|oscd .omcdo. ¯hese lesions aie connon on the lace anu tiunl. A clinical exanple is coneuonal acne (lig. 4-¯, see Chap. ¯8). h08h A hoin is a conical nass ol coini- heu cells aiising ovei an ahnoinally uil- leientiating epiueinis. Associateu un- ueilying pathologic states nay incluue hunan papillona viius ieplication in leiatinocytes ol a vait oi the clonal ex- pansion ol nutateu leiatinocytes in sguanous cell caicinona. A clinical ex- anple is veiiuca vulgaiis (lig. 4-8, see Chap. 1º6). 0AL0|h0S|S Deposits ol calciun in the ueinis oi suhcutaneous tissue nay he appieciateu as haiu, vhitish nouules oi plagues, vith oi vithout visihle altei- ation ol the slin`s suilace. A clinical ex- anple is cutaneous calcinosis in ueina- tonyositis (lig. 4-º, see Chap. 15¯). Dep|eººed |eº|crº £80S|0h An crosion is a noist, ciicun- sciiheu, uepiesseu lesion that iesults lion loss ol a poition oi all ol the viahle epiueinal oi nucosal epitheliun. ¯he uelect extenuing to the nost supeihcial pait ol the ueinis nay iesult in pin- point hleeuing in a sieve-lile lashion. liosions nay iesult lion tiauna, ue- tachnent ol epiueinal layeis vith nac- eiation, iuptuie ol vesicles oi hullae, oi epiueinal neciosis, loi exanple. lxten- sive eiosions nay iesult in laige aieas ol iav uenuuation. Unless they hecone seconuaiily inlecteu, eiosions uo not scai. A clinical exanple is toxic epiuei- nal neciolysis (lig. 4-1O, see Chap. oº). 0L0£8S An ulcei is a uelect in vhich the epiueinis anu at least the uppei (papil- laiy) ueinis has heen ienoveu. Bieach ol the ueinis anu uestiuction ol aunexal stiuctuies inpeue ie-epithelialization, anu the uelect heals vith scaiiing. ¯heie aie nuneious uesciiptive leatuies helplul in ueteinining the cause ol ul- ceis. Location ol the ulcei, such as on the neuial aspect ol the anlle oi ovei piessuie points, nay he telling. Boiueis ol the ulcei nay he iolleu, unueinineu, puncheu out, |aggeu, oi angulai. ¯he hase nay he clean, iaggeu, oi neciotic. Dischaige nay he puiulent, gianulai, oi nalouoious. Suiiounuing slin nay he ieu, puiple, pignenteu, ieticulateu, in- uuiateu, scleiotic, oi inlaicteu. Cthei in- loinative leatuies incluue the piesence ol neaihy nouules, suiiounuing excoiia- tions, vaiicosities, haii, sveat, anu the stiength ol au|acent pulses. A clinical exanple is pyoueina gangienosun (lig. 4-11, see Chap. o2). AT80PhY Atro¡h, ieleis to a uininution in the size ol a cell, tissue, oigan, oi pait ol the houy. A ueciease in the nunhei ol epiueinal cells iesults in thinning ol the epiueinis. Atiophic epiueinis is glossy, alnost tianspaient, papei thin anu viinlleu, anu nay not ietain noi- nal slin lines. lpiueinal atiophy nay also he associ- ateu vith sinilai alteiations in the uei- nis. A ueciease in the papillaiy oi ieticu- lai ueinal connective tissue nanilests as a uepiession ol the slin. ln ueinal atio- phy occuiiing vithout epiueinal in- volvenent, the aiea ol allecteu slin is noinal in coloi anu suilace nailings he- cause the ciicunsciiheu uepiession is piouuceu only hy the ueciease in ueinal tissue. Atiophy ol the panniculus iesults in a noie suhstantial uepiession ol the slin. A thinneu viinlleu suilace inui- cates coexisting epiueinal atiophy. lig. 4-12 shovs ageu slin ol the ain (see Chap. 1O8). P0|k|L00£8NA As a noiphologic tein, ¡oiki|odcrma ieleis to the conhination ol atiophy, telangiectasia, anu vaiieu pig- nentaiy changes (hypei- anu hypo-) ovei an aiea ol slin. ¯his conhination ol leatuies nay give iise to a uappleu appeaiance to the slin. ¯he uistiihution F|608£ 4-7 Ccredc. 0per ard c|cºed ccr- edcreº cr ||e |ace c| |||º pa||er| W||| acre. F|608£ 4-8 Hc|r. A ccr|ca| cc|urr c| |]- pe||e|a|cº|º c.e||]|rç a p|r| papu|e. T||º cu|a- recuº |c|r |ep|eºer|º a .e||uca .u|ça||º. F|608£ 4-9 Ca|c|rcº|º. Ha|d, W||||º| rcd- u|eº cr ||e c|eº| |ep|eºer||rç d]º||cp||c ca|c|- rcº|º |r |||º pa||er| W||| de|ra|cr]cº|||º. F|608£ 4-10 E|cº|cr. S|cuç||rç c| ||e º||r |r |||º pa||er| W||| |c/|c ep|de|ra| rec|c|]º|º |ea.eº |e||rd a |a|çe e|cº|cr. F|608£ 4-11 U|ce|. A |a|çe u|ce| W||| a |aççed |aºe ard |eaped up p|r| e|]||era|cuº |c|de| cr ||e |eç |ep|eºer||rç p|cç|eºº|rç p]c- de|ra çarç|ercºur. 29 ol poililoueina vaiies accoiuing to eti- ology. Because ol sone conlusion in the past stenning lion the use ol the voiu ¡oiki|odcrma in the naning ol specihc synuiones, it is piohahly hest to iestiict its use to a uesciiptive. A clinical exan- ple is chionic iauioueinatitis (lig. 4-1o, see Chap. º5). S|h0S A sinus is a tiact connecting ueep suppuiative cavities to each othei oi to the suilace ol the slin. ¯he contents ol the cavity, usually pus, huiu, oi leiatin, nay uiain to the suilace vhen such connuni- cation exists. ¯hese tiacts aie usually noteu on the scalp, necl, axillae, gioin, anu iectun. A clinical exanple is hiuiauenitis suppuiativa (lig. 4-14, see Chap. 8o). ST8|A£ Stiiae aie lineai uepiessions ol the slin that usually neasuie seveial centineteis in length anu iesult lion changes to the ieticulai collagen that oc- cui vith iapiu stietching ol the slin. ¯he suilace ol stiiae nay he thin anu viinlleu. ¯hey nay he pinl to ieu in coloi anu iaiseu heloie heconing palei anu hatteneu out. Stiiae aie nultiple anu typically synnetiically uistiihuteu along lines ol cleavage in the involveu aiea. A clinical exanple is stiiae uisten- sae (lig. 4-15, see Chap. 1O¯). 80880w A huiiov is a vavy, thieaulile tunnel thiough the outei poition ol the epiueinis excavateu hy a paiasite. Bui- iovs neasuie only a lev nillineteis in length. A clinical exanple is scahetic huiiov (lig. 4-16, see Chap. 2O8). S0L£80S|S :.|crosis ieleis to a ciicun- sciiheu oi uilluse haiuening oi inuuia- tion in the slin that is a iesult ol ueinal hhiosis. lt is uetecteu noie easily hy pal- pation, on vhich the slin nay leel hoaiu-lile, innohile, anu uilhcult to picl up. Hypeipignentation oi hypopig- nentation nay also uistinguish the aiea ol inuuiation lion noinal slin. ¯he epi- ueinis oveilying scleiotic ueinis nay he atiophic. Scleiosis nay extenu ueep into the pannus, lascia, nuscle, oi hone vith iesulting nusculosleletal ueloinity anu loss ol lunction. A clinical exanple is noiphea (lig. 4-1¯, see Chap. 62). ||a| ard |acu|a| |eº|crº NA00L£ A nacule is a hat lesion, even vith the suilace level ol suiiounuing slin, peiceptihle as an aiea ol coloi uil- leient lion the suiiounuing slin oi nu- cous nenhiane. íacules aie non-palpa- hle. ¯heii shapes aie vaiieu anu hoiueis nay he uistinct oi vague. íaculosgua- nous is a neologisn inventeu to ue- sciihe nacules vith hne non-palpahle scaling, vhich nay hecone appaient only altei light sciaping anu sciatching. leihaps the nost inpoitant auuitional leatuie ol a lesion othei than piinaiy noiphology is coloi. Lesional coloi, vhich is olten the hist visual assessnent naue, is ieliahly iepiouucihle vith pai- F|608£ 4-12 A||cp|]. T||r, W||r||ed a||cp||c º||r ||a| |aº |cº| ||º rc|ra| |e/|u|e cr ||e a|r c| |||º e|de||] Wcrar. F|608£ 4-13 Pc||||cde|ra. Pc||||cde|ra W||| |e|arç|ec|a||c e|]||era, |]pe|p|çrer|a||cr, |]pc- p|çrer|a||cr, ard a||cp|] |r c||cr|c |ad|cde|ra||||º. F|608£ 4-14 S|ruº. Suppu|a||.e ccrrur|- ca||rç |||cuº º|ruº ||ac|º |r ||e ç|c|r |ep|eºer|- |rç ||d|ader|||º ºuppu|a||.a. F|608£ 4-15 S|||ae. ||rea| º|||ae cr ||e |ac| c| |||º Wcrar W|c e/pe||erced a |ap|d ç|cW|| ºpu|| ard We|ç|| ça|r. F|608£ 4-16 Bu||cWº. Se.e|a|, º||ç|||] ºca|- |rç, |||ead-|||e |u||cWº cr ||e red|a| aºpec| c| ||e pa|r, aººcc|a|ed W||| a rc|e çere|a||/ed ec- /era|cuº p|cceºº |r |||º pa||er| |r|eº|ed W||| ºca||eº r||eº. F|608£ 4-17 Sc|e|cº|º. |||r, º||ç|||] de- p|eººed ºc|e|c||c p|a(ue cr ||e |eç c| a ç||| W||| rc|p|ea. T|e ºu||ace |º a||cp||c ard ||e|e a|e a|eaº c| |]pc- ard |]pe|p|çrer|a||cr. 30 ticulai types ol pathologies, such as ue- stiuction ol nelanocytes, uilatation ol ueinal hloou vessels, oi inhannation ol vessel valls vith extiavasation ol ieu hloou cells. As such, coloi pioviues neaninglul insight into pathologic pio- cesses ol the slin anu lacilitates clinical uiagnosis. lignentaiy changes iepiesent an inpoitant anu connon type ol nacu- lai coloi change anu nay he uesciiheu as hypeipignenteu (as in post-inhanna- toiy hypeipignentation), hypopignenteu (as in tinea veisicoloi), oi uepignenteu (as in vitiligo). ¯ahle 4-o uesciihes chaiacteiistic col- ois that nay he noteu vith inspection ol alteieu slin. A clinical exanple is len- tigo (lig. 4-18, see Chap. 122). PAT0h A patch is sinilai to a nacule, it is a hat aiea ol slin oi nucous nen- hianes vith a uilleient coloi lion its suiiounuing. A patch, hovevei, is laigei than O.5 cn, anu it nay have a hne, veiy thin scale. Conhuence ol patches nay covei laige aieas ol the houy. ¯he tein ¡at.h is also useu to uesciihe eaily le- sions ol cutaneous ¯-cell lynphona that have a hne scale oi aie nininally atiophic. A clinical exanple is vitiligo (lig. 4-1º, see Chap. ¯2). £8YTh£NA liythena iepiesents the hlanchahle change in coloi ol slin oi nu- cous nenhiane that is uue to uilatation ol aiteiies anu veins in the papillaiy anu ieticulai ueinis. lt exists in uilleient col- ois, anu to uuh a piinaiy lesion as cr,- thcmatous alone is inconplete. Desciihing eiythena vith the coloi it nost closely iesenhles pioviues a neaninglul clue to uiagnosis. loi exanple, violaceous eiy- thena hiings to ninu a uilleiential unigue lion salnon pinlcoloieu eiy- thena, even il hoth types ol eiythena in- volve papules. A clinical exanple is uusly eiythena, iepiesenting a hxeu uiug eiup- tion (lig. 4-2O, see Chap. 4O). £8YTh800£8NA liythioueina is a gen- eializeu ueep ieuness ol the slin involv- ing noie than ºO peicent ol the houy suilace vithin uays to veels. Scaling oi uesguanation geneially lollovs estah- lishnent ol the geneializeu eiythena. ¯he type ol scale noteu is suggestive ol F|608£ 4-18 |acu|e. Ur||c|r cc|c|ed ||cWr racu|e W||| º||ç|||] |||eçu|a|, º|a|p|] de|red |c|de|º |ep|eºer||rç a |er||çc cr ||e ||p. F|608£ 4-19 Pa|c|. Dep|çrer|ed pa|c|eº W||||r a|eaº c| rc|ra| º||r |cre |ep|eºer||rç .|||||çc. F|608£ 4-20 E|]||era. A |a|çe a|ea c| duº|] |ed e|]||era |r ||e ç|u|ea| |eç|cr |ep|e- ºer||rç a |/ed d|uç e|up||cr. Ik8L£ 4-3 |mp||cat|ons of 0o|or 0hangas |n A|tarad Sk|n 00L08 PATH0L00Y 0|A0h0ST|0 00hS|0F8AT|0h App|e je||] 0|aru|cra|cuº |r1arra||cr Tu|e|cu|cº|º, ºa|cc|dcº|º, |e|º|ra- r|aº|º B|ac| |e|ar|r, rec|cº|º |e|arcra, pu|pu|a |u|r|rarº, ca|c|- p|]|a/|º B|ue Deep de|ra| p|çrer|, |educed |ercç|c||r, |a||cc, red|ca||cr B|ue re.uº, ar|cda|cre B|cWr |e|ar|r, |ercº|de||r, c||cr|c |r1arra||cr, pcº|-|r1arra|c|], d||ed ºe|ur \e.uº, re|aºra Ccppe| |r1arra||cr W||| p|aºra ce||º Seccrda|] º]p||||º 0|eer Deep |ercº|de||r, p]cc]ar|r p|çrer|, ||ººue ecº|rcp||||a Isc0ccrcras |r|ec||cr, |a||cc, we||º º]rd|cre 0|e] Deep re|ar|r c| c||e| p|çrer| depcº|||cr C||c|c(u|re |c/|c||], rcrçc||ar ºpc|, e|]||era d]ºc||cr|cur pe|º|arº |||ac |r1arra||cr, d||a|a||cr c| deep de|ra| ||ccd .eººe|º Bc|de|º c| e.c|.|rç rc|p|ea, de|ra- |cr]cº|||º 0|arçe 0|aru|cra|cuº |r1arra||cr W||| ||º||cc]|eº |a.|rç a|urdar| c]|cp|aºr Ju.er||e /ar||cç|aru|cra Pea||] Ep|de|ra| p|c|||e|a||cr W|||cu| ºu||ace |e|a||r Baºa| ce|| ca|c|rcra P|r| Acu|e |r1arra||cr, d||a|a||cr c| ºupe||c|a| de|ra| ||ccd .eººe|º, |erc|||açe Ec/era Red Herc|||açe, acu|e |r1arra||cr, d||a|a||cr c| ||ccd .eººe|º Pºc||aº|º, d|uç e|up||crº Sa|rcr p|r| |r1arra||cr W||| |r.c|.erer| c| ep|de|r|º, d||a|a||cr c| ||ccd .eººe|º |r1arra||cr W||| edera P||]||aº|º |u||a p||a||º, pºc||aº|º, u|||- ca||a V|c|e| Herc|||açe, deep |ercº|de||r, ||c|erc|d |r1arra||cr ||c|er p|aruº, |apcº| ºa|ccra w|||e Reduced c| a|ºer| re|ar|r º]r||eº|º, pcº|- |r1arra|c|] T|rea .e|º|cc|c|, a|||r|ºr, .|||||çc \e||cW Supe||c|a| º|ap|]|cccccuº c| º||ep|cccccuº |r|ec||cr r|/ed W||| |e|a||r|/ed ce||º, ca|c|e- rc|dº, |ercº|de||r, |||e p|çrer|, accuru|a|ed ||p|d |rpe||çc, /ar||craº, ºe|acecuº |]pe|p|aº|a, rec|c||cº|º ||pc|d|ca d|a- |e||cc|ur, jaurd|ce 31 the piinaiy piocess (¯ahle 4-4). A clini- cal exanple is Sézaiy synuione (lig. 4-21, see Chap. 2o). Su||ace C|arçe S0AL£, 0£S00ANAT|0h (S0AL|h6) A scale is hat plate oi hale aiising lion the outei-nost layei ol the stiatun coi- neun. Cioups ol coheient coiniheu cells pacleu vith hlanentous pioteins uesguanate in scales inpeiceptihly lion the slin`s suilace unuei noinal ciicunstances on a iegulai hasis as the epiueinis is ieplaceu conpletely eveiy 2¯ uays. When epiueinal uilleientia- tion is uisoiueieu, accunulation anu casting ol stiatun coineun hecone ap- paient as scale vhich ianges in size lion hne uust-lile paiticles to extensive paichnent-lile sheets. ln sone cases, scale is ohseiveu only altei sciatching the lesion, a phenonenon lnovn as |a- tcnt dcsquamation. Not all scales aie sinilai, anu the ex- peit ueinatologist vith the vell-tiaineu eye can ohtain uiagnostically uselul in- loination lion close exaninations ol the type ol scale piesent. ¯ahle 4-4 ue- sciihes the types ol scale one nay en- countei. A clinical exanple is psoiiasis vulgaiis (lig. 4-22, see Chap. 18). 080STS (£h080ST£0 £X00AT£S) Ciusts aie haiueneu ueposits that iesult vhen seiun, hloou, oi puiulent exuuate uiies on the suilace ol the slin. ¯he appeai- ance ol ciust is lieguently heteioge- neous anu uepenus on the natuie ol secietion. ¯he coloi ol ciust is a yellov- hiovn vhen loineu lion uiieu seious secietion, tuihiu yellovish-gieen vhen loineu lion puiulent secietion, anu ieuuish-hlacl vhen loineu lion hen- oiihagic secietion. Supeihcial ciusts nay he thin, uelicate, anu liiahle. Ciusts nay he thicl anu auheient vhen in- volving the entiie thiclness ol the epi- ueinis. Snall oi punctate ciust nay ie- sult lion sciatching, vheieas laigei, honey-coloieu noist ciusts loin vith inpetiginization, a seconuaiy suppuia- tion. Centle naneuveiing ol ciust nay exuue secietions lion its hase. Renoval ol the ciust nay ieveal an unueilying eiosion oi ulcei. A clinical exanple is inpetigo (lig. 4-2o, see Chap. 1¯¯). £X008|AT|0hS lxcoiiations (lig. 4-24) aie suilace excavations ol epiueinis that iesult lion sciatching anu aie lie- guent hnuings in patients expeiiencing piuiitus. Rigoious oi uncontiollahle sciatching nay piouuce long, paiallel, sonetines ciossing, gioups ol excoiia- F|608£ 4-21 E|]|||cde|ra. 0ere|a||/ed |ed e|]||era ard e/|c||a||.e ºca|e |r |||º e|]|||cde|- r|c pa||er|. F|608£ 4-22 Sca|e. B|||||e º||.e|] ºca|eº |c|r|rç |||r p|a|e|e|º |r ºe.e|a| |ccºe º|ee|º, |||e r|ca, cr |||º p|a(ue c| pºc||aº|º. F|608£ 4-23 C|uº|. 0||º|er|rç, |cre]-cc|- c|ed, de||ca|e c|uº|º urde| ||e rcºe |ep|eºer||rç |rpe||çc. Ik8L£ 4-4 Typas of Sca|a TYPF 0F S0ALF 0FS08|PT|0h P80T0TYPF 0|A0h0S|S C|ac|-|||e/c|a(ue|e Deº(uara||cr ç|.|rç ||e appea|arce c| d||ed, c|ac|ed º||r. Ec/era c|a(ue|e E/|c||a||.e Sca|eº ºp||| c| ||cr ||e ep|de|r|º |r |re| ºca|eº c| |r º|ee|º. D|uç |eac||cr |c|||cu|a| Sca|eº appea| aº |e|a|c||c p|uçº, ºp|reº, c| ||- arer|º. |e|a|cº|º p||a||º 0||||] Derºe|] ad|e|er| ºca|e W||| a ºardpape| |e/|u|e. Ac||r|c |e|a|cº|º |c|||]cº||c|r Sca|eº a|e |eçu|a| pc|]çcra| p|a|eº a||arçed |r pa|a||e| |cWº c| d|arcrd pa||e|rº (|º|-|||e, |eººe|a|ed,. |c|||]cº|º .u|ça||º |e|a|c||c Sca|eº appea| aº |eaped up cc|urr c| ºca|e. Cu|arecuº |c|r |are||a| Sca|eº a|e |||r |a|çe p|a|eº c| º||e|dº a||ac|ed |r ||e r|dd|e ard |ccºe| a|curd ||e edçeº. |are||a| |c|||]cº|º P||]||aº||c|r Sca|e |º ºra|| ard ||arr]. P||]||aº|º |cºea Pºc||aº||c|r (r|ca- cecuº ard cº||acecuº, Sca|e |º º||.e|] ard ||||||e ard |c|rº |||r p|a|e- |e|º |r ºe.e|a| |ccºe º|ee|º, |||e r|ca (r|ca- cecuº ºca|e,. |a|çe ºca|eº ra] accuru|a|e |r |eapº, ç|.|rç ||e appea|arce c| ar c]º|e| º|e|| (cº||acecuº ºca|e,. Pºc||aº|º .u|ça||º Se|c|||e|c Sca|eº a|e |||c|, Wa/] c| ç|eaº], ]e||cW-|c- ||cWr, 1a|eº. Se|c|||e|c de|ra||||º w|c||ar º|||ae Sca|e appea|º aº a |ac] W|||e pa||e|r c.e||]|rç .|c|acecuº 1a|-|cpped papu|eº. ||c|er p|aruº 32 tions vhich nay he henoiihagic vhen light hleeuing is inuuceu. F|SS08£ A hssuie is a lineai loss ol con- tinuity ol the slin`s suilace oi nucosa that iesults lion excessive tension oi uecieaseu elasticity ol the involveu tis- sue. lissuies lieguently occui on the palns anu soles vheie the thicl stiatun coineun is least expanuahle. ¯iansi- tional aieas hetveen slin anu nucosa anu slin oveilying |oints aie susceptihle il elasticity is ieuuceu. A clinical exan- ple is hssuie on the paln associateu vith contact ueinatitis (lig. 4-25). L|0h£h|F|0AT|0h Repeateu iuhhing ol the slin nay inuuce a ieactive thiclen- ing ol the epiueinis, vith changes in the collagen ol the unueilying supeih- cial ueinis. ¯hese changes piouuce a thicleneu slin vith accentuateu nail- ings, vhich nay iesenhle tiee hail. Li- cheniheu plagues nay also shov signs ol sciatching, such as excoiiations anu ciusts. A clinical exanple is lichen sin- plex chionicus (lig. 4-26, see Chap. 15). k£8AT00£8NA leiatoueina is an exces- sive hypeileiatosis ol the stiatun coi- neun that iesults in a yellovish thicl- ening ol the slin, usually on the palns oi soles, that nay he inheiiteu (ahnoi- nal leiatin loination) oi acguiieu (ne- chanical stinulation). A clinical exanple is plantai leiatoueina (lig. 4-2¯, see Chap. 48). £S0hA8 ¯he piesence ol an eschai in- plies tissue neciosis, inlaiction, ueep huins, gangiene, oi othei ulceiating pio- cess. lt is a ciicunsciiheu, auheient, haiu, hlacl ciust on the suilace ol the slin that is noist initially, piotein iich, anu avasculai. ¯his nilieu losteis nicio- hial giovth. ¯he eschai nay slough nat- uially, oi it nay he uéhiiueu suigically to lacilitate ie-epithelialization anu vounu healing. A clinical exanple is theinal huin (lig. 4-28, see Chap. º4). ||u|d-||||ed |eº|crº V£S|0L£ Ah0 80LLA A vesicle is a huiu- hlleu cavity oi elevation snallei than oi egual to O.5 cn, vheieas a hulla (hlistei) neasuies laigei than O.5 cn. ¯he huiu in the cavity exeits egual piessuie in all ui- iections to give iise to a spheiical shape. Vesicles nay he non-palpahle in aieas ol thiclei stiatun coineun such as the paln, vheie theii piesence nay he sug- gesteu hy a ciicunsciiheu tianslucency oi a iesiuual collaiette ol scale lelt hehinu al- tei iuptuie. íucosal vesicles iuptuie eas- ily anu nay only he noteu as an eiosion oi vhite thin plague. Vesicles anu hullae aiise lion cleavage at vaiious levels ol the epiueinis (intiaepiueinal) oi ol the uei- nal-epiueinal inteilace (suh-epiueinal). ¯he anount ol piessuie ieguiieu to col- lapse the lesion nay help pieuict vhethei the hulla is intiaepiueinal oi suh-epiuei- nal. Reliahle uilleientiation, hovevei, ie- guiies histopathologic exanination ol the hlistei cavity euge. Cleavage |ust heneath the stiatun coineun piouuces a suh- coineal vesicle oi hulla. lntiaepiueinal ve- siculation nay iesult lion spongiosis (viueneu inteicellulai spaces uue to euena) oi acantholysis (loss ol cohesion hetveen leiatinocytes uue to the loss ol inteicellulai attachnents). °Ballooning ue- geneiation` (cytoplasnic svelling vith loss ol leiatinocyte attachnents) ol epi- ueinal cells noteu in viial inlections also iesults in epiueinal vesiculation. Because ol theii size, hullae aie easily iuentihahle as tense oi hacciu veepy hlisteis. Cnce collapseu oi toin, hlisteis nay leave hehinu eiosions. ¯he cavity vall is olten thin anu tianslucent enough to allov the visualization ol contents, vhich nay he cleai, seious, henoi- ihagic, oi pus hlleu. Cleavage in tense hullae aie connonly locateu at the ueinal-epiueinal |unction. Suh-epiuei- nal hlisteis aie usually a iesult ol ne- chanical liagility, oi autoinnunity to oi genetic alteiation ol a conponent ol the hasenent nenhiane zone. A clinical ex- anple ol vesicle is toxin-piouucing F|608£ 4-24 E/cc||a||cr. ||rea| ard purc- |a|e e/cc||a||crº cr ||e |ac| |rduced |] ºc|a|c||rç. F|608£ 4-25 ||ººu|e. A ||rea| |cºº c| ccr||ru- ||] c| ||e º||r cr ||e pa|r |ep|eºer||rç a |ººu|e. F|608£ 4-26 ||c|er||ca||cr. Ar a|ea c| |||c|ered º||r W||| accer|ua|ed º||r ra|||rçº |rduced |] |epea|ed |u|||rç, |ep|eºer||rç ||- c|er||ca||cr rc|ed |r ||c|er º|rp|e/ c||cr|cuº. F|608£ 4-27 |e|a|cde|ra. \e||cW|º| |||c|- er|rç c| º||r cr ||e ºc|eº |r |||º pa||er| W||| ar |r|e|||ed |e|a|cde|ra. F|608£ 4-28 Eºc|a|. 0.e||]|rç eºc|a|º ccr- p|cr|º|rç pe||p|e|a| pe||uº|cr |r a |u|r .|c||r. 33 staphylococcal inpetigo (lig. 4-2ºA, see Chap. 1¯8). A clinical exanple ol hulla is a hullous penphigoiu (lig. 4-2ºB, see Chap. 54). P0ST0L£ A pustule is a ciicunsciiheu, iaiseu cavity in the epiueinis oi in- lunuihulun containing pus. ¯he puiu- lent exuuate, conposeu ol leulocytes vith oi vithout cellulai uehiis, nay contain hacteiia oi nay he steiile. A Cian stain anu cultuie ol the exuuate lion pustules shoulu he peiloineu vhen the potential loi inlection exists. Depenuing on its steiility, the exuuate nay he vhite, yellov, oi gieenish-yellov in coloi. lustules nay vaiy in size anu, in ceitain situations, nay coalesce to loin °lales` ol pus. When associateu vith haii lollicles, pustules nay appeai conical anu contain a haii in the centei. ¯heie nay he an eiythenatous halo suiiounuing the pustule. Because ol theii supeihcial location, pustules genei- ally heal vithout scaiiing. A clinical ex- anple is supeihcial pyoueina (lig. 4-oO, see Chap. 1¯¯). F080h0L£ A luiuncle (lig. 4-o1, see Chap. 1¯¯) is a ueep neciotizing lolliculi- tis vith suppuiation. lt piesents as an in- haneu lollicle-centeieu nouule usually gieatei than 1 cn vith a cential neciotic plug anu an oveilying pustule. Seveial lu- iuncles nay coalesce to loin a caihuncle. A8S0£SS An ahscess (lig. 4-o2, see Chap. 1¯º) is a localizeu accunulation ol puiulent nateiial so ueep in the ueinis oi suhcutaneous tissue that the pus is usually not visihle on the suilace ol the slin. An ahscess is a pinl eiythenatous, vain, tenuei, huctuant nouule that nay he associateu vith othei signs ol inlec- tion such as levei. lt lieguently hegins as a lolliculitis iesulting lion stieptococcal oi staphylococcal inlection. Pu|pu|a/Vaºcu|a| |eº|crº P08P08A lxtiavasation ol ieu hloou lion cutaneous vessels into slin oi nu- cous nenhianes iesults in ieuuish- puiple lesions incluueu unuei the tein ¡ur¡ura. ¯he application ol piessuie vith tvo glass sliues oi an unhiealahle cleai lens (uiascopy) on a ieuuish-puiple lesion is a sinple anu ieliahle nethou loi uilleientiating ieuness uue to vascu- lai uilatation (eiythena) lion ieuness uue to extiavasateu eiythiocytes oi eiythiocyte piouucts (puipuia). ll the ieuness is non-hlanching unuei the pies- suie ol the sliue, the lesion is puipuiic. letechiae aie snall, pinpoint puipuiic nacules. lcchynoses aie laigei, hiuise- lile puipuiic patches. ¯hese lesions coi- iesponu to a noninhannatoiy extiava- sation ol hloou. As extiavasateu ieu hloou cells ueconpose ovei tine, the coloi ol puipuiic lesions change lion hluish-ieu to yellovish-hiovn oi gieen. ll a lesion is puipuiic anu palpahle (°pal- pahle puipuia`), the suggestion ol an in- hannatoiy insult to the vessel vall as a cause ol extiavasation ol hloou anu in- hannatoiy cells exists. A clinical exan- ple is leulocytoclastic vasculitis (lig. 4-oo, see Chap. 164). T£LAh6|£0TAS|A ¯elangiectasia (lig. 4-o4, see Chap. 1¯o) aie peisistent uilatations ol snall capillaiies in the supeihcial uei- nis that aie visihle as hne, hiight, non- pulsatile ieu lines oi net-lile patteins on the slin. ¯elangiectasia nay oi nay not uisappeai vith uiascopy. |hFA80T An inlaict is an aiea ol cutane- ous neciosis iesulting lion a hlanu oi inhannatoiy occlusion ol hloou vessels in the slin. A cutaneous inlaict piesents as a tenuei, iiiegulaily shapeu uusly ieuuish-giay nacule oi hin plague that is sonetines uepiesseu slightly helov the plane ol the slin. ¯he uenaication ol an inlaict coiiesponus to the uistiihu- tion ol hloou ol the allecteu vessels. A pinl zone ol hypeienia olten suiiounus the aiea ol inlaiction. A clinical exanple F|608£ 4-29 Veº|c|e (A, ard |u||a (8,. ||aç- ||e ºu|-cc|rea| ||arº|ucer| .eº|c|eº |ep|eºer||rç |rpe||çc cauºed |] a |c/|r-p|cduc|rç º|ap|]|c- ccccuº (A, ard |a|çe |erºe ºu|-ep|de|ra| |u||ae |||ed W||| ºe|cuº c| |erc|||aç|c 1u|d |r |||º pa- ||er| W||| |u||cuº perp||çc|d (8,. A 8 F|608£ 4-30 Puº|u|e. TWc puº|u|eº |ep|e- ºer||rç ºupe||c|a| p]cde|ra. F|608£ 4-31 |u|urc|e. Ar |r1ared |c|||cu|a|- |aºed rcdu|e W||| a cer||a| rec|c||c p|uç ||a| |aº ccre |ccºe. T|e|e |º c|uº||rç c.e| ||e ºu||ace. F|608£ 4-32 A|ºceºº. A |erde| |ed e|]||era- |cuº 1uc|uar| a|ºceºº cr ||e |eç. 34 is cholesteiol enholi (lig. 4-o5, see Chap. 1¯4). S|ape, A||arçerer|, ard D|º||||u||cr c| |eº|crº Cnce the type oi types ol lesions have heen iuentiheu, one neeus to uesciihe theii shape, aiiangenent, anu pattein ol uistiihution, all uselul chaiacteiistics in noiphologic uiagnosis. loi exanple, a single scaly plague on a patient`s tiunl nay have a hioau uilleiential uiagnosis, hut the sane plagues synnetiically uis- tiihuteu on the elhovs, lnees, anu un- hilicus voulu he highly suggestive ol psoiiasis. ¯he lolloving uesciiptions ol shapes anu aiiangenents ol slin lesions nay he applieu to single oi nultiple le- sions. loi exanple, a single lesion nay he lineai oi nultiple lesions nay as- sune a lineai pattein. ShAP£ 08 00hF|608AT|0h 0F Sk|h L£S|0hS º Annulai (lig. 4-o6): iing-shapeu, inplies that the euge ol the lesion uilleis lion the centei, eithei hy heing iaiseu, scaly, oi uilleiing in coloi (e.g., gianulona annulaie, tinea coipoiis, eiythena annulaie cen- tiilugun). º Rounu/nunnulai/uiscoiu (lig. 4-o¯): coin-shapeu, usually a iounu to oval lesion vith uniloin noiphology lion the euges to the centei (e.g., nunnulai eczena, plague-type pso- iiasis, uiscoiu lupus). º lolycyclic (lig. 4-o8): loineu lion coalescing ciicles, iings, oi incon- plete iings (e.g., uiticaiia, suhacute cutaneous lupus eiythenatosus). º Aicuate (lig. 4-oº): aic-shapeu, olten a iesult ol inconplete loination ol an annulai lesion (e.g., uiticaiia, suhacute cutaneous lupus eiythenatosus). F|608£ 4-33 Pu|pu|a. \cr-||arc||rç |ed e|]||era|cuº papu|eº ard p|a(ueº (pa|pa||e pu|pu|a, cr ||e |eçº, |ep|eºer||rç |eu|cc]|cc|aº||c .aºcu||||º. F|608£ 4-34 Te|arç|ec|aº|a. B|arc||rç d||a|ed ºupe||c|a| cap|||a||eº |ep|eºer||rç |e|arç|ec|aº|a. F|608£ 4-35 |r|a|c|. Duº|] pu|p|e d|ºcc|c|- a||cr |ep|eºer||rç ar a|ea c| |r|a|c||cr ||a| e.er- |ua|eº |r ||ººue rec|cº|º. T||º pa||er| |ad c|c|eº- |e|c| er|c|| |cdçed |r ||e d|º|a| erd a||e||eº c| ||e |ceº. 35 F|608£ 4-36 Arru|a| |eº|cr. (|||uº||a||cr |] 0|er H|r|/, |S. De|ra|c|cç] |e/- |ccr P|cjec|., F|608£ 4-37 \urru|a| |eº|cr. (|||uº||a||cr |] 0|er H|r|/, |S. De|ra- |c|cç] |e/|ccr P|cjec|., F|608£ 4-38 Pc|]c]c||c |eº|cr. (|||uº||a||cr |] 0|er H|r|/, |S. De|ra|c|cç] |e/|ccr P|cjec|., F|608£ 4-39 A|cua|e |eº|cr. (|||uº||a||cr |] 0|er H|r|/, |S. De|ra|c|cç] |e/|ccr P|cjec|., 36 º Lineai (lig. 4-4O): iesenhling a stiaight line, olten inplies an exteinal contactant oi loehnei phenonenon has occuiieu in iesponse to sciatch- ing, nay apply to a single lesion (e.g., a scahies huiiov, poison ivy ueinati- tis, oi hleonycin pignentation) oi to the aiiangenent ol nultiple lesions (e.g., lichen nitiuus oi lichen planus). º Reticulai (lig. 4-41): net-lile oi lacy in appeaiance, vith sonevhat iegu- laily spaceu iings oi paitial iings anu spaiing ol inteivening slin (e.g., liveuo ieticulaiis, cutis nainoiata). º Seipiginous (lig. 4-42): seipentine oi snale-lile (e.g., cutaneous laiva ni- gians, in vhich the laiva nigiates this vay anu that thiough the slin in a vanueiing pattein). º ¯aigetoiu (lig. 4-4o): taiget-lile, vith at least thiee uistinct zones (e.g., eiy- thena nultiloine). º Whoileu (lig. 4-44): lile naihle cale, vith tvo uistinct colois inteispeiseu in a vavy pattein, usually seen in nosaic uisoiueis in vhich cells ol uil- leiing genotypes aie inteispeiseu (e.g., incontinentia pignenti, hyponelano- sis ol lto, lineai anu vhoileu nevoiu hypeinelanosis). A||arçerer| c| |u|||p|e |eº|crº º Cioupeu/heipetiloin (lig. 4-45): le- sions clusteieu togethei (e.g., classic exanple is heipes sinplex viius 1 ie- activation noteu as gioupeu vesicles on an eiythenatous hase, also seen vith ceitain aithiopou hites). º Scatteieu (lig. 4-46): iiiegulaily uis- tiihuteu. D|º||||u||crº c| |u|||p|e |eº|crº º Deinatonal/zosteiiloin: unilateial anu lying in the uistiihution ol a sin- gle spinal alleient neive ioot, the classic exanple is heipes zostei. º Blaschloiu (lig. 4-4¯): lolloving lines ol slin cell nigiation uuiing enhiyo- genesis, geneially longituuinally oii- enteu on the linhs anu ciicunleiential on the tiunl, hut not peilectly lineai (see also Whoileu in Shape anu Con- hguiation ol Lesions), uesciiheu hy Allieu Blaschlo anu inplies a nosaic uisoiuei (e.g., incontinentia pignenti, inhannatoiy lineai veiiucous epiuei- nal nevus). º Lynphangitic: lying along the uistii- hution ol a lynph vessel, inplies an F|608£ 4-40 ||rea| d|º||||u||cr c| |eº|crº. (|||uº||a||cr |] 0|er H|r|/, |S. De|ra|c|cç] |e/|ccr P|cjec|., F|608£ 4-41 Re||cu|a| |eº|cr. (|||uº||a||cr |] 0|er H|r|/, |S. De|ra|c|cç] |e/|ccr P|cjec|., F|608£ 4-42 Se|p|ç|rcuº |eº|cr. (|||uº||a||cr |] 0|er H|r|/, |S. De|ra|c|cç] |e/|ccr P|cjec|., 37 F|608£ 4-43 Ta|çe|c|d |eº|cr. (|||uº||a||cr |] 0|er H|r|/, |S. De|ra|c|- cç] |e/|ccr P|cjec|., F|608£ 4-45 0|cuped. c|uº|e|ed. (|||uº||a||cr |] 0|er H|r|/, |S. De|ra|c|- cç] |e/|ccr P|cjec|., F|608£ 4-44 w|c||ed. ra|||ed appea|arce. (|||uº||a||cr |] 0|er H|r|/, |S. De|ra|c|cç] |e/|ccr P|cjec|., 38 inlectious agent that is spieauing cen- tially lion an acial site, usually a ieu stieal along a linh uue to a staphylo- coccal oi stieptococcal cellulitis. º Sun exposeu: occuiiing in aieas usu- ally not coveieu hy clothing, nanely the lace, uoisal hanus, anu a tiiangu- lai aiea coiiesponuing to the opening ol a V-necl shiit on the uppei chest (e.g., photoueinatitis, suhacute cuta- neous lupus eiythenatosus, poly- noiphous light eiuption, sguanous cell caicinona). º Sun piotecteu: occuiiing in aieas usu- ally coveieu hy one oi noie layeis ol clothing, usually a ueinatosis that is inpioveu hy sun exposuie (e.g., paiapsoiiasis, nycosis lungoiues). º Acial: occuiiing in uistal locations, such as on the hanus, leet, viists, anu anlles (e.g., palnoplantai pustu- losis, chilhlains). º ¯iuncal: occuiiing on the tiunl oi cential houy. º lxtensoi: occuiiing ovei the uoisal extienities, oveilying the extensoi nuscles, lnees, oi elhovs (e.g., pso- iiasis). º llexoi: oveilying the hexoi nuscles ol the extienities, the antecuhital anu popliteal lossae (e.g., atopic ueinatitis). º lnteitiiginous: occuiiing in the slin lolus, vheie tvo slin suilaces aie in contact, nanely the axillae, inguinal lolus, innei thighs, inlianannaiy slin, anu unuei an ahuoninal pan- nus, olten ielateu to noistuie anu heat geneiateu in these aieas (e.g., canuiuiasis). º Localizeu: conhneu to a single houy location (e.g., cellulitis). º Ceneializeu: viuespieau. A geneial- izeu eiuption consisting ol inhan- natoiy (ieu) lesions is calleu an cxanthcma (iash). A naculai exan- thena consists ol nacules, a papulai exanthena ol papules, a vesiculai exanthena ol vesicles, etc. (e.g., viial exanthens, uiug eiuption). º Bilateial synnetiic: occuiiing vith niiioi-inage synnetiy on hoth siues ol the houy (e.g., vitiligo, plague-type psoiiasis). º Univeisal: involving the entiie cuta- neous suilace (e.g., eiythioueina, alopecia univeisalis). ¯ahle 4-5 uesciihes sone clinically ielevant naneuveis anu noiphologic signs that point to paiticulai integunen- taiy oi systenic uiseases. As the late ¯honas B. litzpatiicl ol- ten saiu, °ueinatologists aie physicians vho can uiagnose a iash!`. ¯hey nay also he inteinists, suigeons, hiochenists, F|608£ 4-46 Sca||e|ed |eº|cr. (|||uº||a||cr |] 0|er H|r|/, |S. De|ra|c|cç] |e/|ccr P|cjec|., F|608£ 4-47 |eº|crº |r ||e d|º||||u||cr deºc|||ed |] B|aºc||c |c| de.e|cprer|a| |eº|crº. 39 Ik8L£ 4-5 SFLF0T|0h 0F 0UTAhF0US S|0hS a 0UTAhF0US S|0h 0FS08|PT|0h S|0h|F|0Ah0F App|e je||] º|çr A ]e||cW|º| |ue |º p|cduced ||cr p|eººu|e cr ||e |eº|cr W||| a ç|aºº º||de. \c|ed |r ç|aru|cra|cuº p|cceººeº. Aº|ce-Harºer º|çr |a|e|a| e/|erº|cr c| a |||º|e| W||| dcWrWa|d p|eººu|e. \c|ed |r |||º|e||rç d|ºc|de|º |r W||c| ||e pa||c|cç] |º a|c.e ||e |aºerer| rer||are /cre. Auºp||/ º|çr P|rpc|r| ||eed|rç a| ||e |cpº c| |up|u|ed cap|||a||eº W||| |c|c|||e |erc.a| c| cu|e| ºca|eº ||cr a pºc||a||c p|a(ue. \c| er|||e|] ºerº|||.e c| ºpec||c |c| pºc||aº|º. Bu||e|1] º|çr Bu||e|1]-º|aped ºpa||rç ||cr e/cc||a||crº c| ||e rcr|eac|a||e |r|e|ºcapu|a| |eç|cr. \c|ed |r d|ºc|de|º aººcc|a|ed W||| p|u|||uº ard |rp||eº ||a| ||e p|]º|ca| |rd|rçº a|e a ccrºe(uerce c| |u|||rç ard ºc|a|c||rç. Bu||cr|c|e º|çr A 1eº|-cc|c|ed, ºc|| papu|e |ee|º aº ||cuç| || car |e puº|ed |||cuç| a '|u||cr|c|e' |r|c ||e º||r. \c|ed |r a reu|c|||cra. Ca|pe| |ac| º|çr Hc|r] p|uçº a| ||e urde|ºu||ace c| ºca|e |erc.ed ||cr a |eº|cr. \c|ed |r |eº|crº c| c||cr|c cu|arecuº |upuº. C|cWe º|çr A/|||a|] ||ec|||rç. \c|ed |r reu|c|||cra|cº|º |]pe |, ra] |e ºeer aº pa|| c| |er- ||ç|rcº|º p|c|uºe. Da||e| º|çr U|||ca||a| W|ea| p|cduced |r a |eº|cr a||e| || |º |u||ed W||| ||e |curded erd c| a per. T|e W|ea|, W||c| |º º|||c||] ccr|red |c ||e |c|de|º c| ||e |eº|cr, ra] rc| appea| |c| ºe.e|a| r|ru|eº. \c|ed |r u|||ca||a p|çrer|cºa ard |a|e|] W||| cu|arecuº |]r- p|cra c| ||º||cc]|cº|º. De|ra|cç|ap||ºr |||r|] º||c||rç ura||ec|ed º||r p|cduceº a W|ea| a|crç ||e º|ape c| ||e º||c|e W||||r ºeccrdº |c r|ru|eº. S]rp|cra||c de|ra|cç|ap||ºr |ep|eºer|º a p|]º|ca| u|||ca||a. Pºeudc-Da||e| º|çr T|arº|er| |rdu|a||cr c| a |eº|cr c| p||ce|ec||cr a||e| |u|||rç. \c|ed |r ccrçer||a| ºrcc|| ruºc|e |ara||cra. |||/pa|||c| (d|rp|e, º|çr D|rp||rç c| ||e º||r W||| |a|e|a| ccrp|eºº|cr c| ||e |eº|cr W||| ||e ||ur| ard |rde/ |rçe| p|cduceº d|rp||rç due |c |e||e||rç c| ||e ep|de|r|º |c ||e de|ra| |eº|cr. C|a|ac|e||º||c c| de|ra|c|||cra. 0c|||cr º|çr Ra|ºed c| 1a| p|r| |c .|c|acecuº e|]||era ard/c| papu|eº c| re|a- ca|pa| c| |r|e|p|a|arçea| jc|r|º, c|ec|arcr, pa|e||ae, c| ra||ec||. C|aºº|ca||] uºed |r |e|e|erce |c de|ra|cr]cº|||º. Ha|| cc||a| R|rç c| da|| |crç ºca|p |a|| erc||c||rç a ccrçer||a| |eº|cr. Aººcc|a|ed W||| ap|aº|a cu||º, ercep|a|cce|e, rer|rçcce|e, c| |e|e|c|cp|c ||a|r ||ººue. He||c||cpe º|çr V|c|acecuº e|]||era c.e| e]e||dº. \c|ed |r de|ra|cr]cº|||º. He||cç|e º|çr T||rr|rç c| |cºº c| ||e cu|e| ||||d c| ||e e]e||cW. |a] |e aººcc|a|ed W||| a|cp|c de|ra||||º, |]pc||]|c|d|ºr, º]º- |er|c ºc|e|cº|º. Hu|c||rºcr ra|| º|çr Pe||urçua| e/|erº|cr c| p|çrer| |c ||e p|c/|ra| ard |a|e|a| ra|| |c|dº. \c|ed |r ºu|urçua| re|arcra. Hu|c||rºcr rcºe º|çr Veº|c|eº cr ||e ||p c| ||e rcºe |r a pa||er| W||| |e|peº /cº|e| c| ||e |ace. Due |c ||e |r.c|.erer| c| ||e raºcc|||a|] ||arc| c| cp|||a|r|c re|.e (V1, ard |rd|ca|eº a ||ç|e| |||e|||ccd c| ccu|a| d|ºeaºe. |eºe|-T|e|a| º|çr Sudder e|up||cr c| |r1arra|c|] ºe|c|||e|c |e|a|cºeº-|||e |eº|crº. Aººcc|a|ed W||| º]º|er|c ra||çrarc]. A|ºc |epc||ed W||| |er|çr recp|aºrº, ec/era, p|eçrarc], |ep|cº]. \||c|º|] º|çr |a|e|a| p|eººu|e cr ur|||º|e|ed º||r W||| |eºu|||rç º|ea||rç c| ||e ep|de|r|º. \c|ed |r |||º|e||rç d|ºc|de|º |r W||c| ||e pa||c|cç] |º a|c.e ||e |aºerer| rer||are /cre. Re|e.ar| er||||eº |rc|ude per- p||çuº .u|ça||º ard |c/|c ep|de|ra| rec|c|]º|º. 0|| d|cp º|çr A|ea c| ]e||cW|º| d|ºcc|c|a||cr |eºer|||rç ar c|| d|cp |r.c|.|rç ||e ra|| |ed d|º|a||] (|u| rc| |r.c|.|rç ||e ||ee edçe,. |rd|ca|eº cr]c|c|]º|º rc|ed |r pºc||a||c ra|| d|ºeaºe. Ruººe|| º|çr A||aº|crº, |ace|a||crº, ca||cº|||eº c| re|aca|pa| ard p|c/|ra| |r|e|p|a|arçea| jc|r|º. Due |c ||aura ||cr |rc|ºc| |ee|| du||rç ºe||-|rduced .cr|||rç |r |u||r|a. S|aW| º|çr E|]||era c.e| uppe| |ac| ard º|cu|de|º. C|aºº|ca||] uºed |r |e|e|erce |c de|ra|cr]cº|||º. T|cuººeau º|çr Recu||er| r|ç|a|c|] ºupe||c|a| |||cr|cp||e||||º c| ºra|| ard |a|çe cu|arecuº .e|rº. Aººcc|a|ed W||| |r|e|ra| ra||çrarc] (uºua||] parc|ea||c,, Be|çe| d|ºeaºe, ||c|e||º|a| |r|ec||crº. Uç|] duc|||rç º|çr A p|çrer|ed |eº|cr, arcrç rure|cuº a|]p|ca| |u| c||r|ca||] |er|çr re.|, ||a| º|ardº cu| ||cr ||e |eº| ard ra] |e a re|arcra. He|p|u| |r ºc|eer|rç rure|cuº p|çrer|ed |eº|crº |r a |cW-||º| |rd|.|dua|. 0rce ||e |eº|cr |º d|º||rçu|º|ed ||cr ||e c||e|º, || ra] |e e.a|ua|ed |u|||e| |c| a|rc|ra| c||r|ca| |ea|u|eº. a 0||e|º a|e d|ºcuººed |r ||e c|ap|e|º cr d|ºeaºeº |r W||c| ||e º|çrº cccu|. 40 oi innunologists, hut vithout conpe- tency in ueinatologic uiagnosis they cannot gualily as ueinatologists. ¯his slill, hovevei, is not specihc to ueina- tologists. Any physician vho nales the elloit to stuuy the slin anu leain the uei- natologic lexicon can uevelop a lunc- tional appieciation ol the lunuanentals ol uiagnosis. ¯he auvanceu uiagnostic eye can only he acguiieu hy enulessly ie- peateu encounteis in vhich the physi- cian is loiceu not only to lool at, hut also to ohseive, the iash vhile an expeii- enceu nentoi points the vay. ¯he nost connon eiioi in ueinatologic uiagnosis is to iegaiu the lesions as non-specihc °iashes` iathei than as aggiegates ol specihc inuiviuual lesions. As in sui- veying a hloou sneai, a °geneial in- piession` is not enough: ¯he noipho- logic aspects ol each inuiviuual cell nust he caielully sciutinizeu anu |uugeu to he noinal oi ahnoinal. ¯oo olten, physicians auopt a speeuy, su- peihcial appioach to the slin that they voulu not apply to any othei oigan that they exanine (¯ahle 4-6). Levis ¯honas has saiu that °íeui- cine is no longei the laying on ol hanus, it is noie lile the ieauing ol signals lion nachines.` ln ueinatol- ogy, theie can he no ieplacenent loi the laying on ol hanus, anu the physi- cian is iepeateuly giatiheu hy ieauing signals not lion nachines, hut lion people. SU00ESTED READ|\0S Beinhaiu [D et al: íaculopapulaiisn. Am j Dcrmato¡atho| 8:1¯o, 1º86 Beinhaiu [D (eu): lt.h: /c.hanisms and /an- agcmcnt oj lruritus. Nev Yoil, ícCiav- Hill, 1ºº4 Bolognia [L et al: Lines ol Blaschlo. j Am A.ad Dcrmato| 31:15¯, 1ºº4 Deinatology Lexicon lio|ect. http://vvv. l ut uieheal t h. i ochest ei. euu/ul p2/ ahoutDLl/ahtDLl.htn leueinan, DC et al: lull-houy slin exanina- tions: the patient`s peispective. Ar.h Dcrmato| 140:5oO, 2OO4 leinstein AR: C|ini.a| judgmcnt. Baltinoie, Willians 8 Willins, 1º6¯ Haxthausen H: Hov aie ueinatological uiag- noses naue` Trans :t johns Hos¡ Dcrma- to| :o. 30:o, 1º51 [aclson R: ¯he inpoitance ol heing visually liteiate. Ar.h Dcrmato| 111:6o2, 1º¯5 [aclson R: /or¡ho|ogi.a| Diagnosis oj :kin Dis- casc. Cntaiio, Ciinshy, 1ºº8 Leiuei í, Rosenhlun í: A Di.tionar, oj Dcr- mato|ogi.a| \ords. Tcrms. and lhrascs. Nev Yoil, ícCiav-Hill, 1º68 ¯honas L: Thc Youngcst :.icn.c. ^otcs oj a /cdi.inc-\at.hcr. Nev Yoil, Viling liess, 1º8o, p 58 Winlelnann Rl (chaiinan): ¯he lnteina- tional League ol Deinatologic Societies Connittee on Nonenclatuie. Clossaiy ol hasic ueinatologic lesions. A.ta Dcrm Vcncrco| :u¡¡| (:to.kh; 130:1, 1º8¯ C H A P T E R o 0|agoost|c Proced0res aod 0ev|ces A|cr Sccpe A||ar C. Ha|pe|r ´Don´t ¡ust stand thcrc and |ook: do somcthing´ Shelley WB anu Shelley lD 1 With a clinically vell-tiaineu eye anu appiopiiate patient histoiy, the na|oiity ol slin lesions can he uiagnoseu vith sinple visual inspection. Hovevei, ue- tails seen hy the naleu eye aie liniteu in nagnihcation, uepth, anu contiast. ln this chaptei, ve uiscuss pioceuuies anu uevices that can aiu the clinician in nal- ing the coiiect uiagnosis. We piesent the uiagnostic aius in an oiuei that esca- lates in teins ol invasiveness, cost, anu technical conplexity (see elig. 5-O.1 in on-line euition). E\HA\CE \0UR |00|. V|SUA| A|DS T0 |\SPECT|0\ |açr||]|rç |erº íagnihcation ol suilace pathology can he achieveu vith a hanu-helu lens. íag- nilying instiunents vith huilt-in lighting anu a nagnihcation ol 2- to 1O-lolu aie ieauily availahle. Svahhing the slin suilace vith alcohol oi application ol a uiop ol oil heloie nagnihcation can elininate uiit paiticles anu enhance the tianspaiency ol the stiatun coineun. D|aºccp] Diascopy is peiloineu hy hinly piessing a tianspaient, haiu, hat oh|ect (such as tvo nicioscope sliues) on the suilace ol the slin. ¯he usei shoulu he caielul not to in|uie the patient`s oi his oi hei ovn slin vith the shaip euge ol the sliue. Diascopy can he uselul in uistinguish- ing eiythena seconuaiy to vasouila- tion, vhich is hlanchahle vith pies- suie, lion eiythiocyte extiavasation (puipuia) vhich ietains its ieu coloi. ln nevus anenicus, in vhich the hloou vessels in the lesion aie vasoconstiicteu, piessuie on the euge ol the lesion nales the naigins inappaient. Dias- copy is also uselul in uetection ol the yellovish-hiovn (°apple |elly`) coloi in papules oi nouules ol gianulonatous piocesses, such as saicoiuosis, gianu- lona annulaie, anu tuheiculosis. wccd'º ||ç|| ¯he Woou`s light (°hlacl light`), hist ue- sciiheu in 1ºOo, is a uselul uevice loi the clinical evaluation ol vaiieu cutaneous uiseases such as pignent uisoiueis, slin inlections, anu poiphyiias. ¯he Woou`s Ik8L£ 4-6 Tan Po|ntars and P|tfa||s |n 0armato|og|c 0|agnos|s º App|cac| eac| ard e.e|] e.a|ua||cr W||| pa||erce ard ||c|cuç|reºº. º BeWa|e c| 'ºrap,' 'cu||º|de,' c| 'dcc|Wa]' d|açrcºeº. º E/ar|re ||e er|||e rucccu|arecuº ºu|- |ace, aº We|| aº ||e |a|| ard ra||º. º A reW c| c|arç|rç rc|e º|cu|d |e ca|e|u||] e.a|ua|ed. º Dc rc| |erc.e ||ººue W|||cu| ºerd|rç a pc|||cr |c| ||º|c|cç|c e/ar|ra||cr. º || ||e de|ra|cpa||c|cç|c |rd|rçº a|e rc| ccrº|º|er| W||| ||e c||r|ca| |rp|eºº|cr, c||a|r arc||e| ||cpº]. º || |c|ced |c c|ccºe |e|Weer |rccrç|uer| c||r|ca| ard pa||c|cç|c |rp|eºº|cr, |c||cW c||r|ca| |ead (cau||cuº|],. º 0ere|a||/ed p|u|||uº c| rc|e ||ar 1 rcr||'º du|a||cr rarda|eº a ccrp|e|e º]º|er|c Wc||up. º Seer|rç|] rcr-ºpec||c |aº|eº ra] juº| |e carcu1açed ºpec||c d|ºc|de|º. º D|uç-|rduced e|up||crº car r|r|c rcº| º||r ccrd|||crº. º Be Wa|] c| ||e 'a|]p|ca|' d|açrcº|º. A|]p|ca| '|||º' ra] |e '|]p|ca|' ||a| |c ºcrecre W|c |aº ºeer || |e|c|e. º Ccrº|de| a|| c||e| |eaºcra||e pcºº|||||||eº |e|c|e ra||rç a d|açrcº|º c| |ac||||a| d|ºc|de|. 41 light is piouuceu vith a high piessuie neicuiy lanp enitting thiough a °Woou`s hltei` naue ol silicate vith niclel oxiue, vhich is opague to all iaui- ation heyonu a vavelength hetveen o2O nn anu 4OO nn |ultiaviolet A (UVA)], vith peal enission at o65 nn. An exaninei using Woou`s light shoulu use a conpletely uail ioon, allov tine loi acconnouation ol vision to see the contiasts cleaily, holu the lanp at least 1O cn lion the slin, anu notily the pa- tient to avoiu looling uiiectly at the light souice. 2 Woou`s light is stiongly ahsoiheu hy nelanin, naling it a uselul tool in the evaluation ol pignenteu lesions. o A lesion vith an incieaseu concentiation ol epi- ueinal nelanin appeais uailei than sui- iounuing noinal slin, vith noie con- tiast than noinally uisceinihle hy visihle light exanination. ¯hus, Woou`s lanp can he helplul in ueteinining the suhtle clinical hoiueis ol a lentigo naligna. ¯he ahility ol Woou`s light to pio- uuce chaiacteiistic huoiescence in patho- logic conuitions extenus its application to slin inlections anu poiphyiia. ¯he gieen huoiescence ol ectothiix-type tinea capitis, as in /i.ros¡orum sp. inlec- tion, can help nale the coiiect heusiue uiagnosis, it can also seive as a guiue to the scalp site that has a highei lileli- hoou ol yieluing a positive cultuie, al- though not all cases cleaily huoiesce. ¯ ¯ypical huoiescence nay also he seen in eiythiasna (°coial ieu`), tinea veisicoloi (yellov to oiange) anu lscudomonas acruginosa inlection in huin patients (gieen), paiticulaily il the exanineu aiea has not heen cleanseu iecently. 4 ln poi- phyiia cutanea taiua, Woou`s light can he useu to scieen loi pinl-oiange huo- iescence in the uiine. ¯he exaninei shoulu he avaie ol lalse-positive souices ol huoiescence such as scales, ointnents, uiieu soaps, thieaus ol hhei, anu scais. De|rcºccp] Clinicians that use ueinoscopy have cone to appieciate suh-suilace uiagnos- tic cues. ¯hus enteis a nev set ol pii- naiy noiphology teins. Deinoscopy (iepoiteu in the liteiatuie unuei vaiieu nanes, incluuing c¡i|umincs.cn.c mi.ros- .o¡,, dcrmatos.o¡,, skin surja.c mi.ros.o¡,) is a non-invasive technigue that uses a hanu-helu instiunent (ueinoscope) eguippeu vith a light souice anu nagni- lying optics. ¯he application ol a liguiu inteilace (usually oil, vatei, oi alcohol) to the suilace ol the slin uecieases light iehection hy the epiueinis. ¯hus, the ueinoscope inneiseu in the huiu intei- lace allovs loi the visualization ol suh- suilace anatonic stiuctuies ol the epi- ueinis anu papillaiy ueinis that aie otheivise invisihle to the unaiueu eye (lig. 5-1). A polaiizeu-light ueinoscope allovs loi conpaiahle suh-suilace visu- alization hy ahsoihing suilace hacl- scattei, vithout the neeu loi slin con- tact oi liguiu inneision. Deinoscopy incieases clinical uiag- nostic accuiacy loi nelanona uiagnosis hy appioxinately 1O peicent to 2O pei- cent. 8 Deinoscopy lacilitates uilleienti- ating nelanocytic lesions lion othei pignenteu lesions such as sehoiiheic leiatoses, henangionas, anu pignenteu hasal-cell caicinonas. º A tvo-step algo- iithn has heen uevelopeu to appioach such uilleientiation. 1O,11 ln the hist step, the ohseivei ueciues vhethei the lesion is nelanocytic oi non-nelanocytic hy seaiching loi a set ol specihc stiuctuies, such as pignent netvoil anu glohules vhich connote nelanocytic lesions. ¯hese specihc ueinoscopic stiuctuies have heen coiielateu to lnovn histo- pathologic leatuies. 12 When a lesion is classiheu as nelanocytic, the ohseivei then continues to the seconu step, vhich involves assessnent (see Chap. 124) ol the lesion as henign oi nalignant. Seveial ueinoscopic algoiithns have heen uevel- opeu loi the seconu step, incluuing pat- tein analysis, the ABCD iule ol ueinos- copy (see Chap. 124), íenzies nethou, anu the ¯-point checllist ol ueinoscopy. 2 Deinoscopy nay also he helplul in the uiagnosis ol nonnelanona slin cancei. loi exanple, aihoiizing (hianching) hloou vessels aie typical ol hasal cell caicinonas, toituous, gloneiulus-lile (°gloneiuloiu`) hloou vessels aie seen in Boven uisease, anu pin-point, uotteu vessels in sguanous cell caicinona. Deinoscopy has also heen applieu to evaluation ol inhannatoiy lesions. Dei- noscopy ol the pioxinal nail lolus can he useu in place ol hully capillaioscopy to iuentily toituous, uilateu capillaiy loops anu nicio-henoiihages in autoin- nune uiseases such as scleioueina anu ueinatonyositis. 1o P|c|cç|ap|] Cne ol the nost inpoitant signs ol slin cancei is a histoiy ol change. lhysicians lieguently encountei situations in vhich the clinical uiagnosis ol a cutaneous le- sion is unceitain, anu thus, the piesence ol haseline photogiaphs loi conpaiison can lacilitate the uecision vhethei to D|A0\0ST|C PR0CEDURES A\D TECH\|0UES AT A 0|A\CE D|açrcº||c p|ccedu|eº ard |ec|r|(ueº car |e |ar|ed aº a |adde| ||a| eºca|a|eº |r |e|rº c| |r.aº|.ereºº, ccº|, ard |ec|- r|ca| ccrp|e/||]. T|e |aº|º |º c||r|ca| ||º|c|] ard p|]º|ca| e/ar|ra||cr ('aº|, |cc|, rar|pu|a|e',, |u| |u|||e| d|açrcº||c c|ueº car |e c||a|red ||cr .|ºua| a|dº ('er|arce ]cu| |cc|',, ºuc| aº wccd'º ||ç||, d|ç||a| p|c|cç|ap|], ard de|rcºccp]. T|e|e a|e |edº|de ard c||ce p|ccedu|eº, º|c|| c| a ||cpº], ||a| |rc|ude r|c|c- ºccp|c ard r|c|c||c|cç|c e.a|ua||cr c| |||º|e|º, ºca|eº, d|ºc|a|çed 1u|dº, ard |a|| ('ºc|ape, pu||, ºWa|',. |u|||e| |a|c|a|c|] ard |raç|rç e.a|ua||cr ra] |e |e(u||ed |c aººeºº |c| º]º|er|c |r.c|.erer| c| d|ºeaºe. Reºu||º c| d|açrcº||c p|ccedu|eº, |rc|ud- |rç ||cpº], reed |c |e |r|e|p|e|ed |r ||e ccr|e/| c| ||e c||r|ca| aººeººrer|. F|608£ 5-1 V|ºua| a|dº |c d|açrcº|º. ccr- pa||rç |aºe||re d|ç||a| p|c|cç|ap|] (A, |c ar |r- açe |a|er 8 ]ea|º |a|e| (8,, º|cWº a |eº|cr (cir- c!cs, |aº |eccre da||e| ard |a|çe|. C||r|ca| c|cºe-up |raçe |e.ea|º a /-rr ||cWr-|edd|º| papu|e rc| |r|e|er||] ccrce|r|rç |c| ra||çrarc] (0,. HcWe.e|, ||e deç|ee c| c|arçe a|crç W||| de|rcºccp] (0, ||a| º|cWº a ru|||-ccrpcrer| pa||e|r W||| a reça||.e re|Wc||, |||eçu|a| ç|c|- u|eº ard |eç|eºº|cr, p|crp|ed ar e/c|º|cra| ||- cpº]. T|e |eº|cr p|c.ed |c |e a ra||çrar| re|a- rcra 0.o |r B|eº|cW |||c|reºº. A 8 0 0 42 peiloin a hiopsy. ¯hose lesions that aie nev oi have signihcantly changeu nay neeu to he hiopsieu (see lig. 5-1), vheieas il the lesion is lounu to he sta- hle, the patient can he ieassuieu that the lesion is unlilely to he canceious. 1¯ A potential pitlall loi photogiaphically as- sisteu lollov-up is that ieliance on non- itoiing lesions loi change nay ieuuce the sensitivity loi uiagnosis ol slin can- cei at the initial visit, 18 vhich coulu leau to untovaiu outcones in patients vho uo not conply vith the ieconnenueu lollov-up. 1º SCRAPE, PU||, SwAB ¯he sciape, pull, svah step ol the uiag- nostic lauuei consiueis sanpling ol cuta- neous lesions shoit ol peiloining a hi- opsy. Haii can he sanpleu hy pulling oi plucling loi nicioscopic evaluation ol lungal inlection anu haii uisoiueis. Haii pulling, uenoting gentle tiaction ol haiis lion the ioots, is pieleiieu ovei the haii plucling nethou (guicl pulling vith hanu oi clanp), hecause it is less painlul anu iesults in less haii shalt uistoition. 2o A vesiculai lesion can he sciapeu loi ¯zancl sneai anu the huiu sent, il ap- piopiiate, loi cultuie oi othei niciohial analysis nethous, such as innunohuo- iescence oi polyneiase chain ieaction. ¯he lesion can he sciapeu vith a scalpel oi glass sliue to sanple scales in sus- pecteu lungal inlection, huiiovs in sca- hies, anu the hase ol an ulcei in genital lesions loi uiiect nicioscopic iuentihca- tion ol pathogens. 24 íucosal suilaces, such as the naies, oiophaiynx, anu uie- thia, can he svahheu loi niciohial cul- tuies. loi slin lesions, aspiiation ol pus/ huiu collection anu hiopsy aie hettei nethous loi pathogen iuentihcation than supeihcial svah sanpling. 25 lig. 5-2 uepicts exanples ol inlectious enti- ties that can he ieauily uiagnoseu in the olhce setting. B|0PS\ THE |ES|0\ Biopsy ol the slin is a ioutine anu es- sential uiagnostic technigue in ueinato- logic piactice, as the slin is ieauily ac- cessihle to hiopsy. ¯he hiopsy can he uselul to conhin the clinical assessnent vhen a uehnitive uiagnosis is neeueu, auu a uiagnostic clue vhen clinical evi- uence is inconclusive, anu occasionally uncovei an unsuspecteu uiagnosis. ¯he hiopsy nay also he ohtaineu to ieassuie the patient, anu olten the physician, that the uiagnosis is coiiect uespite suh- optinal iesponse to tieatnent. ln case ol lesions that aie ienoveu loi cosnetic puiposes, it is olten piuuent to suhnit the specinen loi pathologic evaluation loi neuicolegal consiueiations. Selecting the appiopiiate hiopsy tech- nigue ieguiies an unueistanuing ol the sanpling extent ol each nethou veigheu against the piohahle uiagnosis. 6 ln auui- tion, the tvo opposing vectois in selecting the hiopsy nethou aie the vish to nini- nize scaiiing, geaiing tovaiu a snallei, noie supeihcial hiopsy, veisus the linita- tions poseu on the histopathologic analy- sis hy inaueguate sanpling. 28 ¯he hip siue ol the cosnetic auvantage ol snall hiopsies is that an insulhcient hi- opsy nay nanuate a seconu pioceuuie that coulu actually iesult in an inleiioi cosnetic outcone than il a piopei hiopsy hau heen uone in the hist place. A hiopsy can conpletely ienove the lesion, oi in le- sions vith a laige suilace aiea, paitially sanple it. A shave hiopsy usually tiansects the supeihcial to niu-ueinis anu thus is noie appiopiiate to exophytic oi vaity piocesses oi lesions liniteu to the epiueinis oi papillaiy ueinis, such as sehoiiheic leiatosis, solai leiatosis, anu epiueinal nevus. A punch hiopsy shoulu he peiloineu il the pathology lies in the ueinis oi suhcutaneous lat. ¯he punch can ienove a snall lesion in its entiiety oi sanple a coie ol tissue in laigei lesions. lt is appiopiiate loi nost inhannatoiy pio- cesses, such as cutaneous vasculitis, oi ueinatoses associateu vith ueposits, such as gianulona annulaie. Hovevei, a punch hiopsy, unless ol sulhcient hoie to encon- pass the entiie lesion, is not the nethou ol choice loi ienoval ol nost neoplastic pio- cesses, hecause theie is a suhstantial iate ol inconplete excision anu uiagnostic sanpling eiioi. lathology iepoits shoulu not he ac- cepteu at lace value vhen inconsistent vith the clinical inpiession. o5 Clinical- pathology coiielation shoulu he pui- sueu thiough luithei sectioning anu ie- evaluation ol the specinen, peiloining auuitional hiopsies, oi hy seeling a sec- onu pathologist`s opinion. linally, theie aie ieaction patteins vith sinilai histo- pathologic appeaiance uespite uistinct etiology, as is olten the case vith chionic ueinatitis, anu thus luithei evaluation, such as patch testing, is vai- ianteu to uncovei the specihc cause. |\VEST|0ATE |URTHER F|608£ 5-2 w|a| |c e/pec| urde| ||e r|c|cºccpe. (A, ºep|a|e |]p|ae |r de|ra|cp|]|e |r|ec||cr, (8, |udd|rç ]eaº|º |r 0arcica, (0, p||]||aº|º .e|º|cc|c| dercrº||a||rç |]p|ae ard ºpc|eº ('ºpaç|e||| ard rea||a||º',, (0, ec|c||||/-|]pe ||rea cap|||º, (£, erdc||||/-|]pe ||rea cap|||º, (F, ru|||ruc|ea|ed ç|ar| ce|| |r |e|pe||c |r|ec||cr (T/arc| ºrea|,, (6, lcisIraria ||ººue araº||çc|eº, ard (h, d|p|ccccc| W||||r |eu|c- c]|eº |r çcrc|||ea. A 8 0 0 £ F 6 h 43 EV0|V|\0 TECH\0|00|ES Conputei-assisteu uiagnostic systens aie heing applieu piinaiily to the evalu- ation ol pignenteu lesions. íost sys- tens analyze the ueinoscopic inage ol a lesion, using a nultituue ol paiane- teis such as uinensions, geonetiy, nunhei ol colois, hue, uistiihution ol stiuctuies, textuie, anu giauient ol change lion the noinal slin. Anothei stiategy is nulti-spectial inaging, vhich applies a iange ol visihle-light anu neai inliaieu vavelengths to the lesion, vaii- ahle in the uepth ol theii slin penetia- tion anu theii enhancenent ol tissue chionophoies (such as nelanin, col- lagen, anu henoglohin). o6 ¯his pioviues the conputei vith a gieatei set ol pa- ianeteis loi analysis than the stanuaiu ueinoscopic inage. Suh-suilace inaging noualities in- cluue cutaneous ultiasonogiaphy, iehec- tance conlocal nicioscopy (RCí), anu optical coheience tonogiaphy (CC¯). Rules ol thunh that apply to suh-suilace inaging aie that (1) the ueepei one sees into the tissue, the lovei the inage ies- olution, anu (2) longei vavelengths pen- etiate ueepei. An inheient linitation ol inaging is ohseivei uepenuency. Ultiasounu inaging is haseu on the lact that tissue conponents inpeue anu iehect acoustic vaves uilleiently. o8 Ul- tiasounu systens piouuce a tvo-uinen- sional inage (°B-scan`) ol the slin hy uisplaying the nagnituue ol acoustic iehection as uegiee ol hiightness. ln- teineuiate lieguency ultiasounu (¯.5 to 1O.O íHz) is useu to evaluate suh- cutaneous nasses loi size, extent, anu consistency (soliu veisus cystic) anu to nonitoi loi the piesence ol ie- gional lynph-noue netastases in nela- nona. High-lieguency ultiasounu (2O íHz) is cuiiently unuei stuuy as a neans to assess tunoi thiclness pie- opeiatively in nelanona anu non-nela- nona slin cancei. ¯he hypoechogenic- ity ol tunois conpaieu vith the sui- iounuing ueinis loins the hasis loi inage contiast. ln contiast, CC¯ piouuces a tvo- uinensional veitical inage ol the slin that is analogous to the aloienentioneu B-noue ultiasounu inaging, except that it uses light iathei than sounu vaves. 48 Again, nelanin piouuces incieaseu hacl- scattei ol light naling this nouality po- tentially uselul loi pignenteu lesion eval- uation. Cuiiently conneicially availahle CC¯ systens uo not uelivei the cellulai- uetail iesolution ol RCí, liniting the ahility to uilleientiate henign anu nalig- nant lesions, hut inages ueepei into the tissue (up to 1 nn), alloving loi assess- nent ol the oveiall lesion aichitectuie anu uepth ol tunoi invasion. 4º |E\ RE|ERE\CES T|e |u|| |e|e|erce ||º| |c| a|| c|ap|e|º |º a.a||a||e a| WWW.d|çr/.ccr. o. laiaslevas LR, Halpein AC, íaighooh AA: Utility ol the Woou`s light: live cases lion a pignenteu lesion clinic. 3r j Dcrmato| 152:1Ooº, 2OO5 1O. Biaun Rl, Sauiat [H: Dilleiential uiag- nosis ol pignenteu lesions ol the slin, in At|as oj Dcrmos.o¡,, euiteu hy AA íaighooh, Rl Biaun, AW lopl. Nev Yoil, ¯ayloi 8 liancis, 2OO5, p 4o 1¯. íaighooh AA et al: lnstiunents anu nev technologies loi the in vivo uiag- nosis ol nelanona. j Am A.ad Dcrmato| 4º:¯¯¯, 2OOo 24. Biouell R¯, Helns Sl: Beusiue testing: the uiagnostic coineistone ol ueinatol- ogy. Com¡r Thcr 23:211, 1ºº¯ 25. Cill V[, leuoilo Dl, Witehsly lC: ¯he clinician anu the niciohiology lahoia- toiy, in lrin.i¡|cs and lra.ti.c oj lnjc.tious Discascs. 6th eu., euiteu hy CL íanuell, [l Bennet, R Dolin. lhilauelphia, llseviei Chuichill Livingstone, 2OO5, p 2Oo o1. llenitsas R, Nousaii CH, Seyloia [¯: Lahoiatoiy nethous, in lcvcr´s Histo¡a- tho|og, oj thc :kin. euiteu hy Dl lluei, R llenitsas, BL [ohnson, et al. lhilauel- phia, Lippincott Willians anu Willins, 2OO5, p 5º o5. Soyei Hl et al: Linitations ol histo- pathologic analysis in the iecognition ol nelanona: a plea loi a conhineu uiag- nostic appioach ol histopathologic anu ueinoscopic evaluation. Ar.h Dcrmato| 141:2Oº, 2OO5 C H A P T E R o 8as|c Patho|og|c 8eact|oos oI the Sk|o |a|||r C. |||r, J|. A|du|-0|ar| ||||| ||auº wc||| ¯he slin is conposeu ol uilleient tissue conpaitnents that inteiconnect ana- tonically anu inteiact lunctionally. lt is uilhcult to envisage epiueinal lunction vithout signals lion the ueinis oi pas- sengei leulocytes tiaveling to anu lion the slin. Cn the othei hanu, epiueinis, ueinis, anu suhcutaneous tissue aie heteiogeneous in natuie anu an analysis ol pathologic piocesses involving the slin shoulu theieloie consiuei hoth this heteiogeneity anu the inteiactions ol the inuiviuual cutaneous conpaitnents, only then vill it he unueistoou vhy a lev hasic ieactions leau to a nultiplicity ol ieaction patteins vithin this tissue. lathophysiologically, the slin can he suhuiviueu into thiee ieactive units that extenu heyonu anatonic hounuaiies (lig. 6-1), they oveilap anu can he ui- viueu into uilleient suhunits that ie- sponu to pathologic stinuli accoiuing to theii inheient ieaction capacities in a cooiuinateu pattein. ¯he supeihcial ieactive unit conpiises the suhunits epiueinis, the |unction zone, the suh|acent loose connective tis- sue ol the papillaiy houy anu its capillaiy netvoil, anu the supeihcial venulai plexus (see lig. 6-1, SRU). ¯he ieticulai layei ol the ueinis iepiesents anothei ie- active unit anu is conposeu ol connective tissue anu the ueepei ueinal vasculai plexus (see lig. 6-1, DRU). ¯he thiiu ieac- tive unit, the suhcutaneous tissue, is ana- tonically anu lunctionally also heteioge- neous, septal anu lohulai conpaitnents nay he involveu eithei alone oi togethei (see lig. 6-1, S). Haii lollicles anu glanus aie a sepaiate (louith) ieactive unit en- heuueu in these thiee hasic units. SUPER||C|A| REACT|VE U\|T Ep|de|r|º (See lig. 6-1, l) leiatinocytes, vhich have the capacity to leiatinize, iepiesent the hull ol the epiueinis. ¯he epiueinis, an ectouei- nal epitheliun, also haihois a nunhei ol othei cell populations such as nel- anocytes, Langeihans cells, íeilel cells, anu cellulai nigiants (see Chap. ¯). ¯he hasal cells ol the epiueinis unueigo pio- lileiation cycles that pioviue loi the ie- neval ol the epiueinis anu, as they nove tovaiu the suilace ol the slin, unueigo a uilleientiation piocess that iesults in leiatinization. ¯he epiueinis is thus a uynanic tissue in vhich cells aie constantly in nonsynchionizeu no- tion, the piolileiation linetics anu the 44 uiiection anu speeu ol nigiation ol the inuiviuual cell populations uillei lion each othei, so that leiatinocytes not only pass each othei hut also pass nel- anocytes oi Langeihans cells as they nove tovaiu the suilace ol the slin. At the sane tine they aie inteiconnecteu thiough loices ol cohesion that guaian- tee the continuity ol the epitheliun. Stahility loi this uiiectional cellulai hov is pioviueu hy the hasal nenhiane conplex (see Chap. 51), vhich anchois the epiueinis to the ueinis, anu the stiatun coineun, vhich encases the epiueinis on the outsiue. lt is heie that inuiviuual cell nigiation ceases as the leiatinizing cells aie hinly inteicon- necteu hy an inteicellulai cenent-lile suhstance (see Chap. 45). ¯hese loices ol cohesion aie hnally lost at the suilace ol the epiueinis vheie the inuiviuual coiniheu cells aie uesguanateu. latho- logic changes vithin the epiueinis nay theieloie ielate to the linetics ol epiuei- nal cells oi theii uilleientiation (see Chap. 44) anu nay involve tiansepiuei- nal nigiation anu intiaepiueinal cohe- sion, they also ielate to peiipatetic leu- locytes anu Langeihans cells tialhcling to anu lion the epiueinis anu auhesion nolecules lacilitating anu uiiecting such cellulai novenents. loi exanple, unless a Langeihans cell expiesses the cheno- line CCR6, it cannot nigiate lion the ueinis to the epiueinis. Without ex- piession ol CCR¯, nigiation to the lynph noue is not possihle. luithei- noie, nany pathologic alteiations aie ielateu to cytolines anu hoinones gen- eiateu hy leiatinocytes, Langeihans cells, nelanocytes, anu peiipatetic leu- locytes. ¯hey nay allect the entiie cell population oi inuiviuual cells, nay he piinaiily taigeteu on leiatinocytes, oi nay enconpass the othei epiueinal cell populations as vell. 0|ST088Ah0£S 0F £P|0£8NAL 0£LL k|h£T- |0S ¯he nitotic iate ol geininative cells, the uesguanation iate ol coineocytes, anu the geneiation tine ol epiueinal cells ue- teinine the honeostasis ol the epiueinis (see Chap. 44). Unuei physiologic conui- tions, theie is a halance anong piolileia- tion, uilleientiation, anu uesguanation. lnhanceu cell piolileiation acconpanieu hy an enlaigenent ol the geininative cell pool anu incieaseu nitotic iates leau to an inciease ol the epiueinal cell population anu thus to a hioauening ol the epiueinis (a.anthosis) (lig. 6-2). A shilt in the iatio ol iesting to piolileiating cell as is the case in psoiiasis (see Chap. 18) vill leau to hoth an inciease in the tuinovei ol the entiie epiueinis anu to a consiueiahle inciease ol the volune ol geininative cells that have to he acconnouateu at the ueinal- epiueinal |unction. ¯his in tuin iesults in an elongation ol the iete iiuges, vhich is acconpanieu hy BAS|C PATH0|00|C REACT|0\S AT A 0|A\CE D|||e|er| ||ººue ccrpa||rer|º |r|e|ccr- rec| ara|cr|ca||] ard |r|e|ac| |urc||cr- a||]. T|eºe a|e ||e |eac||.e ur||º c| º||r. T|e ºupe||c|a| |eac||.e ur|| ccrp||ºeº ||e ep|de|r|º, ||e jurc||cr /cre, ard ||e pap|||a|] |cd] W||| ||º .aºcu|a| º]º|er. T|e |e||cu|a| de|r|º W||| ||e deepe| de|- ra| .aºcu|a| p|e/uº |º ||e ºeccrd |eac- ||.e ur||. T|e ||||d |eac||.e ur|| |º ||e ºu|cu|are- cuº ||ººue W||| ||º ºep|a| ard |c|u|a| ccrpa||rer|º. Ha|| |c|||c|eº ard ç|ardº a|e a |cu||| |eac- ||.e ur|| er|edded |r|c ||eºe |||ee ur||º. Pa||c|cç|c p|cceººeº ra] |r.c|.e ||eºe |eac||.e ur||º a|cre c| ºe.e|a| c| ||er |r a ccrce||ed |aº||cr. T|e |e|e|cçer|c||] ard |r|e|ac||cr c| ||eºe |rd|.|dua| cu|arecuº ccrpa||rer|º e/p|a|r W|] a |eW |aº|c pa||c|cç|c |eac- ||crº |ead |c a ru|||p||c||] c| c||r|ca| ard pa||c|cç|c |eac||cr pa||e|rº. F|608£ 6-1 Reac||.e ur||º c| º||r. T|e ºupe||c|a| |eac||.e ur|| (SRU, ccrp||ºeº ||e ep|de|r|º (E,, ||e jurc||cr /cre (J,, ard ||e pap|||a|] |cd] (PB, W||| ||e ºupe||c|a| r|c|c.aºcu|a| p|e/uº. T|e de|ra| |eac||.e ur|| (DRU, ccrº|º|º c| ||e |e||cu|a| de|r|º (RD, ard ||e deep de|ra| r|c|c.aºcu|a| p|e/uº (DVP,. T|e ºu|cu- |arecuº |eac||.e ur|| (S, ccrº|º|º c| |c|u|eº (|, ard ºep|ae (Sep,. A |cu||| ur|| |º ||e apperdaçeº (A, |a|| ard ºe|acecuº ç|ardº a|e ||e cr|] apperdaçeº º|cWr,. H| = |a|| |c|||c|e. 45 a conpensatoiy elongation ol the con- nective tissue papillae, iesulting in an en- laigenent ol the ueinal-epiueinal intei- lace anu, conseguently, in an incieaseu aiea loi ueinal-epiueinal inteiactions (see lig. 6-2). 0|ST088Ah0£S 0F £P|0£8NAL 0£LL 0|FF£8- £hT|AT|0h A sinple exanple ol uistuiheu epiueinal uilleientiation is paialeia- tosis, in vhich laulty anu acceleiateu coinihcation leaus to a ietention ol pylnotic nuclei ol epiueinal cells (see lig. 6-2). A paialeiatotic stiatun coi- neun is not a conpact sheet ol coini- heu cells hut a loose stiuctuie vith gaps hetveen cells, these gaps leau to a loss ol the haiiiei lunction ol the epiueinis. laialeiatosis can he the iesult ol in- conplete uilleientiation in postnitotic geininative cells. Consiueiing a tiansit tine ol 14 uays loi a postnitotic epiuei- nal cell, a pathologic signal inuucing pai- aleiatosis in a cell eaily in uilleientiation ieguiies alnost 2 veels to appeai histo- logically in the stiatun coineun. Altei- natively, paialeiatosis can also he the ie- sult ol ieuuceu tiansit tine, vhich uoes not peinit epiueinal cells to conplete the vhole uilleientiation piocess, as loi exanple in psoiiasis. Hovevei, °paia- leiatosis` ol cellophane-stiippeu epiuei- nis hecones nicioscopically visihle as eaily as 1 houi altei tiauna, heie, paia- leiatosis uoes not iepiesent uistuiheu uilleientiation, iathei, it iesults lion ui- iect cellulai in|uiy to a viahle epiueinis uepiiveu ol its piotective hoiny layei. ¯heieloie, the noiphologic tein ¡arak- cratosis signihes hoth a piogianneu uis- tuihance ol uilleientiation anu natuia- tion anu uiiect cellulai in|uiy. D,skcratosis is a tein loineily useu loi pienatuie coinihcation ol inuiviuual cells vithin the viahle layeis ol the epi- ueinis. lt is nov unueistoou that uys- leiatosis iepiesents the noiphologic piesentation ol apoptosis ol leiatino- cytes. Dysleiatotic cells have an eosino- philic cytoplasn anu a pylnotic nucleus anu aie pacleu vith leiatin hlanents aiiangeu in peiinucleai aggiegates. Such a cell vill tenu to iounu up anu lose its attachnents to the suiiounuing cells. Dysleiatosis is theieloie olten associ- ateu vith acantholysis (see Distui- hances ol lpiueinal Cohesion) hut not vice veisa (lig. 6-o). ln sone uiseases, uysleiatosis is the ex- piession ol a genetically piogianneu uis- tuihance ol leiatinization as is the case in Daiiei uisease (see Chap. 4º). Dysleiato- sis nay occui in actinic leiatosis anu sguanous cell caicinona. Dysleiatosis nay also he causeu hy uiiect physical anu chenical in|uiy. ln the sunhuin ieaction, eosinophilic, apoptotic cellsso-calleu sunhuin cellsaie lounu vithin the epi- ueinis vithin the hist 24 houis altei iiia- uiation vith UVB (see Chap. 8º), anu sin- ilai °uysleiatotic,` that is, apoptotic, cells nay occui altei high uose systenic cyto- toxic tieatnent. lnuiviuual cell ueath vithin the epiueinis is a iegulai phenon- enon in gialt-veisus-host ieactions ol the slin (see Chap. 28) anu in eiythena nul- tiloine (see Chap. o8). 0|ST088Ah0£S 0F £P|0£8NAL 00h£S|0h lpiueinal cohesion is the iesult ol a uy- nanic eguilihiiun ol loining anu uisso- ciating inteicellulai contacts. Specihc inteicellulai attachnent uevices (uesno- sones) anu the inteicellulai suhstance aie iesponsihle loi inteicellulai cohesion. Hovevei, epiueinal cohesion nust pei- nit epiueinal cell notion. Desnosones uissociate anu ie-loin at nev sites ol inteicellulai contact as cells nigiate thiough the epiueinis. lnteicellulai cohe- sion loices aie stiong enough to guaiantee the continuity ol the epiueinis as an un- inteiiupteu epitheliun hut, on the othei hanu, aie auaptahle enough to peinit lo- conotion, peineahility ol the inteicellulai space, anu inteicellulai inteiactions. ¯he nost connon iesult ol uistuiheu epiueinal cohesion is the intiaepiuei- nal vesicle, a snall cavity hlleu vith huiu. A classihcation ol intiaepiueinal hlisteiing hy anatonic level is shovn in ¯ahle 6-1. F|608£ 6-2 Acar||cº|º. T||º º|çr c| |rc|eaºed ep|de|ra| ||re||cº |º |||uº||a|ed |r a p|c|cr|c|c- ç|ap| c| pºc||aº|º. Pa|a|e|a|cº|º, ||e |e|er||cr c| ruc|e| |r ||e |c|r] |a]e|, |º e.|der|. Ik8L£ 6-1 0|ass|hcat|on of |ntraap|darma| 8||stars by Anatom|c Lava| w|th 0||n|ca| Fxamp|as 0|aru|a| |a]e| |||c||cr |||º|e| Perp||çuº |c||aceuº Su|cc|rea| puº|u|a| de|ra|cº|º S|ap|]|ccccca| ºca|ded-º||r º]rd|cre/ |u||cuº |rpe||çc Sp|rcuº |a]e| Ec/era|cuº de|ra||||º He|peº.||uº |r|ec||cr |ar|||a| |er|çr perp||çuº Sup|a|aºa| Perp||çuº .u|ça||º Da||e| d|ºeaºe Baºa| |a]e| E|]||era ru||||c|re |upuº e|]||era|cºuº ||c|er p|aruº Ep|de|rc|]º|º |u||cºa F|608£ 6-3 T|e aººcc|a||cr c| d]º|e|a|cº|º ard acar||c|]º|º |º ºeer |r |||º ||ç|-pcWe| .|eW c| Da||e| d|ºeaºe, W||c| a|ºc dercrº||a|eº ||e |r||aep|de|ra| c|e|| |c|ra||cr |eºu|||rç ||cr ||eºe p|ercrera. 46 ¯hiee hasic noiphologic patteins ol intiaepiueinal vesicle loination aie clas- sically iecognizeu. :¡ongiosis is an exan- ple ol the seconuaiy loss ol cohesion he- tveen epiueinal cells uue to the inhux ol tissue huiu into the epiueinis. Seious ex- uuate nay extenu lion the ueinis into the inteicellulai conpaitnent ol the epi- ueinis, as it expanus, epiueinal cells ie- nain in contact vith each othei only at the sites ol uesnosones, acguiiing a stel- late appeaiance anu giving the epiueinis a spongelile noiphology (spongiosis). As the inteicellulai euena incieases, in- uiviuual cells iuptuie anu lyse, anu ni- ciocavities (spongiotic vesicles) iesult (lig. 6-4). Conhuence ol such niciocavi- ties leaus to laigei hlisteis. lpiueinal cells nay also he sepaiateu hy leulo- cytes that uistuih intiaepiueinal cohei- ence, thus, the nigiation ol leulocytes into the epiueinis anu spongiotic euena aie olten a conhineu phenonenon, hest illustiateu hy acute contact ueinatitis. ¯he accunulation ol polynoiphonucleai leulocytes vithin the epiueinis, the ie- sulting sepaiation ol epiueinal cells, anu theii suhseguent uestiuction eventually leau to the loination ol a spongiloin pustule, one ol the histopathologic hall- nails ol psoiiasis. A.antho|,sis is a piinaiy loss ol cohe- sion ol epiueinal cells. ¯his is initially chaiacteiizeu hy a sepaiation ol the in- teiuesnosonal iegions ol the cell nen- hianes ol leiatinocytes, lolloveu hy splitting anu a uisappeaiance ol uesno- sones (see Chap. 52). ¯he cells aie in- tact hut aie no longei attacheu, they ac- guiie theii snallest possihle suilace anu iounu up (ligs. 6-o anu 6-5). lnteicellulai gaps anu slits iesult, anu the inhux ol huiu lion the ueinis leaus to a cavity, vhich nay loin in a supiahasal (lig. 6-6), niuepiueinal, oi even suhcoineal location. Acantholytic cells can easily he uenonstiateu in cytologic sneais (see lig. 6-5) anu in sone conuitions have ui- agnostic signihcance. Acantholysis occuis in a nunhei ol uil- leient pathologic piocesses that uo not have a uniloin etiology anu pathogen- esis. Acantholysis nay he a piinaiy event leauing to intiaepiueinal cavita- tion (piinaiy acantholysis) oi a seconu- aiy phenonenon in vhich epiueinal cells aie sheu lion the valls ol estah- lisheu intiaepiueinal hlisteis (seconu- aiy acantholysis). liinaiy acantholysis is a pathogenetically ielevant event in uiseases ol the penphigus gioup (see Chap. 52), in vhich it iesults lion the inteiaction ol autoantihouies anu anti- genic ueteininants on the leiatinocyte nenhianes anu in the staphylococcal scalueu-slin synuione, vheie it is causeu hy a staphylococcal exotoxin (epiueinolysin) (see Chap. 1¯8). ln la- nilial henign penphigus, it iesults lion the conhination ol a genetically ueteinineu uelect ol the leiatinocyte cell nenhiane anu exogenous lactois F|608£ 6-4 Spcrç||c|r .eº|c|e |eºu|||rç ||cr edera|cuº ºepa|a||cr c| |e|a||rcc]|eº. T|eºe a|e º|||| pa|||a||] a||ac|ed |c eac| c||e| |] deºrcºcreº ard |a.e ||uº ac(u||ed a º|e||a|e appea|arce. F|608£ 6-5 Acar||c|]º|º. S|rç|e aº We|| aº c|uº|e|º c| acar||c|]||c ce||º a|e ºeer. T|e |curd º|apeº |eºu|| ||cr ||e |cºº c| |r|e|ce||u|a| ccrrec||crº. C]|c|cç|c ºrea| p|epa|a||cr c| perp||çuº .u|ça||º. F|608£ 6-6 Perp||çuº .u|ça||º. Ar |r||aep|de|ra| ºup|a|aºa| c|e|| |º .|º|||e ||a| |aº |eºu||ed ||cr ºup|a|aºa| acar||c|]º|º. || ccr|a|rº acar||c|]||c ard |r1arra|c|] ce||º. 47 (see Chap. 4º). A sinilai phenonenon, alheit noie conhneu to the supiahasal epiueinis, occuis in Daiiei uisease, vheie it is conhineu vith uysleiato- sis in the uppei epiueinal layeis (see lig. 6-o) anu a conpensatoiy piolileia- tion ol hasal cells into the papillaiy houy (see Chap. 4º). When acantholy- sis iesults lion viial inlection, it is usu- ally conhineu vith othei cellulai phe- nonena such as hallooning giant cells anu cytolysis (lig. 6-¯, see Chaps. 1ºo anu 1º4). lnueeu, a loss ol epiueinal cohesion can also iesult lion a uissolution ol cells (i.e., cytolysis). ln the epiueinolytic loins ol epiueinolysis hullosa, hasal cells iuptuie as a iesult ol tiauna so that the clelt loins thiough the hasal cell layei inuepenuently lion pieexisting anatonic hounuaiies (see Chap. 6O). Cytolytic phenonena in the stiatun gianulosun aie chaiacteiistic loi epiuei- nolytic hypeileiatosis, hullous congen- ital ichthyosiloin eiythioueina, ich- thyosis hystiix, anu sone loins ol heieuitaiy palnoplantai leiatoueina (see Chaps. 4¯ anu 48). De|ra|-Ep|de|ra| Jurc||cr (See lig. 6-1, [) lpiueinis anu ueinis aie inteilocleu hy neans ol the epiueinal iete iiuges anu the coiiesponuing ueinal papillae anu loot-lile cytoplasnic niciopiocesses ol hasal cells that extenu into coiiesponu- ing inuentations ol the ueinis. Deinal- epiueinal attachnent is enloiceu hy heniuesnosones that anchoi hasal cells on the hasal lanina, this, in tuin, is attacheu to the ueinis hy neans ol an- choiing hlanents anu niciohhiils (see Chap. 51). ¯he hasal lanina is not a iigiu stiuctuie hecause leulocytes, Langei- hans cells, oi othei nigiatoiy cells pass thiough it vithout causing a peinanent hieach in the |unction. Altei heing ue- stioyeu hy pathologic piocesses, the hasal lanina is ieconstituteu, this iepie- sents an inpoitant phenonenon in vounu healing anu othei iepaiative piocesses. lunctionally, the hasal lanina is pait ol a unit that, hy light nicios- copy, appeais as the peiiouic aciu- Schillpositive °hasal nenhiane` anu, in lact, iepiesents the entiie |unction zone. ¯his consists ol the lanina luciua, spanneu hy niciohlanents, anu suh|a- cent anchoiing hhiils, snall collagen h- heis, anu extiacellulai natiix (see Chap. 51). ¯he |unction zone is a lunctional conplex that is piinaiily allecteu in a nunhei ol pathologic piocesses. 0|ST088Ah0£S 0F 0£8NAL-£P|0£8NAL 00h£S|0h ¯he uestiuction ol the |unc- tion zone oi its conponents usually nanilests as uistuihance ol ueinal- epiueinal cohesion anu leaus to hlistei loination. ¯hese hlisteis appeai to he suhepiueinal hy light nicioscopy (lig. 6-8) hut in ieality nay he localizeu at uil- leient levels anu iesult lion pathogeneti- cally heteiogeneous piocesses. A classih- cation ol hlisteis at the |unction hy anatonic level is given in ¯ahle 6-2. Suh- epiueinal hlistei loination occuis in loins ol epiueinolysis hullosa (see Chap. 6O) oi can he the iesult ol a con- plex inhannatoiy piocess that involves the entiie |unction zone, as is the case in lupus eiythenatosus, eiythena nulti- loine, oi lichen planus, theieloie, it nay he a phenonenon occuiiing in a gioup ol etiologically anu pathogenetically hetei- ogeneous conuitions. ln hullous penphi- goiu (see lig. 6-8), clelt loination iuns thiough the lanina luciua ol the hasal nenhiane anu is causeu hy autoantihou- ies uiiecteu against specihc antigens on the cytonenhiane ol hasal cells (¡un.- tiona| ||istcring) (see lig. 6-8, see Chap. 54). ¯he piesence ol eosinophil gianules that contain na|oi hasic piotein that is toxic to leiatinocytes also causes leiati- nocyte in|uiy. [unctional hlisteiing also occuis in the |unctional loins ol epiuei- nolysis hullosa, hut heie it is uue to the inpaiinent oi ahsence ol nolecules in- poitant loi epiueinal-ueinal cohesion (see Chap. 6O, see ¯ahle 6-2). ln suh-epiueinal hlisteiing, the taiget ol the pathologic piocess is helov the hasal lanina (ueinolytic hlisteiing) (see ¯ahle 6-2). Reuuceu anchoiing hlanents anu incieaseu collagenase piouuction iesult in ueinolytic ueinal-epiueinal sepaiation in iecessive epiueinolysis hullosa (see Chap. 6O), ciiculating auto- F|608£ 6-7 He|peº º|rp|e/ |r|ec||cr. T|e ep|de|r|º º|cWº ra||ed |a||ccr|rç deçere|a- ||cr, c]|c|]º|º, ard |r||aep|de|ra| .eº|cu|a||cr. Acar||c|]||c ard ru|||ruc|ea|ed ep|de|ra| ç|ar| ce||º a|e a c|ue |c |e|pe||c |r|ec||cr. Ik8L£ 6-2 0|ass|hcat|on of 8||stars at tha 0arma|- Fp|darma| Junct|on by Anatom|c Lava| w|th 0||n|ca| Fxamp|as Jurc||cra| (a| ||e |ar|ra |uc|da, Jurc||cra| ep|de|rc|]º|º |u||cºa Bu||cuº perp||çc|d De|rc|]||c (|e|cW |aºa| |ar|ra, Ep|de|rc|]º|º |u||cºa d]º||cp||carº Ep|de|rc|]º|º |u||cºa ac(u|º||a Pc|p|]||a cu|area |a|da De|ra||||º |e|pe|||c|r|º F|608£ 6-8 Bu||cuº perp||çc|d. Su|ep|de|ra| (jurc||cra|, c|e|| |c|ra||cr ard a pe||.aºcu|a| ard |r|e|º||||a| |]rp|cecº|rcp||||c |r||||a|e a|e c|a|ac|e||º||c. 48 antihouies uiiecteu against type Vll col- lagen in anchoiing hhiils aie the cause ol ueinolytic hlisteiing in acguiieu epiuei- nolysis hullosa (see Chap. 58). Cthei in- nunologically neuiateu inhannatoiy nechanisns iesult in ueinolytic hlistei- ing in ueinatitis heipetiloinis (see Chap. 5º), anu physical anu chenical changes in the |unction zone anu papil- laiy houy aie the cause loi a ueinolytic clelt loination altei tiauna in poiphyiia cutanea taiua (see Chap. 1o2). Pa||c|cç|c Reac||crº c| ||e Er|||e Supe||c|a| Reac||.e Ur|| (See lig. 6-1, SRU) íost pathologic ieactions ol the su- peihcial slin involve the suhunits ol the supeihcial ieactive unit |ointly anu thus incluue the papillaiy houy ol the ueinis vith the supeihcial niciovas- culai plexus. ¯his is a highly ieactive tissue conpaitnent consisting ol cap- illaiies, pie- anu postcapillaiy vessels (see Chap. 16o), hhiohlasts, nacio- phages, uenuiitic cells, anu peiipatetic lynphocytes all enheuueu in a loose connective tissue anu extiacellulai na- tiix (lig. 6-º). ¯he pioninence ol in- volvenent ol one ol the conponents ovei the otheis nay leau to the uevel- opnent ol uilleient clinical pictuies. A lev exanples ol such inteiactions aie uetaileu helov. 00hTA0T 0£8NAT|T|S (See Chap. 1o) l n alleigic contact ueinatitis, theie is an inhannatoiy ieaction ol the papillaiy houy anu supeihcial niciovasculai plexus anu spongiosis ol the epiueinis (see lig. 6-4) vith signs ol cellulai in|uiy anu paialeiatosis. Lynphocytes inhl- tiate the epiueinis eaily in the piocess anu aggiegate aiounu Langeihans cells, anu this is lolloveu hy spongiotic vesic- ulation (lig. 6-1O). laialeiatosis uevel- ops as a conseguence ol epiueinal in- | uiy, anu the i nhannati on i n the papillaiy houy anu aiounu the supeih- cial venulai plexus stinulates nitotic piocesses vithin the epiueinis, vhich, in tuin, iesult in acanthosis anu epiuei- nal hypeiplasia in chionic lesions. PS08|AS|S (See Chap. 18) ¯he initial le- sion ol psoiiatic lesions appeais to he the peiivasculai accunulation ol lynpho- cytes anu nonocytoiu elenents vithin the papillaiy houy anu supeihcial venules anu local nigiation ol leulocytes into the epiueinis. Acanthosis causeu hy in- cieaseu epiueinal piolileiation, papillo- natosis, anu euena ol the elongateu uei- nal papillae togethei vith vasouilatation ol the papillaiy capillaiy loops anu a uensei peiivasculai inhltiate uevelop al- nost sinultaneously (see lig. 6-2), the uistuiheu uilleientiation ol the epiueinal cells iesults in paialeiatosis, anu neutio- phils inhltiating the epitheliun lion toi- tuous capillaiies (sguiiting capillaiies) leau to spongiloin pustules anu, in the paialeiatotic stiatun coineun, to íunio`s ahscesses. ¯he stinulus loi in- cieaseu epiueinal piolileiation lollovs signals ieleaseu lion ¯ cells that aie at- tiacteu to the epiueinis hy the expies- sion ol auhesion nolecules at the leiati- nocyte suilace anu aie naintaineu hy cytolines ieleaseu hy leiatinocytes (see Chap. 18). ¯he conposite pictuie chaiac- teiistic ol psoiiasis, theieloie, iesults lion a conhineu pathology ol the papil- laiy houy vith the supeihcial venules, the epiueinis, anu ciiculating cells. lsoiiasis is a goou exanple ol the lin- iteu specihcity ol histopathologic ieaction patteins vithin the slin hecause psoiiasi- loin histologic leatuies occui in a nun- hei ol uiseases unielateu to psoiiasis. F|608£ 6-9 T|e ccrpa||rer| c| ||e pap|||a|] |cd] ccrº|º|º c| cap|||a||eº (C,, |||c||aº|º (|,, rac|c- p|açeº ard derd||||c ce||º (|,, pe||pa|e||c |]rp|cc]|eº (|, ard raº| ce||º (|c, a|| er|edded |r a |ccºe ccrrec||.e ||ººue c| e/||ace||u|a| ra|||/, |||r cc||açer ||e|º (Cc,, e|aº||c ||e|º (E, ||a| a|e rcº||] c||- er|ed pe|perd|cu|a||] |c ||e º||r ºu||ace, ard ||arc|ed |e||cu||r ||e|º (R,. F|608£ 6-10 Ccr|ac| de|ra||||º. |r||aep|de|ra| ºpcrç|c||c .eº|c|eº ard p|crcurced |r|e|ce||u|a| edera a|e p|eºer| |r ||e ep|de|r|º. T|e de|r|º ccr|a|rº pe||.aºcu|a| açç|eça|eº c| |]rp|cc]|eº ard ||º||cc]|eº adr|/ed W||| cccaº|cra| ecº|rcp|||º. 49 |hT£8FA0£ 0£8NAT|T|S lnhannation along the ueinal-epiueinal |unction as- sociateu vith vacuolation chaiacteiizes inteilace ueinatitis. ¯his connon type ol ieaction nay leau to papules oi plagues in sone slin uiseases anu hullae in otheis. £8YTh£NA N0LT|F08N£ (See Chap. o8) ¯vo types ol ieactions occui. ln hoth theie is inteilace ueinatitis chaiactei- izeu hy lynphocytes scatteieu along a vacuolateu ueinal-epiueinal |unction. L0P0S £8YTh£NAT0S0S (See Chap. 156) lnhannation, euena, anu a lynphocytic inhltiate in the papillaiy houy anu supeih- cial venulai plexus, as vell as in the ueepei layeis ol the ueinis, aie hallnails ol lupus eiythenatosus. ¯he nain taiget is the uei- nal-epiueinal |unction, vheie scatteieu lynphocytes appeai anu innune con- plex ueposition leaus to hioauening ol the lAS-positive hasenent nenhiane zone, acconpanieu hy hyuiopic uegeneiation anu uestiuction ol hasal cells anu piogies- sive atiophy (lig. 6-11). Cytoiu houies ie- sult lion apoptosis ol inuiviuual epiuei- nal cells that aie inhltiateu anu coateu hy innunoglohulins. ¯he changes in the |unctional zone iehect on epiueinal uillei- entiation iesulting in incieaseu oitholeia- tosis anu paialeiatosis. Lupus eiythena- tosus ieauily illustiates the heteiogeneity, as vell as the lacl ol specihcity, ol cutane- ous ieaction patteins: histologically, it is possihle to uistinguish hetveen acute anu chionic lesions hut not hetveen cutaneous anu systenic lupus eiythenatosus. ln chionic peisisting lesions, the changes in the |unctional zone initially associateu vith atiophy seconuaiily iesult in hypei- plasia, hypeileiatosis, anu an incieaseu in- teiuigitation hetveen epiueinis anu con- nective tissue, vheieas in acute cases, the uestiuction ol the hasal cell layei nay leau to suh-epiueinal hlisteiing. L|0h£h PLAh0S (See Chap. 26) ¯his uis- ease also exhihits a piinaiily |unctional ieaction pattein vith accunulation ol a uense lynphocytic inhltiate in the suh- epiueinal tissue anu cytoiu houies at the |unction (lig. 6-12). Lynphocytes en- cioach on the epiueinis, uestioying the hasal cells, hut they uo not inhltiate the supiahasal layeis anu hlistei loination only iaiely ensues. ¯hese alteiations aie acconpanieu hy changes ol epiueinal uilleientiationtheie is a viuening ol the stiatun gianulosun (h,¡crgranu|osis) anu hypeileiatosis. luentical changes can he seen in gialt-veisus-host uisease (see Chap. 28). Cuiient thinling inputes a uelayeu hypeisensitivity ieaction to a leiatinocyte antigen, the natuie ol vhich is uncleai. ¯he association ol CD8 + lyn- phocytes in apposition to apoptotic le- iatinocytes suppoits this viev. ¯he ex- piession ol las/lasL is also in lavoi ol a iole loi apoptosis in the pathogenesis ol these lesions. 0£8NAT|T|S h£8P£T|F08N|S (See Chap. 5º) ¯his conuition is usually incluueu anong the classic hullous ueinatoses, hovevei, it illustiates that the piepon- ueiance ol one oi seveial pathologic ie- action patteins nay ohscuie the tiue pathogenesis ol the conuition. ¯he ue- position ol innunoglohulin A anu conplenent on hhiillai anu nonhhiillai sites vithin the tips ol the ueinal pa- pillae, anu the activation ol the alteina- tive pathvay ol the conplenent cas- caue, leau to an inhux ol leulocytes, vhich loin snall ahscesses at the tips ol the ueinal papillae, as vell as in- hannation anu euena (lig. 6-1o). ¯his explains vhy the piinaiy clinical le- sion in ueinatitis heipetiloinis is uiti- caiial oi papulai in natuie, hecause only in the case ol nassive neutiophil inhltiation vill theie he tissue uestiuc- tion anu clelt loination helov the lan- ina uensa that iesults in clinically visi- hle vesiculation. RET|CU|AR DER||S (See lig. 6-1, DRU) ¯he ueinis iepiesents a stiong hhioelas- tic tissue vith a netvoil ol collagen anu elastic hheis enheuueu in an extiacellu- lai natiix vith a high vatei-hinuing ca- pacity (see Chap. 61). ln contiast to the tightly inteivoven hhious conponents ol this ieticulai layei ol the ueinis (lig. 6-14), the pieviously uesciiheu hhious textuie ol the papillaiy houy anu the peiilolliculai anu peiivasculai conpait- nents is loose (see lig. 6-º), anu the oii- entation ol the collagen hunules heie lol- lovs the stiuctuies they suiiounu. F|608£ 6-11 |upuº e|]||era|cºuº. H]pe||e|a|cº|º, |||rred ep|de|r|º de.c|d c| |e|e ||dçeº, ard .acuc||/a||cr c| ||e |aºerer| rer||are /cre a|e p|eºer|. F|608£ 6-12 ||c|er p|aruº. T|e|e |º |]pe||e|a|cº|º, Wedçe-º|aped |]pe|ç|aru|cº|º, |aºa| ce|| .acuc||/a||cr, ard a |]rp|cc]||c |r||||a|e a| ||e de|ra|-ep|de|ra| jurc||cr. T||º |r||||a|e '|uçº' ||e |aºa| ce|| |a]e| ard |º aººcc|a|ed W||| rar] c]|c|d |cd|eº. 50 ¯he ueinis contains a supeihcial anu ueep vasculai netvoil. ln the uppei ueinis, the supeihcial plexus supplies inuiviuual vasculai uistiicts consisting ol seveial ueinal papillae. Supeihcial anu ueep netvoils aie connecteu so in- tinately that the entiie ueinal vasculai systen iepiesents a single thiee-uinen- sional unit (see Chap. 16o). Cn the othei hanu, theie aie piolounu lunc- tional uilleiences hetveen supeihcial anu ueep ueinal vasculai netvoils (see Chap. 16o), vhich explain the uillei- ences ol honing patteins ol inhanna- toiy cells to these sites. As loi the supeihcial niciovasculai systen, tvo ieaction patteins occui: (1) acute inhannatoiy piocesses in vhich the epiueinis anu |unctional zone aie olten involveu togethei vith the vas- culai systen, anu (2) noie chionic pio- cesses that olten ienain conhneu to the peiivasculai conpaitnent. ln this con- text, it shoulu he noteu that the cytologic conposition ol an inhannatoiy inhl- tiate vithin the slin uoes not alvays niiioi the acuity ol an inhannatoiy piocess. lolynoiphonucleai leulocytic inhltiates aie not alvays synonynous vith an acute piocess, conveisely, chionic piocesses aie not alvays iepie- senteu hy a lynphohistiocytic inhltiate. lnhannation conhneu to the supeih- cial connective tissuevasculai unit is chaiacteiizeu hy enuothelial activation, vasculai uilatation, incieaseu peineahil- ity, euena, a ieuuction ol intiavasculai hloou hov, an accunulation ol ieu hloou cells in the capillaiy loops, anu cellulai inhltiation ol the peiivasculai tissue. Depenuing on the uegiee ol in- hannation, the nacioscopic coiollaiy ol the histologic changes iepiesents eiy- thenatous, uiticaiial, anu inhltiative (papulai) lesions. ¯he ielease ol neuia- tois lion innunoglohulin llauen nast cells in type l innune ieactions, such as uiticaiia, is histologically nanilesteu pii- naiily as vasouilatation, euena ol the papillaiy houy, anu a iathei spaise inhl- tiate ol leulocytes anu histiocytic ele- nents aiounu the supeihcial venules (lig. 6-15). ¯hese lesions usually iesolve iela- tively iapiuly vithout any iesiuual pathology. íoie nassive ieactions, hovevei, leau to a uense peiivasculai in- hltiate (lig. 6-16), anu this nay iepiesent a tiansition to those piocesses vheie euena is less pionounceu anu vheie uense lynphocytic inhltiates suiiounu the vessels in a sleevelile lashion, as is the case in cutaneous uiug eiuptions (see lig. 6-16). íoie uianatic alteiations oc- cui vhen the vasculai systen itsell is the taiget ol the inhannatoiy piocess iesult- ing in a uestiuction ol at least sone ol the vessel conponents, as is the case in neciotizing vasculitis. ¯hese exuuative changes iesult in clinical palpahle pui- puia (lig. 6-1¯, see Chap. 164). Chionic inhannatoiy ieactions ol the supeihcial niciovasculai plexus usually ieveal lynphocytic inhltiates in close as- sociation vith the vasculai valls clinical nanilesting as eiythena. ln puipuia sin- plex (see Chap. 16º), uanage to the vessel vall is nuch less eviuent than in neciotiz- ing vasculitis, hut the integiity ol the ves- sels is also inpaiieu as is eviuenceu hy henoiihage into the tissue. Lynphocytes anu, as a seconuaiy ieaction, histiocytic elenents paitly lauen vith phagocytoseu nateiial incluuing iion constitute the in- hannatoiy inhltiate. F|608£ 6-13 De|ra||||º |e|pe|||c|- r|º. TWc pap|||ae º|cW r|c|ca|ºceººeº ccrpcºed c| reu||cp|||º. Vacuc||/a||cr ard ea||] c|e|| |c|ra||cr a|e e.|der| |r |c|| pap|||ae. F|608£ 6-14 T|e |e||cu|a| de|r|º |º ||ç|||] Wc.er |||ce|aº||c ||ººue W||| a re|Wc|| c| |||c|, |arded cc||açer ||e|º (Cc, ard e|aº||c (E, ||e|º er|edded |r ar e/||ace||u|a| ra|||/. A|| a|e p|cduced |] |||c- ||aº|º (|,. T||º ||ººue |º ruc| derºe|, |e|a||.e|] ace||u|a|, ard |aº |eWe| cap|||a|] .eººe|º ||ar ||e pap||- |a|] |cd] (ccrpa|e W||| ||ç. o-9,. 51 ¯he ieaction patteins uesciiheu loi the vasculai systen ol the papillaiy houy anu the supeihcial venulai plexus also occui in the ueep ueinis, hut theie aie noiphologic anu lunctional uillei- ences hecause heie laigei vessels aie in- volveu. Lynphocytic inhltiates sui- iounuing the vessels in a sleevelile lashion leau to clinical signs only vhen they aie suhstantial, anu then they iep- iesent the histopathologic suhstiate loi papulai oi nouulai lesions. ¯his is the case vith uiug eiuptions (see Chap. 4O, see lig. 6-16B) anu it is also tiue loi ueep-seateu inhltiates in lupus eiythe- natosus. ln the case ol neciotizing vas- culitis ol the neuiun-sizeu anu laigei vessels, theie is usually a nuch noie pionounceu inhannatoiy inhltiate, clin- ically appeaiing as papulai anu nouulai lesions, anu seconuaiy changes uue to the inteiiuption ol the vasculai hov aie noie pionounceu: neciosis, hlisteiing, anu ulceiation iesult as is the case in cutaneous panaiteiitis nouosa ol the nacioscopic type (see Chap. 165). ln contiast to the nacioscopic vaiiant, nicioscopic polyaiteiitis nouosa al- lects vessels ol vaiying sizes incluuing venules anu aiteiioles, allects lungs anu liuneys, anu is peiinucleai neutiophil antihouies positive. Cianulonatous vas- culitis also leaus to nouulai lesions, vheieas the hyalinizing vasculai changes anu vasculai occlusion in liveuoiu vas- culitis iesult in ischenic neciosis (see Chap. 164). |]rp|cc]||c |r||||a|eº Although lynphocytic inhltiates occui in the na|oiity ol inhannatoiy ueina- toses, theie aie a nunhei ol pathologic piocesses in vhich such inhltiates aie the nost pioninent leatuie anu thus ue- teinine the histologic pictuie. Lynpho- cytic inhltiates aie loineu in inhanna- toiy oi piolileiative conuitions anu in the lattei nay iepiesent a henign oi nalig- nant piocess. ¯hey nay uillei in theii cy- tologic appeaiance anu uistiihution, nay he conhneu to the peiiauventitial con- paitnents ol the vasculai systen (supei- hcial anu ueep peiivasculai ueinatitis), oi nay occui uillusely thioughout the collagenous tissue (uilluse ueinatitis). ¯hey nay he conhneu alnost exclu- sively to the papillaiy ueinis (inteilace ueinatitis) anu spaie the suh-epiuei- nal conpaitnent oi nay exhihit pio- F|608£ 6-15 U|||ca||a. A. C|a|ac|e||º||c c| |||º |eac||cr |º a ºpa|ºe, pe||.aºcu|a| |]rp|cc]||c |r||||a|e W||| |eW ecº|rcp|||º. \c|e ||e º||ç|| edera |r ||e de|r|º ard a|curd ||e pcº|cap|||a|] .eru|eº. 8. H|ç|e| raçr||ca||cr |e.ea|º ºepa|a- ||cr c| cc||açer |urd|eº |] edera ard ºpa|ºe |r- |e|º||||a| |r1arra|c|] |r||||a|e W||| ecº|rcp|||º. A 8 F|608£ 6-16 D|uç e|up||cr. A. T||cuç|cu| ||e de|r|º, pe||.aºcu|a| º|ee.eº c| rcrcruc|ea| ce||º, ra|r|] |]rp|cc]|eº, a|e p|eºer| a|cu| ºupe|- |c|a| ard deep .eru|eº. T|e|e |º º||ç|| edera |r ||e pap|||a|] |cd] ard r|r|ra| |r|e||ace de|ra||||º |r |||º |eac||cr |c r||ed|p|re. 8. |c|e p|crcurced, e.er rcdu|a|, rcrcruc|ea| ce|| |r||||a|eº a|curd .eººe|º |r a d|uç |eac||cr |c a ||cc|e|. A 8 F|608£ 6-17 \ec|c||/|rç .aºcu||||º. Ar |r1arra|c|] |r||||a|e ccrpcºed rcº||] c| reu||cp|||º ard ruc|ea| duº| |º p|eºer| |c|| a|curd ard |r ||e Wa|| c| a .eru|e W|e|e ||||r |º a|ºc depcº||ed. 52 nounceu epiueinotiopisn. ¯hey nay he inuepenuent ol vessels, spaise (inteisti- tial ueinatitis) oi nouulai (nouulai uei- natitis). Because lynphocytes aie a het- eiogeneous population ol cells, the analysis ol such inhltiates shoulu tale into account not only the cytonoiphol- ogy anu uistiihution pattein hut his- tochenical piopeities anu innunologic naileis. ¯he analysis ol iounu cell inhl- tiates hy nonoclonal antihouies (innu- nophenotyping) anu ueteinination ol theii clonality aie inpoitant aspects ol ueinatopathology (see Chap. 14¯). Anong the nany possihle ieaction patteins chaiacteiizeu hy lynphocytic inhltiates, seveial typical patteins can he uistinguisheu. º Supeihcial peiivasculai inhltiates aie olten acconpanieu hy seconuaiy ieactions ol the epiueinis. Lyn- phoiu cells suiiounu the vasculai channels in a sleevelile lashion hut olten extenu uillusely to the epiuei- nis, vhich nay ieveal local paia- leiatosis in these aieas. Clinically, these changes aie olten chaiactei- izeu as palpahle hguiate eiythenas such as eiythena annulaie cen- tiilugun, hut polynoiphic light eiup- tion, uiug eiuptions (see lig. 6-16A), oi insect hites can piouuce a sinilai histopathologic pictuie. º Lynphocytic culhng ol venules vith- out involvenent ol the papillaiy houy anu the epiueinis nay occui in hguiate eiythenas anu in uiug eiup- tions (see lig. 6-16B). ¯he inhltiates ol chionic lynphatic leulenia shov a sinilai uistiihution pattein hut aie usually noie pionounceu. º leiivasculai lynphocytic inhltiates vith a nucinous inhltiation ol the nonpeiivasculai connective tissue nay he lounu in lynphocytic inhl- tiation ol [essnei-lanol, ieticulai eiythenatous nucinosis (see Chap. 14¯), oi in lupus eiythenatosus (lig. 6-18) anu ueinatonyositis (see Chaps. 156 anu 15¯). º Nouulai lynphocytic inhltiates, vhich extenu thioughout the ueinis exhih- iting local accunulations ol histio- cytic cells anu thus acguiiing the appeaiance ol lynphoiu lollicles, aie typical ol lynphocytona cutis (see Chap. 14¯). lhagocytoseu polychione houies in histiocytic cells, nitoses in the centei ol the lynphoiu lollicles, anu an aunixtuie ol eosinophils aie chaiacteiistic leatuies, as is the lact that the papillaiy houy is usually spaieu so that a conspicuous gienz zone is lounu hetveen the inhltiate anu the epiueinis. º Non-lolliculai lynphocytic inhltiates spaiing the supeihcial ieactive unit nay also occui in henign lynphoiu hypeiplasias, hut in these cases, the uil- leientiation lion nalignant lynphona is veiy uilhcult. lolynoiphic inhltiates shoving histiocytes, plasna cells, anu occasional eosinophils aie usually henign, vheieas nost nalignant non- Houglin lynphonas exhihit a noie nononoiphous pictuie. º Nouulai accunulations ol lynpho- cytes vith an aunixtuie ol plasna cells anu eosinophils acconpanieu hy vasculai hypeiplasia aie chaiac- teiistic ol angiolynphoiu hypeipla- sia (lig. 6-1º), in vhich hloou vessel valls aie thicleneu anu the enuothe- lial cells appeai piolileiateu, svollen, anu enlaigeu. º Atypical lynphocytic inhltiates involv- ing hoth the supeihcial anu ueepei ueinis, anu cytologically chaiactei- izeu hy pionounceu pleonoiphisn ol the cellulai inhltiate, aie chaiacteiistic ol lynphonatoiu papulosis one ol the spectiun ol CDoO + lynphopio- lileiative uisoiueis (see Chap. 14¯). ¯his conuition exenplihes the pioh- lens that aiise vhen the histopa- thology ol a lesion is useu alone to ueteinine vhethei a piocess is henign oi nalignant. Without lnovl- euge ol the clinical leatuies anu the F|608£ 6-18 |uc|rcº|º |r |upuº e|]||era|cºuº. T|e p|cr|rer| |ea|u|e º|cWr |e|e |º a|urdar| ruc|r |r ||e ºupe||c|a| ard r|d-de|r|º. F|608£ 6-19 Arç|c|]rp|c|d |]pe|p|aº|a. \ure|cuº .aºcu|a| c|arre|º a|e ºu||curded |] açç|e- ça|eº c| |r1arra|c|] ce||º rade up c| |]rp|cc]|eº ard ecº|rcp|||º. \c|e ||e p|c||uº|cr c| erdc||e||a| ce||º |r|c ||e |ar|ra c| ||eºe .eººe|º. 53 couise ol uisease, a uehnite uiagnosis is extienely uilhcult. Pc|]rc|p|cruc|ea| |eu|cc]||c |r||||a|eº Although neutiophils aie the classic in- hannatoiy cells ol acute hacteiial inlec- tions, theie aie uiseases in vhich neutio- phils uoninate the histopathology, even in the ahsence ol a hacteiial cause. ln pyoueina gangienosun, nassive neu- tiophilic inhltiation leaus to steiile ah- scesses, hiealuovn ol the tissue, anu ul- ceiation (see Chap. o2). ln ueinatitis heipetiloinis, neutiophils accunulate in the tips ol ueinal papillae anu loin pap- illaiy ahscesses (see lig. 6-1o) that pie- ceue the ueinolytic hlistei loination uesciiheu in Distuihances ol Deinal- lpiueinal Cohesion (see also Chap. 5º). ln eiythena elevatun uiutinun, neutio- phils aie the pieuoninant cells centeiing aiounu supeihcial anu niu-ueinal ves- sels, vhich exhihit hhiinoiu honogeni- zation ol theii valls (toxic hyalin) anu signs ol vasculitis (see Chap. 166). ¯he neutiophil is also the pieuoninant cell in the eaily stages ol the noie connon neciotizing vasculitis (see lig. 6-1¯). Neu- tiophils also iepiesent the na|oiity ol the olten nassive inhannatoiy inhltiate in acute lehiile neutiophilic ueinatosis, vhich is acconpanieu hy pionounceu suh-epiueinal euena (see Chap. o1). 0|aru|cra|cuº Reac||crº Slin is an iueal tissue loi gianulona loi- nation in vhich histiocytes play a ley iole. Although these cells aie involveu at one tine oi anothei in piactically all in- hannatoiy piocesses, it is only the pio- lileiation anu local aggiegation ol histio- cytic cells that nay he teineu a granu|oma. When such cells aie closely clusteieu they iesenhle epithelial tissue, hence the uesignation c¡ithc|ioid .c||s. De- velopnent ol giant cells, stoiage ol phagocytoseu nateiial, anu the aunix- tuie ol inhannatoiy cells, such as lyn- phocytes, plasna cells, anu eosinophils, nay ienuei the histologic pictuie ol a gianulonatous ieaction noie conplex. ¯o these have to he auueu vasculai changes anu alteiations in the hhious stiuctuie ol the connective tissue. Cianulonas alnost alvays leau to uestiuction ol pie-existing tissue, paiticulaily elastic hheis, anu in such instances iesult in atiophy, hhiosis, oi scaiiing. ¯issue uanage oi uestiuction nanilests eithei as neciohiosis oi hhiin- oiu oi caseous neciosis, oi it nay iesult lion liguelaction anu ahscess loination oi lion ieplacenent ol pie-existing tissue hy hhiohistiocytic inhltiate anu hhiosis. Saicoiual gianulonas (see Chap. 15o) aie typically chaiacteiizeu hy naleu nouules consisting ol epithelioiu cells, occasional Langhans giant cells, anu only a snall nunhei ol lynphocytes (lig. 6-2O). Silica, ziiconiun, anu heiyl- liun gianulonas anu a nunhei ol loi- eign-houy gianulonas nay have such histopathologic leatuies. Cianulonatous ieactions ol the slin conpiise a laige spectiun ol histo- pathologic leatuies. lalisauing gianulo- nas suiiounu neciohiotic aieas ol the connective tissue vith histiocytes in ia- uial alignnent (lig. 6-21). Cianulona annulaie, neciohiosis lipoiuica, iheuna- toiu nouules, anu the |uxta-aiticulai nouules ol syphilis helong to this gioup. ¯hese ieactions nay have signihcance as signs ol systenic uisease. loi exan- ple, vhen theie aie pioninent neutio- phils in the neciohiotic aiea ol gianu- lona annulaie oi neciohiosis one nay suspect an associateu inhannatoiy hovel uisease. lnuociinopathies can also he associateu vith these uisoiueis, uiahetes nellitus is a classic exanple as- sociateu vith neciohiosis lipoiuica. Cl couise, iheunatoiu nouules can he asso- ciateu vith iheunatoiu aithiitis hut can also occui as a iesult ol tiauna in sone cutaneous locations. Diugs nay also cause these ieactions. lnlectious gianulonas vith a saicoi- ual appeaiance nay occui in tuheiculo- sis, syphilis, leishnaniasis, lepiosy, oi lungal inlections. Neciosis can also ue- velop vithin the gianulona piopei, as is the case loi hhiinoiu neciosis in saicoi- uosis, caseation in tuheiculosis, oi the neciosis ueveloping in nycotic gianulo- nas. íany ol the inlectious gianulonas aie associateu vith epiueinal hypeipla- sia, olten exhihiting intiaepiueinal ah- scesses in vhich the causative oiganisn F|608£ 6-20 Sa|cc|da| ç|aru|cra. |r ||e de|r|º, rure|cuº 'ra|ed' |u|e|c|eº ccrº|º||rç c| ep|||e- ||c|d ce||º ard ºcar| |]rp|cc]|eº a|e ºeer. T|e c.e||]|rç ep|de|r|º |º a||cp||c. F|608£ 6-21 0|aru|cra arru|a|e. A We||-c||curºc|||ed pa||ºad|rç ç|aru|cra |º ºeer |r ||e de|r|º. \ec|c||c||c cc||açer |º ºu||curded |] ||º||cc]|eº, |]rp|cc]|eº, ard a |eW ºca||e|ed ru|||ruc|ea|ed ç|ar| ce||º. 54 can he lounu, olten in a nultinucleate giant cell. ln the ueinis theie is a nix- tuie ol cells, incluuing histocytes, epi- thelioiu cells, eosinophils, neutiophils, anu lynphocytes. lt is olten uilhcult to classily gianulo- natous ieactions vithin the slin hy the histopathology alone, loi even con- pletely uilleient etiologic conuitions such as innunopathies anu sone loins ol vasculitis nay uevelop gianulonas. A specihc loin ol gianulonatous ie- action iesults vhen the cellulai inhltiate consists alnost exclusively ol the ley gianulona cell, the histio.,tc. Cne piop- eity ol this cell is its capacity to stoie phagocytoseu nateiial. ln xanthona- tous ieaction patteins, histiocytes tale up anu stoie lat anu aie thus tians- loineu into loan cells. ¯hey aie uistiih- uteu eithei uillusely, as is the case in uilluse noinolipenic xanthonatosis, oi as an aggiegate inhltiate ninicling a tunoi, as in the xanthonas occuiiing in the hypeilipopioteinenias anu xan- thelasna (see Chap. o5). ||||cuº De|r|º ard E/||ace||u|a| |a|||/ (See lig. 6-1, DRU) Scleiosing piocesses ol the slin involve nainly the connective tissue ol the uei- nis (see ligs. 6-1, DRU, anu 6-14) hut usually iehect uynanic changes ol stiuc- tuie anu lunction that involve piactically all conpaitnents ol this oigan. ¯he hall- nail ol scleioueina (see Chap. 158) is the honogenization anu uense pacling ol the collagen hunules, a naiioving ol the inteilasciculai clelts vithin the ietic- ulai ueinis, anu the uisappeaiance ol the hounuaiy hetveen this poition ol the ueinis anu the papillaiy houy. ¯heie is also a uininution ol the snall papillaiy anu suhpapillaiy vessels, vhich appeai naiioveu, anu, in the eaily stages, a peiivasculai lynphocytic inhltiate anu euena. ¯he inpiessive thiclening ol the ueinis not only iesults lion an inciease ol its hhious conponents hut is also causeu hy the hhiosis ol the supeihcial layeis ol the suhcutaneous lat that lol- lovs lynphocytic inhltiation anu a his- tiocytic ieaction. Scleioueinoiu changes nay he lounu in the toxic oil synuione anu L-tiyp- tophan uisease, eosinophilic lasciitis (see Chap. o5), anu nixeu connective tissue uisease, they also occui in pachy- ueinopeiiostosis, vheie an inciease ol hhiohlasts anu giounu suhstance ac- conpany the scleiotic changes, anu in poiphyiia cutanea taiua, vhich shovs typical hyalinization ol the papillaiy vessels. ln lichen scleiosus, theie is a nassive euena ol the papillaiy houy anu a uense lynphocytic inhltiate that initially hugs the epiueinis anu latei sepaiates the euenatous papillaiy houy lion the ieticulai ueinis (see Chap. 6o). As scleiosis sets in, theie is also a uisap- peaiance ol elastic tissue lion the papil- laiy houy, the conconitant involvenent ol the epiueinis incluues hyuiopic ue- geneiation ol hasal cells, atiophy, anu, at the sane tine, hypeileiatosis. Changes in the |unctional zone in this conuition nay occasionally leau to a sepaiation ol the epiueinis lion the ueinis anu thus to hlistei loination. laulty synthesis oi cioss-linling ol collagen iesults in a nunhei ol vell- uehneu uiseases oi synuiones hut leaus to ielatively lev chaiacteiistic histo- pathologic changes. ln the uilleient types ol the lhleis-Danlos synuione (see Chap. 1oº), the laulty collagen cannot he iecognizeu histopathologically, anu only the ielative inciease ol elastic tis- sue nay inuicate that sonething ahnoi- nal has occuiieu in the ueinis. ln gen- eializeu elastolysis, a liagnentation ol elastic hheis is the histopathologic suh- stiate ol the clinical appeaiance ol cutis laxa, anu the liagnentation anu cuileu anu clunpeu appeaiance ol elastic hheis aie sinilaily uiagnostic in pseuuoxan- thona elasticun (see Chap. 1oº). Cn the othei hanu, in actinic elastosis, the histologic suhstiate ol ueinatoheliosis, all conponents ol the supeihcial con- nective tissue aie involveu (see Chap. 8º). lxcept loi a naiiov gienz zone he- lov the epiueinis, the papillaiy houy anu the supeihcial layeis ol the ieticulai ueinis aie hlleu vith clunpeu anu cuileu hheis that piogiessively hecone honogenizeu anu hasophilic. ¯hey aie staineu hy uyes that have an alhnity loi F|608£ 6-22 E|]||era rcdcºur. A c||cr|c ç|aru|cra|cuº |r1arra|c|] |r||||a|e W||| ç|ar| ce||º e/|erdº a|crç ||e |||c|ered ºep|ur |r|c ||e adjacer| |a| |c|u|e. F|608£ 6-23 \cdu|a| .aºcu||||º. T|e c|a|ac|e||º||c |ea|u|eº |||uº||a|ed a|e ºe.e|e .aºcu||||º W||| re- c|cº|º c| ||e |a|çe .eººe| Wa|| ard ccc|uº|cr c| ||e |urer. \ec|cº|º c| ||e |a| |c|u|eº |º p|eºer|, aº We|| aº ar acu|e ard c||cr|c |r1arra|c|] ce|| |r||||a|e. 55 elastic tissue anu thus histochenically hehave sinilai to elastic hheis. Such piolounu changes ol ueinal ai- chitectuie hecone clinically appaient: ¯he taut anu hin connective tissue in scleioueina iehects the scleiotic textuie anu honogenization ol the collagen hunules seen histologically, the loose lolus ol cutis laxa aie a iesult ol the liagnentation ol elastic hheis, the coh- hlestone-lile papules in pseuuoxanth- ona elasticun coiiesponu to the local aggiegation ol the pathologically al- teieu elastic nateiial, anu the coaise- ness ol slin lines anu suilace piohle in ueinatoheliosis aie the clinical nani- lestations ol the local aggiegation ol elastotic nateiial. SUBCUTA\E0US |AT (See lig. 6-1, S) lnhannatoiy piocesses in the suhcutane- ous auipose tissue tale a slightly uilleient couise than in the connective tissue ol the ueinis hecause ol the specihc anatony ol the suhcutis (see Chaps. ¯ anu 68). lnhan- nation ol suhcutaneous lat iehects eithei an inhannatoiy piocess ol the auipose tissue piopei oi the lat lohules (see lig. 6-1, L) oi a piocess aiising in the septa (see lig. 6-1, Sep), it can involve snall venules anu capillaiies oi aiise lion the laigei nusculai vessels. ¯he histopathologic nanilestations nay vaiy accoiuingly. Snall-vessel pathology is usually nani- lesteu locally, involving the neighhoiing lat lohules, vheieas the uestiuction oi oc- clusion ol a laigei vessel inhuences the en- tiie tissue segnent. Destiuction ol lat, he it ol a tiaunatic oi inhannatoiy natuie, leaus to the ielease ol latty acius that hy thenselves aie stiong inhannatoiy stin- uli, attiacting neutiophils anu scavengei histiocytes anu naciophages, phagocyto- sis ol uestioyeu lat usually iesults in lipo- gianulona loination. Septal piocesses that lollov inhan- natoiy changes ol the tiaheculai vessels aie usually acconpanieu hy euena, in- hltiation ol inhannatoiy cells, anu a histiocytic ieaction. ¯his is the classic appeaiance in eiythena nouosun (lig. 6-22, see Chap. 68). Recuiiing septal in- hannation nay leau to a hioauening ol the inteilohulai septa, hhiosis, the accu- nulation ol histiocytes anu giant cells, anu nay iesult in vasculai piolileiation. By contiast, in nouulai vasculitis (lig. 6-2o), laige-vessel vasculitis in the septal aiea is acconpanieu hy neciosis ol the lat, lolloveu hy histiocytic ieactions, epithelioiu cell gianulonas vithin the lat lohules, anu a hhiotic ieaction scle- iosing the entiie suhcutaneous lat. Cn the othei hanu, lohulai panniculitis ie- sults lion the neciosis ol lat lohules as the piinaiy event, as is the case in iuio- pathic nouulai panniculitis (see Chap. 68), lolloveu hy an accunulation ol neutiophils anu leulocytoclasia. ¯he lipiu nateiial ueiiveu lion neciotic aui- pocytes contains liee anu esteiiheu cho- lesteiol, neutial lats, soaps, anu liee latty acius, vhich, in tuin, exeit an in- hannatoiy stinulus. Histiocytic cells nigiate into the inhaneu lat, anu pha- gocytosis leaus to loan cell loination. lpithelioiu gianulonas vith giant cells nay also iesult, anu all types ol hhiosis nay uevelop. lat neciosis is, theieloie, the piinaiy, anu inhannation the sec- onuaiy, event in this type ol panniculitis. ¯he inheient capacity ol the auipose tissue to iesponu to pathologic stinuli also holus tiue loi uisease conuitions that allect the suhcutaneous tissue only seconuaiily oi iesult lion exogenous lactois. ¯iaunatic panniculitis leaus to neciosis ol lat lohules anu a ieactive in- hannatoiy anu gianulonatous tissue iesponse. Altei the in|ection ol oils oi silicone, laige cystic cavities nay he loineu, vheieas altei the in|ection ol pentazocine, loi instance, hhiosis anu scleiosis uoninate the histopathologic pictuie. Cily suhstances nay ienain vithin the auipose tissue loi long peii- ous vithout causing a signihcant tissue ieaction, oil cysts evolve that aie sui- iounueu hy nultiple layeis ol iesiuual connective tissue, so that the tissue ac- guiies a °Sviss cheese` appeaiance. An- inal oi vegetahle oils olten leau to tu- heiculoiu oi lipophagic gianulonas vith nassive histiocytic ieactions, loan cells, anu seconuaiy hhiosis. lanniculitis also occuis as a iesult ol inlectious agents (cocci, nycohacteiia, anu othei hacteiial anu lungal oiganisns) oi a specihc uisease piocess. ln saicoiuo- sis, lat is giauually ieplaceu hy epithe- lioiu cell nouules anu, in lynphona, hy specihc lynphonatous inhltiates. ln lu- pus panniculitis, a uense lynphocytic in- hltiate ol the septal anu lohulai tissue ue- teinines the histopathologic pictuie, as uoes involvenent ol vessels nanilesting as vasculitis. Hovevei, uestiuction ol lat, liguelaction, anu lipogianulona nay he so pionounceu that the vasculai conpo- nent can haiuly he iecognizeu, anu the histopathologic pictuie nay iesenhle iu- iopathic nouulai panniculitis. SU00ESTED READ|\0S Acleinan AB et al: Histo|ogi. Diagnosis oj lnµammator, :kin Discascs: An A|gorith- mi. /cthod 3ascd on lattcrn Ana|,sis, 2nu eu. Baltinoie, Willians 8 Willins, 1ºº¯ Bailey lA et al: íaiginal zone lynphona (lov-giaue B cell lynphona ol nucosa- associateu lynphoiu tissue type) ol slin anu suhcutaneous tissue. Am j :urg latho| 20:1O11, 1ºº6 Bieueinan ¯, Roclen í, Caihalliuo [í: ¯H1 anu ¯H2 lynphocyte uevelopnent anu iegulation ol ¯H cell-neuiateu innune iesponses ol the slin. j lnvcst Dcrmato| :,m¡ lro. º:5, 2OO4 Ceiioni L et al: An l||ustratcd Cuidc to :kin l,m¡homa. Cxloiu, Blaclvell Sciences Ltu, 1ºº8 Ciovson AN, íagio Cí: ¯he cutaneous pathology ol lupus eiythenatosus: A ieviev. j Cutan latho| 28:1, 2OO1 Ciovson AN et al: Cutaneous vasculitis: A ieviev. j Cutan latho| 30:161, 2OOo lluei Dl et al: lcvcr´s Histo¡atho|og, oj thc :kin, 8th eu. lhilauelphia, Lippincott Willians anu Willins, 2OO4 íagio Cí et al: Cianulona annulaie anu neciohiosis lipoiuica tissue ieactions as a nanilestation ol systenic uisease. Hum latho| 27:5O, 1ºº6 íagio Cí et al: Thc l,m¡hoid lro|ijcrations. Nev Yoil, Wiley-Liss, lnc., 2OO6 íclee lH et al: latho|og, oj thc :kin, oiu eu. lhilauelphia, llseviei íoshy, 2OO5 íuiphy Cl, íihn íC [i: lnµammator, Dis- cascs oj thc :kin, Alll lascicle, thiiu seiies, Alll Septenhei 2OO6 Schaeili l, íosei B: Chenoline: contiol ol piinaiy anu nenoiy ¯-cell tialhc. lmmuno| Rcs 31:5¯, 2OO5 Uuey íC: Slin uenuiitic cells in innunity anu autoinnunity. j lnvcstig Dcrmato| :,m¡ lro. º:15O¯, 2OO4 This page intentionally left blank 57 ' c .¯ ' ´' o 0VERV|Ew 0| B|0|00\, DEVE|0P|E\T, A\D STRUCTURE 0| S||\ C H A P T E R / 0eve|opmeot aod Str0ct0re oI Sk|o Da.|d H. C|u S||\. A\ 0VERV|Ew Slin is a conplex oigan that piotects its host lion its enviionnent, at the sane tine alloving inteiaction vith the envi- ionnent. lt is nuch noie than a static, inpenetiahle shielu against exteinal in- sults. Rathei, the slin is a uynanic, conplex, integiateu aiiangenent ol cells, tissues, anu natiix elenents that neuiates a uiveise aiiay ol lunctions: slin pioviues a physical peineahility haiiiei, piotection lion inlectious agents, theinoiegulation, sensation, ultiavio- let (UV) piotection, vounu iepaii anu iegeneiation, anu outvaiu physical ap- peaiance (¯ahle ¯-1). ¯hese vaiious lunctions ol slin aie neuiateu hy one oi noie ol its na|oi iegionsthe epi- ueinis, ueinis, anu hypoueinis (lig. ¯-1, see also lig. 6-1, Chap. 6). ¯hese uivisions aie inteiuepenuent, lunctional units, each iegion ol slin ielies upon anu is connecteu vith its suiiounuing tissue loi iegulation anu nouulation ol noinal stiuctuie anu lunction at nolec- ulai, cellulai, anu tissue levels ol oigani- zation (see Chap. 6). Wheieas the epiueinis anu its outei stiatun coineun pioviue a laige pait ol the physical haiiiei pioviueu hy slin, the stiuctuial integiity ol the slin as a vhole is pioviueu piinaiily hy the ueinis anu hypoueinis. Antiniciohial activities aie pioviueu hy the innate innune systen anu antigen-piesenting uenuiitic cells ol the epiueinis, ciicu- lating innune cells that nigiate lion the ueinis, anu antigen-piesenting cells ol the ueinis (see Chap. 1O). lio- tection lion UV iiiauiation is pioviueu in gieat neasuie hy the nost supeih- cial cells ol the epiueinis. lnhanna- tion hegins vith the leiatinocytes ol the epiueinis oi innune cells ol the ueinis, anu sensoiy appaiatus ena- nates lion neives that initially tiaveise the hypoueinis to the ueinis anu epi- ueinis, enuing in specializeu ieceptive oigans oi liee neive enuings. ¯he laig- est hloou vessels ol the slin aie lounu in the hypoueinis, vhich seive to tianspoit nutiients anu innigiant cells (see lig. 6-1, Chap. 6). ¯he cutaneous lynphatics couise thiough the ueinis anu hypoueinis, seiving to hltei uehiis anu iegulate tissue hyuiation. lpiueinal appenuages pioviue special piotective oi sensoiy lunctions. Slin also uetei- nines a peison`s physical appeaiance, inhuenceu hy pignentation pioviueu hy nelanocytes, vith houy contouis, appeaiance ol age, anu actinic uanage inhuenceu hy the epiueinis, ueinis, anu hypoueinis. ¯he slin hegins to he oiganizeu uuiing enhiyogenesis, vheie inteicellulai anu intiacellulai signals, as vell as iecipiocal ciosstall hetveen uilleient tissue layeis, aie instiunen- tal in iegulating the eventual natuia- tion ol the uilleient conponents ol slin. What lollovs is an integiateu ue- sciiption ol the na|oi stiuctuial lea- tuies ol the slin anu hov these stiuc- tuies allov the slin to achieve its na|oi lunctions, lolloveu hy a ieviev ol theii enhiyologic oiigins. Also high- lighteu aie illustiative cutaneous uis- eases that nanilest vhen these lunc- tions aie uelective. Unueistanuing the genetic anu noleculai hasis ol slin uis- ease has conhineu, anu in sone cases ievealeu, the nany lactois anu iegula- toiy elenents that play ciitical ioles in slin lunction. EP|DER||S Cne ol the nost lunuanental anu visi- hle leatuies ol slin is the stiatiheu, coiniheu epiueinis (lig. ¯-2). ¯he epi- ueinis is a continually ieneving stiuc- tuie that gives iise to ueiivative stiuc- tuies calleu appenuages (pilosehaceous units, nails, anu sveat glanus). ¯he epi- ueinis ianges in thiclness lion O.4 to 1.5 nn, as conpaieu vith the 1.5- to 4.O-nn lull-thiclness slin. ¯he na|oi- ity ol cells in the epiueinis aie leiati- nocytes that aie oiganizeu into loui lay- eis, naneu loi eithei theii position oi a stiuctuial piopeity ol the cells. ¯hese cells piogiessively uilleientiate lion STRUCTURE A\D |U\CT|0\ 0| S||\ AT A 0|A\CE T||ee |ajc| |a]e|º-Ep|de|r|º, De|r|º, H]pcde|r|º. Ep|de|r|º. rajc| pe|rea|||||] |a|||e|, |rra|e |rrure |urc||cr, ad|eº|cr, u|||a.|c|e| p|c|ec||cr. De|r|º. rajc| º||uc|u|a| e|erer|, |||ee |]peº c| ccrpcrer|º-ce||u|a|, |||cuº ra|||/, d|||uºe ard ||arer|cuº ra|||/. A|ºc º||e c| .aºcu|a|, |]rp|a||c, ard re|.e re|Wc||º. H]pcde|r|º (ºu|cu||º,. |rºu|a||cr, rec|ar|ca| |r|eç|||], ccr|a|r|rç ||e |a|çe| ºcu|ce .eººe|º ard re|.eº. Copyright ? 2008 by The McGraw-Hill Companies, Inc. Click here for terms of use. 58 piolileiative hasal cells, attacheu to the epiueinal hasenent nenhiane, to the teininally uilleientiateu, leiatinizeu stia- tun coineun, the outeinost layei anu haiiiei ol slin (see Chap. 45). lnteica- lateu anong the leiatinocytes at vaii- ous levels aie the innigiant iesiuent cellsnelanocytes, Langeihans cells, anu íeilel cells. Cthei cells, such as lynphocytes, aie tiansient inhahitants ol the epiueinis anu aie extienely spaise in noinal slin. ¯heie aie nany iegional uilleiences in the epiueinis anu its appenuages. Sone ol these uil- leiences aie appaient giossly, such as thiclness (e.g., palnoplantai slin vs. tiuncal slin, lig. ¯-o), othei uilleiences aie nicioscopic. lathologic changes in the epiueinis can occui as a iesult ol a nunhei ol uil- leient stinuli: iepetitive nechanical tiauna (as in lichen sinplex chionicus), inhannation (as in atopic ueinatitis anu lichen planus), inlection (as in vei- iuca vulgaiis), innune systen activity anu cytoline ahnoinalities (as in psoii- asis, lig. ¯-4), autoantihouies (as in penphigus vulgaiis anu hullous pen- phigoiu), oi genetic uelects that inhu- ence uilleientiation oi stiuctuial pio- teins |as in epiueinolysis hullosa (lB) sinplex, epiueinolytic hypeileiatosis, the ichthyoses, anu Daiiei uisease]. |a]e|º c| ||e Ep|de|r|º 8ASAL LAY£8 ¯he leiatinocyte is an ec- toueinally ueiiveu cell anu is the pii- naiy cell type in the epiueinis, ac- counting loi at least 8O peicent ol the total cells. ¯he ultinate late ol these cells is to contiihute the conponents loi the epiueinal haiiiei as the stiatun coi- neun. ¯hus, nuch ol the lunction ol the epiueinis can he gleaneu lion the stuuy ol the stiuctuie anu uevelopnent ol the leiatinocyte. leiatinocyte uilleientiation (leiatini- zation) is a genetically piogianneu, caielully iegulateu, conplex seiies ol noiphologic changes anu netaholic events vhose enupoint is a teininally uilleientiateu, ueau leiatinocyte (coi- neocyte) that contains leiatin hlanents, natiix piotein, anu a piotein-ieinloiceu F|608£ 7-1 T|e rajc| |eç|crº c| º||r. S||r |º ccrpcºed c| |||ee |a]e|º. (1, ep|de|r|º, (2, de|r|º, ard (8, |]pcde|r|º. T|e cu|e|rcº| ep|de|r|º |º ºep- a|a|ed ||cr ||e de|r|º |] a |aºerer| rer||are /cre, ||e de|ra|-ep|de|ra| jurc||cr. Be|cW ||e de|- r|º ||eº ||e ºu|cu|arecuº |a| (|]pcde|r|º,. Ep|de|- ra| apperdaçeº, ºuc| aº |a|| |c|||c|eº ard ecc||re ard apcc||re ºWea| ç|ardº, |eç|r |r ||e ep|de|r|º |u| ccu|ºe |||cuç| ||e de|r|º ard/c| ||e ep|de|r|º. B|ccd .eººe|º, |]rp|a||cº, ard re|.eº ccu|ºe |||cuç| ||e ºu|cu|arecuº |a| ard ere|çe |r|c ||e de|r|º. (Uºed W||| pe|r|ºº|cr ||cr 0. |c.|c|, |D., Ik8L£ 7-1 Funct|ons of Sk|n FUh0T|0h T|SSUF LAYF8 S0NF ASS00|ATF0 0|SFASFS Pe|rea|||||] |a|||e| Ep|de|r|º A|cp|c de|ra||||º Ec|cde|ra| d]ºp|aº|aº |c|||]cºeº |e|a|cde|raº E/|c||a||.e de|ra||||º Bu||cuº d|ºeaºeº P|c|ec||cr ||cr pa||cçerº Ep|de|r|º Ve||uca .u|ça||º De|r|º Ec||]ra Ce||u||||º |e|º|rar|aº|º Hurar |rrurcde|c|erc] .||uº T|rea ped|º/cc|pc||º T|e|rc|eçu|a||cr Ep|de|r|º Ec|cde|ra| d]ºp|aº|aº De|r|º Ra]raud H]pcde|r|º H]pe|||e|r|a Serºa||cr Ep|de|r|º D|a|e||c reu|cpa||] De|r|º |ep|cº] H]pcde|r|º P|u|||uº Pcº||e|pe||c reu|a|ç|a U|||a.|c|e| p|c|ec||cr Ep|de|r|º /e|cde|ra p|çrer|cºur 0cu|ccu|arecuº a|||r|ºr wcurd |epa||/|eçere|a||cr Ep|de|r|º |e|c|d De|r|º Vercuº º|aº|º u|ce| P]cde|ra çarç|ercºur P|]º|ca| appea|arce Ep|de|r|º |e|aºra De|r|º V|||||çc H]pcde|r|º Sc|e|cde|ra ||pcd]º||cp|] F|608£ 7-2 Sc|era||c c| ep|de|r|º. T|e ep|de|r|º |º a º||a|||ed, cc|r||ed ep|||e||ur. T|e deepeº| |a]e| ccrº|º|º c| |aºa| ce||º (B|, ||a| |eº| upcr ||e |aºerer| rer||are c| ||e de|ra|-ep|de|ra| jurc- ||cr (DEJ,. T|eºe ce||º d|||e|er||a|e |r|c ||e ce||º c| ||e ºp|rcuº |a]e| (S|,, c|a|ac|e||/ed |] a|urdar| deºrcºcra| ºp|reº. Sp|rcuº ce||º e.er|ua||] |eccre ç|aru|a| |a]e| ce||º (0|,, p|cduc|rç rar] c| ||e ccrpcrer|º c| ||e cc|r||ed er.e|cpe. U|||ra|e|], ||e |e|r|ra||] d|||e|er||a|ed |e|a||rcc]|eº º|ed ||e|| ruc|e| ard |eccre ||e º||a|ur cc|reur (SC,, a c|cºº-||r|ed re|Wc|| c| p|c|e|r ard ç|]cc||p|dº. 59 plasna nenhiane vith suilace-associ- ateu lipius (see Chap. 44). leiatins aie a lanily ol inteineuiate hlanents anu aie the hallnail ol all epi- thelial cells, incluuing leiatinocytes (ie- vieveu in iels. 1 anu 2). ¯hey seive a pieuoninantly stiuctuial iole in the cells. lilty-loui uilleient lunctional lei- atin genes have heen iuentiheu in hu- nanso4 epithelial leiatins anu 1¯ haii leiatins. o ¯he co-expiession ol specihc leiatin paiis is uepenuent on cell type, tissue type, uevelopnental stage, uilleientiation stage, anu uisease conuition (¯ahle ¯-2). luitheinoie, the ciitical iole ol these nolecules is unuei- scoieu hy the nuneious nanilestations ol uisease that aiise hecause ol nuta- tions in these genes (see ¯ahle ¯-2). ¯hus, lnovleuge ol leiatin expiession, iegulation, anu stiuctuie pioviues in- sight into epiueinal uilleientiation anu stiuctuie. ¯he hasal layei (stiatun geininati- vun) contains nitotically active, colun- nai-shapeu leiatinocytes that attach via leiatin hlanents (l5 anu l14) to the hasenent nenhiane zone at heniues- nosones (see Chap. 51), attach to othei suiiounuing cells thiough uesnosones, anu that give iise to cells ol the noie su- peihcial, uilleientiateu epiueinal layeis. Ultiastiuctuial analysis ieveals the pies- ence ol nenhiane-hounu vacuoles that contain pignenteu nelanosones tians- leiieu lion nelanocytes hy phagocyto- sis. 4 ¯he pignent vithin nelanosones contiihutes to the oveiall slin pignenta- tion peiceiveu nacioscopically. 5 ¯he hasal layei is the piinaiy location ol ni- totically active cells ol the epiueinis. Cell linetic stuuies suggest that the hasal layei cells exhihit uilleient piolileiative potentials (sten cells, tiansit anplilying cells, anu postnitotic cells), anu in vivo anu in vitio stuuies suggest that theie ex- ist long-liveu epiueinal sten cells 6 (see Chap. 44). Because hasal cells can he ex- panueu in tissue cultuie anu useu to ie- constitute sulhcient epiueinis to covei the entiie slin suilace ol huin patients, ¯,8 such a staiting population is piesuneu to contain long-liveu sten cells vith exten- sive piolileiative potential. A laige anount ol uata suppoits the existence ol nultipotent epiueinal sten cells vithin the hulge iegion ol the haii lollicle haseu on these tiaits. º1¯ Cells lion this iegion aie ahle to contiihute to the loination not only ol the entiie pilosehaceous unit, hut to the inteilol- liculai epiueinis as vell. 141¯ ¯he existence ol an auuitional piogen- itoi population ol cells, vithin the sui- lace epiueinal hasal layei, is also sup- poiteu hy a nunhei ol lines ol eviuence, hoth in vitio anu in vivo. ¯hese putative hasal sten cells appeai to he clonogenic, piogiess iapiuly thiough S-phase ol the cell cycle, anu uiviue inlieguently uuiing stahle sell-ieneval (ietaining iauiola- heleu nucleotiue lahel ovei long peii- ous). Auuitionally, they aie capahle ol cell uivision in iesponse to exogenous anu enuogenous agents. laily lineage tiacing expeiinents in the epiueinis iuentiheu that leiatinocytes aie oiga- nizeu into veitical colunns ol piogies- sively uilleientiating cells, teineu c¡idcr- ma| ¡ro|ijcrating units. 1821 ¯he seconu type ol cell, the tiansit anplilying cells ol the hasal layei, aiises as a suhset ol uaughtei cells piouuceu hy the inlieguent uivision ol sten cells. ¯hese cells pioviue the hull ol the cell uivisions neeueu loi stahle sell-ieneval anu aie the nost connon cells in the hasal conpaitnent. Altei unueigoing seveial cell uivisions, these cells give iise to the thiiu class ol epiueinal hasal cells, the postnitotic cells that unueigo teininal uilleientiation. Although long helieveu to uetach lion the hasal lanina to nigiate to a noie supeihcial (supia- hasal) position in the epiueinis, iecent eviuence has suggesteu that asynnetiic uivision ol hasal cells ielative to the hase- nent nenhiane can uiiectly give iise to a supiahasal uilleientiating uaughtei cell. oO ln hunans, the noinal tiansit tine loi a hasal cell, lion the tine it loses contact vith the hasal layei to the tine it enteis the stiatun coineun, is at least 14 uays. ¯iansit thiough the stia- F|608£ 7-3 Ara|cr|c .a||- a||cr |r ep|de|ra| |||c|reºº. A. Ac|a| º||r. 8. E]e||d º||r. \c|e ||a| ||e ep|de|r|º |º ccr- º|de|a||] |||c|e| |r (A, ||ar (8,, |rc|ud|rç ||e ccrpac| |a]e|º c| ||e º||a|ur cc|reur, aº We|| aº ||e deepe| ep|de|ra| |a]e|º. (Uºed W||| pe|r|ºº|cr ||cr 0. |c.|c|, |D., F|608£ 7-4 Ep|de|ra| |]- pe|p|aº|a. H]pe|p|c|||e|a||cr c| ||e ep|de|r|º car cccu| due |c a rur|e| c| cauºeº, aº rar|- |eº|ed |r d|ºeaºeº ºuc| aº pºc- ||aº|º (p|c|u|ed,, aº We|| aº ||- c|er º|rp|e/ c||cr|cuº, a|cp|c de|ra||||º, ||c|er p|aruº, ard .e||uca .u|ça||º. (Uºed W||| pe|- r|ºº|cr ||cr 0. |c.|c|, |D., A 8 60 tun coineun anu suhseguent uesgua- nation ieguiie anothei 14 uays. ¯hese peiious ol tine can he alteieu in hypei- piolileiative oi giovth-aiiesteu states. SP|h00S LAY£8 ¯he shape, stiuctuie, anu suhcellulai piopeities ol spinous cells coiielate vith theii position vithin the niu-epiueinis. ¯hey aie naneu loi the spine-lile appeaiance ol the cell naigins in histologic sections. Supia- hasal spinous cells aie polyheuial in shape vith a iounueu nucleus. As these cells uilleientiate anu nove upvaiu thiough the epiueinis, they hecone piogiessively hattei anu uevelop oi- ganelles lnovn as |amc||ar granu|cs (see Cianulai Layei). Spinous cells also con- tain laige hunules ol leiatin hlanents, oiganizeu aiounu the nucleus anu in- seiteu into uesnosones peiipheially. Spinous cells ietain the stahle l5/l14 leiatins that aie piouuceu in the hasal layei hut uo not synthesize nev nes- sengei RNA (nRNA) loi these pioteins, except in hypeipiolileiative uisoiueis. lnsteau, nev synthesis ol the l1/l1O leiatin paii occuis in this epiueinal layei. ¯hese leiatins aie chaiacteiistic ol an epiueinal pattein ol uilleientiation anu thus aie ieleiieu to as the dijjcrcntia- tion-s¡c.iµ. oi kcratini:ation-s¡c.iµ. kcr- atins. ¯his noinal pattein ol uilleienti- ation is svitcheu to an alteinative pathvay in hypeipiolileiative states, hovevei. ln conuitions such as psoiiasis, actinic leiatoses, anu vounu healing, synthesis ol l1 anu l1O nRNA anu pio- tein is uovniegulateu, anu the synthesis anu tianslation ol nessages loi l6 anu l16 aie lavoieu. Coiielateu vith this change in leiatin expiession is a uisiup- tion ol noinal uilleientiation in the suh- seguent gianulai anu coiniheu epiueinal layeis (see Cianulai Layei anu Stiatun Coineun). nRNA loi l6 anu l16 aie piesent thioughout the epiueinis noi- nally, hut the nessage is only tianslateu on stinulation ol piolileiation. ¯he °spines` ol spinous cells aie ahun- uant uesnosones, calciun-uepenuent cell suilace nouihcations that pionote auhesion ol epiueinal cells anu iesis- tance to nechanical stiess (ievieveu in iel. o1, see also Chaps. 44 anu 51). Within each cell is a uesnosonal plague, vhich contains the polypeptiues plalo- glohin, uesnoplalins l anu ll, leia- tocalnin, uesnoyolin, anu plalophilin. ¯iansnenhiane glycopioteinsuesno- gleins 1 anu o anu uesnocollins l anu ll, nenheis ol the cauheiin lanilypio- viue the auhesive piopeities ol the extia- cellulai poition ol the uesnosones, lnovn as the .orc. Wheieas the extiacel- lulai uonains ol the cauheiins loin pait ol the coie, the intiacellulai uonains in- seit into the plague, linling then to the inteineuiate hlanent (leiatin) cytoslel- eton. Although uesnosones aie ielateu to auheiens |unctions, the lattei associ- ate vith actin niciohlanents at cellcell inteilaces, via a uistinct set ol cauheiins (e.g., l-cauheiin) anu intiacellulai cate- nin auaptei nolecules. ¯hat the uesnosones aie integial neuiatois ol inteicellulai auhesion is cleaily uenonstiateu in uiseases in vhich these stiuctuies aie uisiupteu (¯ahle ¯-o). o2 ¯he autoinnune hullous uiseases penphigus vulgaiis anu pen- phigus loliaceus (see Chap. 52) aie causeu hy antihouies that taiget the ues- noglein pioteins vithin the uesno- sones. Loss ol uesnosonal auhesion iesults in the chaiacteiistic iounuing anu sepaiation ol leiatinocytes (acan- tholysis), ultinately loining a hlistei vithin the epiueinis. Stiilingly, the clinical piesentation ol these uiseases iehects the ielative expiession in the tis- sue ol the uesnoglein 1 anu o pioteins Ik8L£ 7-2 Fxprass|on Pattarns of Karat|n 0anas and Karat|n-Assoc|atad 0|saasas 8AS|0 A0|0|0 T|SSUF FXP8FSS|0h 0|SFASF ASS00|AT|0h 1 10 Sup|a|aºa| |e|a||rcc]|eº Bu||cuº ccrçer||a| |c|||]cº||c|r e|]|||c- de|ra, d|||uºe rcrep|de|rc|]||c PP| (|e|a||r 1, 1 9 Sup|a|aºa| |e|a||rcc]|eº (pa|rcp|ar|a| º||r, Ep|de|rc|]||c PP| (ep|de|rc|]||c |]pe|- |e|a|cº|º, 2 10 Uppe| ºp|rcuº ard ç|aru|a| |a]e|º |c|||]cº|º |u||cºa c| S|ererº 8 12 Cc|rea |eeºrarr'º cc|rea| d]º||cp|] 4 18 |uccºa| ep|||e||ur w|||e ºpcrçe re.uº o 14 Baºa| |e|a||rcc]|eº Ep|de|rc|]º|º |u||cºa º|rp|e/ oa 1o 0u|e| |cc| º|ea||, |]pe|p|c|||e|a- ||.e |e|a||rcc]|eº, pa|rcp|ar|a| |e|a||rcc]|eº Pac|]cr]c||a ccrçer||a |]pe |, |cca| rcr- ep|de|rc|]||c PP| o| 1/ \a|| |ed, ep|de|ra| apperdaçeº Pac|]cr]c||a ccrçer||a |]pe ||, º|ea|cc]º- |cra ru|||p|e/ 8 18 S|rp|e ep|||e||ur C|]p|cçer|c c||||cº|º PP| = pa|rcp|ar|a| |e|a|cde|ra. Ik8L£ 7-3 0|saasa 8asu|t|ng from 0|srupt|on of 0asmosoma| Prota|ns P80TF|h 0|SFASFS Deºrcç|e|r 1 Perp||çuº |c||aceuº S|||a|e pa|rcp|ar|a| |e|a|cde|ra S|ap|]|ccccca| ºca|ded-º||r º]rd|cre Bu||cuº |rpe||çc Deºrcç|e|r 8 Perp||çuº .u|ça||º Deºrcç|e|r 4 Au|cºcra| |eceºº|.e |]pc|||c|cº|º P|a|cç|c||r Pa|rcp|ar|a| |e|a|cde|ra W||| Wcc|] |a|| ard a|||]||rcçer|c ||ç|| .er|||c- u|a| ca|d|cr]cpa||] (\a/cº d|ºeaºe, P|a|cp||||r 1 Ec|cde|ra| d]ºp|aº|a/º||r ||aç||||] º]rd|cre (º||r e|cº|crº, d]º||cp||c ra||º, ºpa|ºe |a||, ard pa|r|u| pa|rcp|ar|a| |e|a|cde|ra, P|a|cp||||r 2 A|||]||rcçer|c ||ç|| .er|||cu|a| ca|d|cr]cpa||] Deºrcp|a||r |e||a| acar||c|]||c ep|de|rc|]º|º |u||cºa S|||a|e pa|rcp|ar|a| |e|a|cde|ra, |]pe | Pa|rcp|ar|a| |e|a|cde|ra W||| |e|| .er|||cu|a| ca|d|cr]cpa||] ard Wcc|] |a|| Au|cºcra| dcr|rar| a|||]||rcçer|c ||ç|| .er|||cu|a| ca|d|cr]cpa||] 61 (see Chaps. 51 anu 52). lenphigus vul- gaiis iesults lion autoantihouies ui- iecteu against uesnoglein o anu iesults in uisiuption ol the epiueinis hetveen the hasal anu supiahasal layeis (ie- vieveu in iel. oo). Cn the othei hanu, uesnoglein 1 is expiesseu in the uppei epiueinal layeis, anu antihouies to this piotein in patients vith penphigus loli- aceus iesult in hlisteis in the noie su- peihcial gianulai layei. Cthei uiseases that taiget the sane uesnoglein 1 pio- tein hut hy a uilleient nechanisn aie staphylococcal scalueu slin synuione (see Chap. 1¯8) anu hullous inpetigo, in vhich a hacteiial piotease cleaves anu inactivates uesnoglein 1, iesulting in the sane supeihcial hlisteiing seen in penphigus loliaceus. o4 Cenetic nuta- tions in othei uesnosonal conponents also ieveal a iole loi these pioteins in auhesion as vell as cell signaling (see ¯ahle ¯-o). o2 ¯he inpoitance ol calciun as a neuia- toi ol auhesion is vell illustiateu in the cases ol tvo conuitions that exhihit chai- acteiistic epiueinal uyscohesion, Daiiei uisease (leiatosis lolliculaiis) anu Hailey- Hailey uisease (henign chionic penphi- gus) (see Chap. 4º). o5,o6 Both ol these uis- eases aie causeu hy nutations in genes that iegulate calciun tianspoit, SlRCA2 (saico/enuoplasnic ieticulun Ca 2+ -A¯lase type 2 isoloin) in the case ol Daiiei uis- ease, anu A¯l2C1 (A¯lase, Ca 2+ tians- poiting, type 2C, nenhei 1, a iegulatoi ol cytoplasnic calciun concentiation) in the case ol Hailey-Hailey uisease. Lanellai gianules aie also loineu in this layei ol epiueinal cells (lig. ¯-5). ¯hese secietoiy oiganelles uelivei pie- cuisois ol stiatun coineun lipius into the inteicellulai space. Lanellai gian- ules contain glycopioteins, glycolipius, phospholipius, liee steiols, anu a nun- hei ol aciu hyuiolases, incluuing lipases, pioteases, aciu phosphatases, anu gly- cosiuases. Clucosylceianiues, the pie- cuisois to ceianiues anu the uoninant conponent ol the stiatun coineun lip- ius, aie also lounu vithin these stiuc- tuies (see Chap. 45). Cenetic uiseases uenonstiate the inpoitance ol steioiu anu lipiu netaholisn loi sloughing ol coiniheu cellsin iecessive X-linleu ichthyosis, loi exanple, nutation ol steioiu sullatase iesults in a ietention hypeileiatosis (see Chap. 4¯). o¯,o8 68Ah0LA8 LAY£8 Naneu loi the haso- philic leiatohyalin gianules that aie pioninent vithin cells at this level ol the epiueinis, the gianulai layei is the site ol geneiation ol a nunhei ol the stiuctuial conponents that vill loin the epiueinal haiiiei, as vell as a nunhei ol pioteins that piocess these conponents (see lig. ¯-2) (ievieveu in iels. oº anu 4O). leiatohyalin gianules (see lig. ¯-5) aie conposeu piinaiily ol piohlaggiin, leiatin hlanents, anu loiiciin. lt is in this layei that the coiniheu cell envelope he- gins to loin. Release ol piohlaggiin lion leiatohyalin gianules iesults in the calciun-uepenuent cleavage ol the piohlaggiin polyneiic piotein into hlag- giin nononeis. ¯hese hlaggiin nono- neis aggiegate vith leiatin to loin naciohlanents. lventually, hlaggiin is uegiaueu into nolecules, incluuing uio- canic aciu anu pyiioliuone caihoxylic aciu, vhich contiihute to hyuiation ol the stiatun coineun anu help hltei UV iauiation. Loiiciin is a cysteine-iich pio- tein that loins the na|oi piotein con- ponent ol the coiniheu envelope, ac- counting loi noie than ¯O peicent ol its nass. Upon its ielease lion leiatohyalin gianules, loiiciin hinus to uesnosonal stiuctuies. Loiiciin, along vith involu- ciin, cystatin A, snall pioline-iich pio- teins (SlR1, SlR2, anu coinihn), elahn, anu envoplalin aie all suhseguently cioss-linleu to the plasna nenhiane hy tissue tiansglutaninases (¯Cís, piinai- ily ¯Cís o anu 1), loining the coiniheu cell envelope. íutations in the ¯Cí1 gene have heen shovn to he the hasis ol sone cases ol lanellai ichthyosis, an autoso- nal iecessive conuition chaiacteiizeu hy laige scales anu a uisiuption in the uppeinost uilleientiating layeis ol the epiueinis. 41,42 Anothei loin ol ichthyo- sis, ichthyosis vulgaiis, is causeu hy nu- tations in the gene encouing hlag- giin. 4o,44 Loiiciin ahnoinalities iesult in a loin ol Vohvinlel synuione vith ichthyosis anu pseuuoainhun, as vell as the uisease piogiessive synnetiic leiatoueinia. 454¯ ¯hese hnuings en- phasize the inpoitance ol piopei loi- nation ol the coiniheu envelope in noi- nal epiueinal leiatinization. ¯he hnal stage ol gianulai cell uillei- entiation involves the cell`s ovn pio- gianneu uestiuction. Duiing this pio- cess, in vhich the gianulai cell hecones a teininally uilleientiateu coineocyte, an apoptotic nechanisn iesults in the ue- stiuction ol the nucleus anu alnost all cellulai contents, vith the exception ol the leiatin hlanents anu hlaggiin natiix. ST8AT0N 008h£0N (See Chap. 45) Con- plete uilleientiation ol gianulai cells ie- sults in stacleu layeis ol anucleate, hat- teneu coiniheu cells that loin the stiatun coineun. lt is this layei that pioviues nechanical piotection to the slin anu a haiiiei to vatei loss anu pei- neation ol soluhle suhstances lion the enviionnent (ievieveu in iels. oº anu 48). ¯he stiatun coineun haiiiei is loineu hy a tvo-conpaitnent systen ol lipiu-uepleteu, piotein-eniicheu coi- neocytes suiiounueu hy a continuous extiacellulai lipiu natiix. ¯hese tvo conpaitnents pioviue sonevhat seg- iegateu hut conplenentaiy lunctions that togethei account loi the °haiiiei ac- tivity` ol the epiueinis. Regulation ol peineahility, uesguanation, antinicio- hial peptiue activity, toxin exclusion, anu selective chenical ahsoiption aie all piinaiily lunctions ol the extiacellulai lipiu natiix. Cn the othei hanu, ne- chanical ieinloicenent, hyuiation, cyto- F|608£ 7-5 Jurc||cr c| ||e º||a|ur ç|aru|cºur (S0, ard º||a|ur cc|reur (SC,. |are||a| ç|aru|eº (|0, a|e |r ||e |r|e|ce||u|a| ºpace ard c]|cp|aºr c| ||e ç|aru|a| ce||. |e|a|c|]a||r ç|aru|eº (|H0, a|e a|ºc e.|der|. Irsct. |are||a| ç|aru|e, 28,/o0. (||cr Hc|||cc| |. S||uc|u|e ard de.e|cprer| c| ||e º||r, |r IatIcjIysic!cçy c| 0crratc!cçic 0iscasc, 2rd ed., ed||ed |] Sc|e| \A, Bader HP. \eW \c||, |c0|aW-H|||, 1991, p /, W||| pe|r|ºº|cr. |rºe| uºed W||| pe|r|ºº|cr ||cr EC wc|||-Sc||e|re|, |D., 62 line-neuiateu initiation ol inhanna- tion, anu piotection lion UV uanage aie all pioviueu hy the coineocytes. \cr|e|a||rcc]|eº c| ||e Ep|de|r|º íelanocytes aie neuial ciest-ueiiveu, pignent-synthesizing uenuiitic cells that iesiue piinaiily in the hasal layei (see Chap. ¯O). 4º By light nicioscopy, these cells aie iecognizeu hy theii pale-stain- ing cytoplasn, ovoiu nucleus, anu coloi ol the pignent-containing nelano- sones, the uistinctive oiganelle ol the nelanocyte. ¯he lunction ol nelano- cytes has heen highlighteu hy uisoiueis in nelanocyte nunhei oi lunction. ¯he classic ueinatologic uisease, vitiligo, is causeu hy the autoinnune uepletion ol nelanocytes. 5O Causes ol othei uisoi- ueis ol pignentation aie lounu in vaii- ous uelects in nelanogenesis, incluuing nelanin synthesis, nelanosone piouuc- tion, anu nelanosone tianspoit anu tianslei to leiatinocytes (see Chaps. ¯O anu ¯o). Regulation ol nelanocyte pio- lileiation anu honeostasis is unuei in- tensive stuuy as vell as a neans to un- ueistanuing nelanona (see Chap. 124). 4 leiatinocytenelanocyte inteiactions aie ciitical loi nelanocyte honeostasis anu uilleientiation, inhuencing piolileiation, uentiicity, anu nelanization. íeilel cells aie slov-auapting type l nechanoieceptois locateu in sites ol high-tactile sensitivity (see Chap. 12O). 51 ¯hey aie piesent anong hasal leiati- nocytes in paiticulai iegions ol the houy, incluuing haiiy slin anu in the glahious slin ol the uigits, lips, iegions ol the oial cavity, anu the outei ioot sheath ol the haii lollicle. Lile othei nonleiatinocytes, íeilel cells have a pale-staining cyto- plasn. lnnunohistochenical naileis ol the íeilel cell incluue l8, l18, l1º, anu l2O leiatin peptiues. l2O is iestiicteu to íeilel cells in the slin anu thus nay he the nost ieliahle nailei. Ultiastiuc- tuially, íeilel cells aie easily iuentiheu hy the nenhiane-hounueu, uense-coie gianules that collect opposite the Colgi anu pioxinal to an unnyelinateu neuiite (lig. ¯-6). ¯hese gianules aie sinilai to neuiosecietoiy gianules in neuions anu contain neuiotiansnittei-lile suhstances anu naileis ol neuioenuociine cells, in- cluuing netenlephalin, vasoactive in- testinal peptiue, neuion-specihc enolase, anu synaptophysin. Although incieasingly noie is heing leaineu ahout the noinal lunction ol íeilel cells, they aie ol pai- ticulai clinical note hecause íeilel cell- ueiiveu neoplasns aie paiticulaily aggies- sive anu uilhcult to tieat (see Chap. 12O). Langeihans cells aie uenuiitic antigen- piocessing anu -piesenting cells in the epi- ueinis (see Chap. 1O). 52 Although they aie not unigue to the epiueinis, they loin 2 peicent to 8 peicent ol the total epiueinal cell population. ¯hey aie nostly lounu in a supiahasal position hut aie uistiihuteu thioughout the hasal, spi- nous, anu gianulai layeis. ln histologic piepaiations, Langeihans cells aie pale- staining anu have convoluteu nuclei. ¯he cytoplasn ol the Langeihans cells con- tains chaiacteiistic snall iou- oi iaclet- shapeu stiuctuies calleu langcrhans .c|| granu|cs oi 3ir|c.k granu|cs (lig. ¯-¯). ¯hey piincipally lunction to sanple anu piesent antigens to ¯ cells ol the epiueinis. Be- cause ol these lunctions, they aie in- plicateu in the pathologic nechanisns unueilying alleigic contact ueinatitis, cutaneous leishnaniasis, anu hunan in- nunouehciency viius inlection. Langei- hans cells aie ieuuceu in the epiueinis ol patients vith ceitain conuitions, such as psoiiasis, saicoiuosis, anu contact ueina- titis, they aie lunctionally inpaiieu hy UV iauiation, especially UVB. Because ol theii ellectiveness in anti- gen piesentation anu lynphocyte stin- ulation, uenuiitic cells anu Langeihans cells have hecone piospective vehicles loi tunoi theiapy anu tunoi vaccines. ¯hese cells aie loaueu vith tunoi-spe- cihc antigens, vhich vill then stinulate the host innune iesponse to nount an antigen-specihc, anu theieloie tunoi- specihc, iesponse. DER|A|-EP|DER|A| JU\CT|0\ ¯he ueinal-epiueinal |unction (Dl[) is a hasenent nenhiane zone that loins the inteilace hetveen the epiueinis anu ueinis (see Chap. 51). 5o,54 ¯he na|oi lunctions ol the Dl[ aie to attach the epiueinis anu ueinis to each othei anu to pioviue iesistance against exteinal sheaiing loices. lt seives as a suppoit loi the epiueinis, ueteinines the polaiity ol giovth, uiiects the oiganization ol the cytosleleton in hasal cells, pioviues uevelopnental signals, anu seives as a senipeineahle haiiiei. ¯he Dl[ can he suhuiviueu into thiee supianoleculai netvoils: the heniues- nosone-anchoiing hlanent conplex, the hasenent nenhiane itsell, anu the anchoiing hhiils. ¯he ciitical iole ol this iegion in naintaining slin stiuctuial in- tegiity is ievealeu hy the laige nunhei ol nutations in Dl[ conponents that cause hlisteiing uiseases ol vaiying se- veiity, coveieu in uetail in Chap. 6O. ¯hese hullous uiseases aie gioupeu ac- coiuing to the level ol the cleavage vithin the Dl[the nost supeihcial, lB sinplex, involves hasal leiatinocyte cleavage. [unctional lB occuis vithin the lanina luciua anu lanina uensa ie- gions. Dystiophic lB is the ueepest level ol hlisteiing, vithin the suhlanina uensa/anchoiing hlanents. Chap. 51 pioviues a uetaileu uiscussion ol the Dl[ netvoils. DER||S ¯he ueinis is an integiateu systen ol h- hious, hlanentous, uilluse, anu cellulai connective tissue elenents that accon- nouates neive anu vasculai netvoils, epiueinally ueiiveu appenuages, anu contains nany iesiuent cell types, in- F|608£ 7-6 |e||e| ce||º ||cr ||e |rçe| c| a 180-rr CR (c|cWr-|urp, 21-Wee| |urar |e- |uº. \c|e re|.e (\, |r d||ec| ccr|ac| W||| ||e |a|- e|a| ard |aºa| ºu||aceº c| ||e ce|| ard derºe cc|e c]|cp|aºr|c ç|aru|eº (0,. 18,92o. Irsct. |e||e| ce|| ç|aru|eº, o1,4o0. F|608£ 7-7 |arçe||arº ce||. \c|e |rder|ed ruc|euº, |]ºcºcreº, aº We|| aº |cd- ard |ac|e|- º|aped c]|cp|aºr|c ç|aru|eº (B|||ec| ç|aru|eº,, ard ||e a|ºerce c| |e|a||r ||arer|º. 18,200. Irsct. B|||ec| ç|aru|eº 88,000. (Uºed W||| pe|- r|ºº|cr ||cr \. Rcrar|, |D., 63 cluuing hhiohlasts, naciophages, nast cells, anu tiansient ciiculating cells ol the innune systen (see ligs. 6-º anu 6-14). ¯he ueinis nales up the na|oi- ity ol the slin anu pioviues its pliahility, elasticity, anu tensile stiength. lt pio- tects the houy lion nechanical in|uiy, hinus vatei, aius in theinal iegulation, anu incluues ieceptois ol sensoiy stin- uli. ¯he ueinis inteiacts vith the epi- ueinis in naintaining the piopeities ol hoth tissues, collahoiates uuiing uevel- opnent in the noiphogenesis ol the Dl[ anu epiueinal appenuages (see De- velopnent ol Slin Appenuages), anu in- teiacts in iepaiiing anu ienoueling slin altei vounuing. ¯he ueinis is aiiangeu into tvo na- |oi iegions, the uppei papillaiy ueinis anu the ueepei ieticulai ueinis. ¯hese tvo iegions aie ieauily iuentihahle on histologic section, anu they uillei in theii connective tissue oiganization, cell uensity, anu neive anu vasculai pat- teins. ¯he papillaiy ueinis ahuts the epiueinis, nolus to its contouis, anu is usually no noie that tvice its thiclness (see lig. 6-º). ¯he ieticulai ueinis loins the hull ol the ueinal tissue. lt is con- poseu piinaiily ol laige-uianetei col- lagen hhiils, oiganizeu into laige, intei- voven hhei hunules, vith hianching elastic hheis suiiounuing the hunules (see lig. 6-14). ln noinal inuiviuuals, the elastic hheis anu collagen hunules inciease in size piogiessively tovaiu the hypoueinis. ¯he suhpapillaiy plexus, a hoiizontal plane ol vessels, nails the hounuaiy hetveen the papillaiy anu ieticulai ueinis. ¯he lovest hounu- aiy ol the ieticulai ueinis is uehneu hy the tiansition ol hhious connective tissue to auipose connective tissue ol the hypoueinis. ||||cuº |a|||/ c| ||e De|r|º ¯he connective tissue natiix ol the uei- nis is conpiiseu piinaiily ol collage- nous anu elastic hhious tissue. 55,56 ¯hese aie conhineu vith othei, non- hhious connective tissue nolecules, incluuing hnely hlanentous glycopio- teins, pioteoglycans (lCs), anu gly- cosaninoglycans (CACs) ol the °giounu suhstance.` 5¯ ln teins ol acellulai conponents, col- lagen loins the hull ol the ueinis, ac- counting loi appioxinately ¯5 peicent ol the uiy veight ol slin, anu pioviuing hoth tensile stiength anu elasticity. (loi uetails iegaiuing the polypeptiue stiuc- tuie anu uistiihution ol collagens, see Chap. 61.) ¯he peiiouically hanueu, in- teistitial collagens account loi the gieat- est piopoition ol collagen in auult uei- nis (type l, 8O peicent to ºO peicent, lll, 8 peicent to 12 peicent, anu V, < 5 pei- cent). Although type V collagen ac- counts loi a ielatively snall piopoition ol total collagen, it couistiihutes vith hoth types l anu lll collagen to assist in iegulating hhiil uianetei. lt is locateu piinaiily in the papillaiy ueinis anu the natiix suiiounuing the hasenent nen- hianes ol vessels, neives, anu epiueinal appenuages, anu at the Dl[. ¯ype Vl collagen is associateu vith hhiil anu in the inteihhiillai spaces. ¯ype lV col- lagen is conhneu to the hasal lanina ol the Dl[, vessels, anu epiueinal appen- uages. ¯ype Vll collagen loins anchoi- ing hhiils at the Dl[. llastic connective tissue (see Chap. 61) is conplex noleculai nesh, assen- hleu into a continuous netvoil that ex- tenus lion the lanina uensa ol the Dl[ thioughout the ueinis anu into the con- nective tissue ol the hypoueinis. 56 llas- tic hheis ietuin the slin to its noinal conhguiation altei heing stietcheu oi ueloineu. llastic hheis aie also piesent in the valls ol cutaneous hloou vessels anu lynphatics anu in the sheaths ol haii lollicles. By uiy veight, elastic con- nective tissue accounts loi appioxi- nately loui peicent ol the ueinal na- tiix piotein. ¯he conponents ol elastic hheis incluue hhiillin-1, a o5O-lu nole- cule, nutations in vhich cause íailan synuione (see Chap. 1oº). llastin is the elastic hhei natiix conponent, anu nu- tations in this piotein cause the uisease cutis laxa (see Chap. 1oº). Cxytalan h- heis extenu lion the Dl[ to the papil- laiy/ieticulai ueinal |unction, vheie they neige vith elaunin hheis. llaunin liheis, in tuin, evolve into natuie elas- tic hheis ol the ieticulai ueinis. ¯hese hheis aie noinally locateu hetveen hunules ol collagen hheis, although in ceitain pathologic conuitions, such as Buschle-Cllenuoill synuione, hoth elastic anu collagen hheis hecone as- senhleu vithin the sane hunule. ¯he inpoitance ol this elastic hhei netvoil is cleaily seen in the nunhei ol nulti- systen uiseases that aiise hecause ol nutations in conponents ol this net- voil. Recently, the uelect unueilying pseuuoxanthona elasticun (lXl) vas lounu to he nutation in ABCC6, a nenhei ol the laige auenosine tiiphos- phate-uepenuent tiansnenhiane tians- poitei lanily. ¯hus, this uisease that is chaiacteiizeu hy loss ol slin elasticity anu calciheu elastic hheis is unlilely a piinaiy uelect in elastic tissue, hut iathei a netaholic uisoiuei vith sec- onuaiy involvenent ol elastic hheis. 58 6O ln auuition to genetic nutations, solai iauiation anu aging also contiihute to elastic hhei uanage. 61 |||arer|cuº ard D|||uºe |a|||/ Ccrpcrer|º c| ||e De|r|º (See Chap. 61) ¯he hhious anu cellulai natiix elenents aie enheuueu vithin noie anoiphous natiix conponents, vhich also aie lounu in hasenent nenhianes. 6264 lCs anu CACs suiiounu anu enheu the h- hious conponents. lCs aie laige nole- cules consisting ol a coie piotein that ueteinines vhich CACs vill he incoi- poiateu into the nolecule. ¯he lC/ CAC conplex can hinu vatei up to 1OOO tines its ovn volune anu have ioles in iegulation ol vatei-hinuing anu conpiessihility ol the ueinis, as vell as incieasing local concentiations ol giovth lactois thiough hinuing (e.g., hasic hhiohlast giovth lactoi). ¯hey also linl cells vith the hhiillai anu hla- nentous natiix, inhuencing piolileia- tion, uilleientiation, tissue iepaii, anu noiphogenesis. ¯he na|oi lCs in the auult ueinis aie chonuioitin sullates/ueinatan sullate, incluuing higlycan, uecoiin, anu veisi- can, hepaian/hepaian sullate lCs, in- cluuing peilecan anu synuecan, anu chonuioitin-6 sullate lCs, vhich aie conponents ol the Dl[ (see Chap. 61). ¯he ielative anounts ol these uilleient lCs change vith age, as auult ueinis altei age 4O yeais geneially has in- cieases in ueinatan sullate, hut ue- cieases in chonuioitin-6 sullate anu chon- uioitin sullate. Clycopioteins that aie lounu in the ueinis incluue hhionectin, thionho- sponuin, laninin, vitionectin, anu tenas- cin. Lile the lCs/CACs, they inteiact vith othei natiix conponents via inte- giin ieceptois. ¯hese nolecules lacilitate piocesses ol nigiation, cell auhesion, noiphogenesis, anu uilleientiation. li- hionectin is synthesizeu hy hoth epithe- lial anu nesenchynal cells, anu it coveis collagen hunules anu the elastic netvoil. Vitionectin is piesent on all elastic hheis except loi oxytalan. ¯enascin expiession is lounu aiounu the snooth nuscle ol hloou vessels, aiiectoi pili nuscles, anu appenuages such as sveat glanus. Ce||u|a| Ccrpcrer|º c| ||e De|r|º lihiohlasts, naciophages, anu nast cells aie the iegulai iesiuents ol the ueinis, 64 nostly lounu aiounu the papillaiy ie- gion anu suiiounuing vessels ol the suh- papillaiy plexus (see lig. 6-2O). ¯hey also occui in the ieticulai ueinis in the inteistices hetveen collagen hhei hun- ules. ¯he hhiohlast is a nesenchynally ueiiveu cell that nigiates thiough the tissue anu is iesponsihle loi the synthe- sis anu uegiauation ol hhious anu nonh- hious connective tissue natiix pioteins anu a nunhei ol soluhle lactois. lihio- hlasts pioviue a stiuctuial extiacellulai natiix lianevoil as vell as pionote inteiaction hetveen epiueinis anu uei- nis hy synthesis ol soluhle neuiatois. Stuuies ol hunan hhiohlasts inuicate that even vithin a single tissue, pheno- typically uistinct populations exist, sone ol vhich ielate to iegional anatonical uilleiences. 65,66 ¯hey aie also instiu- nental in vounu healing anu scaiiing, incieasing theii piolileiative anu syn- thetic activity uuiing these piocesses. ¯he nonocytes, naciophages, anu ueinal uenuiocytes constitute the nono- nucleai phagocytic systen ol cells in the slin. íaciophages aie ueiiveu lion piecuisois in the hone naiiov, uillei- entiate into ciiculating nonocytes, then nigiate into the ueinis to uilleientiate. ¯hese cells aie phagocytic, piocess anu piesent antigen to innunoconpetent lynphoiu cells, aie niciohiciual (pio- uucing lysozyne, peioxiue, anu supei- oxiue), tunoiiciual, secietoiy (giovth lactois, cytolines, anu othei innuno- nouulatoiy nolecules), anu henatopoi- etic (see Chap. 1O), anu aie involveu in coagulation, atheiogenesis, vounu heal- ing, anu tissue ienoueling. íast cells (see Chap. 15O) aie special- izeu secietoiy cells that, in slin, aie piesent in gieatest uensity in the papil- laiy ueinis, neai the Dl[, in sheaths ol epiueinal appenuages, anu aiounu hloou vessels anu neives ol the suhpap- illaiy plexus. ¯hey aie also connon in the suhcutaneous lat. íast cells aie iuentiheu histologically hy a iounu oi oval nucleus anu ahunuant, uailly stain- ing cytoplasnic gianules. ¯he suilace ol ueinal nast cells is coateu vith h- hionectin, vhich piohahly assists in se- cuiing cells vithin the connective tissue natiix. íast cells can hecone hypei- plastic anu hypeipiolileiative in nasto- cytosis (see Chap. 15O). íast cells aie secietoiy cells that aie iesponsihle loi inneuiate-type hypeisensitivity ieac- tion in the slin anu aie involveu in the piouuction ol suhacute anu chionic in- hannatoiy uisease. ¯hey synthesize secietoiy gianules conposeu ol hista- nine, hepaiin, tiyptase, chynase, cai- hoxypeptiuase, neutiophil chenotactic lactoi, anu eosinophilic chenotactic lac- toi ol anaphylaxis, vhich aie neuiatois in these piocesses. ¯he ueinal uenuiocyte is a stellate, uenuiitic, oi sonetines spinule-shapeu, highly phagocytic hxeu connective tis- sue cell in the ueinis ol noinal slin. ¯hey aie a suhset ol antigen-piesenting naciophages oi a uistinct lineage that oiiginates in the hone naiiov. Sinilai to nany othei hone naiiov-ueiiveu cells, ueinal uenuiocytes expiess lactoi Xllla anu CD45, anu they lacl typical naileis ol hhiohlasts (e.g., ¯e-¯). ¯hese cells aie paiticulaily ahunuant in the papillaiy ueinis anu uppei ieticulai uei- nis, lieguently in the pioxinity ol ves- sels ol the suhpapillaiy plexus. Deinal uenuiocytes lunction in the alleient linh ol an innune iesponse (see Chap. 1O). ¯hey aie also lilely the cell ol oii- gin ol a nunhei ol henign hhiotic piolil- eiative conuitions in the slin, such as ueinatohhionas anu hhioxanthonas (see Chap. 64). CUTA\E0US VASCU|ATURE B|ccd Veººe|º (See Chap. 16o) ¯he hloou vessels ol the slin pioviue nutiition loi the tissue, hut in auuition, they aie involveu in tenpeiatuie anu hloou piessuie iegulation, vounu iepaii, anu nuneious innunologic events. 6¯ ¯he niciociiculatoiy heus in slin piogiess lion aiteiioles to piecapillaiy sphincteis. lxtenuing lion the sphinc- teis aie aiteiial anu venous capillaiies, vhich hecone postcapillaiy venules, anu hnally, collecting venules. When conpaieu vith vasculatuie ol othei oigans, the vessels ol slin aie auapteu to sheaiing loices, as they have thicl valls suppoiteu hy connective tissue anu snooth nuscle cells. Special cells, lnovn as vci| .c||s, suiiounu the cutane- ous niciociiculation, uehning a uonain loi the vessels vithin the ueinis vhile ienaining sepaiate lion the vessel valls. ¯he iich vasculai netvoil ol the slin is locateu at hounuaiies vithin the uei- nis anu supplies the epiueinal appenu- ages (see lig. 16o-2). ¯he vessels that supply the ueinis hianch lion nuscu- locutaneous aiteiies that penetiate the suhcutaneous lat anu entei the ueep ie- ticulai ueinis. At this point, they aie oi- ganizeu into a hoiizontal aiteiiolai plexus. lion this plexus, ascenuing aite- iioles extenu tovaiu the epiueinis. ¯hese aiteiioles contain tvo layeis ol snooth nuscle cells, as vell as peii- cytes, a seconu type ol contiactile cell ol the vessel vall. At the |unction hetveen the papillaiy anu ieticulai ueinis, teini- nal aiteiioles loin the suhpapillaiy plexus. ¯he aiteiioles at this level have only a single layei ol snooth nuscle cells, oiganizeu in a nannei to suggest that they lunction as piecapillaiy sphincteis. Capillaiy loops then extenu lion the teininal aiteiioles ol the plexus into the papillaiy ueinis. At the apex ol each capillaiy loop is the thin- nest poition, in vhich hoth the enuo- theliun anu hasal lanina ol the vessels aie attenuateu, alloving loi tianspoit ol nateiial out ol the capillaiy. ¯he extia- papillaiy uescenuing linhs ol capillaiy loops aie venous capillaiies that uiain into venous channels ol the suhpapillaiy plexus that lies ahove anu helov the ai- teiiolai vasculai plexus. ¯he postcapil- laiy venules ol the suhpapillaiy plexus aie physiologically inpoitant conpo- nents ol the niciociiculation. ¯hey aie iesponsive to neuiatois such as hista- nine, ueveloping gaps hetveen au|a- cent enuothelial cells that allov loi the extiavasation ol huiu anu cells, anu aie theieloie olten the sites ol inhanna- toiy cells uuiing these iesponses. Ceitain iegions ol the slin, such as the palns anu soles, contain uiiect con- nections hetveen aiteiial anu venous ciiculation as potential shunts aiounu congesteu capillaiy heus. ¯hese sites consist ol an ascenuing aiteiiole (a glo- nus houy), vhich is nouiheu hy thiee to six layeis ol snooth nuscle cells anu has associateu synpathetic neive hheis. ¯he glonus can close conpletely vhen the hloou piessuie is helov a ciitical level. ln the auult, the cutaneous vascula- tuie noinally ienains guiescent, vith the exception ol ceitain haii cycleue- penuent angiogenesis uuiing anagen. Cuiescence ol vessels is in pait uue to inhihition ol angiogenesis in the ueinal natiix hy lactois such as thionhospon- uin. lathogenic stinuli sonetines ie- sult in seconuaiy angiogenesis, lion tu- nois oi uuiing vounuing. Cne ol the ley neuiatois ol such angiogenesis is vasculai enuothelial giovth lactoi (VlCl), olten secieteu hy tunois oi hy leiatinocytes (see Chap. 16o). 68,6º Nuneious uisoiueis can nanilest thenselves vithin the cutaneous vascu- latuie. Leulocytoclastic vasculitis (cuta- neous neciotizing venulitis) occuis vithin the venules in iesponse to a nunhei ol potential pathogenic necha- nisns (see Chap. 164). Stasis ueinatitis, 65 uiticaiia, polyaiteiitis nouosa, thionho- sis, anu thionhophlehitis all allect ves- sels in the slin, ol uilleient sizes, sone hy occlusion ol vessels (vasculopathy) anu otheis hy inhannation ol the ves- sels (vasculitis). |]rp|a||cº ¯he lynph channels ol the slin aie in- poitant in iegulating piessuie ol the in- teistitial huiu hy iesoiption ol huiu ie- leaseu lion vessels anu in cleaiing the tissues ol cells, pioteins, lipius, hacteiia, anu uegiaueu suhstances. ¯O,¯1 ¯he ves- sels hegin in hlinu-enuing initial lyn- phatics (also lnovn as |,m¡hati. .a¡i||ar- ics, ¡rc|,m¡hati. tu|u|cs, anu tcrmina| oi ¡cri¡hcra| |,m¡hati.s) in the papillaiy uei- nis. ¯hey uiain into a hoiizontal plexus ol laigei lynph vessels locateu ueep to the suhpapillaiy venous plexus. A veiti- cal systen ol lynphatics then caiiies huiu anu uehiis thiough the ieticulai ueinis to anothei ueepei collecting plexus at the ieticulai ueinishypouei- nis hoiuei. Lynph hov vithin the slin uepenus on novenents ol the tissue causeu hy aiteiial pulsations anu laigei-scale nus- cle contiactions anu novenent ol the houy, vith haclhov pieventeu hy hi- cuspiu-lile valves vithin the vessels. Although lynphatic vessels aie only seen vith uilhculty on histologic sec- tion, hecause they aie olten collapseu in slin, they aie conposeu ol a laige lu- nen anu a thinnei vall than hloou ves- sels, vith enuotheliun, uiscontinuous hasal lanina, anu elastic hheis. íolecu- lai chaiacteiization ol these vessels has iuentiheu liox1, VlClR-o, anu LYVl-1 as specihc naileis ol lynphatic chaiac- tei, anu one ol the nost heavily-stuuieu lynphangiogenic nolecules is VlCl-C (see Chap. 16o). Ceitain pathologic conuitions in- volve oi highlight the lynphatic vessels, such as lynpheuena, lynphangiona ciicunsciiptun, anu stasis ueinatitis. ¯he inpoitance ol lynphatics in the piogiession anu spieau ol cancei is also heconing noie cleai, as nelanona cells uestioy enuothelial cells ol the initial lynphatics to gain entiy to the lynph ciiculation, anu iecent stuuies have shovn that tunois thenselves can pio- note lynphangiogenesis as pait ol theii eaily piogian on the vay to netasta- sis. 68 ¯he uiscoveiy ol the noleculai ue- lects in heieuitaiy lynpheuenas |type l íilioy uisease VlClR-o, ¯2¯4 type ll lynpheuena piaecox, lynpheuena uis- tichiasis, lynpheuena anu yellov nails, anu lynpheuena anu ptosis ílH1 (loilheau tiansciiption lactoi, loxC2) ¯5 ] has inplicateu the VlClR-o anu loxC2 in lynphatic uevelopnent. CUTA\E0US \ERVES A\D RECEPT0RS (See Chaps. 1O1 anu 1O2) ¯he neive net- voils ol the slin contain sonatic sen- soiy anu synpathetic autononic h- heis. ¯6 ¯he sensoiy hheis alone (liee neive enuings) oi in con|unction vith specializeu stiuctuies (coipusculai ie- ceptois) lunction as ieceptois ol touch, pain, tenpeiatuie, itch, anu nechanical stinuli. ¯he uensity anu types ol iecep- tois aie iegionally vaiiahle, accounting loi the vaiiation in acuity at uilleient sites ol the houy. Receptois aie paiticu- laily uense in haiiless aieas such as the aieola, lahia, anu glans penis. Synpa- thetic notoi hheis aie couistiihuteu vith the sensoiy neives in the ueinis until they hianch to inneivate the sveat glanus, vasculai snooth nuscle, the ai- iectoi pili nuscle ol haii lollicles, anu sehaceous glanus. ¯he neives ol slin hianch lion nus- culocutaneous neives that aiise segnen- tally lion spinal neives. ¯he pattein ol neive hheis in slin is sinilai to the vas- culai patteins. ¯hat is, neive hheis loin a ueep plexus, then ascenu to a supeih- cial, suhpapillaiy plexus. liee neive enuings incluue the peni- cillate anu papillaiy neive hheis anu aie the nost viuespieau anu inpoitant sensoiy ieceptois ol the houy. ln hu- nans, they aie ensheatheu hy Schvann cells anu a hasal lanina. liee neive enu- ings aie paiticulaily connon in the papillaiy ueinis, the hasal lanina ol the hhei nay neige vith the lanina uensa ol the hasenent nenhiane zone. ¯he penicillate hheis aie the piinaiy neive hheis lounu suh-epiueinally in haiieu slin. ¯hese aie iapiuly auapting ieceptois that lunction in the peiception ol touch, tenpeiatuie, pain, anu itch. Be- cause ol oveilapping inneivation, uis- ciinination tenus to he geneializeu in these iegions. Cn the othei hanu, liee neive enuings piesent in non-haiieu, iiugeu slin, such as the palns anu soles, pio|ect inuiviuually vithout oveilapping uistiihution. ¯hese ieceptois aie thought to lunction in hne uisciinination. lapillaiy neive enuings aie lounu at the oiihce ol a lollicle. ¯hese hianches lion neives that inneivate the ueepei levels ol the lollicle aie thought to he paiticulaily ieceptive to colu sensation. Haii lollicles also contain othei iecep- tois, lion nyelinateu sten axons in the ueep ueinal plexus, thought to he slov- auapting ieceptois that iesponu to the henuing oi novenent ol haiis. Cholin- eigic synpathetic hheis en ioute to the ecciine sveat glanu anu auieneigic anu cholineigic hheis en ioute to the aiiec- toi pili nuscle aie caiiieu along vith the sensoiy hheis in the haii haslet. liee neive enuings aie also associateu vith inuiviuual íeilel cells. íeilel cellneive conplexes aie uesciiheu hy a vaiiety ol nanes (tou.h domcs, hcdcrijorm cndings, lggo´s .a¡su|c, linkus .or¡us.|cs, Haars.hci|c), uepenuing on theii conpo- sition anu location. ln haiieu slin, touch uones aie associateu vith haii lollicles. ln palnoplantai slin, these conplexes aie lounu at the site vheie the ecciine sveat uuct penetiates a glanuulai epi- ueinal papilla. Coipusculai ieceptois, hoth íeiss- nei`s anu lacinian, contain a capsule anu innei coie anu aie conposeu ol hoth neuial anu non-neuial conponents. ¯he capsule is a continuation ol the peiineu- iiun, anu the coie incluues the neive h- hei suiiounueu hy lanellateu viap- pings ol Schvann cells. íeissnei`s coipuscles aie elongateu oi ovoiu nech- anoieceptois locateu in the ueinal pa- pillae ol uigital slin anu oiienteu veiti- cally tovaiu the epiueinal suilace (lig. ¯-8). Cne to six axons entei the coipus- cle, ianily extensively, anu teininate in hulhoiu enuings that aie suiiounueu hy lanellae. ¯he lacinian coipuscle lies in the ueep ueinis anu suhcutaneous tissue ol F|608£ 7-8 |e|ººre|'º cc|puºc|e. \c|e ||e capºu|e ard |rre| cc|e |cca|ed |r ||e de|ra| pap||- |ae. T|eºe cc||ec||crº c| ce||º ºe|.e aº rec|arc|e- cep|c|º. (Uºed W||| pe|r|ºº|cr ||cr 0. |c.|c|, |D., 66 slin that coveis veight-heaiing suilaces ol the houy. lt has a chaiacteiistic cap- sule anu lanellai viappings (lig. ¯-º). ¯he peiineuial capsule is oiganizeu into oO oi noie concentiic layeis ol cells anu hhious connective tissue. ¯he niuule suhcapsulai zone is conposeu ol col- lagen anu hhiohlasts, anu the innei coie consists ol Schvann cell-ueiiveu heni- lanellae: hatteneu seniciicles that altei- nate vith those ol the opposite siue. la- cinian coipuscles seive as iapiuly auapting nechanoieceptois that ie- sponu to vihiational stinuli. H\P0DER||S (SUBCUT|S, ¯he tissue ol the hypoueinis insulates the houy, seives as a ieseive eneigy sup- ply, cushions anu piotects the slin, anu allovs loi its nohility ovei unueilying stiuctuies. lt has a cosnetic ellect in noluing houy contouis. ¯he hounuaiy hetveen the ueep ieticulai ueinis anu the hypoueinis is an ahiupt tiansition lion a pieuoninantly hhious ueinal connective tissue to a piinaiily auipose suhcutaneous one (see lig. 6-1, Chap. 6). Despite this cleai uistinction ana- tonically, the tvo iegions aie still stiuctuially anu lunctionally integiateu thiough netvoils ol neives anu vessels anu thiough the continuity ol epiueinal appenuages. Actively gioving haii lolli- cles span the ueinis anu extenu into the suhcutaneous lat, anu the apociine anu ecciine sveat glanus aie noinally con- hneu to this uepth ol the slin. Auipocytes loin the hull ol the cells in the hypoueinis. ¯¯,¯8 ¯hey aie oiga- nizeu into lohules uehneu hy septa ol h- hious connective tissue. Neives, vessels, anu lynphatics aie locateu vithin the septa anu supply the iegion. ¯he syn- thesis anu stoiage ol lat continues thioughout lile hy enhanceu accunula- tion ol lipiu vithin lat cells, piolileiation ol existing auipocytes, oi hy ieciuit- nent ol nev cells lion unuilleientiateu nesenchyne. ¯he hoinone leptin, se- cieteu hy auipocytes, pioviues a long- tein leeuhacl signal iegulating lat nass. Leptin levels aie highei in suhcu- taneous than onental auipose, suggest- ing a iole loi leptin in contiol ol auipose uistiihution as vell. ¯he inpoitance ol the suhcutaneous tissue is appaient in patients vith Weinei synuione (see Chap. 1oº), in vhich suhcutaneous lat is ahsent in le- sion aieas ovei hone, oi vith scleio- ueina (see Chap. 158), vheie the suh- cutaneous lat is ieplaceu vith uense hhious connective tissue. Such iegions in Weinei patients ulceiate anu heal pooily. ¯he slin ol patients vith scleio- ueina is taut anu painlul. ln the heieui- taiy anu acguiieu lipouystiophies, loss ol suhcutaneous lat uisiupts glucose, tii- glyceiiue, anu cholesteiol iegulation, anu causes signihcant cosnetic altei- ation, incieasing the inteiest in possihle hoinonal theiapy loi these uisoiueis (see Chap. 6º). ¯º ¯he suhcutaneous tis- sue is involveu in uilleient inhanna- toiy conuitions, anu these aie uiscusseu in Chap. 68. DEVE|0P|E\T 0| S||\ Signihcant auvances in the unueistanu- ing ol the noleculai piocesses iesponsi- hle loi the uevelopnent ol the slin have heen naue ovei the last seveial yeais. Such auvances inciease the unueistanuing ol clinicopathologic coiielation anong sone inheiiteu uisoiueis ol the slin anu allov loi the eaily uiagnosis ol such uis- eases. 8O,81 ¯he uevelopnental piogies- sion ol vaiious conponents ol the slin is vell uocunenteu, anu a tine line in- uicating the events that occui uuiing enhiyonic anu letal uevelopnent is pioviueu (¯ahle ¯-4). 82,8o Cl note, the estinateu gestational age (lCA) is useu thioughout this chaptei, this systen ie- leis to the age ol the letus, vith leitili- zation occuiiing on uay 1. ¯o avoiu con- lusion, it shoulu he pointeu out that ohstetiicians anu nost clinicians uehne uay 1 as the hist uay ol the last nen- stiual peiiou (nenstiual age), in vhich leitilization occuis on appioxinately uay 14. ¯hus, the tvo uating systens uillei hy appioxinately 2 veels, such that a vonan vho is 14 veels pieg- nant (nenstiual age) is caiiying a 12- veel-olu letus (lCA). Conceptually, letal slin uevelopnent can he uiviueu into thiee uistinct hut tenpoially oveilapping stages, those ol specihcation, noiphogenesis, anu uil- leientiation. ¯hese stages ioughly coiie- sponu to the enhiyonic peiiou (O to 6O uays), the eaily letal peiiou (2 to 5 nonths), anu the late letal peiiou (5 to º nonths) ol uevelopnent. ¯he eailiest stage, specihcation, ieleis to the piocess hy vhich the ectouein lateial to the neuial plate is connitteu to hecone epiueinis, anu suhsets ol nesenchynal anu neuial ciest cells aie connitteu to loin the ueinis. lt is at this tine that patteining ol the lutuie layeis anu spe- cializeu stiuctuies ol the slin occuis, ol- ten via a conhination ol giauients ol F|608£ 7-9 Pac|r|ar cc|puº- c|e. \c|e ||e c|a|ac|e||º||c pe||- reu|a| capºu|e, |||ered |c ||e appea|arce c| ar 'cr|cr-º||r.' Pac|r|ar cc|puºc|eº ºe|.e aº |ap- |d|] adap||rç rec|arc|ecep|c|º ||a| |eºpcrd |c .|||a||cra| º||ru||. (Uºed W||| pe|r|ºº|cr ||cr 0. |c.|c|, |D., Ik8L£ 7-4 T|m|ng of tha Najor Fvants |n tha Fmbryoganas|s of Human Sk|n a F|8ST T8|NFSTF8 SF00h0 T8|NFSTF8 TH|80 T8|NFSTF8 1 2 3 4 5 ö 7 8 9 Ep|de|r|º Appea|arce c| ep|de|ra| ce|| |a]e|º S||a|ur |aºa|e / Pe||de|r / S||a|ur |r|e|red|ur / S||a|ur ç|aru|cºur / S||a|ur cc|reur / Pe||de|r d|ºappea|arce / (ccrtir0cc; 67 pioteins anu cellcell signals. ¯he sec- onu stage, noiphogenesis, is the pio- cess hy vhich these connitteu tissues hegin to loin theii specializeu stiuc- tuies, incluuing epiueinal stiatihcation, epiueinal appenuage loination, suhui- vision hetveen the ueinis anu suhcutis, anu vasculai loination. ¯he last stage, uilleientiation, uenotes the piocess hy vhich these nevly specializeu tissues luithei uevelop anu assune theii na- tuie loins. ¯ahle ¯-5 integiates specih- cation, noiphogenesis, anu uilleientia- tion vith slin noiphology anu genetic uiseases. loi sinplihcation anu gieatei claiity, the stages ol uevelopnent ol the epiuei- nisueinis anu hypoueinis, ueinal epiueinal |unction, anu epiueinal ap- penuagesaie piesenteu seguentially. Ep|de|r|º £N88Y0h|0 0£V£L0PN£hT Duiing the thiiu veel altei leitilization, the hunan enhiyo unueigoes gastiulation, a con- plex piocess ol involution anu cell ieuis- tiihution that iesults in the loination ol the thiee piinaiy enhiyonic gein layeis: ectouein, nesouein, anu enuouein. Shoitly altei gastiulation, ectouein lui- thei suhuiviues into neuioectouein anu piesunptive epiueinis. ¯he specihca- tion ol the piesunptive epiueinis is helieveu to he neuiateu hy the hone noiphogenetic pioteins (Bíls). Latei uuiing this peiiou, Bíls again appeai to play a ciitical iole, along vith ln- giaileu-1 (ln1), in specilying the volai veisus inteilolliculai slin. 8486 By 6 veels lCA, the ectouein that coveis the houy consists ol hasal cells anu su- peihcial peiiuein cells. ¯he hasal cells ol the enhiyonic epi- ueinis uillei lion those ol latei uevel- opnental stages. lnhiyonic hasal cells aie noie colunnai than letal hasal cells, anu they have not yet loineu heniues- nosones. Although ceitain integiins (e.g., 6 4) aie expiesseu in these cells, they aie not yet localizeu to the hasal pole ol the cells. Beloie the loination ol heniuesnosones anu uesnosones, in- teicellulai attachnent hetveen inuiviu- ual hasal cells appeais to he neuiateu hy auhesion nolecules such as l- anu l- cauheiin, vhich have heen uetecteu on hasal cells as eaily as 6 veels lCA. lei- atins l5 anu l14, pioteins iestiicteu to uehnitive stiatiheu epithelia, aie ex- piesseu even at these eaily stages ol epi- ueinal loination. At this stage, peiiuein cells loin a °pavenent epitheliun.` ¯hese cells aie Ik8L£ 7-4 T|m|ng of tha Najor Fvants |n tha Fmbryoganas|s of Human Sk|n a (0ont|nuad} F|8ST T8|NFSTF8 SF00h0 T8|NFSTF8 TH|80 T8|NFSTF8 1 2 3 4 5 ö 7 8 9 Ep|de|ra| ce|| jurc||crº Deºrcºcreº W|||cu| aººcc|a|ed |e|a||r ||arer|º / Deºrcºcreº W||| aººcc|a|ed |e|a||r ||arer|º / T|ç|| jurc||crº / Her|deºrcºcreº / Ar||çerº Perp||çuº ard perp||çc|d ar||çer / A, B, H ||ccd ç|cup ar||çerº / |rr|ç|ar| ce||º P|eºer|, |u| |]pe urce||a|r / |e|arcc]|e w||| p|ere|arcºcreº / w||| re|arcºcreº ||a| º]r||eº|/e re|ar|r / T|arº|e| c| re|arcºcreº |c |e|a||rcc]|eº / |arçe||arº ce||º / |e||e| ce||º / Ep|de|ra| apperdaçeº P||cºe|acecuº appa|a|uº Ha|| |c|||c|e de.e|cprer| |eç|rº / Ha|| e/pcºed cr º||r ºu||ace ard pa||e|rº eº|a|- ||º|ed cr ||e ºca|p / Se|acecuº ç|ard p||rc|d|ur / Se|acecuº ç|ard |urc||cr / Apcc||re ç|ard p||rc|d|ur / Apcc||re ç|ard |urc||cr / Ecc||re ºWea| ç|ardº (||ur|, Duc| ard ç|ard pa|er| ard |urc||cr|rç / \a||º \a|| |c|d ard eº|a|||º|rer| c| ra|||/ p||rc|d|ur / \a|| p|a|e |c|rº / |e|a||r|/a||cr c| ep|de|r|º ard apperdaçeº Dc|ºa| ||dçe c| p|eºurp||.e ra|| / \a|| p|a|e / Pa|ra|/p|ar|a| ºu||ace c| d|ç||º / Ha|| ccre / Ha|| ||ac| / Ha|| º|a|| / Se|acecuº duc| / Ecc||re ºWea| ç|ard duc| (|r||aep|de|ra|, / Apcc||re duc| / De|r|º S||uc|u|a| c|çar|/a||cr Pap|||a|] ard |e||cu|a| |eç|crº eº|a|||º|ed / De|ra| pap|||ae eº|a|||º|ed / De|ra|-ºu|cu|arecuº |curda|] / Parr|cu|uº ad|pcºuº eº|a|||º|ed / Ccrrec||.e ||ººue ra|||/ p|c|e|rº Cc||açer p|eºer| |] u|||aº||uc|u|a| c|ºe|.a||cr / Cc||açer p|eºer| |] ||cc|er|ca| ara|]º|º T]pe | ´ / T]pe ||| ´ / E|aº||c r|c|c|||||º ´ / E|aº||c ra|||/ / E|aº||c |||cuº re|Wc||º / a Da|a a|e |ep|eºer|a||.e c| ||e ||ur| ur|eºº º|a|ed c||e|W|ºe. 68 Ik8L£ 7-5 Prota|ns |nvo|vad |n 0utanaous 0ava|opmant and 0|ffarant|at|on FP|0F8N|S 0F8N|S/S0 0FJ APPFh0A0FS Spec||ca||cr º 8NPs º Lmx-18 (\a||-pa|e||a º]rd|cre, º \c| |rcWr º Lmx-18 º £ogra||ed-1 º wot7a º (Ap|aº|a cu||º, º £ogra||ed-1 º h6F8 º wot7a |c|p|cçereº|º º p63 º Lam|o Al0, INP£ ST£24 (|eº|||c||.e de|- rcpa||], º Lam|o|o 1 º £ctodysp|as|o A (£0A) (/-||r|ed |]pc||d|c||c ec|cde|ra| d]ºp|aº|a, º 0|x-3 (T||c|c-der|c-cººecuº º]r- d|cre, º 0o||ageo |V º hepar|o s0|Iate º 0oooex|o 30 (Au|cºcra| |]pc- ||d|c||c ec|cde|ra| d]ºp|aº|a, |]pe 2, º PT£h (P|c|euº º]r- d|cre, º Proteog|ycaos º £0A receptor (Au|cºcra| |]pc- ||d|c||c ec|cde|ra| d]ºp|aº|a, |]pe 8, º (|cca| de|ra| |]pcp|a- º|a/0c||/ º]rd|cre, º NSX1 (w|||cp º]rd|cre/|cc|| ard ra|| º]rd|cre, º c-k|t (P|e|a|d|ºr, º PAX-3 (waa|der|u|ç |]pe 1,8, º p63 (Ha]-we||º/AEC, EEC, º 8eta-cateo|o (p||cra|||ccraº, º Shh º wot º 8NPs º F6F5 º L£F1 º 0|x-3 D|||e|er||a||cr º S||uc|u|a| p|c|e|rº º 0ap|||ary morphogeo- es|s prote|o-2 (ju.e- r||e |]a||re |||cra|c- º|º, |r|ar|||e º]º|er|c |]a||rcº|º, º 8PA62 º Ha|| º k5, k14 (EB º|rp|e/, º 0o||ageo V|| º 8NPs º P|ect|o (EB W||| |D, º 6 4 |otegr|o º hoxc13 º 8PA62 (0ABEB, º Lam|o|o 5 (jurc||cra| EB, º Foxo1 º 6 4 |otegr|o (EB W||| PA, º P|akog|ob|o (\a/cº d|ºeaºe, º k1, k10 (BC|E, º 0o||ageo |, a1, c| a2 (cº|ecçereº|º |rpe|- |ec|a, º P|akoph|||oldesmosoma| baod 6 (ec|cde|ra| d]ºp|aº|a, º||r ||aç||||] º]rd|cre, º k1, k9 (Vc|re|, Urra-T|cº|, 0|e|||e|, º Lor|cr|o (\C|E, Vc|W|r|e|, p|cç|eº- º|.e º]rre|||c e|]|||c|e|a|cde|r|a, º 0o||ageo V, a1, c| a2 (E||e|º-Dar|cº º]r- d|cre, º ha|r|ess (papu|a| a|||c||a, º F||aggr|o (|c|||]cº|º .u|ça||º, º \a|| º Pcº|-||arº|a||cra| rcd||e|º º k6a, k16 (pac|]cr]c||a ccr- çer||a |]pe |, º L£kT| (\e||e||cr, º 0o||ageo V|| (d]º||c- p||c EB, º Traosg|0tam|oase 1 (|are||a| |c|||]cº|º, \C|E, º k6b, k17 (pac|]cr]c||a ccr- çer||a |]pe ||, º|ea|cc]º|cra ru|||p|e/, º F|br||||o (|a||ar º]r- d|cre, º Phytaooy| 0oA hydroxy|ase (Re|ºur, º £|ast|o (cu||º |a/a, º P|akoph|||o º Fatty a|dehyde dehydrogeoase (Sjcç|er-|a|ººcr, º N8P6 (P/E, º Se|acecuº ç|ard º T|e-2 (|r|e|||ed .ercuº ra||c|ra||crº, º 8||mp-1 º Stero|d s0|Iataselary|s0|Iatase C (/-||r|ed |c|||]cº|º, º k6b, k17 º £odog||o, act|v|o receptor-||ke k|oase 1 (HHT/0º|e|-we|e|- Rerdu, º T|arºpc||e|/c|arre| p|c|e|rº º A80A12 (|a||e(u|r |e|uº, º 0oooex|o 26 (||D º]rd|cre, pa|rc- p|ar|a| |e|a|cde|ra W||| dea|reºº, º V£6F receptor-3 (|e|ed||a|] |]rp|e- dera |]pe |, º 0oooex|o 30.3 c| 31 (e|]|||c|e|a- |cde|ra .a||a||||º, p|cç|eºº|.e º]r- re|||c e|]|||c|e|a|cde|r|a, º NFh1 (|e|ed||a|] |]rp|edera |]pe ||, º S£80A2 (|e|a|cº|º |c|||cu|a||º, º ATP201 (Ha||e]-Ha||e] d|ºeaºe, º Prox-1 º S|çra| ||arºduc||cr p|c|e|rº º LYV£-1 º Patched (|aºa| ce|| re.uº º]rd|cre, AEC = ar|]|c||ep|a|cr-ec|cde|ra| d]ºp|aº|a-c|e|||rç, BC|E = |u||cuº ccrçer||a| |c|||]cº||c|r e|]|||cde|ra, B|Pº = |cre rc|p|cçere||c p|c|e|rº, BPA0 = |u||cuº perp||çc|d ar||çer, EB = ep|de|rc|]º|º |u||cºa, EEC = ec||cdac|]|]-ec|cde|ra| d]ºp|aº|a-c|e|||rç, 0ABEB = çere|a||/ed a||cp||c |er|çr ep|de|rc|]º|º |u||cºa, HHT = |e|ed||a|] |erc|||aç|c |e|arç|ec|aº|a, | = |e|a||r, ||D = |e|a||||º-|c|||]cº|º-dea|reºº, |D = ru|||p|e d]º||cp|], \C|E = rcr-|u||cuº ccrçer||a| |c|||]cº||c|r e|]|||cde|ra, \0|R = re|.e ç|cW|| |ac|c| |ecep|c|, PA = p]|c||c a||eº|a, P/E = pºeudc/ar||cra e|aº||cur. P|c|e|r rareº a|e |rd|ca|ed |r bo|dIace. Aººcc|a|ed d|ºeaºeº/çercde|ra|cºeº a|e ||º|ed |r pa|er||eºeº. |u|||p|e rareº |c| ||e ºare p|c|e|r c| º]rd|cre a|e ºepa- |a|ed |] /. 0ereº ard aººcc|a|ed d|ºeaºeº car |e |curd |r 0r||re |erde||ar |r|e|||arce |r |ar (0|||, a| |||p.//WWW.rc||.r|r.r||.çc./cr|r. 69 enhiyonic epiueinal cells that aie laigei anu hattei than the unueilying hasal cells. Apical suilaces contact the anniotic huiu anu aie stuuueu vith ni- ciovilli. Connections hetveen peiiuein cells aie sealeu vith tight |unctions iathei than uesnosones. By the enu ol the seconu tiinestei, these cells aie slougheu anu eventually loin pait ol the veinix caseosa. Lile stiatiheu epi- thelial cells, peiiuein cells expiess l5 anu l14, hut they also expiess sinple epithelial leiatins l8, l18, anu l1º. Aplasia cutis (see Chap. 1O6) nay ie- hect local uelects in eithei epiueinal specihcation oi uevelopnent causeu hy sonatic nosaicisn, oi nutations that occui postzygotically. ¯he noleculai uelect loi this uisoiuei is not lnovn, hovevei. ¯he lact that lev genetic uis- eases have heen uesciiheu in vhich epi- ueinal specihcation oi noiphogenesis aie uelective lilely iehects the lact that such uelects voulu he inconpatihle vith suivival. £A8LY F£TAL 0£V£L0PN£hT (N08Ph06£h- £S|S) By the enu ol 8 veels ol gestation, henatopoiesis has svitcheu lion the ex- tiaenhiyonic yoll sac to the hone nai- iov, the classical uivision hetveen en- hiyonic anu letal uevelopnent. By this tine, the epiueinis hegins its stiatihca- tion anu loination ol an inteineuiate layei hetveen the tvo pie-existing cell layeis. ¯he cells in this nev layei aie sin- ilai to the cells ol the spinous layei in na- tuie epiueinis. Lile spinous cells, they expiess leiatins l1/l1O anu the uesno- sonal piotein uesnoglein-o. ¯he cells aie still highly piolileiative anu, uuiing this peiiou ol uevelopnent, they evolve into a nultilayei stiuctuie that vill eventually ieplace the uegeneiating peiiuein. lxpiession ol the p6o gene plays a ciit- ical iole in the piolileiation anu nainte- nance ol the hasal layei cells. lpiueinal stiatihcation uoes not occui in nice ueh- cient loi p6o. 8¯8º ln hunans, although no null nutations have heen isolateu, paitial loss ol p6o lunction nutations have heen iuentiheu in anlylohlephaion, ectoueinal uysplasia, anu clelt lip/palate synuione (Hay-Wells synuione) as vell as ectiouactyly, ectoueinal uysplasia, anu clelt lip/palate synuione (see Chap. 14o). ºOº2 ¯he pie-existing hasal cell layei also unueigoes noiphologic changes at this tine, heconing noie cuhoiual anu expiessing nev leiatin genes, l6, l8, l1º, anu l6/l16, that aie usually ex- piesseu in hypeipiolileiative tissues. ¯he hasal layei also hegins to elahoiate pio- teins that vill ultinately anchoi then to the ueveloping hasal lanina (see Deinal- lpiueinal [unction), incluuing heniues- nosonal pioteins BlAC1, BlAC2, anu collagens V anu Vll (see Chaps. 51, 54, anu 6O). lnhiyonic lines ol ectoueinal loina- tion aie ievealeu in nosaic uisoiueis that lollov the lines ol Blaschlo, incluu- ing congenital, nevoiu, anu acguiieu conuitions. ºoº5 íoleculai uenonstiation ol genetic nosaicisn has heen iepoiteu loi a nunhei ol X-linleu uisoiueis (ie- vieveu in iel. º4), as vell as epiueinal nevi in epiueinolytic hypeileiatosis. º6 LAT£ F£TAL 0£V£L0PN£hT (0|FF£8£hT|A- T|0h) Late letal uevelopnent ieveals the luithei specialization anu uilleientia- tion ol leiatinocytes in the epiueinis. lt is at this tine that the gianulai anu stia- tun coineal layeis aie loineu, anu the iuuinentaiy peiiuein is slougheu. leiatinization ol the suilace epiueinis is a piocess ol leiatinocyte teininal uil- leientiation vhich hegins at 15 veels lCA. ¯he gianulai layei hecones pion- inent, anu inpoitant stiuctuial pioteins aie elahoiateu in the hasal layei cells. ¯he heniuesnosonal pioteins plectin anu 6 4 integiin aie expiesseu anu coiiectly localizeu at this tine. íuta- tions in these genes iesult in vaiious hullous genoueinatoses (ievieveu in Chap. 6O). ¯he noie supeihcial cells un- ueigo luithei teininal uilleientiation, anu the leiatin-aggiegating piotein hl- aggiin is expiesseu at this tine. ¯he loination ol the coiniheu enve- lope is a late leatuie ol uilleientiating leiatinocytes, anu it ielies on a nunhei ol uilleient nouihcations to cieate an inpeineahle haiiiei. lnzynes such as tiansglutaninase, Lll¯l (encoueu hy the gene SllNl-5), phytanoyl coen- zyne A ieuuctase, latty aluehyue uehy- uiogenase, anu steioiu sullatase aie all inpoitant in the elahoiation ol the coiniheu envelope anu natuie lipiu hai- iiei, anu uelects in these enzynes can leau to ahnoinal epiueinal haiiiei loi- nation (see Chap. 4¯). SP£0|AL|I£0 0£LLS w|Th|h Th£ £P|0£8- N|S ¯he thiee na|oi nonepiueinal cell typesnelanocytes, Langeihans cells, anu íeilel cellscan he uetecteu vithin the epiueinis hy the enu ol the enhiyonic peiiou. íelanocytes aie ue- iiveu lion the neuial ciest, a suhset ol neuioectouein cells. lignent nosa- icisn (loineily calleu h,¡omc|anosis oj lto anu |incar and vhor|cd h,¡crmc|anosis) (see Chap. ¯o) lolloving the lines ol Blaschlo nay iehect the nigiatoiy paths ol nel- anohlasts, oi alteinatively, nosaic uelects in pignent tianslei lion nelanocytes to leiatinocytes. ¯he lounueis ol each nel- anohlast clone oiiginate at uistinct points along the uoisal niuline, tiaveising ven- tially anu uistally to tale up iesiuence in the epiueinis. íelanocytes aie hist seen vithin the epiueinis at 5O uays lCA. íelanocytes expiess integiin ieceptois in vivo anu in vitio anu nay use these to nigiate to the epiueinis uuiing enhiyonic uevelop- nent. íigiation, colonization, piolileia- tion, anu suivival ol nelanocytes in uevel- oping slin uepenu on the cell suilace tyiosine linase ieceptoi, .-kit, anu its li- ganu, sten cell lactoi. º¯,º8 íelanin he- cones uetectahle hetveen o anu 4 nonths lCA, anu hy 5 nonths, nelanosones he- gin to tianslei pignent to leiatinocytes. íany genetic uisoiueis ol pignentation have heen chaiacteiizeu anu aie piesenteu in uetail in Chaps. ¯1, ¯o, anu 144. ln the auult, a pool ol nelanocyte piecuisoi cells iesiues in the uppei peinanent poition ol the haii lollicle, capahle ol piouucing na- tuie nelanocytes. º¯,ºº,1OO Langeihans cells, anothei innigiant population, aie uetectahle hy 4O uays lCA. ¯hey hegin to expiess CD1 on theii suilace anu to piouuce theii chaiacteiistic Biihecl gianules hy the enhiyonicletal tiansition. By the thiiu tiinestei, nost ol the auult nunheis ol Langeihans cells vill have heen piouuceu. íeilel cells, as uesciiheu eailiei in the chaptei (see Nonleiatinocytes ol the lpiueinis), iesiue in the epiueinis. ¯hey aie hist uetectahle in the volai epi- ueinis ol the 11- to 12-veel lCA hu- nan letus. ¯he enhiyonic ueiivation ol this population ol cells is contioveisial. lviuence loi in situ uilleientiation ol íeilel cells lion epiueinal ectouein veisus innigiation ol íeilel cells lion neuial ciest is suppoiteu hy stuuies in vhich 8- anu 11-veel lCA letal volai slin that lacleu íeilel cells vas tians- planteu to the nuue nouse. ¯issue hai- vesteu 8 veels latei containeu an ahun- uance ol hunan l18-positive íeilel cells vithin the epiueinis, suggesting that the cells uilleientiateu vithin the gialteu tissue. 1O1 Cn the othei hanu, noie iecent lineage tiacing stuuies us- ing a neuial-ciest specihc lahel have sug- gesteu that íeilel cells inueeu have a neuial ciest oiigin. 51 De|ra| ard Su|cu|arecuº De.e|cprer| ¯he oiigin ol the ueinis anu suhcutane- ous tissue is noie uiveise than that ol 70 the epiueinis, vhich is exclusively ec- toueinally ueiiveu. ¯he enhiyonic tis- sue that loins the ueinis uepenus on the specihc houy site. 1O2,1Oo Deinal nesenchyne ol the lace anu anteiioi scalp is ueiiveu lion neuial ciest ecto- uein. ¯he linh anu vential houy vall nesenchyne is ueiiveu lion the lateial plate nesouein. ¯he uoisal houy vall nesenchyne ueiives lion the uei- nonyotones ol the enhiyonic sonite. Llí honeohox tiansciiption lactoi 1 heta (Lnx1B) anu Wnt¯a aie inpoitant in the specihcation ol the uoisal linh. 1O41O6 ln1 anu Bíls, on the othei hanu, specily the volai (vential) linh nesenchyne (see ¯ahle ¯-5). 88,1O5 ¯he enhiyonic ueinis, in contiast to the natuie ueinis, is cellulai anu anoi- phous, vith lev oiganizeu hheis. ¯he natuie ueinis contains a conplex nesh ol collagen anu elastic hheis enheuueu in a natiix ol lCs, vheieas the enhiyonic nesenchyne contains a laige vaiiety ol pluiipotent cells in a hyuiateu gel that is iich in hyaluionic aciu. ¯hese nesenchy- nal cells aie thought to he the piogeni- tois ol caitilage-piouucing cells, auipose tissue, ueinal hhiohlasts, anu intianen- hianous hone. Deinal hheis exist as hne hlanents hut not thicl hheis. ¯he pio- tein conponents ol the lutuie elastin anu collagen hheis aie synthesizeu uuiing this peiiou hut not assenhleu. At this point, theie is no ohvious sepaiation he- tveen cells that vill hecone nusculo- sleletal elenents anu those that vill give iise to the slin ueinis. Although theie is no lnovn inheiiteu uisoiuei ol ueinal uevelopnent, ceitain conuitions, such local ueinal hypopla- sia (Coltz synuione) anu lioteus syn- uione, exhihit local uelects, piohahly a iesult ol genetic nosaicisn allecting genes inpoitant in this piocess (see Chap. 1oº). íutations causing a glohal uelect in this piocess voulu lilely he in- conpatihle vith lile. ¯he supeihcial nesenchyne hecones uistinct lion the unueilying tissue hy the enhiyonicletal tiansition (ahout 6O uays lCA). By 12 to 15 veels, the ietic- ulai ueinis hegins to tale on its chaiac- teiistic hhiillai appeaiance in contiast to the papillaiy ueinis, vhich is noie hnely voven. Laige collagen hheis con- tinue to accunulate in the ieticulai uei- nis, as vell as elastin hheis, heginning aiounu niu-gestation anu continuing until hiith. By the enu ol the seconu tii- nestei, the ueinis has changeu lion a non-scaiiing tissue to one that is capa- hle ol loining scais. As the ueinis na- tuies, it also hecones thiclei anu vell oiganizeu, such that at hiith, it iesen- hles the ueinis ol the auult, although it is still noie cellulai. íany vell-lnovn clinical synuiones anu nolecules have heen uiscoveieu that allect this hnal stage ol ueinal uil- leientiation. ¯hese uiseases incluue uys- tiophic lB (a collagen Vll uelect) (see Chap. 6O), íailan synuione (a uelect in hhiillin), lhleis-Danlos synuione (collagen V), cutis laxa (elastin), lXl, he- ieuitaiy henoiihagic telangiectasia (Cs- lei-Wehei-Renuu synuione), anu osteo- genesis inpeilecta (see Chap. 1oº). ln nany ol these cases, the specihc genetic uelect helps to uehne the nany uillei- ent nanilestations ol these uiseases, al- though in ceitain cases (e.g., lXl), the iuentity ol the gene uoes not ieauily ex- plain the nechanisn ol uisease (see Chap. 1oº). SP£0|AL|I£0 00NP0h£hTS 0F Th£ 0£8- N|S 8|aad ¥esse|s and herves. Cutaneous neives anu vessels hegin to loin eaily uuiing gestation, hut they uo not evolve into those ol the auult until a lev nonths altei hiith. ¯he piocess ol vasculogenesis ieguiies the in situ uilleientiation ol the enuothelial cells at the enuouein nesouein inteilace. Ciiginally, hoiizon- tal plexuses aie loineu vithin the suh- papillaiy anu ueep ieticulai ueinis, vhich aie inteiconnecteu hy gioups ol veitical vessels. ¯his lattice ol vessels is in place hy 45 to 5O uays lCA. At º veels lCA, hloou vessels aie seen at the ueinalhypoueinal |unc- tion. By o nonths, the uistinct netvoils ol hoiizontal anu veitical vessels have loineu. By the hlth nonth, luithei changes in the vasculatuie ueiive lion huuuing anu nigiation ol enuotheliun lion pie-existing vessels, the piocess ol angiogenesis. Depenuing on the houy iegion, gestational age, anu piesence ol haii lollicles anu glanus, this pattein can vaiy vith hloou supply ieguiienents. Delects in vasculai uevelopnent have heen uesciiheu, as in the llippel- ¯iénaunay anu Stuige-Wehei synuiones (see Chap. 1¯o). ln the llippel- ¯iénaunay synuione, unilateial cutane- ous vasculai nalloinations uevelop, vith associateu venous vaiicosities, euena, anu hypeitiophy ol associateu solt tissue anu hone. ln Stuige-Wehei synuione, nany cutaneous capillaiy nalloinations aie seen in the lips, tongue, nasal, anu huccal nucosae. Sone lanilial uelects in vasculai loina- tion iesult lion nutations in the gene encouing ¯ie-2 ieceptoi tyiosine linase. Capillaiy nalloinations seen in heieui- taiy henoiihagic telangiectasia have heen linleu to nutations in tians- loining giovth lactoi- hinuing pio- teins, enuoglin, anu activin ieceptoi- lile linase 1. Lymphat|cs. Accunulating eviuence sug- gests that lynphatics oiiginate lion en- uothelial cells that huu oll lion veins. ¯he pattein ol enhiyonic lynphatic vessel uevelopnent paiallels that ol hloou vessels. Detaileu noleculai stuu- ies into the uevelopnent ol lynphatics uuiing enhiyogenesis anu letal uevel- opnent have long heen hanpeieu hy the lacl ol lynphatic-specihc naileis. Hovevei, iecent stuuies have iuentiheu nev genes that appeai to he specihc loi sone ol the eailiest lynphatic piecui- sois. LYVl-1 anu liox-1 aie genes con- siueieu to he ciitical loi eailiest lyn- phatic specihcation, vheieas VlCl-Ro anu SLC nay he inpoitant in latei lyn- phatic uilleientiation. 1O¯ herves. ¯he uevelopnent ol cutaneous neives paiallels that ol the vasculai sys- ten in teins ol patteining, natuiation, anu oiganization. Neives ol the slin consist ol sonatic sensoiy anu synpa- thetic autononic hheis, vhich aie pie- uoninantly snall anu unnyelinateu. As these neives uevelop, they hecone ny- elinateu, vith associateu ueciease in the nunhei ol axons. ¯his piocess nay continue as long as puheity. Su|cu||º As nentioneu in Specializeu Conpo- nents ol the Deinis, hy 5O to 6O uays lCA, the hypoueinis is sepaiateu lion the oveilying ueinis hy a plane ol thin- valleu vessels. ¯ovaiu the enu ol the hist tiinestei, the natiix ol the hypo- ueinis can he uistinguisheu lion the noie hhious natiix ol the ueinis. By the seconu tiinestei, auipocyte piecui- sois hegin to uilleientiate anu accunu- late lipius. By the thiiu tiinestei, lat lohules anu hhious septae aie lounu to sepaiate the natuie auipocytes. ¯he noleculai pathvays that uehne this piocess aie cuiiently an aiea ol intense investigation. Although lev iegulatois inpoitant in enhiyonic auipose specih- cation anu uevelopnent have heen iuentiheu, seveial lactois ciitical loi pieauipocyte uilleientiation have heen uenonstiateu, incluuing leptin, a hoi- none inpoitant in lat iegulation, anu the peioxisone piolileiatoiactivateu iecep- toi lanily ol tiansciiption lactois. ¯¯,1O8 71 De|ra|-Ep|de|ra| Jurc||cr ¯he ueinalepiueinal |unction is an inteilace vheie nany inuuctive inteiac- tions occui that iesult in the specihcation oi uilleientiation ol the chaiacteiistics ol the ueinis anu epiueinis. ¯his zone in- cluues specializeu hasenent nenhiane, hasal cell extiacellulai natiix, the hasal- nost poition ol the hasal cells, anu the supeihcial-nost hhiillai stiuctuies ol the papillaiy ueinis. Both the epiueinis anu ueinis contiihute to this iegion. As eaily as 8 veels lCA, a sinple hasenent nenhiane sepaiates the uei- nis lion the epiueinis anu contains nany ol the na|oi piotein elenents con- non to all hasenent nenhianes, incluu- ing laninin 1, collagen lV, hepaiin sullate, anu lCs. Conponents specihc to the cu- taneous hasenent nenhiane zone, such as pioteins ol the heniuesnosone anu anchoiing hlanents, aie hist uetecteu at the enhiyonicletal tiansition. By the enu ol the hist tiinestei, oi aiounu the tine ol late enhiyonic uevelopnent, all hasenent nenhiane pioteins aie in place. ¯he 6 anu 4 integiin suhunits aie expiesseu eailiei than nost ol the othei hasenent nenhiane conponents. Hovevei, they aie not localizeu to the hasal suilace until º.5 veels lCA, coinci- uent vith the tine that the heniuesno- sonal pioteins aie expiesseu anu heni- uesnosones aie hist ohseiveu. At the sane tine, anchoiing hlanents (laninin- oo2) anu anchoiing hhiils (collagen Vll) hegin to he assenhleu. ¯he actual syn- thesis ol collagen Vll can he uetecteu slightly eailiei, at 8 veels lCA. íany congenital hlisteiing uisoiueis have heen uenonstiateu to he a iesult ol uelects in pioteins ol the Dl[ (loi uetails, see Chaps. 51 anu 6O). ¯he seveiity ol the uisease, plane ol tissue sepaiation, anu in- volvenent ol non-cutaneous tissues ue- penu on the pioteins involveu anu the specihc nutations. ¯hese genes aie in- poitant canuiuates loi pienatal testing. DEVE|0P|E\T 0| S||\ APPE\DA0ES Slin appenuages, vhich incluue haii, nails, anu sveat anu nannaiy glanus, aie conposeu ol tvo uistinct conpo- nents: an epiueinal poition, vhich pio- uuces the uilleientiateu piouuct, anu the ueinal conponent, vhich iegulates uilleientiation ol the appenuage. Dui- ing enhiyonic uevelopnent, ueinal epiueinal inteiactions aie ciitical loi the inuuction anu uilleientiation ol these stiuctuies (lig. ¯-1O). Disiuption ol these signals olten has piolounu in- huences on uevelopnent ol slin ap- penuages. ¯his uiscussion locuses on haii uilleientiation as a paiauign loi ap- penuageal uevelopnent, hecause it is the appenuage that has heen stuuieu nost intensely. 6,1Oº,11O Ha|| (See Chap. 84) Deinal signals aie initially iesponsihle loi instiucting the hasal cells ol the epi- ueinis to hegin to ciovu at iegulaily spaceu inteivals, staiting hetveen uays ¯5 anu 8O on the scalp. ¯his initial giouping is lnovn as the jo||i.u|ar ¡|a- .odc oi An|agc. Baseu on noleculai local- ization ol -catenin, it has heen inpli- cateu as a canuiuate loi one ol the ellectois ol this °ueinal signal.` lion the scalp, lolliculai placoue loi- nation spieaus ventially anu cauually, eventually coveiing the slin. ¯he pla- coues then signal hacl to the unueilying ueinis to loin a °ueinal conuensate,` vhich occuis at 12 to 14 veels lCA. ¯his piocess is thought to he a halance ol placoue pionoteis anu placoue inhih- itois. 6,1Oº,11O Wnt lanily signaling nole- cules aie pioposeu to neuiate placoue pionoting ellects via the nolecules Lll anu -catenin, as vell as hhiohlast giovth lactoi, tiansloining giovth lac- toi- , ísx1 anu -2, ectouysplasin A (lDA), anu lDAR (lDA ieceptoi). Bíl lanily nolecules, on the othei hanu, act F|608£ 7-10 Apperdaçea| rc|p|cçereº|º. T||cuç| a ºe||eº c| |ec|p|cca| ep|||e||a| (ep|de|ra|,- reºerc|]ra| (de|ra|, º|çra|º, |rc|ud|rç wr|, ºcr|c |edçe|cç (S||,, ard \cçç|r (\cç,, apperdaçeº ºuc| aº ||e |a|| |c|||c|e ard ecc||re ç|ard |eç|r aº ep|de|ra| |r.aç|ra||crº (p|accdeº,, W||c| º|çra| ||e c|çar|/a||cr c| ºpec|a||/ed de|r|º (de|ra| ccrderºa|e,. T||º de|ra| ccrderºa|e ºu|ºe(uer||] º|çra|º ||e d|||e|er||a||cr c| ||e ep|de|ra| dcWrç|cW|| |r|c ||e çe|r, peç, ard ra|u|e apperdaçea| º||uc|u|e. Bu = |u|çe, De|r = de|r|º, Du = duc|, Ep| = ep|de|r|º, 0|d = ç|ard. 72 as inhihitois ol lollicle loination. ln nouel systens, ectopic expiession ol this lanily ol nolecules tenus to suppiess the loination ol lollicles. ln nice, lDAR anu -catenin expiession aie ieguiieu loi ex- piession ol Bíl4 anu Sonic heugehog (Shh), inplicating these nolecules in eaily lolliculai noiphogenesis. luitheinoie, lDAR nay he inpoitant loi lateial inhihi- tion ol cells suiiounuing the lollicles. loination ol the ueinal papilla is thought to he initiateu hy the °hist epi- thelial signal` that is tiansnitteu lion the lollicle epitheliun to the unueilying nesenchyne. íolecules pioposeu to he involveu in this signaling piocess in- cluue platelet-ueiiveu giovth lactoi polypeptiue anu Shh. Altei the lolliculai uilleientiation piocess hegins, the uei- nis senus anothei signal to the epithe- lial placoue cells to piolileiate anu in- vaue the ueinis. ¯he ueinal cells associateu vith the lollicle then uevelop into the ueinal papilla. ¯he epithelial cells go on to loin the innei ioot sheath anu haii shalt ol the natuie haii lollicle. ln auuition to the viueneu hulge at the hase, tvo othei hulges loin along the length ol the ueveloping lollicle, teineu the |u||ous hair ¡cg. ¯he uppeinost hulge is the piesunptive sehaceous glanu, vheieas the niuule hulge seives as the site loi inseition ol the aiiectoi pili nus- cle. ¯his niuule hulge is also the location ol the nultipotent haii sten cells, vhich aie capahle ol uilleientiating into any ol the cells ol the haii lollicle, anu also have the potential to ieplenish the entiie epi- ueinis, as has seen in cases ol extensive suilace vounus oi huins. By 1º to 21 veels lCA, the haii canal has conpletely loineu anu the haiis on the scalp aie visihle ahove the suilace ol the letal epiueinis. ¯hey continue to lengthen until 24 to 28 veels, at vhich tine they shilt lion the active giovth (anagen) phase to the uegeneiative phase (catagen), then to the iesting phase (telo- gen) (see Chap. 84). ¯his conpletes the hist haii cycle. With suhseguent haii cy- cles, haiis inciease in uianetei anu coaiseness. Duiing auolescence, vellus haiis ol anuiogen-sensitive aieas natuie to teininal-type haii lollicles. Se|acecuº 0|ardº (See Chap. ¯¯) Sehaceous glanus natuie uuiing the couise ol lolliculai uilleientiation. ¯his piocess hegins hetveen 1o anu 16 veels lCA, at vhich point the pie- sunptive sehaceous glanu is hist visihle as the nost supeihcial hulge ol the na- tuiing haii lollicle. ¯he outei piolileia- tive cells ol the glanu give iise to the uil- leientiateu cells that accunulate lipiu anu sehun. Altei they teininally uillei- entiate, these cells uisintegiate anu ie- lease theii piouucts into the uppei poi- tion ol the haii canal. Sehun piouuction is acceleiateu in the seconu anu thiiu tii- nesteis, uuiing vhich tine nateinal steioius cause stinulation ol the seha- ceous glanus. Hoinonal activity is once again thought to inhuence the piouuc- tion ol incieaseu sehun uuiing auoles- cence, iesulting in the incieaseu inci- uence in acne at this age. \a|| De.e|cprer| (See Chap. 8¯) liesunptive nail stiuctuies hegin to ap- peai on the uoisal uigit tip at 8 to 1O veels lCA, slightly eailiei than the ini- tiation ol haii lollicle uevelopnent. ¯he hist sign is the uelineation ol the hat suilace ol the lutuie nail heu. A poition ol ectouein huus invaiu at the pioxi- nal hounuaiy ol the eaily nail helu, anu gives iise to the pioxinal nail lolu. ¯he piesunptive nail natiix cells, vhich uil- leientiate to hecone the nail plate, aie piesent on the vential siue ol the pioxi- nal invagination. At 11 veels, the uoi- sal nail heu suilace hegins to leiatinize. By the louith nonth ol gestation, the nail plate giovs out lion the pioxinal nail lolu, conpletely coveiing the nail heu hy the hlth nonth. íutations in p6o allect nail uevelopnent in syn- uiones such as anlylohlephaion, ecto- ueinal uysplasia, anu clelt lip/palate synuione, as vell as ectiouactyly, ecto- ueinal uysplasia, anu clelt lip/palate synuione. lunctional p6o is ieguiieu loi the loination anu naintenance ol the apical ectoueinal iiuge, an enhiy- onic signaling centei essential loi linh outgiovth anu hanu plate loination. Wnt¯a is thought to he inpoitant loi uoisal linh patteining, anu thus nail loi- nation. ln contiast to lolliculai uevelop- nent, Shh is not ieguiieu loi nail plate loination. Also sinilai to lolliculai uil- leientiation, LíX1h anu íSX1 aie in- poitant loi nail specihcation, LíX1h anu íSX1 aie nutateu in nail-patella synuione anu Witlop synuione, ie- spectively. 11111o Hoxc1o appeais to he an inpoitant honeouonain-containing gene loi hoth lolliculai anu nail appen- uages, at least in nuiine nouels. 114 Ecc||re ard Apcc||re SWea| 0|ard De.e|cprer| (See Chap. 81) lcciine glanus hegin to uevelop on the volai suilaces ol the hanus anu leet, he- ginning as nesenchynal paus hetveen 55 anu 65 uays lCA. By 12 to 14 veels lCA, paiallel ectoueinal iiuges aie in- uuceu, vhich oveily these paus. ¯he ec- ciine glanus aiise lion the ectoueinal iiuge. By 16 veels lCA, the secietoiy poition ol the glanu hecones uetect- ahle. ¯he ueinal uuct hegins aiounu veel 16, hut the epiueinal poition ol the uuct anu opening aie not conplete until 2 veels lCA. lnteilolliculai ecciine anu apociine glanus, in contiast, uo not hegin to huu until the hlth nonth ol gestation. Apo- ciine sveat glanus usually huu lion the uppei poition ol the haii lollicle. By ¯ nonths lCA, the cells ol the apociine glanus hecone uistinguishahle. Although not nuch is lnovn vith ie- gaiu to the noleculai signals iesponsi- hle loi the uilleientiation ol these stiuc- tuies, the lDA, lDAR, ln1, anu Wnt1Oh genes have heen inplicateu. Hypohiuiotic ectoueinal uysplasia ie- sults lion nutations in lDA oi the lDAR (see Chap. 14o). |E\ RE|ERE\CES T|e |u|| |e|e|erce ||º| |c| a|| c|ap|e|º |º a.a||a||e a| WWW.d|çr/.ccr. 6. Blanpain C, luchs l: lpiueinal sten cells ol the slin. Annu Rcv Cc|| Dcv 3io| 22:ooº, 2OO6 8. lellegiini C et al: ¯he contiol ol epiuei- nal sten cells (holoclones) in the tieat- nent ol nassive lull-thiclness huins vith autologous leiatinocytes cultuieu on hhiin. Trans¡|antation 68:868, 1ººº º. Cotsaielis C, Sun ¯¯, Lavlei Rí: Lahel-ietaining cells iesiue in the hulge aiea ol pilosehaceous unit: lnplications loi lolliculai sten cells, haii cycle, anu slin caicinogenesis. Cc|| 61:1o2º, 1ººO 11. Rochat A, lohayashi l, Baiianuon Y: Location ol sten cells ol hunan haii lol- licles hy clonal analysis. Cc|| 76:1O6o, 1ºº4 14. ¯unhai ¯ et al: Dehning the epithelial sten cell niche in slin. :.icn.c 303:o5º, 2OO4 16. íoiiis R[ et al: Captuiing anu piohling auult haii lollicle sten cells. ^at 3iotc.h- no| 22:411, 2OO4 22. Chazizaueh S, ¯aichnan LB: íultiple classes ol sten cells in cutaneous epi- theliun: A lineage analysis ol auult nouse slin. l/3· j 20:1215, 2OO1 6º. Detnai í: íoleculai iegulation ol angiogenesis in the slin. j lnvcst Dcrma- to| 106:2O¯, 1ºº6 82. Holhiool lA: Stiuctuie anu lunction ol the ueveloping hunan slin, in lh,sio|- og,. 3io.hcmistr,. and /o|c.u|ar 3io|og, oj thc :kin, euiteu hy Colusnith LA. Nev Yoil, Cxloiu liess, 1ºº1, p 6o 8o. Loonis CA: Developnent anu noipho- genesis ol the slin. Adv Dcrmato| 17:18o, 2OO1 8¯. Yang A et al: p6o is essential loi iegen- 73 eiative piolileiation in linh, cianiolacial anu epithelial uevelopnent. ^aturc 3º8:¯14, 1ººº º4. Happle R: X-chionosone inactivation: Role in slin uisease expiession. A.ta lacdiatr :u¡¡| º5:16, 2OO6 º¯. Nishinuia ll et al: Doninant iole ol the niche in nelanocyte sten-cell late ueteinination. ^aturc 416:854, 2OO2 1O¯. Clivei C, Detnai í: ¯he ieuiscoveiy ol the lynphatic systen: Clu anu nev insights into the uevelopnent anu hiological lunction ol the lyn- phatic vasculatuie. Ccncs Dcv 16:¯¯o, 2OO2 1Oº. íillai Sl: íoleculai nechanisns iegu- lating haii lollicle uevelopnent. j lnvcst Dcrmato| 118:216, 2OO2 C H A P T E R 8 6eoet|cs |o 8e|at|oo to the Sk|o Jc|r A. |c0|a|| w. H. ||W|r |c|ear THE HU|A\ 0E\0|E |\ DER|AT0|00\ ln the oO yeais since the hist hunan gene, placental lactogen, vas cloneu in 1º¯¯, huge investnents in tine, noney, anu elloit have gone into uisclosing the inneinost voilings ol the hunan ge- none. ¯he Hunan Cenone lio|ect, vhich hegan in 1ººO, has leu to se- guence inloination on noie than o hil- lion hase paiis (hp) ol DNA, vith iuenti- hcation ol nost ol the estinateu 25,OOO genes in the entiie hunan genone. 1 Al- though a lev ielatively snall gaps ie- nain, the neai conpletion ol the entiie seguence ol the hunan genone is hav- ing a huge inpact on hoth the clinical piactice ol genetics anu on the stiategies useu to iuentily uisease-associateu genes. Lahoiious positional cloning ap- pioaches anu tiauitional lunctional stuuies aie giauually heing tiansloineu hy the eneigence ol nev genonic anu pioteonic uatahases. 2 Sone ol the ex- citing challenges that clinicians anu ge- neticists nov lace aie ueteinining the lunction ol these genes anu uehning uis- ease associations, anu, vith ielevance to patients, coiielating genotype vith phe- notype. Neveitheless, nany uiscoveiies aie alieauy inhuencing hov clinical ge- netics is piacticeu thioughout the voilu, paiticulaily loi patients anu lan- ilies vith iaie, nonogenic inheiiteu uis- oiueis. ¯he ley henehts ol uissection ol the genone thus lai have heen the uoc- unentation ol nev inloination ahout uisease causation, inpioving the accu- iacy ol uiagnosis anu genetic counsel- ing, anu naling DNA-haseu pienatal testing leasihle. o lnueeu, the genetic ha- sis ol noie than 2OOO inheiiteu single gene uisoiueis has nov heen uetei- nineu, ol vhich ahout 25 peicent have a slin phenotype. ¯hese uiscoveiies, theieloie, have uiiect ielevance to uei- natologists anu theii patients. Recently, stuuies in iaie inheiiteu slin uisoiueis have also leu to nev insight into the pathophysiology ol noie connon conplex tiait slin uisoiueis. 4 ¯his nev inloination is expecteu to have signih- cant inplications loi the uevelopnent ol nev theiapies anu nanagenent stiat- egies loi patients. loi the ueinatologist, theieloie, unueistanuing the hasic lan- guage anu piinciples ol clinical anu no- leculai genetics has hecone a vital pait ol uay-to-uay piactice. ¯he ain ol this chaptei is to pioviue an oveiviev ol ley teininology in genetics that is clinically ielevant to the ueinatologist. THE HU|A\ 0E\0|E Noinal hunan heings have a laige con- plex genone paclageu in the loin ol 46 chionosones. ¯hese consist ol 22 paiis ol autosones, nunheieu in uescenuing oiuei ol size lion the laigest (chiono- sone 1) to the snallest (chionosone 22), in auuition to tvo sex chiono- sones, X anu Y. lenales possess tvo copies ol the X chionosone, vheieas nales caiiy one X anu one Y chiono- sone. ¯he haploiu genone consists ol ahout o.o hillion hp ol DNA. Cl this, only ahout 1.5 peicent coiiesponus to piotein-encouing exons ol genes. Apait lion genes anu iegulatoiy seguences, peihaps as nuch as º¯ peicent ol the ge- none is ol unlnovn lunction, olten ie- leiieu to as °|unl` DNA. Caution shoulu he exeiciseu in laheling the non-couing genone as °|unl,` hovevei, hecause othei unlnovn lunctions nay iesiue in these iegions. íuch ol the non-couing DNA is in the loin ol iepetitive se- guences, pseuuogenes (°ueau` copies ol genes lost in iecent evolution) anu tians- posahle elenents ol unceitain ielevance. Although initial estinates loi the nun- hei ol hunan genes vas in the oiuei ol 1OO,OOO, cuiient pieuictions, haseu on the essentially conplete genone se- guence, aie in the iange ol 2O,OOO to 25,OOO. 1 Suipiisingly, theieloie, the hu- nan genone is conpaiahle in size anu conplexity to piinitive oiganisns such as the liuit hy. lt is thought, hovevei, that the geneiation ol nultiple piotein isoloins lion a single gene via alteinate splicing ol exons, each vith a uisciete lunction, is vhat contiihutes to in- cieaseu conplexity in highei oiganisns, incluuing hunans. ln auuition to piotein- encouing genes, theie aie also nany genes encouing untianslateu RNA nole- cules, incluuing tianslei RNA, iihosonal RNA, anu, as iecently uesciiheu, nicio- RNA genes. íicio-RNA is thought to he involveu in the contiol ol a laige nunhei ol othei genes thiough the RNA inhihi- tion pathvay. ¯he uialt seguence ol the hunan ge- none vas conpleteu in 2OOo. Suhse- guently, snall gaps have heen hlleu, anu the seguence has nov heen extensively annotateu in teins ol genes, iepetitive elenents, iegulatoiy seguences, poly- noiphisns, anu nany othei leatuies iecognizahle hy in silico uata nining nethous inloineu, vheievei possihle, hy lunctional analysis. ¯his annotation piocess vill continue loi sone tine as noie leatuies aie uncoveieu. ¯he hu- nan genone uata, anu that loi an in- cieasing nunhei ol othei species, is lieely availahle on vehsites (¯ahle 8-1). Sone iegions ol the genone, paiticu- laily neai the centioneies, consist ol long stietches ol highly iepetitive se- guences that aie uilhcult oi inpossihle to clone anu/oi seguence. ¯hese heteio- chionatic iegions ol the genone aie unlilely to he seguenceu anu aie thought to he stiuctuial in natuie, neui- ating the chionosonal aichitectuie ie- guiieu loi cell uivision, iathei than con- tiihuting to heiitahle chaiacteiistics. 0E\ET|C A\D 0E\0||C DATABASES Civen the size anu conplexity ol the hunan genone anu othei genones nov availahle, analysis ol these enoi- nous uatasets in any linu ol neaning- lul vay is heavily ieliant on conputeis. lven stoiage anu ietiieval ol the se- guence uata associateu vith nanna- lian genone ieguiie consiueiahle con- putei povei, anu nenoiy anu even the assenhly ol the iav seguence ol any nannalian genone voulu have heen unleasihle vithout conputeis. íany 74 veh hiovseis loi accessing genone uata aie availahle anu the nost uselul ol these aie listeu in ¯ahle 8-1. lach ol these inteilaces, vhich aie the ones vhich the authois hnu nost uselul anu usei-liienuly, contains a viue vaiiety ol tools loi analysis anu seaiching ol se- guences accoiuing to leyvoiu, gene nane, piotein nane, anu honology to DNA oi piotein seguence uata. ¯he nain souice ol histoiical, clinical, noleculai, anu hiochenical uata ielating to hunan genetic uiseases is the Cnline íenuelian lnheiitance in ían (Cílí) (see ¯ahle 8-1). All iecognizeu genetic uis- eases anu non-pathogenic heiitahle tiaits, incluuing connon uiseases vith a genetic conponent, as vell as all lnovn genes anu pioteins, aie listeu anu ievieveu hy Cílí nunhei vith linls to luhíeu. CHR0|0S0|E A\D 0E\E STRUCTURE Hunan chionosones shaie connon stiuctuial leatuies (lig. 8-1). All consist ol tvo chionosonal ains, uesignateu as °p` anu °g.` ll the ains aie ol un- egual length, the shoit ain is alvays uesignateu as the °p` ain. Chionoso- nal naps to seel ahnoinalities aie haseu on the staineu, hanueu appeai- ance ol conuenseu chionosones uuiing netaphase ol nitosis. Duiing intei- phase, the unconuenseu chionosones aie not uisceinihle hy noinal nicios- copy technigues. Cenes can nov he lo- cateu vith ahsolute piecision in teins ol the iange ol hp that they span vithin the DNA seguence loi a given chiono- sone. ¯he hanus aie nunheieu lion the centioneie outvaius using a sys- ten that has evolveu as incieasingly uis- ciininating chionosone stains, as vell as highei iesolution light nicioscopes, hecane availahle. A typical cytogenetic chionosone hanu is 1¯g21.2, vithin vhich the type l leiatin genes iesiue (see lig. 8-1). ¯he enus ol the chionosonal ains aie lnovn as tc|omcrcs, anu these consist ol nultiple tanuen iepeats ol shoit DNA seguences. ln gein cells anu cei- tain othei cellulai contexts, auuitional iepeats aie auueu to teloneies hy a pio- tein-RNA enzyne conplex lnovn as tc|omcrasc. Duiing each iounu ol cell ui- vision in sonatic cells, one ol the telo- neie iepeats is tiinneu oll as a con- seguence ol the DNA ieplication nechanisn. By neasuiing the length ol teloneies, the °age` ol sonatic cells, in teins ol the nunhei ol tines they have uiviueu uuiing the liletine ol the oigan- isn, can he ueteinineu. Cnce the telo- neie length lalls helov a ceitain thiesh- olu, the cell unueigoes senescence. ¯hus, teloneies contiihute to an inpoi- tant hiological clocl lunction that ie- noves sonatic cells that have gone thiough too nany iounus ol ieplication anu aie at a high iisl ol accunulating nutations that coulu leau to tunoiigen- esis oi othei lunctional aheiiation. 5 ¯he chionosone ains aie sepaiateu hy the centioneie, vhich is a laige stietch ol highly iepetitious DNA se- guence. ¯he centioneie has inpoitant lunctions in teins ol the novenent anu inteiactions ol chionosones. ¯he cen- tioneies ol sistei chionatius aie vheie the uouhle chionosones align anu at- tach uuiing the piophase anu anaphase stages ol nitosis (anu neiosis). ¯he cen- tioneies ol sistei chionatius aie also the site ol linetochoie loination. ¯he lattei is a nulti-piotein conplex to vhich niciotuhules attach, alloving nitotic spinule loination, vhich ulti- nately iesults in pulling apait ol the chionatius uuiing anaphase ol the cell uivision cycle. ¯he na|oiity ol chionosonal DNA contains genes inteispeiseu vith non- couing stietches ol DNA ol vaiying sizes. ¯he uensity ol genes vaiies viuely acioss the chionosones so that theie aie gene-uense iegions oi, altei- nately, laige aieas alnost uevoiu ol lunctional genes. An exanple ol a con- paiatively gene-iich iegion ol paiticulai ielevance to inheiiteu slin uiseases is the type l leiatin gene clustei on chio- nosone hanu 1¯g21.2 (see lig. 8-1). ¯his uiagian also gives an iuea ol the sizes in hp ol DNA ol a typical chiono- sone anu a typical gene locateu vithin it. ¯his gene clustei spans ahout ºOO,OOO hp ol DNA anu contains 2¯ lunctional type l leiatin genes, seveial genes en- couing leiatin-associateu pioteins, anu a nunhei ol pseuuogenes (not shovn). Because chionosone 1¯ is one ol the snallei chionosones, lig. 8-1 staits to give sone iuea ol the oveiall conplexity anu oiganization ol the genone. liotein-encouing genes noinally con- sist ol seveial exons, vhich collectively coue loi the anino aciu seguence ol the piotein (oi open ieauing liane). ¯hese aie sepaiateu hy non-couing intions. ln hunan genes, lev exons aie nuch gieatei than 1OOO hp in size, anu intions vaiy lion less than 1OO hp up to noie than 1 nillion hp. A typical exon night he 1OO to oOO hp in size. ¯he lRT1} gene encouing leiatin 14 oi l14 piotein is one ol the genes in vhich nutations leau to epiueinolysis hullosa (lB) sin- plex (see Chap. 6O) anu is illustiateu in lig. 8-1. lRT1} is containeu vithin ahout ¯OOO hp ol DNA anu consists ol eight nouestly sizeu exons intei- speiseu hy seven snall intions. Al- though all genes aie piesent in all hu- nan cells that contain a nucleus, not eveiy gene is expiesseu in all cells ol tis- sues. loi exanple, the lRT1} gene is only active in hasal leiatinocytes ol the epiueinis anu othei stiatiheu epithelial tissues anu is essentially silent in all othei tissues. When a piotein-encouing gene is expiesseu, the RNA polyneiase ll enzyne tiansciihes the couing stianu ol the gene, staiting lion the cap site anu continuing to the enu ol the hnal exon, vheie vaiious signals leau to tei- nination ol tiansciiption. ¯he initial RNA tiansciipt, lnovn as hctcronu.|car R^A, contains intionic as vell as ex- onic seguences. ¯his piinaiy tiansciipt unueigoes splicing to ienove the in- tions, iesulting in the nessengei RNA (nRNA) nolecule. 6 ln auuition, the hases at the 5 enu (stait) ol the nRNA aie chenically nouiheu (capping) anu a laige nunhei ol auenosine hases aie auueu at the o enu, lnovn as the ¡o|,-A tai|. ¯hese post-tiansciiptional nouihca- tions stahilize the nRNA anu lacilitate its tianspoit vithin the cell. ¯he natuie nRNA unueigoes a test iounu ol tians- lation vhich, il successlul, leaus to the tianspoit ol the nRNA to the cyto- plasn, vheie it unueigoes nultiple iounus ol tianslation hy the iihosones, leauing to accunulation ol the encoueu piotein. ll the nRNA contains a non- sense nutation, otheivise lnovn as a ¡rcmaturc tcrmination .odon mutation, the Ik8L£ 8-1 wabs|tas for Accass|ng Human 0anoma 0ata wF8S|TF U8L Ur|.e|º||] c| Ca|||c|r|a, Sar|a C|u/ |||p.//çercre.ucºc.edu/ \a||cra| Cer|e| |c| B|c|ec|rc|cç] |r|c|ra||cr |||p.//WWW.rc||.r|r.r||.çc. E\SE|B| |||p.//WWW.erºer||.c|ç/ 0r||re |erde||ar |r|e|||arce |r |ar |||p.//WWW.rc||.r|r.r||.çc./er||e//(ue|].|cç|´d|=cr|r 75 test iounu ol tianslation lails, anu the cell uegiaues this nRNA via the non- sense-neuiateu nRNA pathvay. ¯ ¯his is a nechanisn that the cell has evolveu to ienove aheiiant tiansciipts, anu it nay also contiihute to gene iegulation, paiticulaily vhen veiy lov levels ol a paiticulai piotein aie ieguiieu vithin a given cell. Splicing out ol intions is a conplex piocess. ¯he genes ol piolaiyotes, such as hacteiia, uo not contain intions, anu so nRNA splicing is a piocess that is specihc to highei oiganisns. ln sone noie piinitive eulaiyotes, RNA nole- cules contain catalytic seguences lnovn as ri|o:,mcs, vhich neuiate the sell- splicing out ol intions vithout any ie- guiienent loi auuitional lactois. ln nannals, splicing involves a laige nunhei ol piotein anu RNA lactois en- coueu hy seveial genes. ¯his allovs an- othei level ol contiol ovei gene expies- sion anu also lacilitates alteinative splicing ol exons, so that a single gene can encoue seveial lunctionally uistinct vaiiants ol a piotein. ¯hese isoloins aie olten uilleientially expiesseu in uillei- ent tissues. ln teins ol the gene se- guences inpoitant loi splicing, a lev hp at the heginning anu at the enu ol an in- tion, lnovn as the 5 splice site (oi splice uonoi site) anu the o splice site (oi splice acceptoi site) aie ciucial. A lev othei hp vithin the intion, such as the hianch point site locateu 18 to 1OO hp avay lion the o enu, aie also ciiti- cal. íutations allecting any ol the in- vaiiant iesiuues ol these splice sites leau to aheiiant splicing anu eithei conplete loss ol piotein expiession oi geneiation ol a highly ahnoinal piotein. F|608£ 8-1 |||uº||a||cr c| ||e ccrp|e/||] c| ||e |urar çercre. 0r ||e |e||, ||e º|c|| (p, ard |crç ((, a|rº c| |urar c||crcºcre 1/ a|e dep|c|ed W||| ||e|| c]|cçere||c c||crcºcre |ardº. 0re c| ||eºe |ard |eç|crº, 1/(21.2, |º ||er ||ç|||ç||ed |c º|cW ||a| || |º rade up c| app|c/|ra|e|] 900,000 |aºe pa||º (|p, ard ccr|a|rº ºe.e|a| çereº, |rc|ud|rç 2/ |urc||cra| |]pe | |e|a||r çereº. Pa|| c| |||º |eç|cr |º ||er |u|||e| arp|||ed |c º|cW cre |e|a||r çere, IIT14, er- ccd|rç |e|a||r 14, W||c| |º ccrpcºed c| 8 e/crº. 76 ¯he nRNA also contains tvo un- tianslateu iegions, the 5 U¯R upstiean ol the initiating A¯C couon anu the o U¯R uovnstiean ol the teininatoi (oi stop couon, vhich can he ¯CA, ¯AA oi ¯AC). ¯he 5 U¯R can anu olten uoes possess intions, vheieas the o U¯R ol noie than ºº peicent ol nannalian genes uoes not contain intions. ¯he nonsense-neuiateu nRNA uecay path- vay iuentihes nutant tiansciipts hy neans ol assessing vheie the teinina- tion couon occuis in ielation to intions. ¯he natuial stop couon is alvays lol- loveu inneuiately hy the o U¯R, vhich in tuin uoes not noinally possess any intions. ll a stop couon occuis in an nRNA upstiean ol a site vheie an in- tion has heen exciseu, this nessage is taigeteu loi nonsense-neuiateu uecay. ¯he only genes that contain intions vithin theii o U¯R seguences aie ex- piesseu at extienely lov levels. ¯his is one ol the vays in vhich the cell can ueteinine hov nuch piotein is naue lion a paiticulai gene. Cene conplexity is viuely vaiiahle anu not necessaiily ielateu to the size ol the piotein encoueu. Sone genes consist ol only a single snall exon, such as those encouing the connexin lanily ol gap |unction pioteins. Such single exon genes aie iapiu anu inexpensive to ana- lyze ioutinely. ln contiast, the type Vll collagen gene, C·l7A1, in vhich nuta- tions leau to the uystiophic loins ol lB (see Chap. 6O), has 118 exons, neaning that 118 uilleient paits ol the gene neeu to he isolateu anu analyzeu loi nolecu- lai uiagnosis ol each uystiophic lB pa- tient. ¯he hlaggiin gene (llC) on chio- nosone 1, iecently shovn to he the causative gene loi ichthyosis vulgaiis (see Chap. 4¯) anu a susceptihility gene loi atopic ueinatitis (see Chap. 14), has only thiee exons. Hovevei, the thiiu exon ol llC is noie than 12,OOO hp in size, is naue up ol iepeats ol a 1OOO-hp seguence, anu vaiies in size lion 12,OOO to 14,OOO hp hetveen uilleient inuiviuu- als in the population. ¯his unusual gene stiuctuie nales ioutine seguencing ol genes such as C·l7A1 oi llC uilhcult, tine consuning, anu expensive. 0E\E E/PRESS|0\ lach specihc gene is geneially only ac- tively tiansciiheu in a suhset ol cells oi tissues vithin the houy. Cene expies- sion is laigely ueteinineu hy the pio- notei elenents ol the gene. ln geneial, the nost inpoitant iegion ol the pio- notei is the stietch ol seguence inne- uiately upstiean ol the cap site. ¯his pioxinal pionotei iegion contains con- sensus hinuing sites loi a vaiiety ol tiansciiption lactois, sone ol vhich aie geneial in natuie anu ieguiieu loi all gene expiession, otheis aie specihc to paiticulai tissue oi cell lineage, anu sone aie ahsolutely specihc loi a given cell type anu/oi stage ol uevelopnent oi uilleientiation. ¯he size ol the pio- notei can vaiy viuely accoiuing to gene lanily oi hetveen the inuiviuual genes thenselves. loi exanple, the lei- atin genes aie tightly spaceu vithin tvo gene clusteis on chionosones 12g anu 1¯g, hut these aie exguisitely tissue spe- cihc in tvo uilleient vays. liist, these genes aie only expiesseu in epithelial cells, anu theieloie theii pionoteis nust possess iegulatoiy seguences that ueteinine epithelial expiession. ¯hese iegulatoiy elenents aie theieloie spe- cihc loi cells ol ectoueinal oiigin. Sec- onu, these genes aie expiesseu in veiy specihc suhsets ol epithelial cells, anu so theie nust he a seconu level ol contiol that specihes vhich epithelial cell layeis expiess specihc leiatin genes. ¯his is hest illustiateu in the haii lollicle, vheie theie aie nany uilleient epithelial cell layeis, each vith a specihc pattein ol leiatin gene expiession (see Chap. 84). 8 ¯iansciiption lactois aie pioteins that eithei hinu to DNA uiiectly oi inuiiectly hy associating vith othei DNA-hinuing pioteins. Binuing ol these lactois to the pionotei iegion ol a gene leaus to acti- vation ol the tiansciiption nachineiy anu tiansciiption ol the gene hy RNA polyneiase ll. ¯he tiansciiption lactoi pioteins aie encoueu hy genes that aie in tuin contiolleu hy pionoteis that aie iegulateu hy othei tiansciiption lactois encoueu hy othei genes. ¯hus, theie aie seveial tieis ol contiol ovei gene expies- sion in a given cell type, anu the intiica- cies ol this can he uilhcult to lully un- iavel expeiinentally. Neveitheless, hy isolation ol pionotei seguences lion genes ol inteiest anu placing these in liont ol iepoitei genes that can he as- sayeu hiochenically, such as hiehy lu- cileiase that can he assayeu hy light enission, the activity ol pionoteis can he iepiouuceu in cultuieu cells that noi- nally expiess the gene. Conhining such a iepoitei gene systen vith site-uiiecteu nutagenesis to nale ueletions oi altei snall nunheis ol hp vithin the pio- notei can help uehne the extent ol the pionotei anu the inpoitant seguences vithin it that aie ieguiieu loi gene ex- piession. A vaiiety ol hiochenical tech- nigues, such as DNA lootpiinting, ii- honuclease piotection, electiophoietic nohility shilt assays, oi chionatin in- nunopiecipitation, can he useu to uetei- nine vhich tiansciiption lactois hinu to a paiticulai pionotei anu help uelineate the specihc pionotei seguences hounu. lxpiession ol iepoitei genes unuei the contiol ol a cloneu pionotei in tians- genic nice also helps sheu light on the inpoitant seguences that aie ieguiieu to iecapitulate the enuogenous expiession ol the gene unuei stuuy. leiatin pionot- eis aie unusual in that, geneially, a snall liagnent ol only 2OOO to oOOO hp up- stiean ol the gene can conlei nost ol the tissue specihcity. loi this ieason, lei- atin pionoteis aie viuely useu in the ueinatology helu to uiive exogenous tiansgene expiession in the vaiious spe- cihc cellulai conpaitnents ol the epiuei- nis anu its appenuages loi a viue vaii- ety ol expeiinents aineu at ueteinining gene, cell, oi tissue lunction. º Sone pionotei oi enhancei se- guences act ovei veiy long uistances. ln sone cases, seguences locateu nillions ol hp uistant, vith seveial othei genes in the inteivening iegion, sonehov inhu- ence expiession ol a taiget gene. ln sone genetic uiseases, nutations allecting such long-iange pionotei elenents aie nov eneiging. ¯hese types ol nuta- tions appeai to he iaie in the genetics helu as a vhole, hut since they occui so veiy lai avay lion the taiget gene anu aie theieloie veiy uilhcult to hnu, this class ol nutation nay, in lact, he noie connon than is inneuiately ohvious. ln geneial, ielatively lev uisease-causing nutations have heen shovn to involve pionoteis, hut this class ol uelect is piohahly gieatly unuei-iepiesenteu he- cause the pionoteis ol nost genes have heen pooily chaiacteiizeu at the piesent tine in teins ol vhat seguences aie tiuly inpoitant loi pionotei activity. lieuiction ol tiansciiption lactoi hinuing sites hy conputei analysis ienains an inexact science anu is an aiea loi luithei stuuy in the lutuie as the hunan ge- none seguence unueigoes gieatei ue- taileu sciutiny anu annotation. ||\D|\0 D|SEASE 0E\ES ln estahlishing the noleculai hasis ol an inheiiteu slin uisease, theie aie tvo ley steps. liist, the gene linleu to a paiticu- lai uisoiuei nust he iuentiheu, anu sec- onu, pathogenic nutations vithin that gene shoulu he ueteinineu. Diseases can he natcheu to genes eithei hy genetic linlage analysis oi hy a canuiuate gene appioach. 1O Cenetic linlage involves 77 stuuying peuigiees ol allecteu anu unal- lecteu inuiviuuals anu isolating vhich hits ol the genone aie specihcally associ- ateu vith the uisease phenotype. ¯he goal is to iuentily a iegion ol the genone that all the allecteu inuiviuuals anu none ol the unallecteu inuiviuuals have in connon, this iegion is lilely to haihoi the gene loi the uisoiuei, as vell as pei- haps othei non-pathogenic neighhoiing genes that have heen inheiiteu hy linl- age uiseguilihiiun. ¯iauitionally, ge- none-viue linlage stiategies nale use ol vaiiahly-sizeu niciosatellite naileis scatteieu thioughout the genone, al- though loi iecessive uiseases involving consanguineous peuigiees, a noie iapiu appioach nay he to caiiy out honozy- gosity napping using single nucleotiue polynoiphisn (SNl) chip aiiays. By contiast, the canuiuate gene appioach in- volves hist looling loi a clue to the lilely gene hy hnuing a specihc uisease ahnoi- nality, peihaps in the expiession (oi lacl theieol) ol a paiticulai piotein oi RNA, oi lion an ultiastiuctuial oi hiochenical uilleience hetveen the uisease anu con- tiol tissue. Neveitheless, the genetic linl- age anu canuiuate gene appioaches aie not nutually exclusive anu aie olten useu in conhination. loi exanple, to iuentily the gene iesponsihle loi the au- tosonal iecessive uisoiuei, lipoiu piotei- nosis (see Chap. 1o¯), genetic linlage us- ing niciosatellites vas hist useu to estahlish a iegion ol linlage on 1g21 that containeu 68 genes. 11 ¯he putative gene loi this uisoiuei, lC/1 encouing extia- cellulai natiix piotein 1, vas then iuen- tiheu hy a canuiuate gene appioach that seaicheu loi ieuuceu gene expiession (lacl ol hhiohlast conplenentaiy DNA) in all these genes. A ieuuction in lC/1 gene expiession in lipoiu pioteinosis conpaieu vith contiol pioviueu the clue to the canuiuate gene hecause theie veie no uilleiences in any ol the othei patteins ol gene expiession. Having iuentiheu a putative gene loi an inheiiteu uisoiuei, the next stage is to hnu the pathogenic nutation(s). ¯his can he uone hy seguencing the entiie gene, a leat vhich is heconing easiei as techno- logic auvances nale autonateu nucleo- tiue seguencing lastei, cheapei, anu noie accessihle. Hovevei, the laige size ol sone genes nay nale conpiehensive seguencing inpiactical, anu theieloie initial scieening appioaches to iuentily the iegion ol a gene that contains the nutation nay he a necessaiy hist step. ¯heie aie nany nutation uetection tech- nigues availahle to scan loi seguence changes in cellulai RNA oi genonic DNA, anu these incluue uenatuiing gia- uient gel electiophoiesis, chenical cleav- age ol nisnatch, single stianueu con- loination polynoiphisn, heteiouuplex analysis, conloination sensitive gel electiophoiesis, uenatuiing high-peiloi- nance liguiu chionatogiaphy anu the piotein tiuncation test. 12 ¯he nost ciiti- cal lactoi that ueteinines the success ol any gene scieening piotocol is the sensi- tivity ol the uetection technigue. ln auui- tion, vhen choosing a nutation scieen- ing stiategy using genonic DNA, the size ol the gene anu its nunhei ol exons nust he talen into account. ¯he sensi- tivities ol these nethous vaiy gieatly, uepenuing on the size ol tenplate scieeneu. loi exanple, single-stianueu conloination polynoiphisn has a sensi- tivity ol > º5 peicent loi liagnents ol 155 hp, hut this is ieuuceu to only o pei- cent loi 6OO hp. Cnce optinizeu, uena- tuiing giauient gel electiophoiesis has a sensitivity ol ahout ºº peicent loi liag- nents ol up to 5OO hp, anu conloination sensitive gel electiophoiesis is expecteu to have a sensitivity ol 8O peicent to ºO peicent loi liagnents ol up to 6OO hp. Chenical cleavage ol nisnatch, on the othei hanu, has a sensitivity ol º5 pei- cent to 1OO peicent loi liagnents > 1.5 lilohases (lh) in size anu is iueal loi scieening conpact genes vheie noie than one exon can he anpliheu togethei using genonic DNA as the tenplate. All these technigues uetect seguence changes such as tiuncating anu nissense nutations as vell as polynoiphisns, hovevei, the piotein tiuncation test scieens only loi tiuncating nutations anu is pieuicteu to have a sensitivity ol > º5 peicent anu can he useu loi RNA oi DNA liagnents in excess ol o lh. Whichevei appioach is talen, having iuentiheu a uilleience in the patient`s DNA conpaieu vith the contiol sanple, the next stage is to ueteinine hov this segiegates vithin a paiticulai lanily anu also vhethei it is pathogenic oi not. 0E\E |UTAT|0\S A\D P0|\|0RPH|S|S Within the hunan genone, the genetic coue ol tvo healthy inuiviuuals nay shov a nunhei ol seguence uissinilaii- ties that have no ielevance to uisease oi phenotypic tiaits. Such changes vithin the noinal population aie ieleiieu to as ¡o|,mor¡hisms (lig. 8-2). lnueeu, even vithin the couing iegion ol the genone, clinically iiielevant suhstitutions ol one hp, lnovn as :^ls, aie connon anu oc- cui appioxinately once eveiy 25O hp. 1o Cltentines, these SNls uo not change the anino aciu conposition, loi exan- ple, a C-to-¯ tiansition in the thiiu posi- tion ol a pioline couon (CCC to CC¯) still encoues loi pioline, anu is ieleiieu to as a si|cnt mutation. Sone SNls, hov- evei, uo change the natuie ol the anino aciu, loi exanple, a C-to-C tiansveision at the seconu position ol the sane pio- line couon (CCC to CCC) changes the iesiuue to aiginine. lt then hecones nec- essaiy to ueteinine vhethei a nissense change such as this iepiesents a non- pathogenic polynoiphisn oi a patho- genic nutation. lactois lavoiing the lat- tei incluue the seguence segiegating only vith the uisease phenotype in a paiticu- lai lanily, the anino aciu change occui- iing vithin an evolutionaiily conseiveu iesiuue, the suhstitution allecting the lunction ol the encoueu piotein (size, chaige, conloination, etc.), anu the nu- cleotiue svitch not heing uetectahle in at least 1OO ethnically natcheu contiol chionosones. Non-pathogenic poly- noiphisns uo not alvays involve single nucleotiue suhstitutions, occasionally, ueletions anu inseitions nay also he non-pathogenic. A nutation can he uehneu as a change in the chenical conposition ol a gene. A nissense nutation changes one anino aciu to anothei. íutations nay also he inseitions oi ueletions ol hases, the conseguences ol vhich vill uepenu on vhethei this uisiupts the noinal ieauing liane ol a gene oi not, as vell as nonsense nutations, vhich leau to pienatuie teinination ol tianslation (see lig. 8-2). loi exanple, a single nu- cleotiue ueletion vithin an exon causes a shilt in the ieauing liane, vhich usu- ally leaus to a uovnstiean stop couon, thus giving a tiuncateu piotein, oi ol- ten an unstahle nRNA that is ieauily uegiaueu hy the cell. Hovevei, a uele- tion ol thiee nucleotiues (oi nultiples theieol ) vill not signihcantly peituih the oveiall ieauing liane, anu the con- seguences vill uepenu on the natuie ol vhat has heen ueleteu. Nonsense nuta- tions typically, hut not exclusively, oc- cui at CpC uinucleotiues, vheie nethy- lation ol a cytosine nucleotiue olten occuis. lnheient chenical instahility ol this nouiheu cytosine leaus to a high iate ol nutation to thynine. Wheie this alteis the couon (e.g., lion CCA to ¯CA), it vill change an aiginine iesiuue to a stop couon. Nonsense nutations usually leau to a ieuuceu oi ahsent ex- piession ol the nutant allele at the nRNA anu piotein levels. ln the heteio- zygous state, this nay have no clinical 78 ellect |e.g., paients ol inuiviuuals vith Heilitz |unctional lB aie typically caiii- eis ol nonsense nutations in one ol the laninin oo2 (laninin 5) genes hut have no slin liagility thenselves, see Chap. 6O], hut a heteiozygous nonsense nuta- tion in the uesnoplalin gene, loi exan- ple, can iesult in the autosonal uoni- nant slin uisoiuei, stiiate palnoplantai leiatoueina (see Chap. 48). ¯his phe- nonenon is ieleiieu to as ha¡|oinsujµ- .icn., (i.e., hall the noinal anount ol piotein is insulhcient loi lunction). Apait lion changes in the couing ie- gion that iesult in lianeshilt, nissense, oi nonsense nutations, appioxinately 15 peicent ol all nutations involve altei- ations in the gene seguence close to the hounuaiies hetveen the intion anu ex- ons, ieleiieu to as s¡|i.c sitc mutations. ¯his type ol nutation nay aholish the usual acceptoi anu uonoi splice sites that noinally splice out the intions uui- ing gene tiansciiption. ¯he conse- guences ol splice site nutations aie conplex, sonetines they leau to slip- ping ol the au|acent exon, anu othei tines they iesult in the geneiation ol nev nRNA tiansciipts thiough utiliza- tion ol ciyptic splice sites vithin the neighhoiing exon oi intion. íutations vithin one gene uo not al- vays leau to a single inheiiteu uisoiuei. loi exanple, nutations in the lRCC` gene nay leau to xeioueina pignento- sun (type D), tiichothiouystiophy, oi ceiehiolaciosleletal synuione, uepenu- ing on the position anu type ol nuta- tion. Cthei tians-acting lactois nay lui- thei nouulate phenotypic expiession. ¯his situation is lnovn as a||c|i. hctcrogc- ncit,. Conveisely, sone inheiiteu uis- eases can he causeu hy nutations in noie than one gene (e.g., non-Heilitz |unctional lB, see Chap. 6O) anu can ie- sult lion nutations in eithei the C·l17A1, lA/A3, lA/33, oi lA/C` genes. ¯his is lnovn as gcncti. hctcrogc- ncit,. ln auuition, the sane nutation in one paiticulai gene nay leau to a iange ol clinical seveiity in uilleient inuiviuu- als. ¯his vaiiahility in phenotype pio- uuceu hy a given genotype is ieleiieu to as the cx¡rcssivit,. ll an inuiviuual vith such a genotype has no phenotypic nanilestations, the uisoiuei is saiu to he non-¡cnctrant. Vaiiahility in expiession iehects the conplex inteiplay hetveen the nutation, nouilying genes, epige- netic lactois, anu the enviionnent anu uenonstiates that inteipieting vhat a specihc gene nutation uoes to an inui- viuual involves noie than |ust uetecting one hit ol nutateu DNA in a single gene. |E\DE||A\ D|S0RDERS ¯heie aie appioxinately 5OOO hunan single-gene uisoiueis anu, although the noleculai hasis ol less than one-hall ol these has heen estahlisheu, unueistanu- ing the pattein ol inheiitance is essential loi counseling piospective paients ahout the iisl ol having allecteu chiluien. ¯he loui nain patteins ol inheiitance aie autosonal uoninant, autosonal ieces- sive, X-linleu uoninant, anu X-linleu iecessive. loi inuiviuuals vith an autosonal uoninant uisoiuei, one paient is al- lecteu, unless theie has heen a ue novo nutation in a paiental ganete. íales anu lenales aie allecteu in appioxi- nately egual nunheis, anu the uisoiuei can he tiansnitteu lion geneiation to geneiation, on aveiage, hall the oll- spiing vill have the conuition (lig. 8-o). lt is inpoitant to counsel allecteu inui- viuuals that the iisl ol tiansnitting the uisoiuei is 5O peicent loi each ol theii F|608£ 8-2 E/arp|eº c| ruc|ec||de ºe(uerce c|arçeº |eºu|||rç |r a pc|]rc|p||ºr ard a rcrºerºe ru|a||cr. A. TWc adjacer| ccdcrº a|e ||ç|||ç||ed. 0u|||red |r pu|p|e, ||e A00 ccdcr erccdeº a|ç|r|re ard ||e ||ue |c/ed ccdcr, CA0 erccdeº ç|u|ar|re. 8. T|e ºe(uerce º|cWº |Wc |crc/]çcuº ruc|ec||de ºu|- º|||u||crº. |r ||e pu|p|e |c/, A00 rcW |eadº A0T (|.e., ccd|rç |c| ºe||re |a||e| ||ar a|ç|r|re,. T||º |º a ccr- rcr ºe(uerce .a||ar| |r ||e rc|ra| pcpu|a||cr ard |º |e|e||ed |c aº a rcr-jatIcçcric risscrsc jc!yrcr- jIisr. |r ccr||aº|, |r ||e ||ue |c/, ||e ç|u|ar|re ccdcr CA0 rcW |eadº TA0, W||c| |º a º|cp ccdcr. T||º |º ar e/arp|e c| a |crc/]çcuº rcrºerºe ru|a||cr. 0. T||º ºe(uerce |º ||cr cre c| ||e pa|er|º c| ||e ºu|- jec| ºe(uerced |r 8 ard º|cWº |e|e|c/]çcº||] |c| |c|| ||e r|ººerºe pc|]rc|p||ºr A00 > A0T ard ||e rcrºerºe ru|a||cr CA0 > TA0, |rd|ca||rç ||a| |||º |rd|.|dua| |º a ca|||e| c| |c|| ºe(uerce c|arçeº. 79 chiluien, anu that this is not inhuenceu hy the nunhei ol pieviously allecteu oi unallecteu ollspiing. Any ollspiing that aie allecteu vill have a 5O peicent iisl ol tiansnitting the nutateu gene to the next geneiation, vheieas loi any unal- lecteu ollspiing, the iisl ol the next geneiation heing allecteu is negligihle, pioviuing that the paitnei uoes not have the autosonal uoninant conuition. ln autosonal iecessive uisoiueis, hoth paients aie caiiieis ol one noinal anu one nutateu allele loi the sane gene anu, typically, they aie phenotypi- cally unallecteu (lig. 8-4). ll hoth ol the nutateu alleles aie tiansnitteu to the ollspiing, this vill give iise to an auto- sonal iecessive uisoiuei, the iisl ol vhich is 25 peicent. ll one nutateu anu one vilu-type allele is inheiiteu hy the ollspiing, the chilu vill he an unallecteu caiiiei, sinilai to the paients. ll hoth vilu-type alleles aie tiansnitteu, the chilu vill he genotypically anu pheno- typically noinal vith iespect to an al- lecteu inuiviuual. ll the nutations lion hoth paients aie the sane, the inuiviu- ual is ieleiieu to as a homo:,gotc, hut il uilleient paiental nutations vithin a gene have heen inheiiteu, the inuiviuual is teineu a .om¡ound hctcro:,gotc. loi soneone vho has an autosonal ieces- sive conuition, he it a honozygote oi conpounu heteiozygote, all ollspiing vill he caiiieis ol one ol the nutateu al- leles hut vill he unallecteu hecause ol inheiitance ol a vilu-type allele lion the othei, clinically anu genetically un- allecteu, paient. ¯his assunes that the unallecteu paient is not a caiiiei. Al- though this is usually the case in non- consanguineous ielationships, it nay not holu tiue in hist-cousin naiiiages oi othei ciicunstances vheie theie is a la- nilial inteiielationship. loi exanple, il the paitnei ol an inuiviuual vith an au- tosonal iecessive uisoiuei is also a cai- iiei ol the sane nutation, alheit clini- cally unallecteu, then theie is a 5O peicent chance ol the ollspiing inheiit- ing tvo nutant alleles anu theieloie also inheiiting the sane autosonal ie- cessive uisoiuei. ¯his pattein ol inheii- tance is ieleiieu to as ¡scudo-dominant. ln X-linleu uoninant inheiitance, hoth nales anu lenales aie allecteu, anu the peuigiee pattein nay iesenhle that ol autosonal uoninant inheiitance (lig. 8-5). ¯heie is, hovevei, one inpoi- tant uilleience. An allecteu nale tians- nits the uisoiuei to all his uaughteis anu to none ol his sons. X-linleu uoni- nant inheiitance has heen postulateu as a nechanisn in incontinentia pignenti (see Chap. ¯o), Coniaui-Huneinann synuione, anu local ueinal hypoplasia (Coltz synuione), conuitions that aie alnost alvays liniteu to lenales. ln nost X-linleu uoninant uisoiueis vith cutaneous nanilestations, allecteu nales nay he ahoiteu spontaneously oi uie heloie inplantation (loi exanple, nost nale patients vith incontinentia pig- nenti have a postzygotic nutation in NlíC, anu no allecteu nothei, in this uisoiuei, tiansnission tenus to he le- nale-to-lenale). X-linleu iecessive conuitions occui al- nost exclusively in nales, hut the gene is tiansnitteu hy caiiiei lenales, vho have the nutateu gene only on one X chionosone (heteiozygous state). ¯he sons ol an allecteu nale vill all he noi- nal (hecause theii single X chionosone cones lion theii clinically unallecteu nothei) (lig. 8-6). Hovevei, the uaugh- teis ol an allecteu nale vill all he caiii- eis (hecause all hau to have ieceiveu the single X chionosone that theii lathei hau, anu that X chionosone caiiies the nutant copy ol the coiiesponuing gene). Sone lenales shov clinical ahnoinali- ties as eviuence ol the caiiiei state (such as in hypohiuiotic ectoueinal uysplasia, F|608£ 8-3 Ped|ç|ee |||uº||a||cr c| ar au|cºcra| dcr|rar| pa||e|r c| |r|e|||arce. |e] c|ºe|.a||crº |rc|ude. ||e d|ºc|de| a||ec|º |c|| ra|eº ard |era|eº, cr a.e|açe, o0 pe|cer| c| ||e c||ºp||rç c| ar a|- |ec|ed |rd|.|dua| W||| |e a||ec|ed, a||ec|ed |rd|.|dua|º |a.e cre rc|ra| ccp] ard cre ru|a|ed ccp] c| ||e çere, a||ec|ed |rd|.|dua|º uºua||] |a.e cre a||ec|ed pa|er|, ur|eºº ||e d|ºc|de| |aº a||ºer de rc.c. |r- pc||ar||], e/arp|eº c| ra|e-|c-ra|e ||arºr|ºº|cr, ºeer |e|e, d|º||rçu|º| |||º ||cr /-||r|ed dcr|rar| ard a|e ||e|e|c|e ||e |eº| |a||ra|| c| au|cºcra| dcr|rar| |r|e|||arce. ||||ed c||c|eº |rd|ca|e a||ec|ed |era|eº, |||ed º(ua|eº |rd|ca|e a||ec|ed ra|eº, ur|||ed c||c|eº/º(ua|eº |ep|eºer| ura||ec|ed |rd|.|dua|º. F|608£ 8-4 Ped|ç|ee |||uº||a||cr c| ar au|cºcra| |eceºº|.e pa||e|r c| |r|e|||arce. |e] c|ºe|.a||crº |rc|ude. ||e d|ºc|de| a||ec|º |c|| ra|eº ard |era|eº, ||e|e a|e ru|a||crº cr |c|| |r|e|||ed ccp|eº c| ||e çere, ||e pa|er|º c| ar a||ec|ed |rd|.|dua| a|e |c|| |e|e|c/]çcuº ca|||e|º ard a|e uºua||] c||r|ca||] ura|- |ec|ed, au|cºcra| |eceºº|.e d|ºc|de|º a|e rc|e ccrrcr |r ccrºarçu|recuº |ar|||eº. ||||ed c||c|e |rd|- ca|eº a||ec|ed |era|e, |a||-|||ed c||c|eº/º(ua|eº |ep|eºer| c||r|ca||] ura||ec|ed |e|e|c/]çcuº ca|||e|º c| ||e ru|a||cr, ur|||ed c||c|eº/º(ua|eº |ep|eºer| ura||ec|ed |rd|.|dua|º. 80 see Chap. 14o), the vaiiahle extent ol phenotypic expiession can he explaineu hy lyonization, the noinally ianuon piocess that inactivates eithei the vilu- type oi nutateu X chionosone in each cell uuiing the hist veels ol gestation anu all piogeny cells. 14 Cthei caiiieis nay not shov nanilestations hecause the allecteu iegion on the X chiono- sone escapes lyonization (as in ieces- sive X-linleu ichthyosis) oi the selective suivival uisauvantage ol cells in vhich the nutateu X chionosone is activateu (as in the lynphocytes anu platelets ol caiiieis ol Wislott-Aluiich synuione, see íosaicisn). CHR0|0S0|A| D|S0RDERS Aheiiations in chionosones aie con- non. ¯hey occui in ahout 6 peicent ol all conceptions, although nost ol these leau to niscaiiiage, anu the lieguency ol chionosonal ahnoinalities in live hiiths is ahout O.6 peicent. Appioxi- nately tvo-thiius ol these involve ah- noinalities in eithei the nunhei ol sex chionosones oi the nunhei ol auto- sones, the ienainuei aie chionosonal ieaiiangenents. ¯he nunhei anu ai- iangenent ol the chionosones is ie- leiieu to as the kar,ot,¡c. ¯he nost connon nuneiical ahnoinality is tii- sony, the piesence ol an extia chiono- sone. ¯his occuis hecause ol non-uis- |unction, vhen paiis ol honologous chionosones lail to sepaiate uuiing neiosis, leauing to ganetes vith an au- uitional chionosone. Loss ol a con- plete chionosone, nonosony, can al- lect the X chionosone hut is iaiely seen in autosones hecause ol non-via- hility. A nunhei ol chionosonal uisoi- ueis aie also associateu vith slin ahnoi- nalities, as uetaileu in ¯ahle 8-2. Stiuctuial aheiiations (liagility hieals) in chionosones nay he ianuon, al- though sone chionosonal iegions ap- peai noie vulneiahle. Loss ol pait ol a chionosone is ieleiieu to as a dc|ction. ll the ueletion leaus to loss ol neighhoiing genes this nay iesult in a contiguous gene uisoiuei, such as a ueletion on the X chionosone giving iise to X-linleu ich- thyosis (see Chap. 4¯) anu lallnan syn- uione. ll tvo chionosones hieal, the uetacheu liagnents nay he exchangeu, lnovn as rc.i¡ro.a| trans|o.ation. ll this piocess involves no loss ol DNA it is ie- leiieu to as a |a|an.cd trans|o.ation. Cthei stiuctuial aheiiations incluue uuplication ol sections ol chionosones, tvo hieals vithin one chionosone leauing to invei- sion, anu lusion ol the enus ol tvo hio- len chionosonal ains, leauing to |oin- ing ol the enus anu loination ol a iing chionosone. A luithei possihle chionosonal ah- noinality is the inheiitance ol hoth cop- ies ol a chionosone paii lion |ust one paient (pateinal oi nateinal), lnovn as uni¡arcnta| disom,. 15 !ni¡arcnta| hctcrodi- som, ieleis to the piesence ol a paii ol chionosone honologs, vheieas uni¡a- rcnta| isodisom, uesciihes tvo iuentical copies ol a single honolog, anu mcroisodi- som, is a nixtuie ol the tvo. Unipaiental uisony vith honozygosity ol iecessive alleles is heing incieasingly iecognizeu as the noleculai hasis loi seveial autosonal iecessive uisoiueis, anu theie have heen noie than o5 iepoiteu cases ol iecessive uiseases, incluuing |unctional anu uystio- phic lB (see Chap. 6O), iesulting lion this type ol chionosonal ahnoinality. loi ceitain chionosones, unipaiental ui- sony can also iesult in uistinct pheno- types uepenuing on the paiental oiigin ol the chionosones, a phenonenon lnovn as gcnomi. im¡rinting. 16,1¯ ¯his pai- ent-ol-oiigin, specihc gene expiession is ueteinineu hy epigenetic nouihcation ol a specihc gene oi, noie olten, a gioup ol genes, such that gene tiansciiption is F|608£ 8-5 Ped|ç|ee |||uº||a||cr c| ar /-||r|ed dcr|rar| pa||e|r c| |r|e|||arce. |e] c|ºe|.a||crº |rc|ude. a||ec|ed |rd|.|dua|º a|e e|||e| |er|/]çcuº ra|eº c| |e|e|c/]çcuº |era|eº, a||ec|ed ra|eº W||| ||arºr|| ||e d|ºc|de| |c ||e|| dauç||e|º |u| rc| |c ||e|| ºcrº (rc ra|e-|c-ra|e ||arºr|ºº|cr,, a||ec|ed |e- ra|eº W||| ||arºr|| ||e d|ºc|de| |c |a|| ||e|| dauç||e|º ard |a|| ||e|| ºcrº, ºcre d|ºc|de|º c| |||º |]pe a|e |e||a| |r |er|/]çcuº ra|eº ard cr|] |e|e|c/]çcuº |era|eº ºu|.|.e. ||||ed c||c|eº |rd|ca|e a||ec|ed |e- ra|eº, |||ed º(ua|eº |rd|ca|e a||ec|ed ra|eº, ur|||ed c||c|eº/º(ua|eº |ep|eºer| ura||ec|ed |rd|.|dua|º. F|608£ 8-6 Ped|ç|ee |||uº||a||cr c| ar /-||r|ed |eceºº|.e pa||e|r c| |r|e|||arce. |e] c|ºe|.a||crº |rc|ude. uºua||] a||ec|º cr|] ra|eº |u| |era|eº car º|cW ºcre |ea|u|eº |ecauºe c| |]cr|/a||cr (/-c||c- rcºcre |rac||.a||cr,, ||arºr|||ed |||cuç| |era|e ca|||e|º, W||| rc ra|e-|c-ra|e ||arºr|ºº|cr, |c| a|- |ec|ed ra|eº, a|| dauç||e|º W||| |e |e|e|c/]çcuº ca|||e|º, |era|e ca|||e| W||| ||arºr|| ||e d|ºc|de| |c |a|| |e| ºcrº, ard |a|| |e| dauç||e|º W||| |e |e|e|c/]çcuº ca|||e|º. Dc|º W||||r c||c|eº |rd|ca|e |e|e|c/]çcuº ca|||e| |era|eº W|c ra] c| ra] rc| d|ºp|a] ºcre p|erc|]p|c a|rc|ra||||eº, |||ed º(ua|eº |rd|ca|e a|- |ec|ed ra|eº, ur|||ed c||c|eº/º(ua|eº |ep|eºer| ura||ec|ed |rd|.|dua|º. 81 Ik8L£ 8-2 0hromosoma| 0|sordars w|th a Sk|n Phanotypa 0H80N0S0NAL A8h08NAL|TY SYh0hYN 0FhF8AL FFATU8FS SK|h NAh|FFSTAT|0hS T||ºcr] 21 DcWr º]rd|cre Sra|| |ead W||| 1a| |ace 1-10 ]|. d|] º||r, /e|cº|º, ||c|er||ca||cr \cºe º|c|| ard º(ua| 10+ ]|. |rc|eaºed ||e(uerc] c| a|cp|c de|ra||||º, a|cpec|a a|ea|a, º|rç|e c|eaºe |r pa|r ard |||| |rçe| Ea|º ºra|| ard r|ºº|aper S|ar||rç pa|pe||a| |ººu|eº 0||e| aººcc|a||crº. º||r |r|ec||crº, arçu|a| c|e|||||º, çecç|ap||c |crçue, ||ep|a||||º, |ed c|ee|º, |c|||cu||||º, ºe|c|||e|c de|ra||||º, |c||º, cr]c|c- r]ccº|º, |re |]pcp|çrer|ed |a||, .|||||çc, de|a]ed der||||cr ard |]pc- p|aº||c |ee||, ac|cc]arcº|º, ||.edc |e||cu|a||º, cu||º ra|rc|a|a, ca|c|rcº|º cu||º, pa|rcp|ar|a| |e|a|cde|ra, p||]||aº|º |u||a p||a||º, º]||rçcraº, e|aº|cº|º pe||c|arº ºe|p|ç|rcºa, are|cde|ra, |]pe||e|a- |c||c |c|r c| pºc||aº|º, cc||açercra, e|up||.e de|ra|c|||craº, u|||ca||a p|çrer|cºa, |eu|er|a cu||º, |e|a|cº|º |c|||cu|a||º ºp|ru|cºa deca|.arº T||c|ered e]e||dº E]e|aº|eº º|c|| ard ºpa|ºe S|c||ered ||r|º, |a/ jc|r|º ||rçe|º º|c||, ºcre||reº We||ed H]pcp|aº||c |||º, ||ç||e| cu|e| /cre (B|uº||e|d'º ºpc|º, T||ºcr] 18 EdWa|dº º]rd|cre Se.e|e rer|a| de|c|erc] Cu||º |a/a (rec|,, |]pe||||c|cº|º c| |c|e|ead ard |ac|, ºupe||c|a| |erarç|craº, a|rc|ra| de|ra|cç|]p||cº, º|rç|e pa|ra| c|eaºe, |]pe|- p|çrer|a||cr, ar|]|c||ep|a|cr ||||c|re adra|ur A|rc|ra| º|u|| º|ape Sra|| c||r, p|cr|rer| ccc|pu| |cW-ºe|, ra||c|red ea|º 'Rcc|e| |c||cr' |ee| S|c|| º|e|rur |a||c|ra||crº c| |r|e|ra| c|çarº 0r|] 10° ºu|.|.e |e]crd ||º| ]ea| T||ºcr] 18 Pa|au º]r- d|cre |er|a| |e|a|da||cr Vaºcu|a| arcra||eº (eºpec|a||] cr |c|e|ead, S|cp|rç |c|e|ead due |c |c|e||a|r ra|de.e|cprer| (|c|cp|cºercep|a|], H]pe|ccr.e/ ra||º |cca||/ed ºca|p de|ec|º ||c|cp|||a|r|a c| arcp|||a|r|a Cu||º |a/a (rec|, C|e|| pa|a|e/c|e|| ||p A|rc|ra| pa|r p||r| (d|º|a| pa|ra| a/|a| ||||ad|uº, |cW-ºe| ea|º 'Rcc|e| |c||cr' |ee| |a||c|ra||crº c| |r|e|ra| c|çarº Su|.|.a| |e]crd o rc |º |a|e C||crcºcre 4, º|c|| a|r de|e||cr ||c|ccep|a|] Sca|p de|ec|º |er|a| |e|a|da||cr H]pcºpad|aº C|e|| ||p/pa|a|e |cW-ºe| ea|º, p|eau||cu|a| p||º C||crcºcre o, º|c|| a|r de|e||cr |er|a| |e|a|da||cr P|era|u|e ç|a]|rç c| |a|| ||c|ccep|a|] Ca|-|||e c|] |cW-ºe| ea|º, p|eau||cu|a| º||r |aç C||crcºcre 18, |crç a|r de|e||cr H]pcp|aº|a c| r|d-|ace Ec/era |r 2o° c| caºeº Sur|er e]eº P|cr|rer| ea| ar||-|e||/ |u|||p|e º|e|e|a| ard ccu|a| a|rc|ra||||eº 4o /0 Tu|re| º]rd|cre Ea||] er||]cr|c |cºº, p|era|a| u|||a- ºcurd |rd|rçº c| c]º||c |]ç|cra, c|]- |c||c|a/, aºc||eº ard |]d|cpº Redurdar| rec| º||r ard pe||p|e|a| edera we||ed rec|, |cW pcº|e||c| |a||||re Cu||º |a/a (rec|, |u||cc|º, S|c|| º|a|u|e, arerc|||ea H]pcp|aº||c, ºc|| up-|u|red ra||º B|cad c|eº|, W|de|] ºpaced r|pp|eº |rc|eaºed |rc|derce c| |e|c|dº w|de ca||]|rç arç|e c| a|rº |rc|eaºed rur|e| c| re|arcc]||c re.| ard |a|c re.| |cW r|ºº|aper ea|º, ||ç| a|c|ed pa|a|e |a||u|e |c de.e|cp |u|| ºeccrda|] ºe/ua| c|a|ac|e||º||cº S|c|| |cu|||/|||| |rçe|º ard |ceº |]rp|a||c |]pcp|aº|a/|]rp|edera S|e|e|a| a|rc|ra||||eº, cca|c|a||cr c| ac||a 4/ //\ |||re|e||e| º]rd|cre \c rar||eº|a||crº |e|c|e pu|e||] |a] de.e|cp ç]reccraº||a Sra|| |eº|eº, pcc||] de.e|cped ºeccr- da|] ºe/ua| c|a|ac|e||º||cº Spa|ºe |cd] ard |ac|a| |a|| |rc|eaºed ||º| c| |eç u|ce|º |r|e||||||] |rc|eaºed |rc|derce c| º]º|er|c |upuº e|]||era|cºuº Ta||, c|eºe, cº|ecpc|cº|º (ccrtir0cc; 82 alteieu, anu only one inheiiteu copy ol the ielevant inpiinteu gene(s) is expiesseu in the enhiyo. ¯his neans that, uuiing uevelopnent, the paiental genones lunc- tion unegually in the ollspiing. ¯he nost connon exanples ol genonic inpiinting aie liaueiWilli (Cílí =1¯62¯O) anu Angelnan (Cílí =1O58oO) synuiones, vhich can iesult lion nateinal oi patei- nal unipaiental uisony loi chionosone 15, iespectively. ¯hiee phenotype ahnoi- nalities connonly associateu vith uni- paiental uisony loi chionosones vith inpiinting aie intiauteiine giovth ietai- uation, uevelopnental uelay, anu ieuuceu statuie. 18 ||T0CH0\DR|A| D|S0RDERS ln auuition to the o.o hillion hp nucleai genone, each cell contains hunuieus oi thousanus ol copies ol a luithei 16.5-lh nitochonuiial genone, vhich is inhei- iteu solely lion an inuiviuual`s nothei. ¯his closeu, ciiculai genone contains o¯ genes, 1o ol vhich encoue pioteins ol the iespiiatoiy chain conplexes, vheieas the othei 24 genes geneiate 22 tianslei RNAs anu tvo iihosonal RNAs useu in nito- chonuiial piotein synthesis. 1º íutations in nitochonuiial DNA veie hist iepoiteu in 1º88, anu noie than 25O pathogenic point nutations anu genonic ieaiiange- nents have heen shovn to unueilie a nunhei ol nyopathic uisoiueis anu neu- iouegeneiative uiseases, sone ol vhich shov slin nanilestations, incluuing lipo- nas, ahnoinal pignentation oi eiy- thena, anu hypo- oi hypeitiichosis. 2O íi- tochonuiial DNA has the capacity to loin a nixtuie ol hoth vilu-type anu nutant DNA vithin a cell, leauing to cel- lulai uyslunction only vhen the iatio ol nutateu to vilu-type DNA ieaches a cei- tain thiesholu. ¯he phenonenon ol hav- ing nixeu nitochonuiial DNA species vithin a cell is lnovn as hctcro¡|asm,. íi- tochonuiial nutations can inuuce, oi he inuuceu hy, ieactive oxygen species, anu nay he lounu in, oi contiihute to, hoth chionologic aging anu photoaging. So- natic nutations in nitochonuiial DNA have also heen iepoiteu in seveial pie- nalignant anu nalignant tunois, incluu- ing nalignant nelanona, although it is not yet lnovn vhethei these nutations aie causally linleu to cancei uevelopnent oi sinply a seconuaiy hystanuei ellect as a conseguence ol nucleai DNA instahility. lnueeu, cuiiently theie is little unuei- stanuing ol the inteiplay hetveen the nu- cleai anu nitochonuiial genones in hoth health anu uisease. Neveitheless, it is evi- uent that the genes encoueu hy the nito- chonuiial genone have nultiple hiologic lunctions linleu to eneigy piouuction, cell piolileiation, anu apoptosis. 21 C0|P|E/ TRA|T 0E\ET|CS loi íenuelian uisoiueis, iuentilying genes that haihoi pathogenic nutations has hecone ielatively stiaightloivaiu, vith hunuieus ol uisease-associateu genes heing uiscoveieu thiough a con- hination ol linlage, positional cloning, anu canuiuate gene analyses. By con- tiast, loi conplex tiaits, such as psoiia- sis anu atopic ueinatitis, these tiaui- tional appioaches have heen laigely unsuccesslul in napping genes inhuenc- ing the uisease iisl oi phenotype he- cause ol lov statistical povei anu othei lactois. 22,2o Conplex tiaits uo not uis- play sinple íenuelian patteins ol in- heiitance, although genes uo have an in- huence, anu close ielatives ol allecteu inuiviuuals nay have an incieaseu iisl. ¯o uissect out genes that contiihute to, anu inhuence susceptihility to, conplex tiaits, seveial stages nay he necessaiy, incluuing estahlishing a genetic hasis loi the uisease in one oi noie populations, neasuiing the uistiihution ol gene el- lects, stuuying statistical povei using nouels, anu caiiying out nailei-haseu napping stuuies using linlage oi associ- ation. lt is possihle to estahlish guantita- tive genetic nouels to estinate the heii- tahility ol a conplex tiait, as vell as to pieuict the uistiihution ol gene ellects anu to test vhethei one oi noie guanti- tative tiait loci exist. ¯hese nouels can pieuict the povei ol uilleient napping appioaches, hut olten only pioviue ap- pioxinate pieuictions. íoieovei, lov povei olten linits othei stiategies such as tiansnission analyses, association stuuies, anu lanily-haseu association tests. Anothei potential pitlall ol asso- ciation stuuies is that they can geneiate spuiious associations uue to popula- tion aunixtuie. ¯o countei this, altei- native stiategies loi association nap- ping incluue the use ol iecent lounuei populations oi unigue isolateu popula- tions that aie genetically honoge- neous, anu the use ol unlinleu naileis (so-calleu gcnomi. .ontro|s) to assign uil- leient iegions ol the genone ol an au- nixeu inuiviuual to paiticulai souice populations. ln auuition, anu ielevant to seveial stuuies on psoiiasis, linlage uiseguilihiiun ohseiveu in a sanple ol unielateu allecteu anu noinal inuiviu- uals can also he useu to hne-nap a uis- ease susceptihility locus in a canuiuate iegion. Recently, hovevei, a conventional ge- netics appioach has ievealeu lascinating nev insight into the pathophysiology ol one paiticulai conplex tiait, nanely 48 //\\ S|r||a| |c |||re|e||e| º]rd|cre |u|||p|e cu|arecuº arç|craº Ac|cc]arcº|º, pe||p|e|a| .aºcu|a| d|ºeaºe 4/ /\\ P|erc|]p|c ra|eº (|a||, Se.e|e acre |er|a| |e|a|da||cr Açç|eºº|.e |e|a.|c| 49 ////\ |cW ||||| We|ç|| H]pc|||c|cº|º (.a||a||e, S|cW rer|a| ard p|]º|ca| de.e|cprer| |a|çe, |cW-ºe|, ra||c|red ea|º Sra|| çer||a||a ||aç||e / º]rd|cre |er|a| |e|a|da||cr - |||d d]ºrc|p||ºr H]pe|e/|erº|||e jc|r|º, 1a| |ee| Ik8L£ 8-2 0hromosoma| 0|sordars w|th a Sk|n Phanotypa (0ont|nuad} 0H80N0S0NAL A8h08NAL|TY SYh0hYN 0FhF8AL FFATU8FS SK|h NAh|FFSTAT|0hS 83 atopic ueinatitis. ¯his hnuing enanateu lion the uiscoveiy that the uisoiuei ich- thyosis vulgaiis vas uue to loss-ol-lunc- tion nutations in the gene encouing the slin haiiiei piotein hlaggiin (see Chaps. 14 anu 4¯). 24 ¯o ueinatologists, the clinical association hetveen this conuition anu atopic ueinatitis is vell lnovn, anu the sane loss-ol-lunction nutations in hlaggiin have suhseguently heen shovn to he a na|oi susceptihility iisl lactoi loi atopic ueinatitis, as vell as asthna associateu vith atopic uei- natitis, hut not asthna alone. 4 ¯his suggests that asthna in inuiviuuals vith atopic ueinatitis nay he seconuaiy to alleigic sensitization, vhich uevelops hecause ol the uelective epiueinal hai- iiei that allovs alleigens to penetiate the slin to nale contact vith antigen- piesenting cells. lnueeu, tiansnission- uiseguilihiiun tests have uenonstiateu an association hetveen hlaggiin gene nutations anu extiinsic atopic ueinati- tis associateu vith high total seiun in- nunoglohulin l levels anu conconitant alleigic sensitizations. 25 ¯hese iecent uata on the genetics ol atopic ueinatitis uenonstiate hov the stuuy ol a °sin- ple` genetic uisoiuei can also pioviue novel insight into a conplex tiait. íen- uelian uisoiueis, theieloie, nay he use- lul in the noleculai uissection ol noie conplex tiaits. 26 |0SA|C|S| ¯he piesence ol a nixeu population ol cells heaiing uilleient genetic oi chio- nosonal chaiacteiistics leauing to phe- notypic uiveisity is ieleiieu to as mosa- i.ism. ¯heie aie seveial uilleient types ol nosaicisn, incluuing single gene, chionosonal, lunctional, anu ieveitant nosaicisn. 2¯ íosaicisn loi a single gene, ieleiieu to as somati. mosai.ism, inuicates a nuta- tional event occuiiing altei leitilization. ¯he eailiei this occuis, the noie lilely it is theie vill he clinical expiession ol a uisease phenotype as vell as involve- nent ol gonaual tissue (gonosonal no- saicisn), loi exanple, vhen inuiviuuals vith segnental neuiohhionatosis suh- seguently have ollspiing vith lull- hlovn neuiohhionatosis (see Chap. 142). Hovevei, in geneial, il the nuta- tion occuis altei geneiation ol cells connitteu to gonau loination, then the nosaicisn vill not involve the gein- line, anu the iepiouuctive iisl ol tians- nission is negligihle. Conosoma| mosa- i.ism ieleis to involvenent ol hoth gonaus anu sonatic tissue, hut nosa- icisn can occui exclusively in gonaual tissue, ieleiieu to as gonada| mosai.ism. Clinically, this nay explain iecuiiences anong sihlings ol autosonal uoninant uisoiueis such as tuheious scleiosis oi neuiohhionatosis, vhen none ol the paients has any clinical nanilestations anu gene scieening using genonic DNA lion peiipheial hloou sanples yielus no nutation. Segnental nosaicisn loi au- tosonal uoninant uisoiueis is thought to occui in one ol tvo vays: eithei theie is a postzygotic nutation vith the slin outsiue the segnent anu genonic DNA heing noinal (type 1), oi theie is a heteiozygous genonic nutation that is then exaceihateu hy loss ol heteiozy- gosity vithin a segnent oi along the lines ol Blaschlo (type 2). ¯his pattein has heen uesciiheu in seveial autosonal uoninant uisoiueis, incluuing Daiiei uisease, Hailey-Hailey uisease (see Chap. 4º), supeihcial actinic poioleiatosis (see Chap. 5O), anu tuheious scleiosis (see Chap. 141). ¯he lines ol Blaschlo veie uelineateu ovei 1OO yeais ago, the pattein is attiih- uteu to the lines ol nigiation anu piolil- eiation ol epiueinal cells uuiing en- hiyogenesis (i.e., the hanus ol ahnoinal slin iepiesent clones ol cells caiiying a nutation in a gene expiesseu in the slin). 28 Apait lion sonatic nutations |eithei in uoninant uisoiueis, such as hullous ichthyosiloin eiythioueina leauing to lineai epiueinolytic hypei- leiatosis (see Chap. 4¯), oi in conui- tions involving nutations in lethal uoninant genes such as in ícCune- Alhiight synuione], nosaicisn lollov- ing Blaschlo`s lines is also seen in chio- nosonal nosaicisn anu lunctional nosaicisn (ianuon X-chionosone inactivation thiough lyonization). Chio- nosonal nosaicisn iesults lion non- uis|unction events that occui altei leitil- ization. Clinically, this is lounu in the lineai pignentaiy uisoiueis hyponel- anosis ol lto (see Chap. ¯o) anu lineai anu vhoileu hypeipignentation. lt is inpoitant to point out that hyponel- anosis ol lto is not a specihc uiagnosis hut nay occui as a conseguence ol sev- eial uilleient chionosonal ahnoinali- ties that peituih vaiious genes ielevant to slin pignentation. lunctional nosa- icisn ielates to genes on the X chiono- sone, hecause uuiing enhiyonic uevel- opnent in lenales, one ol the X chionosones, eithei the nateinal oi the pateinal, is inactivateu. loi X-linleu uoninant uisoiueis, such as local uei- nal hypoplasia (Coltz synuione) oi in- continentia pignenti (see Chap. ¯o), le- nales suivive hecause ol the piesence ol sone cells in vhich the X chionosone vithout the nutation is active anu ahle to lunction. loi nales, these X-linleu uoninant uisoiueis aie typically lethal, unless associateu vith an ahnoinal laiy- otype (e.g., llineleltei synuione, 4¯, XXY) oi il the nutation occuis uuiing enhiyonic uevelopnent. loi X-linleu iecessive conuitions, such as X-linleu ie- cessive hypohiuiotic ectoueinal uyspla- sia (see Chap. 14o), the clinical leatuies aie eviuent in henizygous nales (vho have only one X chionosone), hut le- nales nay shov suhtle ahnoinalities uue to nosaicisn causeu hy X-inactiva- tion, such as uecieaseu sveating oi ie- uuceu haii in aieas ol the slin in vhich the noinal X is selectively inactivateu. ¯heie aie 1o1¯ lnovn genes on the X chionosone, anu nost unueigo ianuon inactivation hut a snall peicentage (ap- pioxinately 2¯ genes on Xp, incluuing the steioiu sullatase gene, anu 26 genes on Xg) escape inactivation. Reveitant nosaicisn, also lnovn as natura| gcnc thcra¡,, ieleis to genetic coi- iection ol an ahnoinality hy piesence ol a seconu nutation that eithei coiiects a nutant gene oi silences it. 2º,oO Such events have heen uesciiheu in a lev genes expiesseu in the slin, incluuing the leiatin 14, laninin oo2, anu collagen XVll genes in uilleient loins ol lB (lig. 8-¯, see Chap. 6O). Hovevei, the clinical ielevance ol the conveision piocess ue- penus on seveial lactois, incluuing the nunhei ol cells involveu, hov nuch ie- veisal actually occuis, anu at vhat stage in lile the ieveision tales place. Apait lion nutations in nucleai DNA, nosaicisn can also he inhuenceu hy enviionnental lactois, such as viial DNA seguences (ietiotiansposons) that can he incoipoiateu into nucleai DNA, ieplicate, anu activate oi silence genes thiough nethylation oi uenethylation. ¯his phenonenon is lnovn as c¡igcncti. mosai.ism, such events nay he inpli- cateu in tunoiigenesis hut have not heen associateu vith any genetic slin uisoiuei. EP|0E\ET|CS Disease phenotypes iehect the iesult ol the inteiaction hetveen a paiticulai genotype anu the enviionnent, hut it is eviuent that sone vaiiation, loi exanple, in nonozygotic tvins, is attiihutahle to neithei. Auuitional inhuences at the hio- chenical, cellulai, tissue, anu oiganisn levels occui, anu these aie ieleiieu to as c¡igcncti. ¡hcnomcna. o1 Single genes aie 84 not solely iesponsihle loi each sepaiate lunction ol a cell. Cenes nay collahoiate in ciicuits, he nohile, exist in plasnius anu cytoplasnic oiganelles, anu can he inpoiteu hy nonsexual neans lion othei oiganisns oi as synthetic piou- ucts. lven piion pioteins can sinulate sone gene piopeities. lpigenetic ellects iehect chenical nouihcations to DNA that uo not altei DNA seguence hut uo altei the piohahility ol gene tiansciip- tion. Analysis ol these changes is lnovn as c¡igcnomi.s. o2 lxanples ol nouihca- tions incluue uiiect covalent nouihca- tion ol DNA hy nethylation ol cy- tosines anu alteiations in pioteins that hinu to DNA. Such changes nay allect DNA accessihility to local tiansciiptional conplexes as vell as inhuencing chio- natin stiuctuie at iegional anu genone- viue levels, thus pioviuing a linl he- tveen genone stiuctuie anu iegulation ol tiansciiption. lnueeu, epigenone analysis is nov heing caiiieu out in pai- allel vith gene expiession to iuentily ge- none-viue nethylation patteins anu piohles ol all hunan genes. loi exanple, theie is consiueiahle inteiinuiviuual vaii- ation in cytosine nethylation ol CpC ui- nucleotiues vithin the na|oi histocon- patihility conplex (íHC) iegion genes, although vhethei this has any heaiing on the expiession ol slin uisoiueis such as psoiiasis ienains to he seen. A luithei hut as yet uniesolveu issue is vhethei theie is heiitahility ol epigenetic chaiac- teiistics. Lilevise, it is uncleai vhethei enviionnentally inuuceu changes in epi- genetic status, anu hence gene tiansciip- tion anu phenotype, can he tiansnitteu thiough noie than one geneiation. Such a phenonenon night account loi the cancei susceptihility ol gianuchiluien ol inuiviuuals vho have heen exposeu to uiethylstilhestiol, hut this has not heen pioveu. Ceinline epinutations, hov- evei, have heen iuentiheu in othei hu- nan uiseases, such as coloiectal canceis chaiacteiizeu hy niciosatellite instahil- ity anu hypeinethylation ol the /lH1 DNA nisnatch iepaii gene, although the iisl ol tiansgeneiational epigenetic inheiitance ol cancei lion such a nuta- tion is not vell estahlisheu anu pioha- hly snall. Cvei the couise ol an inui- viuual`s lilespan, epigenetic nutations nay occui noie lieguently than DNA nutations, anu it is expecteu that, ovei the next uecaue, the iole ol epigenetic phenonena in inhuencing phenotypic vaiiation vill giauually hecone hettei unueistoou. oo H|ST0C0|PATAB|||T\ A\T|0E\ D|SEASE ASS0C|AT|0\ HLA nolecules aie glycopioteins that aie expiesseu on alnost all nucleateu cells. ¯he HLA iegion is locateu on the shoit ain ol chionosone 6, at 6p21, ieleiieu to as the /HC. ¯heie aie thiee classic loci at HLA class l: HLA-A, -B, anu -Cv, anu hve loci at class ll: HLA-DR, -DC, -Dl, -Dí, anu -DC. ¯he HLA nolecules aie highly polynoiphic, theie heing nany alleles at each inuiviuual locus. ¯hus, allelic vaiiation contiihutes to ue- hning a unigue °hngeipiint` loi each pei- son`s cells, vhich allovs an inuiviuual`s innune systen to uehne vhat is loieign anu vhat is sell. ¯he clinical signihcance ol the HLA systen is highlighteu in hu- nan tissue tiansplantation, especially in liuney anu hone naiiov tiansplanta- tion, vheie elloits aie naue to natch at the HLA-A, -B, anu -DR loci. íHC class l nolecules, conplexeu to ceitain pep- tiues, act as suhstiates loi CD8 + ¯-cell activation, vheieas íHC class ll nole- cules on the suilace ol antigen-piesent- ing cells uisplay a iange ol peptiues loi iecognition hy the ¯-cell ieceptois ol CD4 + ¯ helpei cells (see Chap. 1O). íHC nolecules, theieloie, aie cential to ellec- tive auaptive innune iesponses. Con- veisely, hovevei, genetic anu epiue- niologic uata have inplicateu these nolecules in the pathogenesis ol vaiious autoinnune anu chionic inhannatoiy uiseases. Seveial slin uiseases, such as psoiiasis (see Chap. 18), psoiiatic aithiop- athy (cential anu peiipheial), ueinatitis heipetiloinis, penphigus, ieactive ai- thiitis synuione (see Chap. 2O), anu Beh- çet uisease (see Chap. 16¯), all shov an association vith inheiitance ol ceitain HLA haplotypes (i.e., theie is a highei in- ciuence ol these conuitions in inuiviuuals anu lanilies vith paiticulai HLA alleles). Hovevei, the noleculai nechanisns hy vhich polynoiphisns in HLA nolecules conlei susceptihility to ceitain uisoiueis aie still uncleai. ¯his situation is luithei conplicateu hy the lact that, loi nost uiseases, it is unlnovn vhich autoanti- gens (piesenteu hy the uisease-associateu íHC nolecules) aie piinaiily involveu. loi nany uiseases, the íHC class asso- ciation is the nain genetic association. Neveitheless, loi nost ol the íHC-asso- ciateu uiseases, it has heen uilhcult to un- eguivocally ueteinine the piinaiy uis- ease-iisl gene(s), oving to the extenueu linlage uiseguilihiiun in the íHC ie- gion. Hovevei, iecent genetic anu lunc- tional stuuies suppoit the long-helu as- sunption that connon íHC class l anu ll alleles thenselves aie iesponsihle loi nany uisease associations, such as the HLA cv6 allele in psoiiasis. 0E\ET|C C0U\SE||\0 ln 2OO6, the National Society ol Cenetic Counselois (http://vvv.nsgc.oig) ue- hneu genetic counseling as °the piocess ol helping people unueistanu anu auapt to the neuical, psychological anu lanil- ial inplications ol genetic contiihutions to uisease.` Cenetic counseling shoulu incluue: (1) inteipietation ol lanily anu neuical histoiies to assess the chance ol uisease occuiience oi iecuiience, (2) eu- ucation ahout inheiitance, testing, nan- agenent, pievention, iesouices, anu ie- seaich, anu (o) counseling to pionote inloineu choice anu auaptation to the iisl oi conuition. o4 F|608£ 8-7 Re.e||ar| rcºa|c|ºr |r ar |rd|.|dua| W||| rcr-He||||/ jurc||cra| ep|de|rc|]º|º |u||cºa. T|e ºu|jec| |aº |cºº-c|-|urc||cr ru|a||crº cr |c|| a||e|eº c| ||e |]pe /V|| cc||açer çere, 00l1//1, |u| ºpcr|arecuº çere||c cc||ec||cr c| ||e ru|a||cr |r ºcre a|eaº |aº |ed |c pa|c|eº c| rc|ra|-appea||rç º||r (a|eaº W||||r ||ac| ra||e| cu|||re, ||a| dc rc| |||º|e|. (||cr Jcr|rar || e| a|. Re.e||ar| rcºa- |c|ºr |r ep|de|rc|]º|º |u||cºa cauºed |] r||c||c çere ccr.e|º|cr. 0c!! 88.o48, 199/, W||| pe|r|ºº|cr., 85 Cenetic counseling is an integial pait ol the piactice ol ueinatology. Cnce the uiagnosis ol an inheiiteu slin uisease is estahlisheu anu the noue ol inheiitance is lnovn, eveiy ueinatologist shoulu he ahle to auvise patients coiiectly anu appiopiiately, although auuitional sup- poit lion specialists in neuical genetics is olten necessaiy. Cenetic counseling nust he haseu on an unueistanuing ol genetic piinciples anu on a laniliaiity vith the usual hehavioi ol heieuitaiy anu congenital ahnoinalities. lt is also inpoitant to he laniliai vith the iange ol clinical seveiity ol a paiticulai uis- ease, the social conseguences ol the uis- oiuei, the availahility ol theiapy (il any), anu the options loi nutation uetection anu pienatal testing in suhseguent pieg- nancies at iisl loi iecuiience (one uselul site is http://vvv.genetests.con). A ley conponent ol genetic counsel- ing is to help paients, patients, anu lani- lies lnov ahout the iisls ol iecuiience oi tiansnission loi a paiticulai conuition. ¯his inloination is not only piactical hut olten ielieves guilt anu can allay iathei than inciease anxiety. loi exanple, it nay not he cleai to the peison that he oi she cannot tiansnit the given uisoiuei. ¯he unallecteu hiothei ol a patient vith an X-linleu iecessive uisoiuei such as lahiy uisease (see Chap. 1o6), X-linleu ichthyosis (see Chap. 4¯), Wislott- Aluiich synuione (see Chap. 144), oi íenles synuione (see Chap. 86) neeu not voiiy ahout his chiluien heing al- lecteu oi even caiiying the ahnoinal al- lele, hut he nay not lnov this. liognosis anu counseling loi conui- tions such as psoiiasis in vhich the ge- netic hasis is conplex oi still uncleai is noie uilhcult (see Chap. 18). leisons can he auviseu, loi exanple, that il hoth pai- ents have psoiiasis, the piohahility is 6O peicent to ¯5 peicent that a chilu vill have psoiiasis, il one paient anu a chilu ol that union have psoiiasis, then the chance is oO peicent that anothei chilu vill have psoiiasis, anu il tvo noinal paients have piouuceu a chilu vith psoii- asis, the piohahility is 15 peicent to 2O peicent loi anothei chilu vith psoiiasis. o5 PRE\ATA| D|A0\0S|S ln iecent yeais, theie has heen consiuei- ahle piogiess in ueveloping pienatal test- ing loi seveie inheiiteu slin uisoiueis (lig. 8-8). lnitially, ultiastiuctuial exani- nation ol letal slin hiopsies vas estah- lisheu in a liniteu nunhei ol conuitions. ln the late 1º¯Os, the hist uiagnostic ex- anination ol letal slin vas iepoiteu loi epiueinolytic hypeileiatosis anu Heilitz |unctional lB (see Chap. 6O). o6,o¯ ¯hese initial hiopsies veie peiloineu vith the aiu ol a letoscope to visualize the letus. Hovevei, vith inpiovenents in sono- giaphic inaging, hiopsies ol letal slin aie nov talen unuei ultiasounu guiuance. ¯he letal slin hiopsy sanples ohtaineu uuiing the eaily 1º8Os coulu he exan- ineu only hy light nicioscopy anu tians- nission election nicioscopy. Hovevei, the intiouuction ol a nunhei ol nono- clonal anu polyclonal antihouies to vaii- ous hasenent nenhiane conponents uuiing the niu-1º8Os leu to the uevelop- nent ol innunohistochenical tests to help conplenent ultiastiuctuial analysis in estahlishing an accuiate uiagnosis, es- pecially in cases ol lB. o8 letal slin hiop- sies aie talen uuiing the niu-tiinestei. loi uisoiueis such as lB, testing at 16 veels` gestation is appiopiiate. Hov- evei, loi sone loins ol ichthyosis, the uisease-uehning stiuctuial pathology nay not he eviuent at this tine, anu letal slin sanpling nay neeu to he ueleiieu until 2O to 22 veels ol uevelopnent. Neveitheless, since the eaily 1ººOs, as the noleculai hasis ol an incieasing nunhei ol genoueinatoses has heen elu- ciuateu, letal slin hiopsies have giauu- ally heen supeiseueu hy DNA-haseu ui- agnostic scieening using letal DNA lion anniotic huiu cells oi sanples ol choii- onic villi, the lattei aie usually talen at 1O to 12 veels` gestation (i.e., at the enu ol the hist tiinestei). oº,4O ln auuition, au- vances vith in vitio leitilization anu en- hiyo nicionanipulation have leu to the leasihility ol even eailiei DNA-haseu as- sessnent thiough pieinplantation ge- netic uiagnosis, an appioach hist suc- cesslully applieu in 1ººO, loi iisl ol iecuiience ol cystic hhiosis. 41 Successlul pieinplantation testing has also heen ie- poiteu loi seveie inheiiteu slin uisoi- ueis. 42 ¯his is lilely to hecone a noie F|608£ 8-8 0p||crº |c| p|era- |a| |eº||rç c| |r|e|||ed º||r d|ºeaºeº. A. |e|a| º||r ||cpº], |e|e º|cWr a| 18 Wee|º' çeº|a||cr. 8. C|c||cr|c .|||| ºarp|ed a| 11 Wee|º' çeº|a||cr. 0. P|e|rp|ar|a||cr çere||c d|açrc- º|º. A º|rç|e ce|| |º |e|rç e/||ac|ed ||cr a 12-ce|| er||]c uº|rç a ºuc- ||cr p|pe||e. A 8 0 86 populai, though still technically challeng- ing, option loi sone couples, in viev ol iecent auvances in anplilying the vhole genone in single cells anu the applica- tion ol nultiple linlage naileis in an ap- pioach teineu ¡rcim¡|antation gcncti. ha¡- |ot,¡ing. 4o loi sone uisoiueis, alteinative less invasive nethous ol testing aie nov also heing uevelopeu, incluuing analysis ol letal DNA lion vithin the nateinal ciiculation anu the use ol thiee-uinen- sional ultiasonogiaphy. ln the cuiient ahsence ol ellective tieatnent loi nany heieuitaiy slin uis- eases, pienatal uiagnosis can pioviue nuch appieciateu inloination to cou- ples at iisl ol having allecteu chiluien, although uetaileu anu suppoitive ge- netic counseling is also a vital elenent ol all pienatal testing pioceuuies. 0E\E THERAP\ ¯he helu ol gene theiapy can he suhui- viueu in uilleient vays. 44 liist, theie aie appioaches aineu at tieatnent ol ieces- sive genetic uiseases vheie honozygous oi conpounu heteiozygous loss-ol-lunc- tion nutations leau to conplete ahsence oi conplete lunctional ahlation ol a vital piotein. ¯hese types ol uiseases aie ane- nahle to gene ieplacenent theiapy, anu it is this loin ol gene theiapy that has tenueu to pieuoninate hecause it is gen- eially technically noie leasihle than tieatnent ol uoninant genetic conui- tions. 45 ln ueinatology, these incluue uiseases such as lanellai ichthyosis (see Chap. 4¯), vheie in nost cases, theie is heieuitaiy ahsence ol tiansglutaninase-1 activity in the outei epiueinis, oi the se- veie Hallopeau-Sienens loin ol ieces- sive uystiophic lB, vheie theie is con- plete ahsence ol type Vll collagen expiession uue to iecessive nutations. 46 ¯he seconu loin ol gene theiapy, in hioau teins, is aineu at tieatnent ol uoninant-negative genetic uisoiueis anu is lnovn as gcnc inhi|ition thcra¡,. Heie, theie is a conpletely uilleient type ol piohlen to he taclleu hecause these pa- tients alieauy caiiy one noinal copy ol the gene anu one nutateu copy. ¯he uis- ease iesults hecause an ahnoinal piotein piouuct piouuceu hy the nutant allele, uoninant-negative nutant piotein, hinus to anu inhihits the lunction ol the noinal piotein piouuceu hy the vilu-type allele. ln nany cases, it can he shovn lion the stuuy ol iaie iecessive vaiiants ol uoni- nant uiseases that one allele is sulhcient loi noinal slin lunction, anu so il a neans coulu he lounu ol specihcally in- hihiting the expiession ol the nutant al- lele, this shoulu he theiapeutically heneh- cial. Hovevei, hnuing a gene theiapy agent that is capahle ol uisciininating the vilu-type anu nutant alleles, vhich can uillei hy as little as one hp ol DNA, is challenging , until iecently, has iesulteu in little success. A typical uoninant-negative genetic slin uisease is lB sinplex (see Chap. 6O), causeu hy nutations in eithei ol the genes encouing leiatins 5 oi 14. ¯he vast na|oiity ol cases aie causeu hy uoninant-negative nissense nutations, changing only a single anino aciu, caiiieu in a heteiozygous nannei on one allele. 4¯ ¯he othei vay that gene theiapy ap- pioaches can he hioauly suhuiviueu is ac- coiuing to vhethei they involve in vivo oi ex vivo stiategies. 44 Using an in vivo appioach, the gene theiapy agent voulu he applieu uiiectly to the patient`s slin oi anothei tissue. ln an ex vivo appioach, a slin hiopsy voulu he talen, leiati- nocytes oi hhiohlasts voulu he giovn anu expanueu in cultuie, tieateu vith the gene theiapy agent, anu then gialteu onto oi in|ecteu hacl into the patient. ¯he slin is a goou oigan systen loi hoth these ap- pioaches hecause it is veiy accessihle loi in vivo applications. ln auuition, the slin can he ieauily hiopsieu, anu cell cultuie anu ie-gialting ol leiatinocytes can he auapteu loi ex vivo gene theiapy. A uisauvantage ol the slin as a taiget oigan loi gene theiapy is that it is a hai- iiei tissue that is lunuanentally ue- signeu to pievent entiy ol loieign nu- cleic aciu in the loin ol viiuses oi othei pathogenic agents. ¯his is an inpeui- nent to in vivo gene theiapy uevelop- nent hut is not insuinountahle uue to uevelopnents in liposone technology anu othei nethous loi cutaneous nac- ionolecule ueliveiy. 48 Cene ieplacenent theiapy systens have heen uevelopeu loi lanellai ichthyo- sis (see Chap. 4¯) anu the iecessive loins ol lB (see Chap. 6O), anong othei uis- eases. ¯hese nostly consist ol expiessing the noinal conplenentaiy DNA encou- ing the gene ol inteiest lion sone loin ol gene theiapy vectoi auapteu lion viiuses that can integiate theii genones stahly into the hunan genone. Such viial vec- tois can theieloie leau to long-tein stahle expiession ol the ieplacenent gene. 4º laily stuuies tenueu to use ietioviial vec- tois oi aueno-associateu viial vectois, hut these have a nunhei ol linitations. loi exanple, ietioviiuses only tiansuuce ui- viuing cells anu theieloie lail to taiget sten cells, conseguently, gene expiession is guiclly lost uue to tuinovei ol the epi- ueinis thiough leiatinocyte uilleientia- tion. luitheinoie, theie have heen sone salety issues in snall-scale hunan tiials loi hoth ietioviial anu aueno-associateu viial vectois. Lentiviial vectois, ueiiveu lion shoit integiating seguences lounu in a nunhei ol innunouehciency viiuses, have the auvantage ol heing ahle to stahly tiansuuce uiviuing anu non-uiviuing cells, vith close to 1OO peicent elhciency anu at lov copy nunhei. ¯hese nay he the cui- ient vectoi ol choice, hut they also have potential piohlens hecause theii pie- leiieu integiation sites in the hunan ge- none aie cuiiently ill-uehneu anu nay leau to conceins ahout salety. Hovevei, vith a viue vaiiety ol vectois unuei ue- velopnent anu testing, it shoulu hecone cleai in lutuie yeais vhich vectois aie el- lective anu sale loi hunan use. Ulti- nately, lile all novel theiapeutics, aninal testing can only act as a guiue hecause the hunan genone is guite uilleient anu nay ieact uilleiently to loieign DNA integia- tion, so that phase l, ll, anu lll hunan tii- als oi auaptations theieol vill ultinately have to he peiloineu to ueteinine elh- cacy anu salety. Cuiiently, snall-scale clinical tiials aie ongoing loi |unctional lB anu aie planneu loi a nunhei ol othei genoueinatoses, nainly concentiating on the noie seveie iecessive conuitions. ¯ieatnent ol uoninant-negative uisoi- ueis has iecently staiteu to ieceive a gieat ueal ol attention vith the uiscoveiy ol the RNA inhihition pathvay in hunans anu the hnuing that snall synthetic uouhle- stianueu RNA nolecules ol 1º to 21 hp, lnovn as short inhi|itor, R^A (siRNA), can elhciently inhihit expiession ol hunan genes in a seguence-specihc, usei-uehneu nannei. 4¯,5O ¯heie is cuiiently a gieat ueal ol attention heing locuseu on uevelop- nent ol siRNA inhihitois to selectively si- lence nutant alleles in uoninant-negative genetic uiseases, such as the leiatin uisoi- ueis lB sinplex oi pachyonychia congen- ita. Because siRNAs can he uesigneu against nany uilleient nRNA seguences vith ease, anu hecause they aie nuch snallei nolecules than gene theiapy vec- tois, this nev, iapiuly evolving technol- ogy hts in hetveen snall nolecule thei- apy anu gene theiapy. ln a nunhei ol cases, siRNAs have heen iuentiheu that can uisciininate hetveen noinal anu nutant alleles that uillei hy only a single hp nutation. ln paiallel, a nunhei ol gioups aie voiling on neans ol uelivei- ing siRNA to slin anu othei oigan sys- tens, anu theie is cuiiently nuch opti- nisn ahout these ueveloping into clinically applicahle agents in the neai lu- tuie. Sone snall scale clinical tiials aie unuei vay anu otheis aie planneu, incluu- ing loi leiatinizing uisoiueis. A nunhei ol aninal nouels have shovn positive ie- sults vith lov toxicity, incluuing in non- hunan piinates. Hovevei, at least one 87 stuuy has shovn livei toxicity vith cei- tain seguences hut not otheis. |E\ RE|ERE\CES T|e |u|| |e|e|erce ||º| |c| a|| c|ap|e|º |º a.a||a||e a| WWW.d|çr/.ccr. 1. Hsu l et al: ¯he UCSC lnovn genes. 3ioinjormati.s 22:1Oo6, 2OO6 2. ¯songalis C[, Silveinan Lí: íoleculai uiagnostics: A histoiical peispective. C|in Chim A.ta 36º:188, 2OO6 14. Happle R: X-chionosone inactivation: Role in slin uisease expiession. A.ta lacdiatr :u¡¡| º5:16, 2OO6 2O. Schapiia AH: íitochonuiial uisease. lan.ct 368:¯O, 2OO6 26. Antonaialis Sl, Beclnann [S: íenue- lian uisoiueis ueseive noie attention. ^at Rcv Ccnct 7:2¯¯, 2OO6 o2. Callinan lA, leinheig Al: ¯he eneiging science ol epigenonics. Hum /o| Ccnct 15:Rº5, 2OO6 o4. Resta RC: Dehning anu ieuehning the scope anu goals ol genetic counseling. Am j /cd Ccnct C :cmin /cd Ccnct 142:26º, 2OO6 44. Hengge UR: liogiess anu piospects ol slin gene theiapy: A ten yeai histoiy. C|in Dcrmato| 23:1O¯, 2OO5 45. leiiaii S et al: Cene theiapy in conhi- nation vith tissue engineeiing to tieat epiueinolysis hullosa. lx¡crt ·¡in 3io| Thcr 6:o6¯, 2OO6 C H A P T E R 9 8as|c Sc|eoce Approaches to the Pathophys|o|ogy oI Sk|o 0|sease Pau| R. Be|çº||eººe| T00|S T0 |\VEST|0ATE S||\ D|SEASE Deinatologists anu slin hiologists, lile scientists in othei uisciplines, use as nany tools as possihle to uniavel nech- anisns ol uisease. ¯hey even invent tools to auuiess the unigue leatuies ol slin. Contenpoiaiy neuical science is viitually univeisal in its technigues, anu investigatois lion uiveise helus con- nonly use the sane cutting-euge nethous to auuiess the pathogenesis ol uisease. A signihcant poition ol giounu-hiealing activity uoes not occui in conventional hasic science oi clinical uepaitnents, hut, iathei, in uepaitnent-inuepenuent °centeis` (oi °centeis ol excellence`), vhich conhine the iesouices anu spe- cial expeitise ol investigatois lion sev- eial uisciplines. BAS|C SC|E\CE APPR0ACHES. A H|ST0R|CA| PERSPECT|VE With this pieanhle ahout the univeisal- ity ol nethous useu hy investigatois, this chaptei continues vith a sinple guestion: °Hov have |asi. s.icn.c a¡- ¡roa.hcs to thc ¡atho¡h,sio|og, oj skin dis- casc ht into contenpoiaiy nouels ol hioneuical investigation`` ¯his gues- tion is auuiesseu vith an asseition anu loui piinciples (¯ahle º-1). ¯he hest vay to illustiate hov nev lnovleuge has heen geneiateu loi slin uisease is thiough exanples ol successlul achievenent. What lollovs aie thiee ex- anples ol ellective lahoiatoiy ieseaich, each vith inpoitant contenpoiaiy el- lects. ¯hese exanples hegin 4O yeais ago, anu they illustiate that the piinciples loi scientihc success have not changeu. Repa|| c| U|||a.|c|e| Rad|a||cr-|rduced Daraçe. A |cde| c| D|ºcc.e|] 8A0k6800h0 ¯ieatnent ol slin cancei has occupieu an incieasingly laige poi- tion ol ueinatologists` clinical activity since the 1º5Os, as lile expectancies have incieaseu, anu as leisuie tine has leu to noie outuooi iecieation. lnpoi- tantly, ultiaviolet iauiation (UVR) ie- tains its position as the na|oi ielevant etiologic lactoi. Because ol the cential iole ol slin cancei anu slin cancei thei- apy in ueinatologic piactice, uetaileu lnovleuge ahout the veiy iaie genetic uisoiuei xeioueina pignentosun seives as a uselul nouel loi hov hasic science anu clinical ohseivations have cone togethei. kh0wL£06£ L|hkS T0 Th£ LA808AT08Y ¯he seninal uiscoveiy in unueistanuing the pathogenesis ol xeioueina pignen- tosun vas naue hy [anes Cleavei vho, as a lh.D. scientist, heaueu a hasic science lahoiatoiy at the Univeisity ol Caliloinia in San liancisco. 1 His voil hau incluueu the uevelopnent ol tech- nigues to stuuy DNA iepaii in cells in vitio. íaling use ol the iich intellectual enviionnent ol an acauenic neuical centei, he intiouuceu hinsell to one ol the ueinatologists, [ohn lpstein, asl- ing vhethei theie night he a genetic hunan photosensitive slin uisease in vhich theie vas excess ol slin cancei. Di. lpstein tolu hin that xeioueina pignentosun voulu he his hest choice. ST00|£S |h h0NAhS ¯he auvice to exan- ine patients vith xeioueina pignento- sun leu to the hist set ol ohseivations naue in vitio, that the iepaii ol UVR- inuuceu uanage in hhiohlasts talen lion patients vith the uisease vas uelective. 1 Cleavei`s voil vas lolloveu iapiuly hy a seconu papei lion [ohn lpstein anu his associates, in vhich the iepaii ol DNA altei ultiaviolet iiiauiation in vivo vas ohseiveu to he uelective in hoth leiati- nocytes anu hhiohlasts. 2 ¯his voil set the stage loi a seiies ol uiscoveiies naue hy an incieasingly laige nunhei ol scien- tists, vho uenonstiateu that the genetic eiioi in xeioueina pignentosun vas a loss in the ahility to excise DNA that hau heen uanageu thiough iiiauiation. S08S£00£hT 08S£8VAT|0hS Suhse- guently, cell lusion stuuies haseu on the concept ol °conplenentation` uenon- Ik8L£ 9-1 Assart|on and Pr|nc|p|as about 8as|c Sc|anca Approachas to Sk|n 0|saasa º Aººe|||cr. Baº|c ºc|erce |eºea|c| |r de|ra- |c|cç] a| acader|c red|ca| cer|e|º |º ºuc- ceºº|u| |c ||e e/|er| ||a| || '||º' ||e |eºcu|ceº ard cc|e .a|ueº c| ||a| |rº|||u||cr. º P||rc|p|e 1 (cc|e .a|ueº,. H|ç||] e||ec||.e |a|c|a|c|] |eºea|c| |r º||r d|ºeaºe |º rc|e |||e|] |c cccu| W|er ccrduc|ed |r cer|e|º W||| cc|e .a|ueº ard |eºcu|ceº ||a| p|c- rc|e |eºea|c|. º P||rc|p|e 2 (pecp|e,. |rº|||u||crº dc rc| ccr- duc| |eºea|c|, pecp|e dc. we||-||a|red, ere|çe||c, cp||r|º||c, ard er||uº|aº||c pec- p|e dc ||e |eº| |eºea|c|, a|||cuç| |r|e|||- çerce |e|pº aº We||. º P||rc|p|e 8 (cc||a|c|a||cr,. Reºea|c| |º rcW ºc ccrp|e/ ||a| ºc|er|||c cc||a|c|a||cr |º |e(u||ed. (Sc|er||º|º Wc||, rc| aº |rd|.|du- a|º, |u| |r ç|cupº. |ar] ç|cupº a|e |r|e|- ra||cra| |r ºccpe., º P||rc|p|e 4 (|eºcu|ceº,. || |a|eº ||re |c dc |eºea|c|, ard ||re ccº|º rcre]. 88 stiateu that theie vas a lanily ol exci- sion uelects, any one ol vhich coulu he iesponsihle loi the uisease. o Conple- nentation thiough cell lusion vas an estahlisheu genetic technigue, anu its use in uehning xeioueina pignentosun illustiateu the application ol a geneial genetic concept to slin uisease. ¯iacl- ing uovn the specihc steps in the DNA excision piocess openeu an entiiely nev helu ol DNA iepaii, 4 anu a |ouinal is nov uevoteu entiiely to this helu. 5 An inpoitant intellectual ciicle has heen closeu iecently: [anes Cleavei ueliveieu the Lila Ciuhei Cancei Reseaich Lectuie at the Annual íeeting ol the Aneiican Acaueny ol Deinatology in 1º¯6 in vhich he uesciiheu his initial voil, anu in 2OO¯ liiol liieuheig uiu so again, o1 yeais latei, vith a piesentation entitleu °DNA Repaii anu DNA Danage ¯olei- ance: lunuanental íechanisns ¯hat liotect Against Cancei.` ¯hese expeiinents veie not con- uucteu in a vacuun, vithout attention to the possihility ol henehting patients. ln auuition to pieventing slin cancei thiough piotection against UVR, phai- naceutical enhancenent ol DNA iepaii has nov heen uevelopeu. 6 lt appeais to uininish the iate ol cancei uevelopnent, at least in patients vith xeioueina pig- nentosun. ¯his line ol investigation he- gan vith a seiies ol guestions: (1) ls it possihle loi iepaii enzynes lion a hacte- iial souice to iepaii UVR-inuuceu uan- age in hunan cells` (2) ls it possihle to uevelop a liposone systen that allovs one to intiouuce the enzynes into cells` (o) Can one ohtain an ellect hy topical application ol liposones containing the enzynes` (4) ls it possihle to uevelop anu nanulactuie a clinical piouuct (uiug) that iepaiis UVR-inuuceu uanage in hu- nans` anu (5) Does this piouuct ieuuce the inciuence ol nalignancy in patients vith xeioueina pignentosun` ¯hiough an extensive seiies ol expeiinents anu clinical tiials, the ansvei to each gues- tion appeais to he °yes.` lach ol these uevelopnents vas iooteu in the oiiginal ohseivation ol [anes Cleavei, anu ietuining to that ohseiva- tion, vhat veie the ciitical elenents` liinciple 1 (coie values): ¯he Univei- sity ol Caliloinia in San liancisco has heen an institution vheie hasic science anu clinical science have heen valueu anu pionoteu loi sev- eial geneiations. liinciple 2 (people): Di. [ohn lpstein stuuieu photosensitive uiseases, lnev hov to hnu patients vith xeioueina pignentosun, anu hau eneigy, inventiveness, anu ahility. [anes Cleavei then tool the iight guestions to the lahoiatoiy, using contenpoiaiy genetic technigues. liinciple o (collahoiation): lncieasing nunheis ol investigatois have heen involveu vith each step ol this piocess. liinciple 4 (iesouices): ¯alling, plan- ning, thinling, anu leaining all tale tine. ¯he anount ol peisonal investnent ol tine anu talent has heen consiueiahle. Receºº|.e D]º||cp||c Ep|de|rc|]º|º Bu||cºa ard S||r Carce|. A Seccrd |cde| c| D|ºcc.e|] 8A0k6800h0 A ielateu seguence ol oh- seivations nay he lounu in a papei puh- lisheu, not oO yeais ago, hut 2 yeais ago, in vhich clinical insight leu to a ciitical set ol ohseivations. ¯ lt hegan vith stuu- ies ol iecessive uystiophic epiueinolysis hullosa (RDlB), vhich is causeu hy any one ol seveial collagen Vll uelects, sone nutations piouuce no piotein, anu sone piouuce a tiuncateu piotein. ¯his voil vas ueiiveu lion ongoing geneial stuu- ies ol epiueinolysis hullosa at Stanloiu Univeisity, vith the ultinate goal ol ue- veloping technigues ol gene theiapy. Th£ P808L£N 0F 0Ah0£8 lt vas also lnovn that patients vith RDlB con- nonly uevelop lethal sguanous cell cai- cinonas. ¯his clinical lnovleuge vas ley to the suhseguent papei. Hovevei, this voil coulu only he conuucteu in lahoiatoiies in vhich in vitio nouels ol cutaneous caicinogenesis veie alieauy in uevelopnent, as vas happening in the uepaitnent ol ueinatology at Stan- loiu Univeisity. Th£ 08|T|0AL £XP£8|N£hTS ¯he investi- gatois exanineu Ras-uiiven tunoiigene- sis in leiatinocytes talen lion patients vith RDlB. lt vas noteu that cells en- tiiely uevoiu ol collagen Vll uiu not loin tunois (in nice), vheieas those ietaining specihc collagen Vll liagnents veie tu- noiigenic. lnpoitantly, the loiceu ex- piession ol liagnents iestoieu tunoiige- nicity to the collagen Vll-null epiueinis. linally, hhionectin-lile seguences in that poition ol the liagnent pionoteu tunoi cell invasion. ¯hus, tunoi-stiona inteiac- tions neuiateu hy collagen Vll appeaieu to pionote neoplasia. ¯he conclusion is that the ietention ol collagen Vll se- guences in a suhset ol RDlB patients nay contiihute to theii incieaseu suscep- tihility loi sguanous cell caicinona. But the ciitical issue vas the intellec- tual context in vhich this voil tool place. Ultinately, it vas the lnovleuge that caicinogenesis is connon in pa- tients vith RDlB, conhineu vith ongo- ing lahoiatoiy stuuies in cutaneous caici- nogenesis anu in the hlisteiing uiseases that leu to this inpoitant uiscoveiy. Cl couise, one shoulu not ignoie the inpact ol eneigetic anu inguisitive investigatois. liinciple 1 (coie values): Stanloiu Uni- veisity has heen an institution vheie hasic science anu clinical science have heen valueu anu pionoteu. liinciple 2 (people): Dating hacl to the 1º8Os, investigatois at Stanloiu, leu initially hy Di. lugene Bauei, veie inteiesteu in epiueinolysis hullosa, stenning lion his voil on collage- nase at Washington Univeisity in St. Louis. With the aiiival ol Dis. lhavaii anu íaiinlovich, nouels ol caicinogenesis anu nouels ol hlistei- ing slin uiseases veie uevelopeu. Cne ol the investigatois uevelopeu the iuea that type Vll night he a ciit- ical elenent in caicinogenesis. liinciple o (collahoiation): lncieasing nunheis ol investigatois have heen involveu vith each step ol this piocess. liinciple 4 (iesouices): ¯alling, plan- ning, thinling, anu leaining all tale tine. Cl couise, success is not liniteu to lah- oiatoiies in the San liancisco Bay aiea ol Caliloinia, sinilai events occui in aca- uenic neuical centeis aiounu the voilu. Perp||çuº Vu|ça||º. 0re 0|ºe|.a||cr 0perº a \eW ||e|d 8A0k6800h0 A lanunail stuuy in chai- acteiizing the pathogenesis ol penphi- gus vulgaiis illustiates hov one stuuy can piecipitate uecaues ol investigation. ln the eaily 1º6Os, unuei the leaueiship ol linst Witehsly, linst Beutnei anu his colleagues at the Univeisity ol Bullalo hau heen stuuying uiseases in vhich cii- culating autoantihouies night cause in- |uiy to oigans such as the thyioiu. At the sane tine, the chaii ol ueinatology at the neuical centei, [anes [oiuon, ovei- sav the caie ol patients vith penphigus. lt tuineu out that his son, Roheit [oiuan, voileu as a neuical stuuent in linst Beutnei`s innunologic lahoiatoiy on uiseases allecting oigans othei than slin. lt shoulu he noteu that the ohseivation that lollovs uiu not tale place in a vac- uun. Waltei Levei hau stuuieu penphi- gus loi sone tine, anu he hau alieauy 89 uilleientiateu penphigus anu penphi- goiu on the hasis ol classical histopatho- logic ohseivations. 8 Cn the othei hanu, it vas not an acciuent that the ohseivation vas naue in Bullalo. linst Beutnei hau heen inteiesteu in lunuanental aspects ol autoinnunity loi nany yeais, anu he vas a paiticipant in an active gioup ol in- vestigatois put togethei hy Witehsly, he- ginning in 1ºo5. Th£ 08S£8VAT|0h ¯hus, given a convei- gence anong clinical iesponsihilities ([anes [oiuon), hasic innunologic sci- ence (linst Beutnei), anu an enteipiising neuical stuuent (Roheit [oiuon), the ieseaicheis uenonstiateu hy uiiect innunohuoiescence nicioscopy that patients vith penphigus possesseu au- toantihouies uiiecteu against an epiuei- nal inteicellulai suhstance. 8,º Antihou- ies veie lounu piecisely vheie the pathology uevelops. S08S£00£hT ST00|£S ¯his ohseivation vas lolloveu ovei the next 4O yeais hy a seiies ol stuuies iuentilying the nolecu- lai chaiacteiistics ol such antihouies, theii specihc taigets, anu incieasingly novel theiapies loi patients vith the uis- ease. ln lact, theie aie too nany investi- gatois vho have playeu inpoitant ioles in extenuing the oiiginal ohseivation to iecognize any one in paiticulai, although the sunnaiy ol a iecent conleience viitten in 2OO5 hy Colusnith, 1O as vell as the ielevant chapteis in this text, aie sulhcient to assign cieuit appiopiiately. So, hov uoes this ohseivation con- loin vith the iules citeu pieviously: liinciple 1 (coie values): ln 1º64, the Univeisity ol Bullalo vas a iec- ognizeu centei loi innunologic ieseaich. Di. Beutnei hau estahlisheu a highly ellective lahoiatoiy, Di. [anes [oiuon hau access to a suitahle cohoit ol patients vith the uisease, anu the lutuie Di. Roheit [oiuon uiu the na|oi poition ol the voil. liinciple 2 (people): Dis. [anes [oi- uon anu linst Beutnei incluueu all that vas necessaiy, once the eneigy anu enthusiasn ol Roheit [oiuon veie hainesseu. liinciple o (collahoiation): lven 4O yeais ago, this voil coulu not have heen acconplisheu vithout the collahoiation citeu ahove. liinciple 4 (iesouices): ¯his voil uiu tale tine, anu the tine ol Roheit [oi- uon vas olleieu vithout conpen- sation. íoieovei, Di. Beutnei`s laho- iatoiy vas appiopiiately lunueu. ¯his last exanple intiouuces a noie conplicateu set ol issues, hecause the uisease unuei stuuy is not causeu hy a single gene uelect. Rathei, the exanple shovs that investigatois nust auuiess conplex uiseases, such as psoiiasis, atopic ueinatitis, cutaneous ¯-cell lyn- phona, anu toxic epiueinolytic necioly- sis, in vhich nany genes play ioles. Re- cent piogiess in all ol these uiseases vill he lounu in the chapteis that lollov, anu peihaps theie vill he even noie to say in the next euition ol this hool. ¯hese exanples also piesage a tienu tovaiu incieaseu collahoiation acioss lahoiatoiies anu acioss cities anu na- tions. As a iesult, contenpoiaiy cutane- ous ieseaich has hecone inteinational in scope. ln the thiee exanples citeu ahove in the sections Repaii ol Ultiaviolet Ra- uiation-lnuuceu Danage: A íouel ol Discoveiy, Recessive Dystiophic lpiuei- nolysis Bullosa anu Slin Cancei: A Sec- onu íouel ol Discoveiy, anu lenphi- gus Vulgaiis: Cne Chseivation Cpens a Nev lielu, collahoiation occuiieu pii- naiily vithin one institution. lt shoulu he noteu, hovevei, that the expeitise ie- guiieu loi cutting-euge ieseaich nov ol- ten ieguiies collahoiation hy investiga- tois in noie than one institution anu even anong investigatois in noie than one countiy. ¯his nay he seen in the journa| oj lnvcstigativc Dcrmato|og, (jlD;, vhich has seiveu as one ol the pieleiieu iepositoiies ol cutaneous ieseaich ie- sults loi noie than 5O yeais. lnpoi- tantly, the extent ol collahoiation anong investigatois has incieaseu suhstantially ovei that tine. ¯vo 6-nonth peiious sepaiateu hy 5O yeais in the jlD veie exanineu (¯ahle º-2). ¯he uneguivocal anu uianatic iesults nale tvo points. liist, the nunhei ol authois pei papei has incieaseu loui-lolu in 5O yeais, ie- hecting the incieasing ieguiienent loi collahoiation anong investigatois. Sec- onu, collahoiation nov incluues investi- gatois locateu in uilleient institutions, sonetines in the sane countiy (o6 pei- cent) anu olten in uilleient countiies (o8 peicent), even lion uilleient continents (24 peicent). lully one-louith ol the nanusciipts in 2OO6 incluueu collahoiat- ing investigatois lion tvo uilleient con- tinents. ¯he countiies iepiesenteu in 1º56 veie six in nunhei: the Uniteu States, lsiael, Biazil, Hungaiy, Spain, anu the Netheilanus. By 2OO6, 16 countiies veie iepiesenteu (11 in luiope, 4 in Asia, anu 1 in Noith Aneiica). ¯he voilu ol science is heconing snallei. THE |UTURE 0| |AB0RAT0R\ |\VEST|0AT|0\ |\ DER|AT0|00\ A Reºu|çerce c| C||r|ca| Sc|erce Car Be Ar||c|pa|ed Although it is lilely that the pace in the uevelopnent ol scientihc technologies vill only acceleiate vith tine, access to such technologies nay not he the iate- liniting step in cutaneous ieseaich. ln lact, a stiong case nay he naue that the liniting step vill he the availahility ol vell-chaiacteiizeu patient populations loi stuuy. 11 ln neaily ¯O yeais ol puhlication, one can ohseive in the jlD seveial tiansitions in enphasis, each iehecting changes in the scientihc connunities that it iepie- sents. ln the hist hall ol its lile, clinical ohseivation vas giauually ieplaceu hy expeiinentation. By the 1º¯Os, theie vas incieasing enphasis on lahoiatoiy investigation, as vas ieguiieu hy the cu- taneous scientists vho laiu the lounua- tion ol scientihc ueinatology. Cl couise, this vas aiueu hy lnovleuge that con- petition anong the specialties loi na- tional anu inteinational lunuing ieguiieu excellence in the lahoiatoiy. Anu, since the 1º8Os, one can ohseive continuing inteiest in hiochenistiy anu physiology, Ik8L£ 9-2 Authors, |nst|tut|ons, and 0ountr|as of 0r|g|n for Nanuscr|pts a 195ö (27:1-4ö9, 195ö} (JULY TH80U0H 0F0FN8F8} 200ö (12ö:1429-1921} (JULY Ah0 AU0UST} |aruºc||p|º (|c|a|, 4o 42 Au||c|º Au||c|º/raruºc||p| (rear, 2.2 8.1 S|rç|e-au||c| raruºc||p|º 14 0 0||ç|r c| raruºc||p|º 0re |rº|||u||cr 40 11 TWc |rº|||u||crº (cre ccur||], o 1o TWc c| rc|e ccur|||eº (|Wc ccr||rer|º, 0 1o (10, a Pu|||º|ed |r |Wc .c|ureº c| ||e Jc0rra! c| Irvcstiçativc 0crratc!cçy, ºepa|a|ed |] o0 ]ea|º. 90 vith a gioving inteiest in genetics anu hioinloinatics. An astounuing aiiay ol genetic chaiacteiizations anu iuentihca- tions have heen iepoiteu, hovevei pii- naiily loi single gene °uelects.` íoie iecently, hovevei, theie has heen gioving enphasis on clinical inves- tigation anu clinical science. ¯hese stuu- ies have ieguiieu vell-chaiacteiizeu anu uniloin patient populations, anu the pa- peis ieveal a tienu in vhich cohoits ol patients aie ieguiieu loi the cutting-euge lahoiatoiy stuuies that aie nov iepoiteu in the jlD. lt is not to say that hiochenis- tiy anu physiology anu single-patient stuuies have heen ahanuoneu, iathei, this has heen a piocess ol supplenentation. loui exanples can he citeu: 1. Wintei anu colleagues iuentiheu a single nucleotiue polynoiphisn chang- ing the seguence ol leiatin l6Hl gene, vhich vas °ieguiieu` loi the expiession ol pseuuololliculitis hai- hae in Aliican Aneiican nen. 12 ¯heii uiscoveiy hegan vith access to a vell-uehneu population ol Aneii- can seivicenen in Ceinany. 2. Alanaitine anu colleagues iepoiteu that inteileulin 1O pionotei poly- noiphisns conleiieu susceptihility to cutaneous sguanous cell caicinonas in iecipients ol ienal tiansplants. 1o ¯his uiscoveiy ieguiieu access to a vell-uehneu cohoit ol ienal tians- plant patients. o. Waiien anu colleagues iepoiteu that autoantihouies to uesnoglein 1 ol the innunoglohulin C4 suhclass alone veie ieguiieu loi the expies- sion ol enuenic penphigus loliaceus in Biazil. 14 Access to nultiple seia sanples lion patients anu contiol suh|ects in a unigue iegion ol the voilu vas ieguiieu loi this voil. 4. lalnei anu colleagues stuuieu the el- lect ol solai-sinulateu iauiation on elicitation phases ol contact sensi- tivity (contact alleigic ueinatitis). 15 ¯hese investigatois testeu the hy- pothesis that patients vith polynoi- phic light eiuption aie iesistant to the expecteu suppiession ol contact sensitivity elicitation ieactions hy UVR. lnpoitantly, theii hypothesis aiose lion the eailiei ohseivation that patients vith this uisease veie iesistant to the UVR-inuuceu sup- piession that occuis noinally uuiing sensitization. ¯heii ultinate conclu- sion that nechanisns ol innuno- logic sensitization anu elicitation uiveige suhstantially uepenueu on the availahility ol patients vith a unigue cutaneous uisoiuei. |rpac| c| P||c||||eº Se| B] ||e \a||cra| |rº|||u|eº c| Hea||| ¯he laigest souice ol lunuing loi slin ieseaich in the Uniteu States is the Na- tional lnstitute ol Aithiitis anu íuscu- losleletal anu Slin Diseases (NlAíS), 1 ol 2¯ institutes anu centeis unuei the unhiella ol the National lnstitutes ol Health. ¯he leaueis at NlAíS puh- lisheu iecently a °Long-Range llan loi Reseaich` (http://vvv.nians.nih.gov/an/ stiatplan/inuex.htn), vhich is uselul in exanining the lutuie ol hasic science appioaches to the pathophysiology ol slin uisease. Although othei institutes vithin the National lnstitutes ol Health, especially the National Cancei lnstitute, also lunu cutaneous ieseaich, hecause ol the size ol its lunuing, NlAíS tales the leau in setting piioiities. lt shoulu he noteu that iepoits ol this soit possess suhstantial inhuence on the uiiection ol hioneuical ieseaich, incluuing the types ol lahoiatoiy science that aie lunueu anu the piioiities loi lunuing. Although the entiie iepoit shoulu he exanineu, a hiiel sunnaiy pioviues consiueiahle in- sight into the lutuie. Leaueis ol NlAíS anticipate the lolloving: 1. Nev enphasis on hiologic necha- nisns ol uisease, genetic anu enviion- nental inhuences, anu neuioinnune anu neuioenuociine pathvays, 2. A seaich loi hionaileis ol slin uis- eases, o. lncieasing enphasis on clinical ie- seaich, 4. A seaich loi conplex genetic inhu- ences on uisease, 5. lnteiest in nev aninal nouels, 6. lnphasis on ieseaich inliastiuctuie, anu ¯. lnphasis on uisease-specihc ieseaich. linally, ieseaich neeus anu oppoituni- ties aie pieuicteu hy NlAíS to he in the uisciplines ol: Developnental anu noleculai hiology leicutaneous penetiation anu ahsoip- tion Wounu healing lnhannatoiy anu innune slin uis- eases íoleculai genetics ol slin uiseases ¯echnology ieseaich Diug theiapies anu hiologic agents loi slin uiseases Cene theiapies loi slin uiseases oi gene theiapies that use slin Regeneiative neuicine Clinical anu outcones ieseaich Slin uisease pievention anu aging slin Cutting-euge lahoiatoiy investigation touay, anu loi the loieseeahle lutuie, vill continue to lollov the piinciples enu- neiateu in ¯ahle º-1. lt vill nost lilely he conuucteu in acauenic centeis vith coie values anu iesouices that pionote ieseaich, hy people vho aie notivateu anu vell tiaineu, connonly hy investi- gatois vho collahoiate vith otheis, anu vheie hnancial iesouices aie availahle. linally, clinicians vho caie loi patients vill have oppoitunities vith incieasing lieguency to play ciitical ioles in patient- centeieu investigation. National hoiueis have viitually uisappeaieu in cutaneous science, as investigatois collahoiate ol- ten, anu vith vhonevei they helieve to he appiopiiate. lnpoitantly, collahoia- tion vith scientists in othei countiies neans that theie is a chance loi a lively exchange ol peisonal anu cultuial inloi- nation, sinply put, uoing science can he inloinative anu ievaiuing. RE|ERE\CES 1. Cleavei [l: Xeioueina pignentosun: A hunan uisease in vhich the initial stage ol DNA iepaii is uelective. lro. ^at| A.ad :.i ! : A 63:428, 1º6º 2. lpstein [H et al: Delect in DNA synthe- sis in slin ol patients vith xeioueina pignentosun uenonstiateu in vivo. :.icn.c 168:14¯¯, 1º¯O o. Rohhins [H, íoshell AN: DNA iepaii piocesses piotect hunan heings lion pienatuie solai slin uanagelviuence lion stuuies on xeioueina pignento- sun. j lnvcst Dcrmato| 73:1O2, 1º¯º 4. íaichetto íCN et al: Cene tiansuuc- tion in slin cells: lieventing cancei in xeioueina pignentosun nice. lro. ^at| A.ad :.i ! : A 101:1¯¯5º, 2OO4 5. liieuheig lC: Ciovth ol a |ouinal. D^A Rc¡air (Anst) 4:1, 2OO5 6. Yaiosh D et al: lllect ol topically applieu ¯4 enuonuclease V in liposones on slin cancei in xeioueina pignen- tosun: A ianuoniseu stuuy. Xeio- ueina lignentosun Stuuy Cioup. lan.ct 357:º26, 2OO1 ¯. Citiz-Uiua S et al: ¯ype Vll collagen is ieguiieu loi Ras-uiiven hunan epiuei- nal tunoiigenesis. :.icn.c 307:1¯¯o, 2OO5 8. Levene Cí: ¯he tieatnent ol penphi- gus anu penphigoiu. C|in lx¡ Dcrmato| 7:64o, 1º82 º. Beutnei lH, [oiuon Rl: Denonstiation ol slin autoantihouies in seia ol pen- phigus vulgaiis patients hy inuiiect innunohuoiescent staining. lro. :o. lx¡ 3io| /cd 117:5O5, 1º65 1O. Colusnith LA: lenphigus: lathogene- sis, phainacology anu piogiess. j lnvcst Dcrmato| 125:vii, 2OO5 11. Beigstiessei lR: Resuigent clinical sci- ence (anu it`s all ahout health). j lnvcst Dcrmato| 124:xvii, 2OO5 12. Wintei H et al: An unusual Ala12¯hi polynoiphisn in the 1A alpha-helical segnent ol the conpanion layei-spe- cihc leiatin l6hl: lviuence loi a iisl 91 lactoi in the etiology ol the connon haii uisoiuei pseuuololliculitis haihae. j lnvcst Dcrmato| 122:652, 2OO4 1o. Alanaitine l et al: lnteileulin-1O pio- notei polynoiphisns anu susceptihil- ity to slin sguanous cell caicinona altei ienal tiansplantation. j lnvcst Dcr- mato| 120:ºº, 2OOo 14. Waiien S[l et al: ¯he iole ol suhclass svitching in the pathogenesis ol enuenic penphigus loliaceus. j lnvcst Dcrmato| 120:1O4, 2OOo 15. lalnei RA et al: ¯he ellect ol solai-sin- ulateu iauiation on the elicitation phase ol contact hypeisensitivity uoes not uil- lei hetveen contiols anu patients vith polynoiphic light eiuption. j lnvcst Dcr- mato| 124:1oO8, 2OO5 This page intentionally left blank 2 ' ^ ' ¯ D|ºc|de|º P|eºer||rç |r S||r ard |uccuº |er||areº Copyright ? 2008 by The McGraw-Hill Companies, Inc. Click here for terms of use. 95 ' c .¯ ' ´' 4 |\||A||AT0R\ D|S0RDERS BASED 0\ T-CE|| REACT|V|T\ A\D D\SRE0U|AT|0\ C H A P T E R 1 0 |ooate aod Adapt|ve |mm0o|ty |o the Sk|o Rc|e|| |. |cd||r Jerr] ||r D|e|e| |au|e| C|||º||re Barçe|| 0ec|ç S||rç| ¯he hunan innune systen is conpiiseu ol tvo uistinct lunctional paits: innate anu auaptive. ¯hese tvo conponents have uilleient types ol iecognition iecep- tois anu uillei in the speeu in vhich they iesponu to a potential thieat to the host (lig. 1O-1). Cells ol the innate innune systen, incluuing naciophages anu uen- uiitic cells (DCs), use pattein iecognition ieceptois encoueu uiiectly hy the gein- line DNA, iesponu to hiochenical stiuc- tuies connonly shaieu hy a vaiiety ol uilleient pathogens, anu elicit a iapiu ie- sponse against these pathogens, although no lasting innunity is geneiateu. ln con- tiast, cells ol the auaptive innune sys- ten, ¯ anu B lynphocytes, heai specihc antigen ieceptois encoueu hy ieaiiangeu genes, anu in conpaiison to the innate ie- sponse, auaptive innunity uevelops noie slovly. A unigue leatuie ol the auaptive innune iesponse is its ahility to geneiate anu ietain nenoiy, thus, it has the capahility ol pioviuing a noie iapiu iesponse in the event ol suhseguent in- nunologic challenge. Although the innate anu auaptive innune iesponses aie uis- tinct, they inteiact anu can each inhuence the nagnituue anu type ol theii countei- pait. ¯ogethei, the innate anu auaptive innune systens act in syneigy to uelenu the host against inlection anu cancei. ¯his chaptei uesciihes the ioles ol the innate anu auaptive innune iesponse in genei- ating host uelense nechanisns in slin. |\\ATE |||U\E RESP0\SE lnnune nechanisns that aie useu hy the host to inneuiately uelenu itsell aie ie- leiieu to as innatc immunit,. ¯hese incluue physical haiiieis such as the slin anu nu- cosal epitheliun, soluhle lactois such as conplenent, antiniciohial peptiues, che- nolines, anu cytolines, anu cells, incluu- ing nonocytes/naciophages, DCs, natuial lillei cells (Nl cells), anu polynoiphonu- cleai leulocytes (líNs) (lig. 1O-2). P|]º|ca| ard C|er|ca| Ba|||e|º 1 lhysical stiuctuies pievent nost patho- gens anu enviionnental toxins lion haining the host. ¯he slin anu the epithe- lial lining ol the iespiiatoiy, gastiointesti- nal, anu the genitouiinaiy tiacts pioviue physical haiiieis hetveen the host anu the exteinal voilu. Slin, once thought to he an ineit stiuctuie, plays a vital iole in pio- tecting the inuiviuual lion the exteinal en- viionnent. ¯he epiueinis inpeues pene- tiation ol niciohial oiganisns, chenical iiiitants, anu toxins, ahsoihs anu hlocls solai anu ionizeu iauiation, anu inhihits vatei loss (see Chap. 45). |c|ecu|eº c| ||e |rra|e |rrure S]º|er 00NPL£N£hT 2 (See elig. 1O-2.1 in on- line euition, see also Chap. o6) Cne ol the hist innate uelense nechanisns that |\\ATE A\D ADAPT|VE |||U\|T\ AT A 0|A\CE |rra|e |rrure |eºpcrºeº a|e uºed |] ||e |cº| |c |rred|a|e|] de|erd ||ºe||, de|e|r|re ||e (ua|||] ard (uar|||] c| rar] adap||.e |rrure |eºpcrºeº, a|e º|c|| ||.ed, |a.e rc rerc|], |rc|ude p|]º|ca| |a|||e|º (º||r ard ruccºa| ep|||e||a,, |rc|ude ºc|u||e |ac|c|º ºuc| aº ccr- p|erer|, ar||r|c|c||a| pep||deº, c|e- rc||reº, ard c]|c||reº, |rc|ude ce||º ºuc| aº rcrcc]|eº/rac- |cp|açeº, derd||||c ce||º, ra|u|a| ||||e| ce||º, ard pc|]rc|p|cruc|ea| |eu|c- c]|eº. Adap||.e |rrure |eºpcrºeº |a.e rerc|], |a.e ºpec||c||], a|e |crç-|aº||rç, |r º||r, a|e |r|||a|ed |] derd||||c ar||- çer-p|eºer||rç ce||º |r ||e ep|de|r|º (|arçe||arº ce||º, ard |] de|ra| der- d||||c ce||º, a|e e/ecu|ed |] T |]rp|cc]|eº ard ar|||cd|eº p|cduced |] B |]rp|c- c]|eº. Pºc||aº|º .u|ça||º. c||cr|c º|a||e |]pe. |u|||- p|e |a|çe ºca||rç p|a(ueº cr ||e ||ur|, a|r, |u|- |cc|º, ard a|dcrer. |eº|crº a|e pc|]c]c||c ard ccr1uer| ard |c|r çecç|ap||c pa||e|rº. T||º pa- ||er| Waº c|ea|ed |] ac|||e||r/pºc|a|er ard u|||a.|- c|e| A ||ç|| ccr||ra||cr ||ea|rer| W||||r 4 Wee|º. Copyright ? 2008 by The McGraw-Hill Companies, Inc. Click here for terms of use. 96 avaits pathogens that oveicone the ep- ithelial haiiiei is the alteinative path- vay ol conplenent. Unlile the classic conplenent pathvay that ieguiies an- tihouy tiiggeiing, the lectin-uepenuent pathvay as vell as the alteinative path- vay ol conplenent activation can he spontaneously activateu hy niciohial suilaces in the ahsence ol specihc anti- houies (see elig. 1O-2.1 in on-line eui- tion). ln this vay, the host uelense nechanisn is activateu inneuiately al- tei encounteiing the pathogen vithout the 5 to ¯ uays ieguiieu loi antihouy piouuction. h£080P£PT|0£S ¯he slin is a iich souice ol neuiopeptiues, incluuing neu- iotiansnitteis |e.g., calcitonin geneie- lateu peptiue (CCRl), suhstance l, so- natostatin] anu neuiohoinones (see Chap. 1O1). ¯he inhihitoiy ellects ol CCRl anu suhstance l on Langeihans cell (LC) antigen piesentation lunction aie uiscusseu latei. ¯he neuiohoinone pioopionelanocoitin (lCíC) is pio- uuceu hy the pituitaiy glanu as vell as hy a nunhei ol cell types, incluuing leiatinocytes. AhT|N|0808|AL P£PT|0£S 6 Antiniciohial peptiues aie an inpoitant evolutionaiily conseiveu innate host uelense necha- nisn in nany oiganisns. Also, leiati- nocytes piouuce such peptiues, incluu- ing catheliciuins (LL-o¯) anu -uelensins (BD-1, BD-2, BD-o). ¯heii antiniciohial nechanisn ol action nay ielate to F|608£ 10-2 T|e |rra|e |rrure |eºpcrºe |r º||r. |r |eºpcrºe |c e/cçercuº |ac|c|º, ºuc| aº |c|e|çr pa||cçerº, u|||a.|c|e| (UV, |ad|a||cr, ard c|er|ca| ||- |||ar|º, |rra|e |rrure ce||º [ç|aru|cc]|eº, rcrcruc|ea| p|açcc]|eº, ra|u|a| ||||e| (\|, ce||º, |e|a||rcc]|eº| rcur| d|||e|er| |]peº c| |eºpcrºeº |rc|ud|rç. (1, |e- |eaºe c| ar||r|c|c||a| açer|º, (2, |rduc||cr c| |r1arra|c|] red|a|c|º, ºuc| aº c]|c||reº, c|erc||reº, reu|cpep||deº, ard e|ccºarc|dº, ard (8, |r|||a||cr ard rcdu|a||cr c| ||e adap||.e |rrure |eºpcrºe. DDC = de|ra| derd||||c ce||, |C = |e|a||rcc]|e, |C = |arçe||arº ce||, |HC || = rajc| ||º|cccrpa|||||||] ccrp|e/ c|aºº ||, T|1, T|2, 1/ = T |e|pe| 1, 2, T|1/, T|eç = T |eçu|a|c|] ce||. 1. Autimicrooial respouse. º defeusius º cathelicidius/psoriasiu º reactive ox]geu iutermediates 2. luflammator] respouse. º c]tokiues º chemokiues º ueuropeptides º eicosauoids UV radiatiou lrritauts Pathogeus NH0 ll l0/DD0 Nacrophage K0 hK cell 8. luflueuce adaptive immuue respouse º activatiou of T cells T cell respouse (Th1, Th2, Treg, Th17} F|608£ 10-1 T|e |rrure º]º|er c| ||ç|e| .e||e||a|eº uºeº |c|| |rra|e ard adap||.e |rrure |e- ºpcrºeº. T|eºe |rrure |eºpcrºeº d|||e| |r ||e Wa] ||e] |eccçr|/e |c|e|çr ar||çerº ard ||e ºpeed W||| W||c| ||e] |eºpcrd, ]e|, ||e] ccrp|erer| eac| c||e| |r e|ad|ca||rç |c|e|çr pa||cçerº. The immuue respouse Fore|go pthogeo |oote respoose Adpt|ve respoose º rapid respouse º patteru recoguitiou receptors - germliue eucoded - 0D14, mauuose aud scaveuger º c]tokiues, co-stimulator] molecules - iustructive role for adaptive respouse º direct respouse for host defeuse - phagoc]tosis - autimicrooial activit] º slow respouse º recoguitiou - iuitiall] low affiuit] receptors geue rearraugemeut cloual expausiou º respouse - T aud B cells with receptors eucoded o] full] rearrauged geues º memor] 97 nenhiane inseition anu poie loina- tion. Auienoneuullin, nenheis ol the CCRl supeilanily, nelanocyte-stin- ulating hoinone, anu secietoiy leulo- cyte piotease inhihitoi (antileulopio- tease, hunan seninal inhihitoi l) aie anong pieviously iuentiheu peptiues vhose antiniciohial activities veie uis- coveieu latei. -Delensins aie cysteine-iich cationic lov-noleculai-veight antiniciohial pep- tiues. ¯he hist hunan -uelensin, HBD-1, vas isolateu lion hunan henohltiate ohtaineu lion a patient vith enu-stage ie- nal uisease. lt is constitutively expiesseu in the epiueinis anu is not tiansciiption- ally iegulateu hy inhannatoiy agents. HBD-1 has antiniciohial activity against Cian-negative hacteiia anu appeais to play a iole in leiatinocyte uilleientiation. A seconu hunan -uelensin, HBD-2, vas uiscoveieu in extiacts ol lesions lion pso- iiasis patients. ¯ Unlile HBD-1 expiession, HBD-2 expiession is inuucihle hy ni- ciohes, incluuing lscudomonas acruginosa, :ta¡h,|o.o..us aurcus, anu Candida a||i- .ans. ¯ Not only can niciohes stinulate ex- piession ol HBD-2, hut pio-inhannatoiy cytolines such as tunoi neciosis lactoi- (¯Nl- anu inteileulin 1 (lL-1) can also inuuce HBD-2 tiansciiption in leiatino- cytes. ¯ When testeu loi antiniciohial ac- tivity, HBD-2 shoveu ellective activity against Cian-negative hacteiia such as ls.hcri.hia .o|i anu l. acruginosa hut not against Cian-positive hacteiia such as :. aurcus. ¯ A thiiu -uelensin, HBD-o, has nov heen isolateu anu chaiacteiizeu. Contact vith ¯Nl- anu vith hacteiia vas lounu to inuuce HBD-o nessengei RNA expiession in leiatinocytes. ln auui- tion, HBD-o uenonstiateu potent anti- niciohial activity against :. aurcus anu vanconycin-iesistant lntcro.o..us jac.ium. ¯heieloie, HBD-o is anong the hist hunan -uelensins in slin to uenon- stiate ellective antiniciohial activity against Cian-positive hacteiia. ¯he local- ization ol hunan -uelensins to the outei layei ol the slin anu the lact the -uelensins have antiniciohial activity against a vaiiety ol niciohes suggest that hunan -uelensins aie an essential pait ol cutaneous innate innunity. lui- theinoie, eviuence inuicating that hu- nan -uelensins attiact DCs anu nen- oiy ¯ cells via CC chenoline ieceptoi 6 (CCR6) 8 pioviues a linl hetveen the in- nate anu the auaptive innunity in slin. Catheliciuins aie cationic peptiues vith a stiuctuially vaiiahle antiniciohial uonain at the C-teininus. Wheieas in nannals lile pigs oi cattle a vaiiety ol catheliciuin genes exists, nen (anu nice) possess only one gene. ¯he hunan pie- cuisoi piotein hCAl18 (hunan cathelici- uin antiniciohial piotein 18) is piouuceu hy slin cells, incluuing leiatinocytes, nast cells, neutiophils, anu uuctal cells ol ecciine glanus. Neutiophil pioteases (i.e., pioteinase o) piocess hCAl18 into the ellectoi nolecule LL-o¯, vhich plays an inpoitant iole in cutaneous host uelense hecause ol its pionounceu antihacte- iial, º,1O antilungal, 11 anu antiviial 12,1o ac- tivities. LL-o¯ luithei contiihutes to in- nate innunity hy attiacting nast cells anu neutiophils via loinyl peptiue ie- ceptoilile 1 anu hy inuucing neuiatoi ielease lion the lattei cells via a C pio- teinuepenuent, innunoglohulin l (lgl) inuepenuent nechanisn. 14 lt has nov heen shovn that LL-o¯ is secieteu into hunan sveat, vheie it is cleaveu hy a seiine pioteaseuepenuent nechanisn into its peptiues Rl-o1 oi lS-oO. lntei- estingly, these conponents uisplay an even noie potent antiniciohial activity than intact LL-o¯. 15 ln atopic ueinatitis (see Chap. 14), LL-o¯ is uovniegulateu, piohahly uue to the ellect ol the ¯2 cytolines lL-4 anu lL-1o, vhich ienueis atopic slin noie susceptihle to slin inlections vith, loi exanple, :. aurcus, vaccinia vi- ius (eczena vaccinatun), oi heipes sin- plex viius (eczena heipeticun). 1O,12,1o Anothei inpoitant hunan antinicio- hial peptiue has nov heen iuentiheu, psoiiasin (S1OOA¯). 16 lt is secieteu pie- uoninantly hy leiatinocytes anu plays a na|oi iole in lilling the connon gut hacteiiun l. .o|i. ln lact, in vivo tieat- nent ol hunan slin vith anti-psoiiasin antihouies iesults in the nassive giovth ol l. .o|i. 16 0Th£8 N£0|AT08S Cthei secieteu pio- tein neuiatois that can he synthesizeu anu ieleaseu lion leiatinocytes anu that nay play a iole in host uelense aie the conplenent conponents Co anu lactoi B. leiatinocytes aie anong the cells that synthesize eicosanoius, an ensenhle ol lipiu neuiatois iegulating inhannatoiy anu innunologic ieactions. ¯hey can piouuce anu ielease the cyclooxygenase piouuct piostaglanuin l 2 , vhich has hoth pio-inhannatoiy anu innunosup- piessive piopeities anu, vhen acting on DCs, pionotes the uevelopnent ol lL-4 uoninateu type 2 ¯-cell iesponses. 1¯ Cthei leiatinocyte-ueiiveu eicosanoius incluue the neutiophil chenoattiactant leulotiiene B 4 , the pio-inhannatoiy 12- lipoxygenase piouuct 12(s)-hyuioxyeico- satetiaenoic aciu, anu 15-hyuioxyeico- satetiaenoic aciu, an anti-inhannatoiy anu innunosuppiessive netaholite ol the 15-lipoxygenase pathvay. Anothei gioup ol hiologic iesponse nouiheis oiiginating in leiatinocytes anu othei epiueinal cells is liee iauical nolecules, nov geneially ieleiieu to as rca.tivc ox,gcn s¡c.ics. ¯hese incluue the supeioxiue iauical (C 2 ), hyuiogen pei- oxiue (H 2 C 2 ), the hyuioxyl iauical ¯hese iauicals aie geneially vieveu as uangeiously ieactive entities thieaten- ing the integiity ol nany tissues. ¯he slin is paiticulaily at iisl hecause it is exposeu to oxygen lion hoth insiue anu outsiue anu hecause ol the activation ol oxygen hy light (see Chaps. 88 anu 8º). liee iauicals piohahly contiihute to so- lai uanage anu photoaging ol the slin. Hovevei, ceitain ieactive oxygen spe- cies have potent inhannation-inuucing piopeities (e.g., liee oxygen iauicals) as vell as innunonouulatoiy piopeities (e.g., NC), anu thus pioviue an inpoi- tant host uelense nechanisn against niciohial invasion. loi uiscussion ol these nolecules, the ieauei is ieleiieu to the ieviev hy Bicleis anu Athai. 18 PATT£8h 8£006h|T|0h 8£0£PT08S Hov uo the cells ol the innate innune systen iecognize loieign pathogens` Cne vay that pathogens can he iecognizeu anu uestioyeu hy the innate innune systen is via ieceptois on phagocytic cells. Un- lile auaptive innunity, the innate in- nune iesponse ielies on a ielatively snall set ol geinline-encoueu ieceptois that iecognize conseiveu noleculai pat- teins that aie shaieu hy a laige gioup ol pathogens. ¯hese aie usually noleculai stiuctuies ieguiieu loi suivival ol the ni- ciohes anu theieloie aie not suh|ect to selective piessuie. ln auuition, pathogen- associateu noleculai patteins aie specihc to niciohes anu aie not expiesseu in the host systen. ¯heieloie, the innate in- nune systen has nasteieu a clevei vay to uistinguish hetveen sell anu nonsell anu ielays this nessage to the auaptive innune systen. Cl ley inpoitance vas the uiscoveiy ol the ¯oll-lile ieceptois (¯LRs), naneu altei the Droso¡hi|a ¯oll gene vhose pio- tein piouuct, ¯oll, paiticipates in innate innunity anu in uoisovential uevelop- nent in the liuit hy. 1º,2O ¯he inpoitance ol ¯oll signaling in nannalian cells vas conhineu hy the uenonstiation that the tiansnenhiane leucine-iich piotein ¯LR4 is involveu in lipopolysacchaiiue (LlS) iecognition. 21 ln auuition to ¯LRs, theie exist a vaii- ety ol othei tiansnenhiane nolecules 98 that sense the piesence ol pathogens. ¯hese incluue the tiiggeiing ieceptois expiesseu on nyeloiu cells (¯Rlí) pio- teins, 25 the lanily ol Siglec nolecules, 26 anu a gioup ol C-type lectin ieceptois. 2¯ ¯he lattei aie pioninently expiesseu on antigen-piesenting cells (AlCs) as, loi instance, uectin-1 anu DC-SlCN |DC- specihc inteicellulai auhesion nolecule o (lCAí-o) giahhing nonintegiin]. ¯hey aie ahle to neuiate elhcient hinuing ol niciooiganisns such as yeast anu ny- cohacteiia, iespectively, achieve theii phagocytosis, anu inuuce activation ol signaling pathvays that iesult in the natuiation ol phagosones as vell as in the piouuction ol ieactive oxygen anu nitiogen ueiivatives. íenheis ol the ¯Rlí piotein lanily lunction as anpliheis ol innate iesponses. lxtiene exanples ol the conseguences ol niciohe activation ol ¯Rlí pioteins aie lile-thieatening septicenia anu the ueauly henoiihagic leveis causeu hy íaihuig anu lhola viius inlection. 28 T0LL-L|k£ 8£0£PT08S 29 ¯heie is nov suhstantial eviuence to suppoit a iole loi nannalian ¯LRs in innate innu- nity (lig. 1O-o). liist, ¯LRs iecognize pathogen-associateu noleculai patteins piesent in a vaiiety ol hacteiia, lungi, anu viiuses. Seconu, ¯LRs aie expiesseu at sites that aie exposeu to niciohial thieats. ¯hiiu, the activation ol ¯LRs in- uuces signaling pathvays that, on the one hanu, stinulate the piouuction ol ellectoi nolecules (ieactive oxygen spe- cies, NC), anu, on the othei, pionote the expiession ol co-stinulatoiy nole- cules anu the ielease ol cytolines anu, as a iesult, the augnentation ol the auaptive iesponse. louith, ¯LRs uiiectly activate host uelense nechanisns that then conhat the loieign invauei. ¯LRs veie initially lounu to he ex- piesseu in all lynphoiu tissues hut veie nost highly expiesseu in peiipheial hloou leulocytes, incluuing nonocytes, B cells, ¯ cells, gianulocytes, anu DCs. Ceitain ¯LRs (e.g., ¯LR2) aie inteinal- izeu altei ligation. ln such a situation, ¯LRs aie ieciuiteu to the pathogen- containing phagosones anu uisciini- nate hetveen Cian-positive anu Cian- negative hacteiia, o1 thus suiveying the intiacellulai conpaitnents ol the cells loi niciohial invaueis. ¯he expiession ol ¯LRs on cells ol the nonocyte/naciophage lineage is consis- tent vith the iole ol ¯LRs in nouulating inhannatoiy iesponses via cytoline ie- lease. Because these cells nigiate into sites that inteilace vith the enviion- nentlung, slin, anu gutthe location ol ¯LR-expiessing cells voulu situate then to uelenu against invauing ni- ciohes. ¯LR expiession hy auipocytes, intestinal epithelial cells, anu ueinal en- uothelial cells suppoits the notion that ¯LRs seive a sentinel iole vith iegaiu to invauing niciooiganisns. ¯he iegulation ol ¯LR expiession is ciitical to theii iole in host uelense, yet lev lactois have heen iuentiheu that nouulate this pio- cess. lL-4 acts to uovniegulate ¯LR ex- piession, o2 vhich suggests that ¯ helpei 2 (¯h2) auaptive innune iesponses night inhihit ¯LR activation. ln Droso¡hi|a, ¯oll is ciitical loi host uelense. ¯he susceptihility ol nice vith spontaneous nutations in ¯LRs to hac- teiial inlection inuicates that nanna- lian ¯LRs play a sinilai iole. Activation ol ¯LR2 hy niciohial lipopioteins in- uuces activation ol the inuucihle NC synthase (NCS-ll oi iNCS) pionotei, o¯ vhich leaus to the piouuction ol NC, a lnovn antiniciohial agent. ¯heie is stiong eviuence that ¯LR2 activation F|608£ 10-3 Tc||-|||e |ecep|c|º (T|Rº, red|a|e |rra|e |rrure |eºpcrºe |r |cº| de|erºe. Ac||.a||cr c| T|Rº |] ºpec||c ||çardº |rduceº (1, c]|c||re |e|eaºe ard cc-º||ru|a|c|] rc|ecu|eº ||a| |rº||uc| ||e |]pe c| adap||.e |rrure |eºpcrºe, (2, d||ec| ar||r|c|c||a| |eºpcrºe, ard (8, ||ººue |rju|]. Cp0 D\A = |rrurc- º||ru|a|c|] c]|cº|re- ard çuar|re-||c| ºe(uerceº c| D\A, dºR\A = dcu||e-º||arded R\A, |PS = ||pcpc|]ºacc|a||de, \|- B = ruc|ea| |ac|c| B, ººR\A = º|r- ç|e-º||arded R\A, / = ||çard ur|rcWr. Toll-like receptors aud host defeuse lipoproteius Flagelliu 0p0 DhA ssRhA lP8 dsRhA Profiliu (?} X? TlR 1/2 TlR 2/O TlR5 TlR9 TlR7 TlR8 TlR4 TlR8 TlR11 TlR10 Trauscriptiou factors (e.g., hF- B} lmmuuomodulator] geues Tissue iujur] º apoptosis º septic shock Direct autimicrooial respouse º reactive ox]geu iutermediates luflueuce adaptive respouse º c]tokiue productiou º co-stimulator] molecules º cell-mediated immuuit] º humoral immuuit] 99 leaus to lilling ol intiacellulai /,.o|a.- tcrium tu|cr.u|osis in hoth nouse anu hu- nan naciophages. o8 ln nouse nacio- phages, hacteiial lipopiotein activation ol ¯LR2 leaus to a NC-uepenuent lill- ing ol intiacellulai tuheicle hacilli. ln hu- nan nonocytes anu alveolai nacio- phages, hacteiial lipopioteins sinilaily activate ¯LR2 to lill intiacellulai /. tu- |cr.u|osis, hovevei, this occuis hy an antiniciohial pathvay that is NC inue- penuent, hut uepenuent on the activation ol the vitanin D ieceptoi anu poten- tially the inuuction ol catheliciuin. oº ¯hese uata pioviue eviuence that nan- nalian ¯LRs have ietaineu not only the stiuctuial leatuies ol Droso¡hi|a ¯oll that allov then to iesponu to niciohial li- ganus hut also the ahility to uiiectly ac- tivate antiniciohial ellectoi pathvays at the site ol inlection. ¯he activation ol ¯LRs can also he uetiinental, leauing to tissue in|uiy. ¯he auninistiation ol LlS to nice can iesult in nanilestations ol septic shocl, vhich is uepenuent on ¯LR4. 21 lviuence sug- gests that ¯LR2 activation hy lro¡ioni- |a.tcrium a.ncs inuuces inhannatoiy ie- sponses in acne vulgaiis, vhich leau to tissue in|uiy. 4O Alipiantis et al. uenon- stiateu that niciohial lipopioteins in- uuce leatuies ol apoptosis via ¯LR2. 41 ¯hus, niciohial lipopioteins have the ahility to elicit hoth ¯LR-uepenuent acti- vation ol host uelense anu tissue pathol- ogy. ¯his uual signaling pathvay is sini- lai to ¯Nl ieceptoi anu CD4O signaling, vhich leaus to hoth nucleai lactoi- B ac- tivation anu apoptosis. 42,4o ln this nan- nei, it is possihle loi the innune systen to use the sane nolecules to activate host uelense nechanisns anu then, hy apoptosis, to uovniegulate the iesponse lion causing tissue in|uiy. Activation ol ¯LR can leau to the inhihition ol the na- |oi histoconpatihility conplex (íHC) class ll antigen piesentation pathvay, vhich can uovniegulate innune ie- sponses leauing to tissue in|uiy hut nay also contiihute to innunosuppiession. 44 linally, ¯oll activation has heen inpli- cateu in hone uestiuction. o5 ¯he ciitical hiologic iole ol ¯LRs in hunan host uelense can he ueuuceu lion the hnuing that ¯LR4 nutations aie associateu vith LlS hypo-iespon- siveness in hunans. 45 By inleience, one can anticipate that hunans vith genetic alteiations in ¯LR nay have incieaseu susceptihility to ceitain niciohial inlec- tions. luitheinoie, it shoulu he possihle to exploit the pathvay ol ¯LR activa- tion as a neans to enuoise innune ie- sponses in vaccines anu tieatnents loi inlectious uiseases as vell as to ahio- gate iesponses uetiinental to the host. Ce||º c| ||e |rra|e |rrure S]º|er PhA600YT£S ¯vo ley cells ol the innate innune systen aie chaiacteiizeu hy theii phagocytic lunction: naciophages anu líNs. ¯hese cells have the capac- ity to tale up pathogens, iecognize then, anu uestioy then. Sone ol the lunctions ol these cells aie iegulateu via ¯LRs anu conplenent ieceptois as out- lineu eailiei. líNs aie noinally not piesent in slin, hovevei, uuiing inhannatoiy piocesses, these cells nigiate to the site ol inlection anu inhannation, vheie they aie the eailiest phagocytic cells to he ieciuiteu. ¯hese cells have ieceptois that iecognize pathogens uiiectly (see lattein Recognition Receptois), anu uue to theii expiession ol lc Rlll/CD16 anu CohR/CDo5, can phagocytose niciohes coateu vith antihouy anu vith the conplenent conponent Coh. As a con- seguence, gianules (containing nyelo- peioxiuase, elastase, lactoleiiin, collage- nase, anu othei enzynes) aie ieleaseu, anu niciohiciual supeioxiue iauicals (C 2 ) aie geneiateu (see Chap. oO). Effectar Funct|ans af Phagacytes. Activa- tion ol phagocytes hy pathogens in- uuces seveial inpoitant ellectoi necha- ni sns, l oi exanpl e, t ii ggeii ng ol cytoline piouuction. A nunhei ol in- poitant cytolines aie secieteu hy nac- iophages in iesponse to niciohes, in- cluuing lL-1, lL-6, ¯Nl- , lL-8, lL-12, anu lL-1O. lL-1, lL-6, anu ¯Nl- play a ciitical iole in inuucing the acute-phase iesponse in the livei anu in inuucing le- vei loi ellective host uelense. ¯Nl- in- uuces a potent inhannatoiy iesponse to contain inlection. lL-8 is inpoitant as a neuiatoi ol líN chenotaxis to the site ol inlection (see also Chap. 11 on cytolines). Anothei inpoitant uelense necha- nisn tiiggeieu in phagocytes in ie- sponse to pathogens is the inuuction ol uiiect antiniciohial iesponses. lhago- cytic cells such as líNs anu nacio- phages iecognize pathogens, engull then, anu inuuce antiniciohial ellectoi nech- anisns to lill the pathogens. líNs geneiate oxygen-uepenuent oi oxygen- inuepenuent lilling. ¯he ielease ol toxic oxygen iauicals, lysosonal enzynes, anu antiniciohial peptiues such as the hunan neutiophil uelensins leaus to ui- iect lilling ol the niciohial oiganisns. 6 Sinilaily, activation ol ¯LRs on nacio- phages hy niciohial liganus upiegu- lates iNCS (NCS-ll), vhich iesults in iapiu geneiation ol NC anu poveilul niciohiciual activity. o¯ íaciophages use this nechanisn to contain sone in- lectious oiganisns not susceptihle to líN attacl, such as nycohacteiia, cei- tain lungi, anu paiasites. lhagocytic cells ol the innate innune systen can also he activateu hy cells ol the auaptive innune systen. CD4O is a 5O-lu glycopiotein piesent on the sui- lace ol B cells, nonocytes, DCs, anu en- uothelial cells. ¯he liganu loi CD4O is CD4OL, a type ll nenhiane piotein ol oo lu, pieleientially expiesseu on acti- vateu CD4 + ¯ cells anu nast cells. CD4O-CD4OL inteiaction plays a ciucial iole in the uevelopnent ol ellectoi lunctions. CD4 + ¯ cells activate nacio- phages anu nonocytes to piouuce ¯Nl- , lL-1, lL-12, inteileion- (llN- ), anu NC via CD4O-CD4OL inteiaction. CD4OL has also heen shovn to iescue ciiculating nonocytes lion apoptotic ueath, thus piolonging theii suivival at the site ol inhannation. ln auuition, CD4O-CD4OL inteiaction uuiing ¯-cell activation hy AlCs iesults in lL-12 pio- uuction. ¯heieloie, it can he concluueu that CD4O-CD4OL inteiactions hetveen ¯ cells anu naciophages play a iole in naintenance ol ¯h1-type cellulai ie- sponses anu neuiation ol inhannatoiy iesponses. Cthei stuuies have estah- lisheu a iole loi CD4O-CD4OL inteiac- tions in B-cell activation, uilleientiation, anu lg class svitching. 55 ln auuition, CD4O-CD4OL inteiaction leaus to up- iegulation ol B¯.1 (CD8O) anu B¯.2 (CD86) on B cells. ¯his co-stinulatoiy activity inuuceu on B cells then acts to anplily the iesponse ol ¯ cells. ¯hese nechanisns unueiscoie the inpoi- tance ol the inteiplay hetveen the in- nate anu the auaptive innune systen in geneiating an ellective host iesponse. £0S|h0Ph|LS (See Chap. oO) losinophils aie a uistinct class ol hone naiiov ueiiveu gianulocytes that noinally con- stitute only a snall liaction ol peiipheial hloou leulocytes anu occui in even snallei nunheis in peiipheial tissues. ¯he cytolines gianulocyte-naciophage colony-stinulating lactoi (Cí-CSl), lL-o anu, nost inpoitantly, lL-5 aie ciitical loi theii uevelopnent anu natuiation. hAT08AL k|LL£8 0£LLS 58 Nl cells appeai as laige gianulai lynphocytes. ln hu- nans, the vast na|oiity ol these cells ex- hihit the CDo , CD56 + , CD16 + , CDº4 + , CD161 + phenotype. ¯heii lunction is to 100 suivey the houy looling loi alteieu cells, he they tiansloineu oi inlecteu vith vi- iuses (e.g., cytonegaloviius), hacteiia (e.g., listcria mono.,togcncs), oi paiasites (e.g., Toxo¡|asma gondii). ¯hese pathogens aie then lilleu uiiectly via peiloiin/ gianzyne- oi las/lasL-uepenuent nech- anisns oi inuiiectly via the secietion ol cytolines (e.g., llN- ). Hov uo Nl cells uisciininate he- tveen noinal anu tiansloineu oi pathogen-inlecteu tissue` All nucleateu cells expiess the íHC class l nolecules. Nl cells have iecep- tois, teineu ki||cr inhi|itor, rc.c¡tors, that iecognize the sell íHC class l nole- cules. ¯his iecognition iesults in the ue- liveiy ol a negative signal to the Nl cell that paialyzes it. ll a nucleateu cell loses expiession ol its íHC class l nolecules, hovevei, as olten happens altei nalig- nant tiansloination oi viius inlection, the Nl cell, on encounteiing it, vill he- cone activateu anu lill it. ln auuition, Nl cells have activating ieceptois that hinu íHC-lile liganus on taiget cells. Cne such ieceptoi is NlCD2, vhich hinus to the hunan non-classic íHC class l chain-ielateu A anu B nolecules, ílCA anu ílCB. 5º ílCA anu ílCB aie not expiesseu in suhstantial anounts on noinal tissues hut aie oveiexpiesseu on caicinonas. 6O Nl cells aie ahle to lill ílCA/ílCB- heaiing tunois, vhich suggests a iole loi NlCD2 in innune suiveillance. Anothei cell type that, at least in nice, coulu seive a sinilai lunction is the llN-piouucing lillei DC, vhich shaies seveial leatuies vith DCs anu Nl cells. 61,62 ¯heii hunan eguivalent has yet to he iuentiheu. k£8AT|h00YT£S Cnce thought to he in- eit, leiatinocytes, the pieuoninant cells in the epiueinis, can nount an innune anu/oi inhannatoiy iesponse thiough secietion ol cytolines anu chenolines, aiachiuonic aciu netaholites, conple- nent conponents, anu antiniciohial peptiues. leiatinocytes ol unpeituiheu slin piouuce only a lev ol these neuiatois, such as the cytolines lL-1, lL-¯, anu tiansloining giovth lactoi- (¯Cl- ), constitutively. Resiuent leiatinocytes contain laige guantities ol pie-loineu anu hiologically active lL-1 as vell as innatuie lL-1 in theii cytoplasn. 6o ¯he lilely in vivo iole ol this stoieu in- tiacellulai lL-1 is that ol an inneuiate initiatoi ol inhannatoiy anu iepaii pio- cesses altei epiueinal in|uiy. lL-¯ is an inpoitant lynphocyte giovth lactoi that nay have a iole in the suivival anu piolileiation ol the ¯ lynphocytes ol hunan slin. Sone eviuence exists loi the lL-¯uiiven piopagation ol lyn- phona cells in Sézaiy synuione. ¯Cl- , in auuition to its giovth-iegu- lating ellects on leiatinocytes anu hhio- hlasts, nouulates the inhannatoiy as vell as the innune iesponse 64 anu is in- poitant loi LC uevelopnent (see luithei in Developnent, íaintenance, anu late ol Slin Denuiitic Cells unuei Langeihans Cells anu Cthei Denuiitic Cells). 65 Cn ueliveiy ol ceitain noxious, oi at least po- tentially hazaiuous, stinuli (e.g., hy- poxia, tiauna, non-ionizing iauiation, haptens oi othei iapiuly ieactive cheni- cals lile poison ivy catechols, silica, LlSs, anu niciohial toxins), the piouuction anu/oi ielease ol nany cytolines is olten uianatically enhanceu. ¯he hiologic con- seguences ol this event aie nanilolu anu incluue the initiation ol inhannation (lL-1, ¯Nl- , lL-6, nenheis ol the che- noline lanily), the nouulation ol LC phenotype anu lunction (lL-1, Cí-CSl, ¯Nl- , lL-1O, lL-15), ¯-cell activation (lL- 15, lL-18), 66,6¯ ¯-cell inhihition (lL-1O, ¯Cl- ), 68 anu sleving ol the lynpho- cytic iesponse in eithei the type 1 (lL-12, lL-18), 6º type 2 (thynic stional lyn- phopoietin), ¯O oi ¯h1¯ (lL-2o) uiiection. ¯1 ln sone cases, leiatinocytes nay also play a iole in anplilying inhannatoiy signals in the epiueinis oiiginating lion nuneiically ninoi epiueinal cell suh- sets. Cne pioninent exanple is the in- uuction ol pio-inhannatoiy cytolines such as ¯Nl- in leiatinocytes hy LC- ueiiveu lL-1 in the initiation phase ol alleigic contact ueinatitis. ¯2 ln the pies- ence ol a iohust stinulus, leiatinocyte- ueiiveu cytolines nay he ieleaseu into the ciiculation in guantities that cause systenic ellects. Duiing a seveie sunhuin ieaction, loi exanple, seiun levels ol lL- 1, lL-6, anu ¯Nl- aie cleaily elevateu anu piohahly iesponsihle loi the systenic nanilestations ol this ieaction, such as levei, leulocytosis, anu the piouuction ol acute-phase pioteins. ¯o ¯heie is also evi- uence that the ultiaviolet (UV) iauiation inuucihle cytolines lL-6 anu lL-1O can in- uuce the piouuction ol autoantihouies anu thus he involveu in the exaceihation ol autoinnune uiseases such as lupus eiythenatosus. ¯he lact that secieteu piouucts ol leiatinocytes can ieach the ciiculation coulu conceivahly also he useu loi theiapeutic puiposes. ¯he uenonstia- tion hy len|ves et al. ¯4 that gialting ol apolipopiotein l genetianslecteu hu- nan leiatinocytes onto nice iesults in the uetection ol apolipopiotein l in the ciiculation ol the nouse suppoits the lea- sihility ol such an appioach. Anothei inpoitant lunction ol leiatino- cytes is the piouuction/secietion ol lactois goveining the inhux anu elhux ol leulo- cytes into anu out ol the slin. ¯vo goou exanples aie the chenolines thynus anu activation-iegulateu chenoline (¯ARC, CC chenoline liganu 1¯, oi CCL1¯) anu cutaneous ¯ cellattiacting chenoline (C¯ACl)/CCL2¯ anu theii coiiesponuing ieceptois CCR4 anu CCR1O, selectively expiesseu on slin-honing ¯ lynphocytes. Blocling ol hoth chenolines uiastically inhihits the nigiation ol ¯ cells to the slin in a nuiine nouel ol contact hypeisensi- tivity (CHS). ¯5 Anothei noie uistinct lunc- tion ol a leiatinocyte-ueiiveu chenoline in the ieciuitnent ol leulocyte suh-popu- lations to the epiueinis is suggesteu hy the selective expiession ol the naciophage in- hannatoiy piotein o (íll-o )/CCL2O ieceptoi, CCR6, on LCs anu LC piecuisois ¯6 (see Developnent, íainte- nance, anu late ol Slin Denuiitic Cells anu ¯ Lynphocyte Suh-lopulations). ¯he uenonstiation ol cytoline iecep- tois on anu cytoline iesponsiveness hy leiatinocytes estahlisheu that the lunc- tional piopeities ol these cells can he suh- |ect to iegulation hy cells ol the innune systen. As a conseguence, leiatinocytes expiess oi aie inuuceu to expiess innu- nologically ielevant suilace noieties that can he taigeteu hy leulocytes loi stinula- toiy oi inhihitoiy signal tiansuuction. ln auuition to cytolines, leiatino- cytes seciete othei lactois such as neu- iopeptiues, eicosanoius, anu ieactive oxygen species. ¯hese neuiatois have potent inhannatoiy anu innunonou- ulatoiy piopeities anu play an inpoitant iole in the pathogenesis ol cutaneous in- hannatoiy anu inlectious uiseases as vell as in aging. leiatinocytes can also synthesize conplenent anu ielateu ieceptois, in- cluuing the Coh ieceptoi |conplenent ieceptoi 1 (CR1), CDo5], the lpstein- Baii viius ieceptoi CR2 (Cou ieceptoi, CD21), the C5a ieceptoi (CD88), the nenhiane co-lactoi piotein (CD46), the uecay-acceleiating lactoi (CD55), anu conplenent piotectin (CD5º). CD5º nay piotect leiatinocytes lion attacl hy conplenent. lts engagenent hy CD2 stinulates the secietion ol pio- inllannatoiy cytolines lion leiatino- cytes. íenhiane co-lactoi (CD46) is ie- poiteu to he a ieceptoi loi í piotein ol gioup A stieptococci anu loi neasles vi- ius. 8O lts ligation inuuces pio-inhanna- toiy cytolines in leiatinocytes such as lL-1 , lL-6, anu Cí-CSl. 101 ADAPT|VE |||U\E RESP0\SE ¯he stiength anu the type ol the innate iesponse ueteinines hoth the guantity anu guality ol an auaptive iesponse ini- tiateu hy uenuiitic AlCs in the epiuei- nis (LCs) anu ueinis (ueinal DCs oi DDCs) anu executeu hy ¯ lynphocytes anu antihouies. |]rp|cc]|eº ¯he auaptive innune iesponse is neui- ateu hy ¯ anu B lynphocytes. ¯he unigue iole ol these cells is the ahility to iecognize antigenic specihcities in all theii uiveisity. All lynphocytes ueiive lion a connon hone naiiov sten cell. ¯his hnuing has heen exploiteu in vaiious clinical settings, vith attenpts to iestoie the entiie lynphocyte pool hy hone nai- iov oi sten cell tiansplantation. TYP£S 0F LYNPh00YT£S B cells natuie in the letal livei anu auult hone naiiov. ¯hey piouuce antihouiespiotein con- plexes that hinu specihcally to paiticulai nolecules uehneu as antigens. As a con- seguence ol ieconhinatoiial events in uilleient lg gene segnents (V oi vaiiahle, D oi uiveisity, [ oi |oining), each B cell piouuces a uilleient antihouy nolecule (lig. 1O-4). Sone ol this antihouy is piesent on the suilace ol the B cell, con- leiiing the unigue ahility ol that B cell to iecognize a specihc antigen. B cells then uilleientiate into plasna cells, the actual antihouy-piouucing anu -secieting cells. ¯he secieteu antihouy neuiates hunoial innune iesponses. ln slin, hunoial in- nunity contiihutes to the innune ue- lense against extiacellulai pathogens. Antihouies hinu to niciohial agents anu neutialize then oi lacilitate uptale ol the pathogen hy phagocytes that uestioy then. Antihouies aie also iesponsihle loi neuiating ceitain pathologic conuitions in slin. ln paiticulai, antihouies against sell-antigens leau to autoinnune uis- ease, typiheu in the pathogenesis ol penphigus anu hullous penphigoiu. lui- theinoie, lgl antihouies to loieign suh- stances elicit anaphylactic ieactions (e.g., penicillin uiticaiia). ¯ cells natuie in the thynus, vheie they aie selecteu to live oi to uie. ¯hose ¯ cells that vill have the capacity to iec- ognize loieign antigens aie positively se- lecteu anu can entei the ciiculation. ¯hose ¯ cells that ieact to sell aie nega- tively selecteu anu uestioyeu. ll the in- nune systen is envisioneu as a huieau- ciacy, the ¯ cell is the iueal huieauciat. ¯ cells have the unigue ahility to uiiect othei cells ol the innune systen. ¯hey uo this, in pait, hy ieleasing cytolines. loi exanple, ¯ cells contiihute to cell- neuiateu innunity (Cíl), ieguiieu to elininate intiacellulai pathogens, hy ie- leasing cytolines that activate nacio- phages anu othei ¯ cells. ¯ cells ielease cytolines that activate Nl cells anu also ielease cytolines that peinit the giovth, uilleientiation, anu activation ol B cells. Duiing theii natuiation in the thy- nus, thynocytes stait to expiess the nolecules that allov ¯ cells to uisplay theii unigue lunctional capacity, that is, to specihcally iecognize antigen in an íHC-iestiicteu lashion (see Ceneial liinciples ol Antigen liesentation). ¯hese aie the ¯-cell antigen ieceptoi (¯CR) anu the accessoiy nolecules CD4 anu CD8. ¯he vast na|oiity ol posi- tively selecteu natuie thynocytes aie eithei CD4 + /CD8 (single positive) íHC class lliestiicteu cells oi CD8 + / F|608£ 10-4 T-ce|| |ecep|c| (TCR, çere |ea||arçerer|º. T||º d|aç|ar º|cWº |cW d|.e|º||] |r TCRº ard ar|||cd|eº |º çere|a|ed |] çere |ea||arçerer|. |c| ||e TCR, |ea||arçerer| c| ||e c|a|r |º º|cWr, ard |c| ar|||cd|eº, ||a| c| |rrurcç|c|u||r | |ea.] ard ||ç|| c|a|rº |º dep|c|ed. T|e erccded ar|||cd] |eccç- r|/eº ||e rcr|ra| ar||çer pe| ºe, W|e|eaº ||e erccded TCR |eccçr|/eº ar||çer |r ||e ccr|e/| c| ar app|cp||a|e ar||çer-p|eºer||rç rc|ecu|e. Aç = ar||çer, APC = ar||çer-p|eºer||rç ce||, C = ccrº|ar| ºeçrer|, D = d|.e|º||] ºeçrer|, J = jc|r|rç ºeçrer|, |HC = rajc| ||º|cccrpa|||||||] ccrp|e/, V = .a||a||e ºeçrer|. hH 2 hH 2 light chaiu V 1 J 1 0 V H1 D H1 J H1 0  T ce|| J V V V D 0 T0R 0 0 J J V D V NH0 AP0 Ag Heav] chaiu Disulfide liukage Ag- comoiuiug site Effector site -s-s- -s-s- Ag- comoiuiug site J V D 0 Recomoiuatiou trauscriptiou light chaiu Heav] chaiu 8 ce|| H000 000H V J 0 V D J 0 0 V 0 0 V V V 0 102 CD4 (single positive) íHC class l iestiicteu cells, hut sone ol then ex- piess the ¯CR hut no accessoiy nole- cules (uouhle-negative thynocytes). ¯hese natuie thynocytes leave the thynus anu nigiate to the peiipheial lynphoiu tissues (lynph noues, spleen, leyei`s patches, etc.). ¯his piocess is nost ac- tive in eaily inlancy anu chiluhoou hut continues vith uecieasing output vell into auult lile. ¯he ¯CR is a conplex ol nolecules consisting ol an antigen-hinuing het- eiouinei ( / oi / chains) that is non- covalently linleu vith hve CDo suh- units ( , , , / ). ¯CR / oi ¯CR / nolecules nust he paiieu vith CDo nolecules to he inseiteu into the ¯-cell suilace nenhiane 81 (see lig. 1O-4). ¯he ¯CR chains loin the actual anti- gen-hinuing unit, vheieas the CDo conplex neuiates signal tiansuuction, vhich iesults in eithei piouuctive acti- vation oi nonpiouuctive silencing ol the ¯ lynphocyte. ¯he ¯CR chains have anino aciu se- guence honology vith anu stiuctuial sinilaiities to lg heavy anu light chains. ¯he genes encouing ¯CR nolecules aie encoueu as clusteis ol gene segnents (V, [, D, C oi constant) that ieaiiange uui- ing ¯-cell natuiation. ¯ogethei vith the auuition ol nucleotiues at the |unction ol ieaiiangeu gene segnents, this ie- conhinatoiial piocess, vhich involves the enzynes ieconhinase activating gene 1 anu 2, iesults in a heteiogeneity anu uiveisity ol the antigen iecognition unit that is hioau enough to allov loi a successlul host uelense. ¯he accessoiy nolecules CD4 anu CD8 stahilize the inteiaction ol the ¯CR vith the íHC-linleu peptiue antigen. Although CD4 hinus to íHC class ll nolecules, CD8 acts as an auhesive hy hinuing to íHC class l nolecules. T-LYNPh00YT£ S08-P0P0LAT|0hS ¯ cells can he classiheu anu suhuiviueu in uil- leient vays: (1) on the hasis ol the ac- cessoiy nolecules CD4 anu CD8, (2) on the hasis ol theii activation status (na- ive, nenoiy, ellectoi ¯ cells), anu (o) on the hasis ol theii lunctional iole in the innune iesponse, vhich is olten linleu to the cytoline secietion piopeity ol the iespective cell population. As lai as the activation status ol ¯ cells is conceineu, it appeais that the stiength ol the antigenic signal also ue- teinines the ultinate late ol a naive ¯ cell. Cn iohust activation, these cells uilleientiate into ellectoi cells, vhich aie then selecteu to entei the nenoiy pool accoiuing to theii capacity to ac- cess anu use suivival signals. lllectoi- nenoiy cells hone to peiipheial tissues anu aie iesponsihle loi inneuiate pio- tection against challenge. CCR¯ + cen- tial-nenoiy cells, on the othei hanu, hone to seconuaiy lynphoiu oigans anu aie iesponsihle loi seconuaiy oi long-tein iesponses to antigen anu night he involveu in long-tein nainte- nance ol ellectoi-nenoiy cells. 82 With iegaiu to the lunctional capaci- ties ol vaiious ¯-cell suhsets, it vas oiig- inally assuneu that CD4 + cells pieuon- inantly suhseive helpei lunctions anu that CD8 + cells act as lillei cells. íany exceptions to this iule aie nov lnovn to exist, loi exanple, hoth CD4 + anu CD8 + iegulatoiy cells aie lounu, hut CD4 + cells aie still connonly ieleiieu to as helpei ¯ cells (¯h cells) anu CD8 + cells as cytotoxic ¯ cells. Naive ¯h cells, so-calleu Th0 .c||s, can uilleientiate into seveial lunc- tional classes ol cells uuiing an in- nune iesponse: (1) ¯h1 cells (type 1 ¯ cells), (2) ¯h2 cells (type 2 ¯ cells), (o) ¯h1¯ cells, (4) iegulatoiy ¯ cells (¯ieg), anu (5) natuial lillei ¯ cells (Nl¯). T h£LP£8 1lT h£LP£8 2 PA8A0|6N ¯ cells that piouuce lL-2, llN- , anu ¯Nl aie teineu Th1 .c||s. ¯hey aie the nain cai- iieis ol Cíl. Cthei ¯ cells piouuce lL-4, lL-5, lL-6, lL-1o, anu lL-15. ¯hese aie teineu Th` .c||s anu aie piinaiily ie- sponsihle loi extiacellulai innunity (see latei). 8o,84 íany lactois inhuence vhethei an unconnitteu ¯h cell uevel- ops into a natuie ¯h1 oi ¯h2 cell. ¯he cytolines lL-12 anu lL-4, acting thiough signal tiansuucei anu activatoi ol tians- ciiption (S¯A¯) 4 anu 6, iespectively, aie ley ueteininants ol the outcone, as aie antigen uose, level ol co-stinulation, anu genetic nouiheis. Ceitain tiansciip- tion lactois have causal ioles in the gene-expiession piogians ol ¯h1 anu ¯h2 cells. loi exanple, the ¯-hox tians- ciiption lactoi ¯-het is centially involveu in ¯h1 uevelopnent, inuucing hoth tian- sciiptional conpetence ol the llN- lo- cus anu selective iesponsiveness to the giovth lactoi lL-12. 85 By contiast, the zinc-hngei tiansciiption lactoi CA¯A-o seens to he ciucial loi inuucing cei- tain ley attiihutes ol ¯h2 cells, such as the tiansciiptional conpetence ol the ¯h2 cytoline clustei, vhich in- cluues the genes encouing lL-4, lL-5, anu lL-1o. 86,8¯ ln nuiine nouels ol intiacellulai in- lection, iesistant veisus susceptihle innune iesponses appeai to he iegu- lateu hy these tvo ¯-cell suh-popula- tions. 5O,51,88 ¯h1 cells, piinaiily hy the ielease ol llN- , activate naciophages to lill oi inhihit the giovth ol the pathogen anu tiiggei cytotoxic ¯-cell iesponses, vhich iesults in nilu oi sell-cuiing uisease. ln contiast, ¯h2 cells lacilitate hunoial iesponses anu inhihit sone cell-neuiateu innune ie- sponses, vhich iesults in piogiessive inlection. ¯hese cytoline patteins aie cioss-iegulatoiy. ¯he ¯h1 cytoline llN- uovniegulates ¯h2 iesponses. ¯he ¯h2 cytolines lL-4 anu lL-1O uovniegulate hoth ¯h1 iesponses anu naciophage lunction. ¯he iesult is that the host iesponus in an elhcient nannei to a given pathogen hy naling eithei a ¯h1 oi ¯h2 iesponse. Sone- tines the host chooses an inappiopii- ate cytoline pattein, vhich iesults in clinical uisease. ¯he uiscoveiy that ¯h1/¯h2 ie- sponses coulu contiihute to the out- cone ol hunan uisease uue to a single antigen vas hist uelineateu hy the stuuy ol lepiosy. Because lepiosy pie- sents as a spectiun ol clinical naniles- tations that coiielate vith the innune iesponse to the pathogen, it pioviues an extiaoiuinaiy vinuov into innune iegulation in hunans. At one enu ol the spectiun, patients vith tuheiculoiu lep- iosy typily the iesistant iesponse that iestiicts the giovth ol the pathogen. ¯he nunhei ol lesions is lev, although tissue anu neive uanage is lieguent. At the opposite enu ol this spectiun, pa- tients vith lepionatous lepiosy iepie- sent extiene susceptihility to /. |c¡rac inlection. ln lepionatous lepiosy, the slin lesions aie nuneious anu giovth ol the pathogen is unahateu, vhich ie- sults in nany viahle /. |c¡rac thiough- out the slin lesions. ¯hese clinical pie- sentations coiielate vith the level ol Cíl against /. |c¡rac. ¯he stanuaiu neasuie ol Cíl to the pathogen is the íitsuua ieaction. latients aie chal- lengeu hy intiaueinal in|ection ol /. |c¡rac, anu inuuiation is neasuieu o veels latei. ¯he test iesult is positive in tuheiculoiu patients anu negative in lep- ionatous patients. lt is viuely agieeu that ¯ cells involveu in Cíl aie pivotal in ueteinining the outcone ol inlection vith /. |c¡rac, hecause, in coiielation vith slin test iesults, lynphocyte ieac- tivity is positive in tuheiculoiu patients hut is negative in lepionatous patients. Yet, theie is an inteiesting paiauox in that Cíl anu hunoial iesponses ex- hihit an inveise ielationship. Anti/. |c¡rac antihouy levels aie nost elevateu 103 in patients vith the lepionatous loin ol the uisease anu theieloie aie not thought to play a iole in piotection. ¯his paiauox can hest he explaineu in teins ol the patteins ol cytolines in the lesions. 52,8º ¯he ¯h1 cytolines, piinci- pally, lL-2 anu llN- aie noie stiongly expiesseu in tuheiculoiu lesions, vheieas the ¯h2 cytolines, notahly lL- 4, lL-5, anu lL-1O, aie chaiacteiistic ol lepionatous lesions. ¯hese cytoline patteins can he assigneu to the na|oi ¯- cell suhsets ohseiveu in the lesions: CD4 + ¯ cells pieuoninate in tuheicu- loiu lesions anu CD8 + ¯ cells pieuoni- nate in lepionatous lesions. All ol the /. |c¡racspecihc CD4 + ¯ cells ueiiveu lion tuheiculoiu patients piouuce lL-2 anu llN- anu aie uesignateu CD4 + t,¡c 1 cells. ¯he CD8 + ¯ cells ueiiveu lion lepionatous lesions piouuce high lev- els ol lL-4 anu lov levels ol llN- anu aie uesignateu CD8 + t,¡c ` cells. ln teins ol the innunopathogenesis ol lepiosy (see Chap. 186), the ahun- uance ol lL-2 anu llN- in tuheiculoiu lesions is lilely to contiihute to the ie- sistant state ol innunity in these pa- tients. lL-2 nay contiihute to the host uelense hy inuucing the clonal expan- sion ol activateu, cytoline-piouucing ¯ cells anu augnents the piouuction ol llN- . llN- is vell lnovn to enhance piouuction ol ieactive oxygen anu ni- tiogen inteineuiates hy naciophages anu stinulates then to lill oi iestiict the giovth ol intiacellulai pathogens. ¯he cytolines lounu to he incieaseu in lepionatous lesions night he expecteu to contiihute to the innune uniespon- siveness anu lailuie ol naciophage acti- vation in these inuiviuuals. lL-4 anu lL- 1O nay contiihute to the elevateu anti /. |c¡rac antihouies in lepionatous pa- tients via theii iole in uilleientiation anu lg class svitching ol B cells, hut they also have a negative innunoiegu- latoiy ellect on Cíl, uovniegulating ¯- cell anu naciophage lunction. Cl paiticulai inteiest to innunologists is the uelineation ol lactois that inhuence the ¯-cell cytoline pattein. ¯he innate innune iesponse is one inpoitant lactoi involveu in ueteinining the type ol ¯-cell cytoline iesponse (lig. 1O-5). ¯he ahility ol the innate innune ie- sponse to inuuce the uevelopnent ol a ¯h1 iesponse is neuiateu hy ielease ol lL-12, a ¯O-lu heteiouineiic piotein. 46 loi exanple, in iesponse to an intiacel- lulai pathogen, naciophages ielease lL- 12, vhich acts on Nl cells to ielease llN- . ¯he piesence ol lL-12, lL-2, anu llN- , vith the ielative lacl ol lL-4, la- cilitates ¯h1 iesponses. ln contiast, in iesponse to alleigens oi extiacellulai pathogen, nast cells oi hasophils ielease lL-4, vhich in the ahsence ol llN- leaus to uilleientiation ol ¯ cells along the ¯h2 pathvay. lt is intiiguing to speculate that leiatinocytes nay also inhuence the natuie ol the ¯-cell cyto- line iesponse. leiatinocytes can pio- uuce lL-1O, paiticulaily altei exposuie to UVB iauiation. 68 ¯he ieleaseu lL-1O can specihcally uovniegulate ¯h1 ie- sponses, thus lacilitating the uevelop- nent ol ¯h2 iesponses. T h£LP£8 17 0£LLS Not eveiy ¯ cellne- uiateu uisease can he easily explaineu hy the ¯h1/¯h2 paiauign. Sone ¯-cell suh-populations aie chaiacteiizeu hy the secietion ol lL-1¯. ¯hese cells aie theieloie teineu Th17 .c||s. lL-2o, a nenhei ol the lL-12 lanily, is appai- ently ol ley inpoitance loi the uevelop- nent ol ¯h1¯ cells, ºO vhich have heen linleu to a gioving list ol autoinnune anu inhannatoiy uiseases such as neu- ioinhannatoiy uisoiueis, asthna, lu- pus eiythenatosus, iheunatoiu aithii- tis, anu, nost notahly, psoiiasis. ¯1 lL-1¯ is helieveu to contiihute to the patho- genesis ol these uiseases hy acting as a potent pio-inhannatoiy neuiatoi. lt vas oiiginally assuneu that ¯h1 anu ¯h1¯ cells aiise lion a connon ¯h1 piecuisoi, hut it nov appeais that ¯h1¯ cells aie a conpletely sepaiate anu eaily lineage ol ellectoi CD4 + ¯h cells pio- uuceu uiiectly lion naive CD4 + ¯ cells. F|608£ 10-5 T|e |c|e c| |rra|e |rrur||] |r de|e|r|r|rç ||e |]pe c| c]|c||re |eºpcrºe. ||\ = |r|e||e|cr, || = |r|e||eu||r, \| = ra|u|a| ||||e|, T|1, T|2 = T |e|pe| 1, 2. Nast cell other cells ll-4 ll-4 Autigeu preseutiug cell Viruses oacteria Allergeus helmiuths Humoral immuuit] Eosiuophil respouses Nacrophage suppressiou B-cell stimulatiou ll-12 lFh- lFh- ll-4 Th1 cell lFh- 0ell-mediated immuuit] Nacrophage Th2 cell ll-4 ll-10 ll-5 hK cell ll-4 lFh- 104 0YT0T0X|0 T 0£LLS ln iesponuing to an intiacellulai pathogen (e.g., a viius) the ¯ cell nust lyse the inlecteu cell. ¯o uo so, it nust he ahle to iecognize anu ie- sponu to antigenic peptiues encoueu hy this pathogen anu uisplayeu on the cell suilace. loi this to occui, antigens aiis- ing in the cytosol aie cleaveu into snall peptiues hy a conplex ol pioteases, calleu the ¡rotcasomc. ¯he peptiue liag- nents aie then tianspoiteu lion the cy- tosol into the lunen ol the enuoplasnic ieticulun, vheie they associate vith íHC class l nolecules. ¯hese peptiue class l conplexes aie expoiteu to the Colgi appaiatus anu then to the cell sui- lace (see Ceneial liinciples ol Antigen liesentation loi noie uetails). ¯he nat- uiation ol a CD8 + ¯ cell to a lillei ¯ cell ieguiies not only the uisplay ol the anti- genic signal hut also the ueliveiy ol helpei signals lion CD4 + ¯ cells, loi vhich the lunctional inteiaction he- tveen CD4O on the AlC anu CD4OL on the CD8 + ¯ cell can suhstitute. ¯vo uistinct suhsets ol cytotoxic ¯ cells have heen iuentiheu anu can he uil- leientiateu hy the nechanisn hy vhich they lill taigets, º1 the enu iesult heing the inuuction ol a piogianneu cell ueath lnovn as a¡o¡tosis. º2,ºo ¯he hist nechanisn ol cytotoxicity involves the inteiaction ol tvo cell suilace pioteins, las liganu (CDº5L) on the ¯ cells anu las (CDº5) on the taiget. Ligation ol these nolecules ueliveis a signal thiough las that inuuces the apoptosis cascaue in the taiget. ¯he seconu nech- anisn involves the ielease ol cytoplas- nic gianules piesent in such ¯ cells. ¯hese gianules contain peiloiin, vhich inuuces a poie in the taiget, anu gianzynes, seiine esteiases that, vhen in|ecteu into cells, tiiggei the apoptotic pathvay. Such gianules also contain gianulysin, a piotein vith a hioau spec- tiun ol antiniciohial activity against hacteiia, lungi, anu paiasites. º1,º4 ln this nannei, cytotoxic ¯ cells can uiiectly lill niciohial invaueis. Besiues contiih- uting to host uelense against inlection anu tunois, cytotoxic ¯ cells can also contiihute to tissue in|uiy. loi exanple, cytotoxic ¯ cells iecognize sell-antigens ol nelanocytes anu thus nay contiihute to the pathogenesis ol vitiligo. º5 8£60LAT08Y T 0£LLS An inpoitant type ol innunonouulatoiy ¯ cells that con- tiols innune iesponses is the so-calleu rcgu|ator, T .c||s (Trcg .c||s;, loineily lnovn as T su¡¡rcssor .c||s. º6 ¯ieg cells aie inuuceu hy innatuie AlCs/DCs anu play ley ioles in naintaining tolei- ance to sell-antigens in the peiipheiy. Loss ol ¯ieg cells is the cause ol oigan- specihc autoinnunity in nice that ie- sults in thyioiuitis, auienalitis, oophoii- tis/oichitis, anu so on. ¯ieg cells aie also ciitical loi contiolling the nagnituue anu uuiation ol innune iesponses to niciohes. Unuei noinal ciicunstances, the initial antiniciohial innune ie- sponse iesults in the elinination ol the pathogenic niciooiganisn anu is then lolloveu hy an activation ol ¯ieg cells to suppiess the antiniciohe iesponse anu pievent host in|uiy. Sone niciooi- ganisns (e.g., lcishmania paiasites, ny- cohacteiia) have uevelopeu the capacity to inuuce an innune ieaction in vhich the ¯ieg conponent uoninates the el- lectoi iesponse. ¯his situation pievents elinination ol the niciohe anu iesults in chionic inlection. Regulatoiy lunctions aie neuiateu hy uistinct gioups ol CD4 + , CD8 + , anu Nl¯ cells. ¯he hest-chaiacteiizeu ¯ieg suhset is the CD4 + /CD25 + /C¯LA-4 + / Cl¯R (glucocoiticoiu-inuuceu ¯Nl ie- ceptoi lanilyielateu gene) + /loxlo + lynphocytes. ¯he tiansciiption lactoi loxlo is specihcally linleu to the sup- piessoi lunction, as eviuenceu hy the hnuings that nutations in the loxlo gene cause the latal autoinnune anu inhannatoiy uisoiuei ol scuily in nice anu lllX (innune uysiegulation, ¡oly- enuociinopathy, cnteiopathy, X-linleu) in hunans. ¯he cytolines ¯Cl- anu lL-1O aie thought to he the nain neuia- tois ol suppiession. CD8 + cells can he activateu to he- cone suppiessoi cells hy antigenic pep- tiues that aie piesenteu in the context ol an íHC class lh nolecule |Ca1 in nice, hunan leulocyte antigen l (HLA-l) in hunans]. CD8 + ¯ieg cells suppiess ¯ cells that have inteineuiate alhnity loi sell oi loieign antigens anu aie piinaiily involveu in sell-nonsell uisciinination. Nl¯ cells aie a uistinctive population ol ¯ cells. ¯hey have piopeities ol Nl cells hut, at the sane tine, expiess ¯CR / that consists ol an invaiiant chain (V 24-[ C) paiieu vith vaiious V chains. ¯hese cells specihcally iecognize ceitain tunoi cellassociateu oi hacteiial glycolipius in the context ol CD1 nole- cules anu aie theieloie inplicateu in tu- noiiciual anu hacteiiciual host iesponses (see CD1-Depenuent Antigen liesenta- tion). Cn antigenic stinulation, Nl¯ cells piouuce laige guantities ol cyto- lines, paiticulaily lL-4 anu lL-1O, anu can use then to suppiess ¯h1 iesponses. ¯he hiologic ielevance ol these in vitio uata can he ueuuceu lion the ohseivation that uepletion ol Nl¯ cells can aggiavate anu acceleiate ¯h1-neuiateu autoin- nune uiseases in nice, such as insulin- uepenuent uiahetes, nultiple scleiosis, anu inhannatoiy hovel uisease. º¯ LYNPh00YT£S 0F Th£ Sk|h Noinal slin is the piototype ol a nonlynphoiu oi- gan, that is, an oigan in vhich piinaiy lynphocyte iesponses aie not initiateu. As opposeu to noinal nouse slin, in vhich a iesiuent population ol uenuiitic epiueinal ¯ cells uniloinly eguippeu vith a nonpolynoiphic, canonical ¯CR / exists, noinal hunan slin contains only snall nunheis ol lynphocytes, the na|oiity ol vhich aie locateu in the uei- nis anu expiess ¯CR / iathei than / . º8,ºº ¯hese ¯ cells ol noinal hunan uei- nis aie pieleientially clusteieu aiounu postcapillaiy venules ol the supeihcial plexus high in the papillaiy ueinis anu aie olten situateu |ust heneath the uei- nal-epiueinal |unction anu vithin, oi in close pioxinity to, aunexal appenu- ages such as haii lollicles anu ecciine sveat uucts. íost ol then helong to the CD45RC + nenoiy populationvith the CD4 + /CD8 uoninating ovei the CD4 /CD8 + phenotypeanu expiess the slin-honing ieceptoi cutaneous lynpho- cyteassociateu antigen (CLA). 1OO At peiivasculai sites, nost ¯ cells stain positively loi HLA-DR anu CD25, vhich inuicates that sone ol then iep- iesent ellectoi cells anu otheis peihaps ¯ieg cells. lpiueinal ¯ cells account loi appioxi- nately 2 peicent to o peicent ol all CDo + cells in noinal hunan slin. ¯hey iesiue piinaiily in the hasal anu supia- hasal layeis, olten in close apposition to LCs. íost ol then aie CD8 + /CD4 lyn- phocytes that heai ¯CR / uineis. ¯heie also exists a ninoi suhset ol uou- hle-negative (CD4 /CD8 ) intiaepiuei- nal ¯ cells vith ¯CRs ol eithei the / oi the / phenotype. ¯heii ielation- ship, il any, to the nuiine uenuiitic epi- ueinal ¯ cell is not lnovn. ¯he nechanisn hy vhich ¯ lynpho- cytes tialhc into slin uepenus on a chain ol noleculai events hetveen cells. ln slin-uiaining lynph noues, the intei- action ol naive ¯ cells vith antigen- heaiing cutaneous DCs (LCs, DDCs) ie- sults in the inuuction ol the cell suilace nolecule CLA. 1O1 CLA is a glycopiotein that uehnes a suhset ol nenoiy ¯ cells that hone to slin. CLA is a glycosylateu loin ol l- selectin glycopiotein liganu 1 that is ex- piesseu constitutively on all hunan pe- iipheial hloou ¯ cells. ¯he level ol CLA 105 on cells is iegulateu hy an enzyne, (1,o)-lucosyl tiansleiase Vll, that noui- hes l-selectin glycopiotein liganu 1. ln this nannei, CLA + cells hinu to hoth l- selectin anu l-selectin, stiengthening the inteiaction hetveen ciiculating ¯ cells anu cutaneous enuotheliun, vheieas CLA cells hinu l-selectin hut uo not hinu l-selectin. 1O2,1Oo ln patients vith alleigic contact uei- natitis (see Chap. 1o), the CLA + suhset, hut not the CLA suhset, contains the ¯ cells vith the capacity to iesponu to the alleigen. 1O4 luitheinoie, noie than ºO peicent ol ¯ cells in inhannatoiy slin uisease aie CLA + . CLA lacilitates the entiy ol ¯ lynphocytes into slin hy neuiating tetheiing anu iolling ol ¯ cells on vasculai enuothelial cells thiough hinuing to l-selectin. Cheno- lines ieleaseu hy the enuothelial cells inciease the hinuing alhnity ol ¯-cell au- hesion nolecules. ¯ cells hinly auheie to enuotheliun hy the inteiaction ol lynphocyte lunctionassociateu anti- gen 1 (LlA-1) vith lCAí-1 anu veiy late antigen 4 vith vasculai cell auhe- sion nolecule. ¯he inteiaction vith the enuothelial cells is nov sulhciently stiong to peinit tiansnigiation ol the ¯ cells into the slin anu allov theii paitic- ipation in the inhannatoiy piocess. A uiveisity ol chenolines (see Chap. 12) contiihutes to tissue-specihc ¯-cell honing. Leulocytes anu nonleulocytes iesiuing in the slin can piouuce cheno- lines vith ¯-cell chenotactic piopei- ties, such as lL-8/CXC chenoline li- ganu 8 (CXCL8), Cio /CXCL1, llN- inuucihle piotein-1O/CXCL1O, nono- line inuuceu hy llN- /CXCLº, nacio- phage chenoattiactant piotein-1 (íCl- 1)/CCL2, íCl-2/CCL8, íCl-o/CCL¯, iegulateu on activation noinal ¯-cell ex- piesseu anu secieteu (RAN¯lS)/CCL5, íll-1 /CCLo, íll-1 /CCL4, anu lyn- photactin/XCL1. Cl paiticulai inpoitance loi slin hon- ing ol nenoiy ¯ cells is the inteiaction ol ¯ARC/CCL1¯ anu C¯ACl/CCL2¯ vith theii coiiesponuing chenoline ie- ceptois on CLA + ¯ cells, CCR4 anu CCR1O, iespectively. ¯he CC chenoline ¯ARC/CCL1¯ is expiesseu hy vasculai enuothelial cells ol venules in noinal anu inhaneu hu- nan slin 1O5 (see Chap. 16o). CLA + nenoiy ¯ cells in peiipheial hloou uis- playing CCR4 auheie to cutaneous ves- sels via ¯ARC/CCL1¯-inuuceu hinuing to lCAí-1 anu aie theiehy attiacteu to the slin. ln auuition, the ieciuitnent ol type 2 (¯h2) ¯ cells into uiseaseu slin can he neuiateu hy ¯ARC/CCL1¯. ln atopic ueinatitis, a pioninent exanple loi a ¯h2-neuiateu innune iesponse, this chenoline is lnovn to he upiegu- lateu in hasal leiatinocytes. 1O6 C¯ACl/CCL2¯, anothei CC cheno- line, is also ciitically involveu in the honing piocess unuei physiologic anu inhannatoiy conuitions. ¯5 lt is constitu- tively piouuceu hy hasal leiatinocytes anu is also uisplayeu on the suilace ol ueinal enuothelial cells. lts expiession is upiegulateu hy lL-1 anu ¯Nl- anu uovniegulateu hy glucocoiticosteioius. ¯he ieceptoi loi CCL2¯, CCR1O, is ex- piesseu on CLA + ¯ cells, anu in vivo ex- peiinents have uenonstiateu a pivotal iole loi CCL2¯-CCR1O inteiactions in ¯ cellneuiateu slin inhannation. 1O¯ Auhesion nolecule inteiactions that help to anchoi ¯ cells in the epiueinis in- cluue the attachnent ol LlA-1 (CD11a) heaiing ¯ cells to lCAí-1 + (CD54) leiat- inocytes in inhaneu slin anu, noie physiologically, the l ¯ -l-cauheiin neuiateu hinuing ol ¯ cells to nonacti- vateu leiatinocytes. ¯he accunulation ol ¯ cells in slin is not stochastic. lt is ahunuantly cleai that specihc populations ol ¯ cells, iuentiheu hy cell suilace ueteininants anu theii cytoline piohle, localize to the slin. Vaiious cell suilace ueteininants on ¯ cells allov uetection ol theii piesence. lnitially, lunctional ¯-cell populations coulu he uelineateu in slin accoiuing to theii expiession ol the CD4 anu CD8 nolecules. ln the na|oiity ol inhanna- toiy conuitions stuuieu, incluuing lichen planus, psoiiasis, anu atopic ueinatitis, CD4 + ¯ cells outnunhei CD8 + ¯ cells, in piopoitions sinilai to oi sonevhat gieatei than those seen in the peiipheial hloou. Hovevei, in the stuuy ol the slin lesions ol hunan lepiosy, CD4 + ¯ cells veie lounu to he pieuoninant in the tu- heiculoiu loin ol the uisease, vheieas CD8 + ¯ cells veie lounu to he pieuoni- nant in the lepionatous loin ol the uis- ease. 1O8 Because all lepiosy patients have an excess ol CD4 + ¯ cells in theii hloou, the ahunuance ol CD8 + ¯ cells in lepionatous slin lesions pioviues cleai eviuence loi the specihc accunulation ol ¯-cell populations in slin. A peihaps noie ielevant nailei ol ¯- cell populations is the uiveisity ol theii ¯CRs. ¯he cleaiest exanple is the clonality ol the ¯-cell population in cu- taneous ¯-cell lynphona, in vhich a single V gene usage is lounu to pieuon- inate in uilleient slin lesions lion the sane inuiviuual 1Oº,11O (see Chap. 146). ¯he uoninant expiession ol seveial ¯CR V genes in an inhltiate is thought to inuicate that a snall nunhei ol anti- gens uiive the local inhannatoiy ie- sponse. Unlile in noinal hunan slin vhose ¯CR iepeitoiie is iathei uivei- gent, 111 a liniteu ¯CR V gene usage has heen iepoiteu to he piesent in the slin lesions ol lepiosy, 112 psoiiasis, 11o hasal cell caicinona, anu countless othei ieac- tions in vhich ¯ cells aie piesent. Hov- evei, in no instance has the liniteu set ol antigens heen uehneu anu coiielateu vith the ¯CR usage. ¯he nost uiiect inuication ol ielevant ¯-cell populations in slin is ueteinina- tion ol the nunhei ol ¯ cells that iecog- nize the antigen. lt has heen uocunenteu that 1 in 1OOO to 1 in 1O,OOO ¯ cells in the peiipheial hloou iecognize a given anti- gen. ln the slin, hovevei, appioxinately 1 in 5O to 1 in 1OO ¯ cells iecognize the antigen causing the uisease. 114,115 ¯hus theie is as nuch as a 1OO-lolu eniich- nent ol antigen-ieactive ¯ cells at the site ol cutaneous inhannation. With iegaiu to suivival anu/oi expan- sion ol ¯ cells ol hunan slin/epiueinis, it appeais that lL-2, lL-¯, anu lL-15 111 play inpoitant ioles. ¯he lattei tvo ¯- cell giovth lactois can he piouuceu hy hunan epiueinal cells, anu all aie ovei- expiesseu in ¯ celliich slin lesions ol patients vith tuheiculoiu lepiosy. ¯he ¯h1/¯h2 paiauign pioviues in- sight into the pathogenesis ol nany slin uiseases in vhich ¯ cells have an innunologic iole. ¯heie is anple evi- uence that the ¯h1/¯h2 paiauign is not iigiu, theie aie situations in vhich a nixtuie ol cytolines is lounu anu ex- anples ol ¯-cell clones, lnovn as Th0 .c||s, that seciete a conhination ol ¯h1 anu ¯h2 cytolines. Hovevei, it has heen possihle to hnu a nunhei ol uei- natologic conuitions in vhich eithei a ¯h1 oi ¯h2 cytoline pattein pieuoni- nates. ln the iealn ol cutaneous inlec- tion, lepiosy (see ¯ Helpei 1/¯ Helpei 2 laiauign) anu leishnaniasis aie out- stanuing exanples ol uiseases vith a clinical spectiun in vhich ¯h1 anu ¯h2 cytolines appeai to have a pathogenic iole. Leishnaniasis, lile lepiosy, is not a single uisease entity hut a set ol clinical entities, each vith a uilleiing innuno- pathogenesis. As in lepiosy, the type 1 cytoline pattein is chaiacteiistic ol leishnaniasis lesions (see Chap. 2O6) in vhich Cíl to the paiasite is stiong anu the lesions sell-cuie, the type 2 pattein typihes lesions in vhich innunity to the paiasite is veal anu the cutaneous lesions aie piogiessive. 11¯,118 Stuuies in aninal nouels suggest that it nay he possihle to inuuce ellective Cíl hy vac- 106 cination using a conhination ol paiasite antigens anu ieconhinant lL-12. 11º ¯his innunotheiapeutic stiategy engenueis a ¯h1 cytoline iesponse. ¯h1 iesponses aie involveu in innunologic iesistance to 3orrc|ia |urgdorjcri 12O anu Trc¡oncma ¡a||idum, 121 the causative agents ol Lyne uisease anu syphilis, iespectively. Concepts ol the pathogenesis ol atopic ueinatitis (see Chap. 14) incluue a cential iole loi alleigen-specihc ¯ cells that piouuce ¯h2 oi type 2 cytolines, incluuing lL-4 anu lL-5. Alleigen-specihc ¯ cells vith this cytoline piohle have heen uenonstiateu in the peiipheial hloou anu slin lesions ol suh|ects vith active uisease. 122124 ln auuition, the le- sions ol atopic ueinatitis contain ahun- uant expiession ol lL-1O, although the souice ol this cytoline is lilely to he tis- sue naciophages anu leiatinocytes. 125 ¯he ¯h2 pattein ol cytolines togethei is thought to inuuce incieaseu lg piouuc- tion, paiticulaily ol lgl, nast cell giovth, anu the inhltiation ol eosino- phils. ¯hese cytolines nay also uovn- iegulate ¯h1 iesponses, vhich voulu account loi the incieaseu susceptihility to cutaneous hacteiial inlection. lviuence suggests that piuiitus, a ley synpton ol atopic ueinatitis, nay also he linleu to the ¯h2 iesponse. ¯he cy- toline lL-o1 inuuces seveie piuiitus anu ueinatitis in nice anu is pieleientially expiesseu in ¯h2 cells. Hunan lL-o1 is signihcantly upiegulateu in piuiitic loins ol slin inhannation (atopic uei- natitis, piuiigo nouulaiis) hut not in non-piuiitic loins (psoiiasis), anu ciicu- lating CLA + nenoiy ¯ cells ol patients vith atopic ueinatitis piouuce highei levels ol lL-o1 that the ¯ cells ol uonois vith psoiiasis. 126,12¯ Clinical tiials attenpting to altei the ¯h2 iesponse in atopic ueinatitis thiough the auninistiation ol llN- have shovn that this tieatnent inuuces signihcant hut nouest clinical inpiovenent hut no ieuuction in lgl levels in sone pa- tients. 128 ¯his vas notevoithy, hecause ¯h2 cytolines help B cells piouuce auto- antihouies in penphigus vulgaiis 12º (see Chap. 52). ¯he henehcial ellect ol llN- cane as sonevhat ol a suipiise in that a neuiatoi shilt has heen uesciiheu in atopic ueinatitis, vith ¯h2 cytolines uoninating in acute lesions anu ¯h1 cy- tolines in chionic lesions. 1oO ln alleigic contact ueinatitis (see Chap. 1o), sensitization involves the ue- velopnent ol a ¯h1 iesponse, as evi- uenceu hy the pieuoninating lL-2 anu llN- piouuction ol nuiine ¯ cells sen- sitizeu in vitio to haptenateu AlCs. 1o1 ¯he situation in the elicitation phase is less cleai. ln niclel contact ueinatitis, antigen-specihc ¯h1-type ¯-cell clones veie uesciiheu, 1o2 as veie ¯h2-type in- hltiating ¯ cells in lesional slin. 1oo ¯h1/¯h2 iesponses nay he involveu in antitunoi innunity. loi exanple, lL- 4 anu lL-1O pieuoninate in the lesions ol hasal cell anu sguanous cell caici- nona, vheieas the ¯h1 iesponse is piesent in henign neoplasns 54 (see Chaps. 114 anu 115). ¯he souice ol the lL-1O in these cutaneous caicinonas is the tunoi itsell, a nechanisn hy vhich the cancei can uovniegulate antitunoi ¯-cell iesponses. Within the spectiun ol cutaneous ¯-cell lynphona, nycosis lungoiues iepiesents a ¯h1 cytoline ie- sponse, vheieas patients vith the noie piogiessive Sézaiy synuione exhihit a ¯h2 cytoline iesponse 1o4 (see Chap. 146). lt vas oiiginally assuneu that ¯h1 cytoline iesponses pieuoninate in in- volveu anu, to a lessei extent, unin- volveu slin ol patients vith psoiiasis. 1o5 íoie iecent eviuence suggests that lL- 2o, iathei than lL-12, is the ley cytoline in this uisease 1o6 anu that it exeits its el- lects hy tiiggeiing lL-22 piouuction hy ¯h1¯ cells, vhich iesults in ueinal in- hannation anu acanthosis. 1o¯ Although it is unceitain, these ¯h1¯ cells nay he autoinnune, iesponuing to sell-anti- gens in the epiueinis. Whatevei the iole loi the ohseiveu cy- toline patteins in hunan uisease, the ¯h1-¯h2-¯h1¯ paiauign exposes nev taigets loi theiapy. ¯iials aie unuei vay to exploit this lnovleuge thiough the use ol cytoline agonists anu antagonists to shilt the halance hetveen the uilleient ¯h patteins loi the heneht ol the patient. |arçe||arº Ce||º ard 0||e| Derd||||c Ce||º 0£F|h|T|0h ln 1868, the neuical stuuent laul Langeihans, uiiven hy his inteiest in the anatony ol slin neives, iuentiheu a population ol uenuiitically shapeu cells in the supiahasal iegions ol the epi- ueinis altei inpiegnating hunan slin vith golu salts. 1o8 ¯hese cells, vhich latei veie lounu in viitually all stiatiheu sguanous epithelia ol nannals, aie nov eponynously ieleiieu to as langcr- hans .c||s. ¯heie also exist suhstantial nunheis ol uenuiitic leulocytes in the ueinis. Although sone ol then iepie- sent LCs on theii vay into oi out ol the epiueinis, nost ol these cells aie phe- notypically slightly uilleient lion LCs anu aie geneially ieleiieu to as dcrma| dcndriti. .c||s. 1oº LCs anu DDCs aie lin- eage-negative (Lin ), hone naiiov ueiiveu leulocytes enuoveu vith ex- guisite nigiatoiy anu antigen-piesent- ing piopeities. ¯hus, they phenotypi- cally anu lunctionally iesenhle othei DCs piesent in nost, il not all, lyn- phoiu anu nonlynphoiu tissues. 14O As the gateleepeis ol the innune systen, they contiol the iesponse to events pei- tuihing tissue honeostasis (lig. 1O-6A). Ph£h0TYP|0 P80P£8T|£S 0F Sk|h-800h0 LAh6£8hAhS 0£LLS Ah0 0£8NAL 0£h- 08|T|0 0£LLS ¯he expiession ol the Ca 2+ -uepenuent lectin Langeiin (CD2O¯) is cuiiently the single hest leatuie uis- ciininating LCs lion othei cells. Lang- eiin is a tiansnenhiane nolecule asso- ciateu vith anu sulhcient to loin Biihecl gianules, the piototypic anu cell typeuehning oiganelles ol LCs (see lig. 1O-6B). Biihecl gianules aie pentilani- nai cytoplasnic stiuctuies lieguently uisplaying a tennis iaclet shape at the ultiastiuctuial level. ¯he auuitional piesence ol Langeiin on the LC cell sui- lace coupleu vith its hinuing specihcity loi nannose suggests that Langeiin is involveu in the uptale ol nannose- containing pathogens hy LCs. Hovevei, the uisiuption ol the Langeiin gene in expeiinental aninals uoes not iesult in a naileu loss in LC lunctionality. 141 Notahly, Langeiin is expiesseu on viitu- ally all LCs in stiatiheu epithelia as vell as on a na|oi suhset ol DCs in the lung, 142 vhich nay oi nay not he ui- iectly ielateu to epiueinal LCs. ¯he expiession ol auuitional nole- cules hesiues Langeiin allovs the iuenti- hcation ol LCs vithin noinal unpei- tuiheu epiueinis. ¯hese incluue CD1a, the íHC class ll antigens HLA-DR, HLA-DC, anu HLA-Dl, anu CDoº, a nenhiane-hounu, loinalin-iesistant, sull- hyuiyl-uepenuent auenosine tiiphospha- tase (A¯lase). DDCs aie phenotypically less vell chaiacteiizeu. ¯heii hest naileis aie piohahly the nolecules CD1h anu CD1c as vell as the suhunit A ol the clotting pioenzyne lactoi Xlll (lactoi Xllla). DDCs can he uistinguisheu lion LCs hy the ahsence ol Langeiin expiession anu Biihecl gianules, anu lion naciophages hy the ahunuant expiession ol íHC class ll nolecules, DlC2O5/CD2O5, anu the ahsence ol phagolysosones at the ultiastiuctuial level. T|SS0£ 0|ST8|80T|0h 0F LAh6£8hAhS 0£LLS Ah0 0£8NAL 0£h08|T|0 0£LLS ln the epiueinis, the uensity ol the LC population vaiies iegionally in hunan 107 slin. Cn heau, lace, necl, tiunl, anu linh slin, the LC uensity ianges he- tveen 6OO anu 1OOO/nn 2 . Conpaia- tively lov uensities (appioxinately 2OO/ nn 2 ) aie encounteieu in palns, soles, anogenital anu saciococcygeal slin, anu the huccal nucosa. ¯he uensity ol hu- nan LCs uecieases vith age, anu LC counts in slin vith chionic actinic uan- age aie signihcantly lovei than those in slin not exposeu to UV light. DDCs aie locateu piinaiily in the vi- cinity ol the supeihcial vasculai plexus. 0£V£L0PN£hT, NA|hT£hAh0£, Ah0 FAT£ 0F Sk|h 0£h08|T|0 0£LLS (lig. 1O-¯) HLA- DR + /A¯lase + DCs can he iuentiheu in the hunan epiueinis hy 6 to ¯ veels ol estinateu gestational age. ¯hese cells nust oiiginate lion henopoietic pio- genitoi cells in the yoll sac oi letal livei, the piinaiy sites ol henopoiesis uuiing the enhiyonic peiiou. Until the tvellth veel ol piegnancy, these cell s aie CD1a anu l acl Bi ihecl gianul es. ¯heiealtei, anu coinciuing vith the ini- tiation ol hone naiiov lunction, theie occuis a uianatic inciease in CD1a ex- piession hy epiueinal DCs, vhich inui- cates the eneigence ol a tiue LC popu- lation. ¯he ielative nuneiic stahility ol LC counts uuiing latei lile nust he achieveu hy a uelicate halance ol LC geneiation anu innigiation into the epiueinis anu LC ueath anu enigiation lion the epiueinis. Within the epiueinis, LCs aie an- choieu to suiiounuing leiatinocytes hy l-cauheiinneuiateu honotypic auhe- sion. 14¯ ¯his anchoiing anu the uisplay ol ¯Cl- 1 also pievent teininal uillei- entiation anu nigiation (see latei), thus secuiing intiaepiueinal iesiuence loi the cells unuei honeostatic conuitions. ¯vo nonnutually exclusive path- vays ol LC iepopulation ol the epiuei- nis nay exist: LC uivision vithin the epiueinis, anu the uilleientiation ol LCs lion slin-iesiuent oi hloou-hoine piecuisois. lviuence loi the hist possi- hility is the uenonstiation ol cycling/ nitotic LCs in the epiueinis, 148 al- though it ienains to he estahlisheu vhethei this cell uivision alone sulhces loi naintaining the epiueinal LC popu- lation. Notahly, it has nov heen uiscov- eieu that DDCs piolileiate constitu- tively in situ in nuiine anu hunan guiescent ueinis, 14º vhich inuicates that honeostatic cell uivision also con- tiihutes to the naintenance ol this slin DC population. ¯he ohseivation that the hall-lile ol LCs vithin unpeituiheu nuiine epiuei- nis is aiounu 2 to o nonths 15O suggests a signihcant tuinovei ol the epiueinal LC population even unuei noninhan- natoiy conuitions. ln seening contia- uiction stanus the ohseivation that the LC population ol hunan slin gialteu onto a nuue nouse ienains iathei con- stant loi the lile ol the gialt, uespite epi- ueinal piolileiation anu the ahsence ol ciiculating piecuisois loi hunan LCs. íoieovei, epiueinal LCs in nice vhose hone naiiov vas lethally iiiaui- ateu anu suhseguently tiansplanteu aie only paitially ieplaceu hy LCs ol uonoi oiigin, 151 vheieas DCs in othei oigans aie elhciently exchangeu loi uonoi DCs. 152 ¯ogethei, these ohseivations F|608£ 10-6 A. |arçe||arº ce||º |r a º|ee| p|epa|a||cr c| ru||re ep|de|r|º aº |e.ea|ed |] ar||-rajc| ||º|cccrpa|||||||] ccrp|e/ c|aºº || (1u- c|eºce|r |ºc|||cc]ara|e, |rrurcº|a|r|rç. 8. E|ec- ||cr r|c|cç|ap| c| a |arçe||arº ce|| |r |urar ep|de|r|º. /rrcWs derc|e B|||ec| ç|aru|eº. \ = ruc|euº. (||cr S||rç| 0. \eW aºpec|º c| |arçe|- |arº ce|| |urc||crº. Irt J 0crratc! 19.189, 1980, W||| pe|r|ºº|cr., Irsct. H|ç|-pcWe| e|ec||cr r|- c|cç|ap| c| B|||ec| ç|aru|eº. T|e c0rvcc arrcWs |rd|ca|e ||e /|ppe|-|||e |uº|cr c| ||e |u//] cca|º c| ||e .eº|cu|a| pc|||cr c| ||e ç|aru|e. T|e de||r|||rç rer||are er.e|cpº |Wc º|ee|º c| pa|||c|eº a|- |ac|ed |c || ard a cer||a| |are||a ccrpcºed c| |Wc ||rea| a||a]º c| pa|||c|eº. (||cr wc||| |. T|e |re º||uc|u|e c| ||e |arçe||arº ce|| ç|aru|e. J 0c!! 8ic! 35.4oo, 19o/, W||| pe|r|ºº|cr., A 8 108 suggest that a piecuisoi cell population iesiues in the ueinis that is engageu constantly in the sell-ieneval ol the epi- ueinal LC population unuei noninhan- natoiy conuitions. ¯he piine canuiuate LC piecuisois aie ueinal CD14 + / CD11c + cells that have the potential to uilleientiate in vitio into LCs in a ¯Cl- 1uepenuent lashion. 15o Unuei inhannatoiy conuitions (e.g., UV iauiation exposuie, gialt-veisus-host uisease), an auuitional pathvay ol epi- ueinal LC ieciuitnent hecones opeia- tive. ln this situation, LC piecuisois en- tei the tissue, anu theii piogeny populate the epiueinis in a lashion ue- penuent on chenoattiaction neuiateu hy LC-expiesseu chenoline ieceptois CCR2 anu CCR6, 154 the liganus ol vhich aie secieteu hy enuothelial cells anu leiatinocytes. lnteiestingly, a sini- lai pathvay ol inhannation-uepenuent piecuisoi ieciuitnent exists loi DDCs, vhich in contiast to that ol LCs, ielies on CCR2 hut not CCR6-uepenuent cell nigiation. 14º ¯hus, CCR6 anu its liganu íll-o /CCL2O nay he essential loi epi- ueinal LC localization in vivo, as postu- lateu pieviously in stuuies ol LCs uillei- entiateu lion hunan piogenitoi cells in vitio. ¯6 ¯he action ol íll-o /CCL2O nay he assisteu oi ieplaceu unuei non- inhannatoiy situations hy the cheno- line BRAl/CXCL14, vhich is constitu- tively piouuceu hy leiatinocytes. 155 ¯he uilleientiation stage ol the hiologically ielevant ciiculating LC piecuisois entei- ing inhaneu slin in vivo ienains to he iesolveu. Hovevei, eviuence exists that connon nyeloiu piogenitois, gianulo- cyte-naciophage piogenitois, nono- cytes, anu even connon lynphoiu pio- genitois can give iise to the eneigence ol an epiueinal LC population in expeii- nental aninals. 156,15¯ Unuei inhannatoiy conuitions, DC types that aie not iesiuents ol the noi- nal cutaneous enviionnent appeai in the slin. ¯hese incluue plasnacytoiu DCs (pDCs) anu DCs that phenotypi- cally iesenhle nyeloiu DCs ol the pe- iipheial hloou. ¯he pDCs aie DC pie- cuisois that aie chaiacteiizeu hy a highly uevelopeu enuoplasnic ieticulun, vhich iesults in theii plasna cell-lile appeai- ance. 158 lunctionally, pDCs uisplay a unigue ahility to piouuce enoinous anounts ol natuial llNs in iesponse to ¯LR liganus anu thus veie also naneu ¡rin.i¡a| t,¡c 1 ll^-¡rodu.ing .c||s. 15º Un- uei honeostatic conuitions, pDCs aie lounu in peiipheial hloou anu ¯ celliich aieas ol seconuaiy lynphatic tissue. ln ceitain types ol slin inhannation (e.g., viius inlection, lupus eiythenatosus, psoiiasis, alleigic contact ueinatitis, atopic ueinatitis), pDCs entei the slin in a lashion that engages the CXC che- noline ieceptoi CXCRo. 16O,161 Within the slin, pDCs localize in peiivasculai clusteis vith ¯ cells anu, on activation in situ, nay contiihute to antiniciohial F|608£ 10-7 Sc|era||c d|aç|ar c| ||e cr|cçer], r|ç|a||cr, ard ra|u|a||cr pa||Wa]º c| cu|arecuº derd||||c |eu|cc]|eº. o / 1,4 = o / 1,4 |r|eç||rº, B = B ce||º, CC| = CC c|erc||re ||çard, CCR = CC c|erc||re |ecep|c|, CD = c|uº|e| c| d|||e|er||a||cr-rcrerc|a|u|e c| |eu|cc]|e ar||çerº, C|A = cu|arecuº |]rp|c- c]|e-aººcc|a|ed ar||çer, C|P = ccrrcr |]rp|c|d p|cçer||c| ce||, C|P = ccrrcr r]e|c|d p|cçer||c| ce||, Cp0 D\A = |rrurcº||ru|a|c|] c]|cº|re- ard çuar|re- ||c| ºe(uerceº c| D\A, DC = derd||||c ce||, DDC = de|ra| derd||||c ce||, dºR\A = dcu||e-º||arded R\A, E-Cad = E-cad|e||r, 0|-CS| = ç|aru|cc]|e-rac|cp|açe cc|cr]-º||ru|a||rç |ac|c|, || = |r|e||eu||r, |C = |arçe||arº ce||, |PS = ||pcpc|]ºacc|a||de, | = rac|cp|açe, |-CS| = rac|cp|açe cc|cr]-º||ru|a||rç |ac|c|, ||P = ra|||/ re|a||cp|c|e|raºe, T = T ce||º, T0|- 1 = ||arº|c|r|rç ç|cW|| |ac|c|- 1, T|R = Tc||-|||e |ecep|c|, T\|- = |urc| rec|cº|º |ac|c|- . ll-1 0oger s|go|s lP8 0p0 DhA dsRhA hecrosis Allergeu TlR l0 Adhes|oo E-0ad 00l27 00l20 ThF- ll-1O ll-18 Act|vt|oo 00R7 + E-0ad + /- ll-1 O/ 1,4 NNP-2 NNP-9 0steopoutiu/0D44 8 044 T L1 L21 Lymph oode 0D1a + 0D11c + 00RO + pre-l0 Progeo|tors 0NP 0N-08F ThF- 0lA + 0D84 + T0F- 1 DD0 8tem cell 0lP 0lA - 0D84 + Plasma- c]toid D0 D02 D01 0D128 + 0D14 - 0D110 - pre-D02 0D14 + mouoc]te/ pre-D0 N T0F- 1 N|grt|oo N-08F 109 innune uelense oi (auto)innune-neui- ateu tissue inhannation hy the secie- tion ol natuial llNs anu othei necha- nisns that aie still to he iuentiheu. Anothei non-inuigenous DC popula- tion oiiginates lion nyeloiu piecuisois anu has heen uetecteu in inhannatoiy slin uiseases such as atopic ueinatitis anu contact eczena. ¯he so-calleu in- µammator, dcndriti. c¡idcrma| .c||s aie chaiacteiizeu hy the expiession ol CD1a, CD1h, lc Rl, CD2o, HLA-DR, anu CDo6. 162 lviuence exists that an innune iesponse tiiggeieu hy these cells is sleveu in the ¯h1 uiiection. 16o linally, theie ienains the guestion as to the ultinate late ol the epiueinal anu ueinal DC populations. ía|oi peitui- hation ol the cutaneous nicioenviion- nent (uangei signal 164 ) leaus to theii ac- tivation, vhich iesults eithei in theii elinination via the stiatun coineun in the case ol LCs 165 oi, noie inpoitantly, in the nigiation ol LCs/DDCs to lyn- phoiu tissues, vheie they initiate type 1 (¯h1/cytotoxic ¯ cell 1)uoninateu ¯- cell iesponses (see ¯he Slinlnitiation Site anu ¯aiget ol lnnune Response). By contiast, it is less cleai vhat happens in noinal slin. Does LC sheuuing occui unuei physiologic (nonuangei) conui- tions` ls theie a natuial hux ol LCs/ DDCs to the iegional lynph noues` ll so, vhat aie the lunctional conse- guences ol such an occuiience` lvi- uence exists that nelanin gianules cap- tuieu in the slin accunulate in the iegional lynph noues hut not in othei tissues. ¯he luithei ohseivation ol only veiy lev nelanin gianulecontaining cells in ¯Cl- 1 / nice suggests that, unuei steauy-state conuitions, epiuei- nal anu/oi ueinal antigens aie caiiieu to the iegional lynph noues hy ¯Cl- 1uepenuent cells (nost lilely LCs/ DDCs) only. lt appeais that ¯ lynpho- cytes encounteiing such AlCs in vivo aie ienueieu uniesponsive in an anti- gen-specihc nannei. 166 lt nay theieloie he assuneu that ahsence ol pathogenic ¯-cell autoinnunity anu/oi lacl ol ieac- tivity against seeningly innocuous envi- ionnental conpounus (e.g., aeioallei- gens) in the peiipheiy is piinaiily the conseguence ol an active innune ie- sponse iathei than the iesult ol its non- occuiience. Cn ieceipt ol uangei signals (e.g., ¯LR liganus, chenical haptens, hypoxia), the situation is guite uilleient. Altei a lev houis, LCs hegin to enlaige, to uisplay in- cieaseu anounts ol suilace-hounu íHC class ll nolecules, anu to nigiate uovn- vaiu in the ueinis, vheie they entei al- leient lynphatics anu, hnally, ieach the ¯- cell zones ol uiaining lynph noues. 16¯ Duiing this piocess, LCs unueigo pheno- typic changes sinilai to those that occui in single epiueinal cell cultuies 168 , that is, uovniegulation ol nolecules oi stiuc- tuies iesponsihle loi antigen uptale anu piocessing as vell as loi LC attachnent to leiatinocytes (e.g., lc ieceptois, l-cau- heiin) anu upiegulation ol noieties ie- guiieu loi active nigiation anu stinula- tion ol iohust iesponses ol naive ¯ cells (e.g., CD4O, CD8O, CD8o, CD86). ¯he nechanisns goveining LC nigiation aie heconing incieasingly cleai. ¯Nl- anu lL-1 (in a caspase 1uepenuent lashion) aie ciitical pionoteis ol this piocess, vheieas lL-1O inhihits its occuiience. ln- cieaseu cutaneous piouuction anu/oi ie- lease ol the pio-inhannatoiy cytolines is piohahly one ol the nechanisns hy vhich ceitain innunostinulatoiy con- pounus applieu to oi in|ecteu into the slin |e.g., iniguinou, unnethylateu cytosine- phosphate-guanosine (CpC) oligonucle- otiues] acceleiate LC/DDC nigiation. ln- teiestingly enough, Cunheihatch et al. 16º iepoiteu that, in psoiiasis, LCs aie in- paiieu in theii nigiatoiy capacity. ¯his vas sonevhat unexpecteu in viev ol the ienailahle oveiexpiession ol ¯Nl- in psoiiatic slin. ¯hese investigatois also lounu that the lailuie ol ¯Nl- anu/oi lL- 1 to inuuce LC nigiation lion unin- volveu slin vas not attiihutahle to an alteieu expiession ol ieceptois loi these cytolines. ¯he natuie ol this LC nigia- tion inhihition lactoi is as yet unlnovn. lL-16 also inuuces LC nohilization. ¯his piocess coulu peihaps he opeiative in atopic ueinatitis. ln this uisease, DCs ol lesional slin exhihit suilace lgl hounu to high-alhnity lc ieceptois (lc Rl), anu alleigen-neuiateu ieceptoi cioss-linling iesults in enhanceu lL-16 piouuction. An inpoitant huiule loi enigiating LCs is the hasenent nenhiane. Duiing theii uovnvaiu |ouiney, LCs piohahly attach to it via 6 -containing integiin ie- ceptois anu piouuce pioteolytic en- zynes such as type lV collagenase (na- tiix netallopioteinase º) to penetiate it anu to pave theii vay thiough the uense ueinal netvoil into the lyn- phatic systen. lviuence is accunulating that LC/DDC nigiation occuis in an ac- tive, uiiecteu lashion. Csteopontin is a chenotactic piotein that is essential in this iegaiu. lt initiates LC enigiation lion the epiueinis anu attiacts LCs/ DDCs to uiaining noues hy inteiacting vith an N-teininal epitope ol the CD44 nolecule. 1¯O ¯he entiy into anu active tianspoit ol cutaneous DCs vithin lyn- phatic vessels appeais to he neuiateu hy íCls hinuing to CCR2 anu hy seconuaiy lynphoiu-oigan chenoline/ CCL21 piouuceu hy lynphatic enuo- thelial cells ol the ueinis anu hinuing to CCR¯ on natuiing LCs anu DDCs. 1¯1,1¯2 lnteiestingly, CCL21 expiession is up- iegulateu in iiiitant anu alleigic contact ueinatitis, vhich inplicates its iegu- lateu inpact on DC enigiation lion the slin. 1¯o F0h0T|0hAL P80P£8T|£S 0F 0£h08|T|0 0£LLS Lile the othei nenheis ol the DC lanily, LCs anu DDCs aie °pioles- sional` AlCs, enuoveu vith the unigue capacity ol stinulating antigen-specihc iesponses in naive, iesting ¯ cells. ¯o pioviue a hettei unueistanuing ol this lunctional piopeity, the hasic piinciples ol antigen uptale, piocessing, anu pie- sentation aie hiiehy ievieveu. 6£h£8AL P8|h0|PL£S 0F AhT|6£h P8£S£h- TAT|0h (lig. 1O-8) Unlile B cells, ¯ cells cannot iecognize soluhle piotein antigen pei se, theii antigen ieceptoi ¯CR is ue- signeu to see antigen-ueiiveu peptiues hounu to íHC locusencoueu nole- cules expiesseu hy AlCs. 1¯6 loi the anti- gen-specihc activation ol ¯h cells, exog- enous antigenueiiveu peptiues aie usually piesenteu in the context ol íHC class ll nolecules. 1¯¯ ln this situation, peptiues aie geneiateu in the enuocytic, enuosonal/lysosonal pathvay anu aie hounu to íHC class ll nolecules. ¯he iesulting íHC-peptiue conplex is ex- piesseu at the AlC suilace loi encountei hy the ¯CR ol CD4 + ¯h cells. ln con- tiast, nost CD8 + ¯ cells, uestineu to he- cone cytotoxic ¯ cells, iecognize the en- uogenous antigen in association vith íHC class l nolecules. 1¯¯ Because nost nucleateu cells tiansciihe anu expiess íHC class l genes anu gene piouucts, it is eviuent that nany cell types can seive as AlCs loi íHC class liestiicteu anti- gen piesentation anu/oi as taigets loi íHC class luepenuent attacl hy ¯ cells. ln the íHC class lluepenuent an- tigen-piesentation pathvay, DCs, in- cluuing LCs anu DDCs, B cells, anu nonocytes/naciophages, aie the na|oi AlC populations. Majar B|stacampat|b|||ty 0amp|ex 0|ass l- Bestr|cted Ant|gen Presentat|an 178 . CLAS- SIC MA) OR HI STOCOMPATIBILI TY COMPLEX CLASS I PRESENTATION PATHWAY. lnneuiately altei theii hio- synthesis, íHC class l heavy anu light ( 2 -nicioglohulin) chains aie inseiteu 110 into the nenhianes ol the enuoplasnic ieticulun. ¯he thiiu suhunit ol the lunctional íHC class l conplex is the peptiue itsell. ¯he na|oi souices ol pep- tiues loi íHC class l loauing aie cyto- solic pioteins, vhich can he taigeteu loi theii iapiu uestiuction thiough the cata- lytic attachnent ol uhiguitin. Cytosolic pioteinaceous nateiial unueigoes enzy- natic uigestion hy the pioteasone to yielu shoit peptiue chains ol 8 to 12 anino acius, an appiopiiate length loi íHC class l hinuing. ln its hasic conloi- nation, the pioteasone is a constitu- tively active °lactoiy` loi sell-peptiues. llN- , hy ieplacing oi auuing ceitain pioteasonal suhunits, inuuces °innu- nopioteasones,` piesunahly to hne- tune the uegiauation activity anu speci- licity to the uenanus ol the innune iesponse. ¯he piocesseu peptiues aie tianslocateu to the enuoplasnic ieticu- lun hy the tianspoitei associateu vith antigen piocessing (¯Al), an íHC- encoueu uineiic peptiue tianspoitei. With the aiu ol chapeions (calnexin, cal- ieticulin, tapasin), íHC class l nole- cules aie loaueu vith peptiues, ieleaseu lion the enuoplasnic ieticulun, anu tianspoiteu to the cell suilace. Seveial inlectious agents vith ielevance to slin hiology have auopteu stiategies to suh- veit íHC class l piesentation, anu thus the suiveillance ol cell integiity, hy in- teileiing vith uehneu noleculai taigets. lnpoitant exanples ol such inteileience aie the inhihition ol pioteasonal lunc- tion hy the lpstein-Baii viiusencoueu lBNA-1 piotein, the conpetition loi peptiue-¯Al inteiactions hy a heipes sinplex viius piotein, anu the ietention oi uestiuction ol íHC class l nolecules hy auenoviius- anu hunan cytonegalo- viius-encoueu piouucts. ALTERNATIVE MA)OR HISTOCOMPATI- BILITY COMPLEX CLASS I PRESENTATION PATHWAYS (CROSS-PRESENTATION). Unuei ceitain conuitions, exogenous an- tigen can ieach the íHC class l piesen- tation pathvay. Signihcant eviuence loi this cioss-piesentation hist cane lion in vivo expeiinents in nice uenon- stiating that viial, tunoi, anu íHC an- tigens can he tiansleiieu lion íHC- nisnatcheu uonoi cells to host hone naiiovueiiveu AlCs to elicit antigen- specihc cytotoxic ¯-cell iesponses that aie iestiicteu to sell íHC nolecules. 1¯º ln vitio stuuies have nov uehneu that exosones (i.e., snall secietoiy vesicles ol appioxinately 1OO nn in uianetei secieteu hy vaiious cell types, incluuing F|608£ 10-8 Ar||çer-p|cceºº|rç pa||Wa]º. T|e |r||ace||u|a| ar||çer-p|cceºº|rç pa||Wa]º |c| rajc| ||º|cccrpa|||||||] ccrp|e/ (|HC, c|aºº |, |HC c|aºº ||, ard CD1 p|eºer|a||cr a|e º|cWr. T|e |HC c|aºº | pa||Wa] |r.c|.eº ||e p|cceºº|rç c| c]|cp|aºr|c p|c|e|rº, W|e|eaº ||e |HC c|aºº || pa||Wa] |r.c|.eº ||e p|cceºº|rç c| e/cçercuº p|c|e|rº. T|e CD1 pa||Wa] |eçu|a|eº ||e p|cceºº|rç ard p|eºer|a||cr c| ºe||-ç|]ccºp||rçc||p|dº ard |ac|e||a| ||pcç|]carº. D\ T ce|| = dcu||e-reça||.e (CD4 - /CD8 - , T ce||, ER = erdcp|aºr|c |e||cu|ur, |||C = |HC c|aºº || |]ºcºcra| pep||de-|cad|rç ccrpa||rer|, \|T ce|| = ra|u|a| ||||e| T ce||, TAP = ||arºpc||e| aººcc|a|ed W||| ar||çer p|cceºº|rç, TCR = T-ce|| |ecep|c|. 0D8+ T cell hKT cell/ Dh T cell 0D4+ T cell T0R 0D8 NH0 class l pathwa] Proteasome TAP ER NH0 0lass l NH0 class ll 0olgi NH0 class ll pathwa] Eudosome pH<5 Nll0 Eudosome 0D4 T0R Biroeck grauule T0R V 24 lipid autigeu 111 tunoi cells), heat shocl pioteins, in- nune conplexes, anu apoptotic cells (talen up via CDo6 anu o oi 5 integiins) can all seive as vehicles loi the ueliveiy ol antigen to DCs in a nan- nei that peinits the cioss-piesentation ol antigen. ln all in vitio systens in vhich a uiiect conpaiison has heen naue, DCs, incluuing LCs, hut not nonocytes/naciophages, veie capahle ol cioss-piesentation. 18O,181 ¯hiee uis- tinct pathvays aie cuiiently exploiteu hy vhich antigen can access íHC class l nolecules ol DCs: (1) a iecycling path- vay loi íHC class l in vhich antigen is loaueu in the enuosone, (2) a pathvay hy vhich ietiogiaue tianspoit ol the an- tigen lion the enuosone to the enuo- plasnic ieticulun lacilitates entiy into the classic íHC class l antigen piesen- tation pathvay, anu (o) an enuosone to the cytosol tianspoit pathvay, vhich again allovs antigen piocessing via the classic íHC class l antigen piesentation pathvay. Majar B|stacampat|b|||ty 0amp|ex 0|ass ll- Bestr|cted Ant|gen Presentat|an 177 . íHC class ll nolecules pieuoninantly hinu peptiues vithin enuosonal/lysosonal conpaitnents. Sanpling peptiues in these suh-cellulai oiganelles allov class ll nolecules to associate vith a hioau aiiay ol peptiues ueiiveu lion pioteins taigeteu loi uegiauation altei inteinal- ization hy huiu phase oi ieceptoi-neui- ateu enuocytosis, naciopinocytosis, oi phagocytosis. Cne ol the stiiling stiuc- tuial uilleiences hetveen íHC class l anu class ll nolecules is the conloina- tion ol theii peptiue-hinuing giooves. Wheieas íHC class l nolecules have hinuing poclets to acconnouate the chaigeu teinini ol peptiues anu thus se- lectively associate vith shoit peptiues, the hinuing sites ol íHC class ll nole- cules aie open at hoth enus. ¯hus, íHC class ll nolecules hinu peptiues vith pieleiieu lengths ol 15 to 22 anino ac- ius hut can also associate vith longei noieties. Nevly synthesizeu íHC class ll anu suhunits assenhle in a stoichionetiic conplex vith tiineis ol the type ll tians- nenhiane glycopiotein invaiiant chain (li). ¯he association vith li contiihutes in at least thiee uilleient vays to the lunc- tion ol class ll nolecules: (1) li assenhly pionotes the piopei loluing ol class ll nolecules in the enuoplasnic ieticulun, (2) the ahluninal poition ol li contains signal seguences that lacilitate the expoit ol íHC class llli conplexes thiough the Colgi systen to enuosones/lysosones, anu (o) li pievents class ll nolecules lion pienatuie loauing hy peptiues intenueu loi hinuing to íHC class l nolecules in the enuoplasnic ieticulun. ¯he segnent ol li lunctioning as a conpetitoi loi pep- tiue hinuing to class ll is teineu .|ass ll asso.iatcd li ¡c¡tidc (CLll, iesiuues 81 to 1O4 ol li). Cnce the nascent íHC class ll / li tiineis aiiive in the enuosonal/ lysosonal systen, li is suh|ect to pioteol- ysis hy aciu hyuiolases. ¯he last pio- teolytic step, the geneiation ol CLll, is catalyzeu hy cathepsin S in DCs, hy ca- thepsin L in thynic epithelial cells, anu hy cathepsin l in naciophages. Cn HLA- Díchapeioneu exchange ol CLll loi exogenous antigen-ueiiveu peptiue, lully assenhleu class ll nolecules aie expoiteu to the cell suilace anu acguiie a stahle conloination. Depenuing on the cell type anu the activation status ol a cell, the hall-lile ol class llpeptiue conplexes vaiies lion a lev houis to uays. lt is pai- ticulaily long (noie than 1OO houis) on DCs that have natuieu into potent in- nunostinulatoiy cells ol lynphoiu oi- gans on encountei vith an inhannatoiy stinulus in nonlynphoiu tissues. ¯he veiy long ietention ol class llpeptiue conplexes on natuie DCs ensuies that only those peptiues geneiateu at sites ol inhannation vill he uisplayeu in lyn- phoiu oigans loi ¯-cell piining. Cyto- lines have long heen lnovn to iegulate antigen piesentation hy DCs. ln lact, pio- inhannatoiy (¯Nl- , lL-1, llN- ) anu anti-inhannatoiy (lL-1O, ¯Cl- 1) cyto- lines iegulate piesentation in íHC class ll nolecules in an antagonistic lashion. íechanistically, iegulatoiy ellects in- cluue the synthesis ol íHC conponents anu pioteases, anu the iegulation ol en- uolysosonal aciuihcation. 182,18o 001-0ependent Ant|gen Presentat|an 184 . Besiues peptiues, sell-glycosphingolipius anu hacteiial lipoglycans nay also act as ¯ cellstinulatoiy liganus. íolecules that hinu anu piesent these noieties he- long to the lanily ol nonpolynoiphic, íHC class l anu llielateu CD1 pio- teins. ln the slin, nenheis ol the CD1 lanily aie expiesseu nainly hy LCs anu DDCs (see Developnent, íaintenance, anu late ol Slin Denuiitic Cells). ¯he CD1 isoloins CD1a, CD1h, CD1c, anu CD1u sanple hoth iecycling enuosones ol the eaily enuocytic systen anu late enuosones anu lysosones to vhich lipiu antigens aie ueliveieu. Unlile in the íHC class ll pathvay, antigen loauing in the CD1 pathvay occuis in a vacuolai aciuihcation-inuepenuent lashion. ¯ cells expiessing a V 24-containing canonic ¯CR, Nl¯ cells, anu CD4 /CD8 ¯ cells incluue the nost pioninent suhsets ol CD1-iestiicteu ¯ cells. CD1-iestiicteu ¯ cells play inpoitant ioles in host uelense against niciohial inlections. Accoiuingly, hunan suh|ects inlecteu vith /. tu|cr.u- |osis shoveu stiongei iesponses to CD1c- neuiateu piesentation ol a niciohial lipiu antigen than contiol suh|ects, anu activation ol CD1u-iestiicteu Nl¯ cells vith a synthetic glycolipiu antigen ie- sulteu in inpioveu innune iesponses to seveial inlectious pathogens. ¯hus, the CD1 pathvay ol antigen piesentation anu glycolipiu-specihc ¯ cells nay pio- viue piotection uuiing hacteiial anu paia- site inlection, piohahly hy the secietion ol pio-inhannatoiy cytolines, the ui- iect lilling ol inlecteu taiget cells, anu B- cell help loi lg piouuction. Conpelling eviuence exists that LCs anu othei slin DCs, as nenheis ol the lanily ol piolessional AlCs, play a piv- otal iole in the inuuction ol auaptive in- nune iesponses against pathogens anu neoantigens intiouuceu into anu/oi gen- eiateu in the slin (innunosuiveillance). ¯his is hest illustiateu hy the eaily oh- seivation that LC-containing, hut not LC-uepleteu, epiueinal cell suspensions pulse-exposeu to eithei soluhle piotein antigens oi haptens elicit a genetically iestiicteu, antigen-specihc, piolileiative in vitio iesponse in naive ¯ cells. 185 Al- though these ohseivations inply that the LC/DC systen is inuispensahle loi the occuiience ol antigen-specihc slin innunity, it is egually cleai that LCs/ DCs as they occui in theii tissue iesi- uence aie pooily, il at all, stinulatoiy loi naive ¯ cells. lnaha et al. 186 lounu that lieshly isolateu LCs (°innatuie` LCs) can piesent soluhle antigen to piineu íHC class lliestiicteu ¯ cells hut aie only veal stinulatois ol naive, allogeneic ¯ cells. ln contiast, LCs puii- heu lion epiueinal cell suspensions al- tei a cultuie peiiou ol ¯2 houis oi LCs puiiheu lion lieshly isolateu nuiine epiueinal cells anu cultuieu loi ¯2 houis in the piesence ol Cí-CSl anu lL-1 (°natuie` LC) aie extienely potent stinulatois ol piinaiy ¯ cellpiolileia- tive iesponses to alloantigens, 186 soluhle piotein antigens, 18¯ anu haptens. 18¯ ¯he stiong innunostinulatoiy potential ol natuie LCs loi iesting ¯ cells uoes not nean that they aie supeiioi to lieshly isolateu, innatuie LCs in eveiy lunc- tional aspect. ln lact, innatuie LCs lai excel cytoline-activateu LCs in theii ca- pacity to tale up anu piocess native piotein antigens. 188 Accoiuingly, inna- tuie iathei than natuie LCs/DCs ex- 112 piess antigen uptale ieceptois. íatuie LCs, although lully capahle ol piesent- ing pie-piocesseu peptiues, have lost theii capacity to piocess anu piesent na- tive piotein antigens. 188 ¯his cytoline- inuuceu/cultuie-inuuceu svitch lion the piocessing/peptiue loauing to the piesentation noue is a highly iegulateu LC/DC lunction attiihutahle to lunua- nental noleculai changes in piotein synthesis anu vesicle tialhcling. LCs in theii innatuie state uisplay íHC class ll antigens in lysosonal peptiue-loauing conpaitnents (íllC) anu, to a nuch lessei extent, on the cell suilace. When LCs natuie in situ, íHC class ll nole- cules aie tiansleiieu to the plasna nenhiane. Lilevise, íHC class l sui- lace expiession is upiegulateu uuiing the piocess ol DC natuiation. ¯he uisplay ol íHC-peptiue con- plexes on the DC suilace ueliveis the °hist signal` to ¯ cellsthat is, the tiiggei- ing ol the ¯CR hy the AlC-hounu pep- tiue-íHC conplex. Although this event nay he sulhcient to inuuce the piolileia- tion ol piineu ¯ cells, it is insulhcient loi the piouuctive activation ol naive ¯ cells. ¯he occuiience ol the lattei ieguiies the ieceipt ol °seconu signals,` vhich can he ueliveieu hy piolessional AlCs. ln lact, antigen-specihc ¯ cells that encountei íHC-expiessing cells that cannot uelivei seconu signals (e.g., íHC class llinuuceu leiatinocytes, enuothelial cells, hhio- hlasts) entei a state ol aneigy. 18º Seconu signals also ueteinine the nagnituue anu guality ol piinaiy anu seconuaiy ¯-cell iesponses. ln slin DCs, as vell as in DCs lion othei locations, co-stinulatoiy nol- ecules that uelivei seconu signals aie up- iegulateu uuiing natuiation inuuceu hy suilace ieceptois tiiggeieu hy liganus se- cieteu oi piesenteu hy othei sonatic cells oi, alteinatively, hy niciohial piouucts (uangei oi conpetence signals). Seconu signals incluue secieteu cytolines anu nenhiane-hounu co-stinulatois, the hest uehneu ol vhich aie the tvo nenheis ol the B¯ lanily, B¯.1/CD8O anu B¯.2/ CD86. LCs/DCs in situ uo not expiess oi expiess only ninute anounts ol these co- stinulatoiy nolecules, hut gieatly upieg- ulate these noieties uuiing natuiation. Cthei co-stinulatoiy nolecules incluue the lCAí-1 that hinus to LlA-1, anu LlA-o, the liganu ol ¯ cellexpiesseu CD2. Cthei inpoitant liganu-ieceptoi paiis that positively allect ¯-cell activa- tion hy DCs incluue heat-stahle antigen (CD24)/CD24L, CD4O/CD4OL, CD¯O/ CD2¯L, CX4O (CD1o4)/CX4OL, anu ie- ceptoi activatoi ol nucleai lactoi B (RANl)/RANlL. THE S||\-|\|T|AT|0\ S|TE A\D TAR0ET 0| |||U\E RESP0\SES (lig. 1O-º) ln 1º8o, Wayne Stieilein coineu the tein skin-asso.iatcd |,m¡hoid tissucs 1º1 to ue- sciihe a lunctionally inteiactive ciicuit ol cells anu tissues (uenuiitic AlCs, cyto- line-piouucing leiatinocytes, anu slin- honing ¯ cells oiiginating in slin-uiain- ing peiipheial lynph noues) that pioviue the slin vith unigue innunosuiveil- lance nechanisns loi the successlul pievention ol oi conhat against cancei anu inlectious uiseases. ¯hese cells anu tissues also secuie the honeostasis ol the host hy pieventing the uevelopnent oi uovniegulating the expiession ol exag- geiateu tissue-uestiuctive innune ie- sponses against pei se innocuous noieties such as autoantigens anu ceitain alleigens. Ciitical to the unueistanuing ol this yin-yang situation vas the ohseivation that, unuei honeostatic conuitions, the oveivhelning na|oiity ol antigen- piesenting DCs aie in an innatuie state that allovs then to elhciently tale up antigen vith the help ol specihc ie- ceptoi sites (e.g., Langeiin, naciophage nannose ieceptoi, C-type lectin iecep- toi DlC-2O5, lov-alhnity lgC ieceptoi CDo2/lc Rll, high-alhnity lgl iecep- toi lc Rl, the thionhosponuin ieceptoi CDo6, DC-SlCN), hut uoes not enuov then vith innunostinulatoiy piopei- ties loi naive iesting ¯ cells. Cn the ue- liveiy ol uangei signals, 164 hovevei, DCs unueigo a phenotypic anu lunc- tional netanoiphosis that enahles then to elicit piouuctive anu, unuei optinal ciicunstances, piotective piinaiy in- nune iesponses. lt vas oiiginally assuneu that the in- uuction ol antigen-specihc non-iespon- siveness occuis vhen antigens aie pie- senteu in the context ol non-uenuiitic AlCs (nonpiolessional AlCs). ¯he eaily ohseivation that the application ol hapten to LC-uehcient slin oi nucosa iesults in hapten-specihc toleiance 1º2 points in this uiiection. íoie iecent eviuence nov suggests that DCs/LCs thenselves can actively in- uuce innune toleiance. ln vitio, inna- tuie DCs pieleientially activate ¯ieg cells. 1ºo ln vivo, in the steauy state, DCs inuuce toleiance to specihc antigens tai- geteu to these cells. 166,1º4,1º5 íechanisns iesponsihle loi the toleiance-inuucing piopeity ol nonactivateu DCs, although not entiiely unueistoou, incluue (1) a ie- uuceu expiession ol íHC-antigen con- plexes 1º6 anu co-stinulatoiy nolecules 1º¯ on the cell suilace, (2) the secietion ol in- nunosuppiessive cytolines such as lL- 1O, 1º8 vhich hts vell to the hnuing ol ¯ieg inuuction hy UV-iiiauiateu, lL-1O piouucing ¯ieg cells 1ºº , (o) the expies- sion ol innunoinhihitoiy enzynes such as inuoleanine 2,o-uioxygenase 2OO , (4) the ieceipt ol signals inteileiing vith the natuiation anu nigiation ol DCs, loi ex- anple, neuiopeptiues such as CCRl 2O1 anu vasoactive intestinal peptiue, 2O2 the engagenent ol the CD4¯/SHlS-1 signal tiansuuction cascaue, 2Oo anu otheis. lt appeais that these uilleient lactois aie not egually opeiative in all situa- tions. LCs, loi exanple, can activate sell-antigenspecihc CD8 ¯ cells in the steauy state, vhich leaus to chionic slin uisease, 2O4 anu, at the sane tine, LCs aie uispensahle loi 2O5 oi can even uovniegulate 2O6 the inuuction ol CHS. leituihation ol tissue honoeostasis (i.e., the ueliveiy ol a uangei signal) ini- tiates a seiies ol noleculai events that allov peiipheial DCs to iapiuly nigiate to seconuaiy lynphoiu oigans, a |oui- ney uuiing vhich they natuie into po- tent innunostinulatoiy cells capahle ol sensitizing unpiineu lynphocytes loi piouuctive iesponses. ¯his can he vell exenpliheu hy a iathei sinple nanipu- lation: cultuie ol explanteu slin loi vhich hypoxia appaiently sulhces to tiiggei nigiation anu natuiation ol cu- taneous DCs. 16¯ Anothei exanple is the topical application ol contact sensitizeis (e.g., uinitiohuoiohenzene), vhich leaus to the activation ol ceitain piotein ty- iosine linases, the nouihcation ol cellu- lai content anu stiuctuie ol intiacyto- plasnic oiganelles (inciease in coateu pits anu vesicles, enuosones anu lyso- sones, Biihecl gianules), anu incieaseu in situ notility ol these cells. 2O¯ lt appeais that cytolines, ieleaseu as a conseguence ol physicochenical oi inlection-associateu tissue peituihation (e.g., leiatinocyte-ueiiveu Cí-CSl, ¯Nl- , lL-1) anu/oi ligation ol CD4O nole- cules on DC/LC suilaces, pioviue the ciitical signal loi the inuuction ol LC natuiation. But hov uo slin cells iecog- nize a uangei signal anu tianslate it into incieaseu cytoline piouuction` Cne hiologically ielevant pathvay is ceitainly the natuiation signal that is ueliveieu to DCs/LCs hy the uptale ol neciotic cells. ¯he lact that LCs aie ca- pahle ol cioss-piesentation 181,18O coulu nale this an inpoitant nechanisn in the geneiation ol a piotective antitunoi innune iesponse. Successlul uelense against invauing niciooiganisns involves the iecogni- tion ol pathogen-associateu noleculai 113 patteins thiough nenheis ol the ¯LR piotein lanily, 11 nenheis ol vhich have heen classiheu so lai (see eailiei). lviuence nov exists that hunan LCs ex- piess nessengei RNA encouing ¯LR1, ¯LR2, ¯LRo, ¯LR5, ¯LR6, anu ¯LR1O. 2O8 Liganus ol ¯LR1, ¯LR2, anu ¯LR6 in- cluue lipopioteins lion /. tu|cr.u|osis, 3. |urgdorjcri, T. ¡a||idum, nycohacteiial lipo- aiahinonannan, peptiuoglycan, zyno- san, anu glycophosphatiuyl inositol anchois lion T. ¡a||idum anu T. .ru:i lipopioteins. Wheieas ¯LR5 uetects hac- teiial hagellin, ¯LRo is associateu vith the iecognition ol viial uouhle-stianueu RNA. LCs nount a paiticulaily iohust antiviial iesponse to ¯LRo agonists, 2Oº vhich inplies that natuial oi synthetic liganus loi ¯LRo night piove uselul in the tieatnent ol viial slin inlections. loi innunotheiapeutic puiposes, paiticulai attention has also locusseu on ¯LR¯, ¯LR8, anu ¯LRº, vhich aie intia- cellulai ieceptois loi nucleic acius. ¯LR¯ anu ¯LR8 aie engageu hy viial single- stianueu RNA anu hy synthetic snall nolecules ninicling leatuies ol nucleic F|608£ 10-9 T|e rec|ar|ºrº cpe|a||.e |r ||e |r|||a||cr, e/p|eºº|cr, ard dcWr|eçu|a||cr c| cu|arecuº |rrure |eºpcrºeº. |rduc||cr c| p|cduc||.e T-ce|| |rrur||] .|a ||e º||r. T|e ep|cu|arecuº ard/c| |r||acu|arecuº de rc.c appea|arce c| ar||çerº (|.e., pa||cçerº ºuc| aº r|c|cc|çar|ºrº ard |ap|erº, |eºu||º |r ||e e||c||a||cr c| p|cduc||.e ar||çer-ºpec||c |rrur||] W|er 'darçe| º|çra|º' (|.e., |ac|e||a| D\A ||c| |r urre||]|a|ed c]|cº|re-p|cºp|a|e-çuar|re |epea|º ard c||e| Tc||-|||e |ecep|c| ||çardº, a|e p|eºer| a| ||e ||re c| ar||çer|c e/pcºu|e. T|e |ece|p| c| darçe| º|çra|º |eadº |c ||ººue pe||u||a||cr, aº e.|derced |] ||e |rc|eaºed ºec|e||cr c| ç|aru|cc]|e-rac|cp|açe cc|cr]-º||ru|a||rç |ac|c|, |urc| rec|cº|º |ac|c|- , ard |r|e||eu||r 1 (||-1, |] |e|a||rcc]|eº (|Cº, ard c||e| º||r ce||º. Ar||çer-p|eºer||rç ce||º (APCº, [|arçe||arº ce||º (|Cº,, de|ra| derd||||c ce||º (DDCº,| ||a| p|c| up ||e ar||çer, p|cceºº ||, ard |e-e/p|eºº || aº a pep||de- rajc| ||º|cccrpa|||||||] ccrp|e/ (|HC, p|cduc| cr ||e ºu||ace a|e a|ºc p|c|curd|] a||ec|ed |] darçe| º|çra|º c| darçe| º|çra|-|rduced c]|c||reº. T|e a||e|- a||crº c| |Cº/DDCº |rc|ude ||e |rc|eaºed e/p|eºº|cr c| |HC ar||çerº, cc-º||ru|a|c|] rc|ecu|eº, ard c]|c||reº (||-1 , ||-o, ||-12,, aº We|| aº ||e er|arced er|ç|a||cr c| ||eºe ce||º ||cr ||e º||r |c ||e pa|acc|||ca| a|eaº c| ||e d|a|r|rç |]rp| rcdeº. A| |||º º||e, ||e º||r-de||.ed derd||||c ce||º (DCº, p|c.|de ac||.a||cr º||ru|| |c ||e ra|.e |eº||rç T ce||º ºu||curd|rç ||er. T||º cccu|º |r ar ar||çer-ºpec||c |aº||cr ard ||uº |eºu||º |r ||e e/parº|cr c| ||e |eºpec||.e c|cre(º,. T|eºe p||red T ce||º |eç|r |c e/p|eºº º||r-|cr|rç |ecep|c|º (e.ç., C|A, aº We|| aº |ecep|c|º |c| .a||cuº c|erca|||ac|ar|º ||a| p|crc|e ||e|| a||ac|rer| |c de|- ra| r|c|c.aºcu|a| erdc||e||a| ce||º c| |r1ared º||r ard, u|||ra|e|], ||e|| er||] |r|c |||º ||ººue. E||c||a||cr c| T ce||-red|a|ed ||ººue |r1arra||cr ard pa||cçer de|erºe. 0r |ece|p| c| a |ereWed ar||çer|c º||ru|uº |] cu|arecuº APCº (|Cº, DDCº,, ||e º||r-|cr|rç p||red T ce||º e/pard |cca||] ard d|ºp|a] ||e e||ec|c| |urc||crº reeded |c| ||e e||r|ra||cr, c| a| |eaº| ||e a||ac|, c| ||e pa||cçer. A||e|ra||.e|], p||red T ce||º ra] erccur|e| ||e ar||çer cr ||e ºu||ace c| rcrp|c|eº- º|cra| APCº (e.ç., |HC c|aºº ||-|ea||rç |Cº,, a º||ua||cr ||a| ccrce|.a||] |eºu||º |r a º|a|e c| c|cra| T-ce|| are|ç]. DcWr|eçu|a||cr ard p|e.er||cr c| cu|arecuº T-ce|| |rrur||]. |r ||e a|ºerce c| darçe| º|çra|º (||ººue |crecº|aº|º,, ar||çer-|caded |Cº/DDCº a|ºc |ea.e ||e cu|arecuº ccrpa||rer| ard r|ç|a|e |cWa|d ||e d|a|r|rç |]rp| rcde. T|eºe ce||º c|, a||e|ra||.e|], |eº|der| |]rp| rcde DCº ||a| |ad p|c|ed up ar||çer|c rc|e||eº ||cr a||e|er| |]rp|a||cº p|eºer| |||º ar- ||çer |r a rcrp|cduc||.e |aº||cr-||a| |º, ||e] |rduce ar||çer-ºpec||c T-ce|| ur|eºpcrº|.ereºº c| a||cW ||e |eºpcrd|rç T ce||(º, |c d|||e|er||a|e |r|c |rrurcºup- p|eºº|.e T |eçu|a|c|] ce||º. T|e |a||e| ra] ||r|| ar||çer-d||.er c|cra| T-ce|| e/parº|cr du||rç p||ra|] |rrure |eac||crº |r |]rp| rcdeº ard du||rç ºeccrda|] |rrure |eac||crº a| ||e |e.e| c| ||e pe||p|e|a| ||ººue. Suc| e.er|º car |eºu|| |r ||e dcWr|eçu|a||cr c| |c|| deº||ed (ar|||urc|, ar||r|c|c||a|, ard urdeº||ed (|ap|er-ºpec||c, au|c|eac||.e, |rrure |eºpcrºeº. Aç = ar||çer, T = T ra|.e ce||, T¯ = are|ç|c T ce||, TCR = T-ce|| |ecep|c|. Dauger siguals T T8 l]mph uode Affereut phase Effereut phase T* T T* lmmature l0/DD0 Nature l0/DD0 DD0 Ag Ag Ag Ag l0 K0 DD0 l0 DD0 Ag l0 K0 Ag 0]tokiues 0hemokiues Eudothelial cells Primed T cell T l]mphoc]te Affereut l]mphatic vessel 0loual expausiou Epidermis Dermis 114 acius, such as iniguinou anu R-848. ¯LRº, on the othei hanu, iecognizes oli- goueoxynucleotiues (CDNs) containing unnethylateu CpC notils (CpC CDN), vhich aie unueiiepiesenteu in nanna- lian genones hut ahunuant in viial anu hacteiial DNA. Both ¯LR¯ anu ¯LRº li- ganus have piolounu ellects on the slin`s innune systen. lniguinou anu the othei iniuazoguinolines inuuce stiong inhannation anu, ultinately, ie- giession ol viial acanthonas anu othei supeihcial slin neoplasns. 21O CpC CDNs pionote LC nigiation 211 anu pionote the uevelopnent ol ¯h1 ie- sponses. 212 lt is still not cleai hov the topical application ol ¯LR¯ anu ¯LR8 li- ganus coulu elicit such a iohust inhan- natoiy iesponse, hecause the iespective ieceptois aie pieuoninantly expiesseu on pDCs, vhich aie the nain piouuceis ol type l llNs anu aie viitually ahsent in noinal hunan slin. 21o ¯he uenonstia- tion ol ¯LR¯ on supiahasal leiatino- cytes 2O8 coulu inuicate that these cells, iathei than LCs oi DDCs, aie the piine slin taigets ol topical iniuazoguino- lines anu, hy tiiggeiing the piouuction ol pio-inhannatoiy cytolines anu che- nolines in these cells, aie iesponsihle loi the inhux ol uilleient types ol leulo- cytes, incluuing plasnacytoiu anu nye- loiu inhannatoiy-type DCs. ¯he iole ol these lattei cells in the innune ie- sponse has yet to he claiiheu. lviuence exists that inhannatoiy-type nyeloiu DCs slev the innune iesponse in a ¯h1 uiiection 16o anu that pDCs, ue- penuing on theii state ol activation, la- voi the activation ol ¯h2 anu ¯ieg cells, iespectively. When topical iniguinou tieatnent (see Chap. 221) iesults in the iegiession anu, ultinately, iesolution ol slin neoplasns, these inhannatoiy- type DCs aie ahunuantly piesent aiounu iegiessing tunoi cell islanus 214 anu can expiess nolecules ol the lytic nachineiy such as peiloiin, gianzyne B, anu ¯Nl-ielateu apoptosis-inuucing liganu, vhich suggests theii cytotoxic potential. ¯he inuuction ol slin cell in|uiy anu/ oi uenise hy cells ol the innate innune systen shoulu not uetiact lion the lact that auaptive nechanisns aie iesponsi- hle loi nost ol the uesiieu innune ieac- tions in the slin (i.e., the elinination ol pathogenic niciooiganisns anu neo- plastic cells) as vell as loi innune- neuiateu in|uiy ol the slin. lxanples ol the lattei aie hullous uiseases such as penphigus anu hullous penphigoiu. Al- though these entities aie neuiateu hy autoantihouies, othei slin uiseases aie appaiently the iesult ol exaggeiateu anu/oi nisuiiecteu ¯-cell ieactions. ¯he slin innune systen is also al- lecteu hy vaiious innunonouulating conpounus applieu to oi intiouuceu into the slin. ¯he elhcacy ol iniuazo- guinolines anu CpC oligonucleotiues in cutaneous neoplasns has alieauy heen uiscusseu, anu one voulu pieuict that a noie selective taigeting ol LCs/DDCs vill inciease theii elhcacy, toleiahility, anu salety. Coiticosteioius, the nost lieguently useu innunoinhihitoiy anu anti-inhan- natoiy suhstances in ueinatology, have a piolounu inhuence on the phenotype anu lunction ol cutaneous leulocytes at hoth the topical anu systenic levels. Al- tei topical application ol hetanethasone valeiate loi only a lev uays, apoptotic events aie cleaily visihle in the epiuei- nal LC population, anu on continuation ol this tieatnent the epiueinis can he essentially uepleteu ol these cells. ¯he so-calleu inµammator,-t,¡c DCs (i.e., in- hannatoiy uenuiitic epiueinal cells anu pDCs) aie sinilaily susceptihle to coiticosteioius, vhich is one ol the iea- sons loi the excellent elhcacy ol topical coiticosteioius in tieating acute ueina- titis/eczena. 22O ¯he ellects ol the topical calcineuiin inhihitois taciolinus anu pineciolinus aie noie selective. ¯heii application to the slin ol patients vith atopic ueinati- tis leaus to an apoptosis-inuuceu ueple- tion ol ¯ cells anu to a giauual uisap- peaiance ol inhannatoiy-type DCs hut leaves the epiueinal LC population es- sentially unalteieu. 22O ¯ine vill tell vhethei the uilleiential ellects ol topi- cal coiticosteioius anu calcineuiin inhih- itois on the slin innune systen vill have an inhuence on the long-tein salety ol these conpounus. ¯he entiie helu ol topical innuno- nouulation is nov auvancing iapiuly hecause ol (1) an incieasingly hettei un- ueistanuing ol the slin`s innune lunc- tion anu, as a conseguence, the iuentih- cation ol pionising uiug taigets, (2) nev conputei-assisteu nethous ol uiug ue- sign, anu (o) nev technologies that al- lov loi a hettei penetiation ol a given conpounu into the slin anu its guiu- ance to the uesiieu taiget. ¯hese uevel- opnents aie heialuing a nev goluen eia ol slin-haseu innunotheiapy, anu the slills ol a vell-tiaineu ueinatologist aie ieguiieu to use the theiapy loi the nax- inun heneht ol patients. |E\ RE|ERE\CES T|e |u|| |e|e|erce ||º| |c| a|| c|ap|e|º |º a.a||a||e a| WWW.d|çr/.ccr. 2. Casgue l: Conplenent: A unigue innate innune sensoi loi uangei signals. /o| lmmuno| 41:1O8º, 2OO4 6. Biall íH et al: Cutaneous uelense nechanisns hy antiniciohial peptiues. j lnvcst Dcrmato| 125:º, 2OO5 2º. Aliia S, Uenatsu S, ¯aleuchi C: latho- gen iecognition anu innate innunity. Cc|| 124:¯8o, 2OO6 55. van looten C, Bancheieau [: CD4O- CD4O liganu. j lcuko. 3io| 67:2, 2OOO ¯1. Haiiington Ll, íangan lR, Weavei C¯: lxpanuing the ellectoi CD4 ¯-cell iep- eitoiie: ¯he ¯h1¯ lineage. Curr ·¡in lmmuno| 18:o4º, 2OO6 81. von Boehnei H: Selection ol the ¯-cell iepeitoiie: Receptoi-contiolleu checl- points in ¯-cell uevelopnent. Adv lmmu- no| 84:2O1, 2OO4 84. Ahhas Al, íuiphy lí, Shei A: lunc- tional uiveisity ol helpei ¯ lynpho- cytes. ^aturc 383:¯8¯, 1ºº6 º2. Beile C: ¯he hinuing anu lysis ol taiget cells hy cytotoxic lynphocytes: íolec- ulai anu cellulai aspects. Annu Rcv lmmuno| 12:¯o5, 1ºº4 1O1. Butchei lC, liclei L[: Lynphocyte hon- ing anu honeostasis. :.icn.c 272:6O, 1ºº6 115. íoulin RL et al: Leaining lion lesions: latteins ol tissue inhannation in lep- iosy. lro. ^at| A.ad :.i ! : A 85:121o, 1º88 1o8. Langeihans l: Ühei uie Neiven uei nen- schlichen Haut. Vir.hovs Ar.h 44:o25, 1868 14O. Bancheieau [, Steinnan Rí: Denuiitic cells anu the contiol ol innunity. ^aturc 3º2:245, 1ºº8 15º. Siegal ll et al: ¯he natuie ol the piinci- pal type 1 inteileion-piouucing cells in hunan hloou. :.icn.c 284:18o5, 1ººº 164. íatzingei l: An innate sense ol uangei. Ann ^ Y A.ad :.i º61:o41, 2OO2 184. loicelli SA, íoulin RL: ¯he CD1 sys- ten: Antigen-piesenting nolecules loi ¯ cell iecognition ol lipius anu glycolip- ius. Annu Rcv lmmuno| 17:2º¯, 1ººº 185. Stingl C, ¯anali l, latz Sl: Ciigin anu lunction ol epiueinal Langeihans cells. lmmuno| Rcv 53:14º, 1º8O 1º1. Stieilein [W: Slin-associateu lynphoiu tissues (SAL¯): Ciigins anu lunctions. j lnvcst Dcrmato| 80 Suppl:12s, 1º8o 1º¯. Lutz íB, Schulei C: lnnatuie, seni- natuie anu lully natuie uenuiitic cells: Which signals inuuce toleiance oi innu- nity` Trcnds lmmuno| 23:445, 2OO2 2O2. louali S et al: Vasoactive intestinal pep- tiue nouulates Langeihans cell innune lunction. j lmmuno| 173:6O82, 2OO4 21O. Docliell DH, linghoin CR: lniguinou anu iesiguinou as novel innunonouu- latois. j Antimi.ro| Chcmothcr 48:¯51, 2OO1 115 C H A P T E R 1 1 0ytok|oes ||c| R. w||||arº Berjar|r E. R|c| T|craº S. |uppe| THE C0\CEPT 0| C\T0||\ES When cells anu tissues in conplex oigan- isns neeu to connunicate ovei uis- tances gieatei than one cell uianetei, sol- uhle lactois nust he enployeu. A suhset ol these lactois is nost inpoitant vhen piouuceu oi ieleaseu tiansiently unuei eneigent conuitions. When laceu vith an inlection- oi in|uiy-ielateu challenge, the host nust oichestiate a conplex anu caielully choieogiapheu seiies ol steps. lt nust nohilize ceitain ciiculating vhite hloou cells piecisely to the ielevant in- |uieu aiea (hut not elsevheie) anu guiue othei leulocytes involveu in host ue- lense, paiticulaily ¯ anu B cells, to spe- cializeu lynphatic tissue ienote lion the inlectious lesion hut sulhciently close to contain antigens lion the ielevant pathogen. Altei a liniteu peiiou ol tine in this setting (i.e., lynph noue), antihou- ies piouuceu hy B cells, anu ellectoi nenoiy ¯ cells, can he ieleaseu into the ciiculation anu vill localize at the site ol inlection. Soluhle lactois piouuceu hy iesiuent tissue cells at the site ol in|uiy, hy leulocytes anu platelets that aie ie- ciuiteu to the site ol in|uiy, anu hy nen- oiy ¯ cells ultinately ieciuiteu to the aiea, all conspiie to geneiate an evolving anu ellective iesponse to a challenge to host uelense. íost inpoitant, the level ol this iesponse nust he appiopiiate to the challenge anu the uuiation ol the ie- sponse nust he tiansient, that is, long enough to uecisively elininate the pathogen, hut shoit enough to nininize uanage to healthy host tissues. íuch ol the cell-to-cell connunication involveu in the cooiuination ol this iesponse is ac- conplisheu hy cytolines. Ceneial leatuies ol cytolines aie theii pleiotiopisn anu ieuunuancy. Be- loie the auvent ol a systenatic nonen- clatuie loi cytolines, nost nevly iuen- tiheu cytolines veie naneu accoiuing to the hiologic assay that vas heing useu to isolate anu chaiacteiize the ac- tive nolecule (e.g., ¯-cell giovth lactoi loi the nolecule that vas latei ienaneu intcr|cukin `, oi lL-2). Veiy olten, inue- penuent gioups stuuying guite uispaiate hioactivities isolateu the sane nolecule, vhich ievealeu the pleiotiopic ellects ol these cytolines. loi exanple, heloie he- ing teineu intcr|cukin 1, this cytoline hau heen vaiiously lnovn as cndogcnous ¡,rogcn, |,m¡ho.,tc-a.tivating ja.tor, anu |cuko.,ti. cndogcnous mcdiator. íany cy- tolines have a viue iange ol activities, causing nultiple ellects in iesponsive cells anu a uilleient set ol ellects in each type ol cell capahle ol iesponuing. ¯he ieuunuancy ol cytolines typically neans that in any single hioassay (such as inuuction ol ¯-cell piolileiation), nultiple cytolines vill uisplay activity. ln auuition, the ahsence ol a single cyto- line (such as in nice vith taigeteu nu- tations in cytoline genes) can olten he laigely oi even conpletely conpensateu loi hy othei cytolines vith oveilapping hiologic ellects. C|ASS|||CAT|0\S 0| C\T0||\ES P||ra|] ard Seccrda|] C]|c||reº A sinple concept that continues to he extienely uselul loi uiscussion ol cyto- line lunction is the concept ol °pii- naiy` anu °seconuaiy` cytolines. 5 lii- naiy cytolines aie those cytolines that can, hy thenselves, initiate all the events ieguiieu to hiing ahout leulo- cyte inhltiation in tissues. lL-1 (hoth anu loins) anu tunoi neciosis lactoi (¯Nl, incluues hoth ¯Nl- anu ¯Nl- ) lunction as piinaiy cytolines, as uo ceitain othei cytolines that signal thiough ieceptois that tiiggei the nu- cleai lactoi B (Nl- B) pathvay. lL-1 anu ¯Nl aie ahle to inuuce cell auhe- sion nolecule expiession on enuothelial cells |selectins as vell as innunoglohu- lin supeilanily nenheis such as intei- cellulai auhesion nolecule 1 (lCAí-1) anu vasculai cellulai auhesion nolecule 1 (VCAí-1)], to stinulate a vaiiety ol cells to piouuce a host ol auuitional cy- tolines, anu to inuuce expiession ol chenolines that pioviue a chenotactic giauient alloving the uiiecteu nigia- tion ol specihc leulocyte suhsets into a site ol inhannation (see Chaptei 12). liinaiy cytolines can he vieveu as pait ol the innate innune systen (see Chap. 1O), anu in lact shaie signaling pathvays vith the so-calleu To||-|ikc rc- .c¡tors (TlRs;, a lanily ol ieceptois that iecognize noleculai patteins chaiactei- istically associateu vith niciohial piouucts. 6 Although othei cytolines sonetines have potent inhannatoiy activity, they uo not uuplicate this lull iepeitoiie ol activities. íany gualily as seconuaiy cytolines vhose piouuction is inuuceu altei stinulation hy lL-1 anu/ oi ¯Nl lanily nolecules. ¯he tein sc.- ondar, uoes not inply that they aie less inpoitant oi less active than piinaiy cytolines, iathei, it inuicates that theii spectiun ol activity is noie iestiicteu. T-Ce|| Su|ºe|º D|º||rçu|º|ed |] Pa||e|r c| C]|c||re P|cduc||cr Anothei valuahle concept that has vith- stoou the test ol tine is the assignnent ol nany ¯ cellueiiveu cytolines into gioups haseu on the specihc helpei ¯- cell suhsets that piouuce then (lig. 11-1). ¯he oiiginal tvo helpei ¯-cell suhsets veie teineu Th1 anu Th`. Connit- nent to one ol these tvo patteins ol cy- toline secietion also occuis vith CD8 cytotoxic ¯ cells anu / ¯ cells. Doni- nance ol type 1 oi type 2 cytolines in a ¯-cell innune iesponse has piolounu conseguences loi the outcone ol in- nune iesponses to ceitain pathogens anu extiinsic pioteins capahle ol seiving as alleigens. ¯ Neaily tvo uecaues altei the oiiginal uesciiption ol the ¯h1 anu ¯h2 suhsets, stiong eviuence has eneigeu that theie aie othei lunction- C\T0||\ES AT A 0|A\CE C]|c||reº a|e pc|]pep||de red|a|c|º ||a| |urc||cr |r ccrrur|ca||cr |e|Weer |era|cpc|e||c ce||º ard c||e| ce|| |]peº. C]|c||reº c||er |a.e ru|||p|e ||c|cç|c ac||.|||eº (p|e|c||cp|ºr, ard c.e||app|rç ||c|cç|c e||ec|º (|edurdarc],. P||ra|] c]|c||reº, ºuc| aº |r|e||eu||r 1 ard |urc| rec|cº|º |ac|c|- , a|e ºu||- c|er| cr ||e|| cWr |c |||ççe| |eu|cc]|e |r1u/ |r|c ||ººue. |cº| c]|c||reº º|çra| |||cuç| e|||e| ||e ruc|ea| |ac|c| B c| ||e Ja|/STAT º|çra|- |rç pa||Wa]º. C]|c||re-|aºed ||e|apeu||cº rcW |r uºe |rc|ude |eccr||rar| c]|c||reº, |r|||||c|] rcrcc|cra| ar|||cd|eº, |uº|cr p|c|e|rº ccrpcºed c| c]|c||re |ecep|c|º ard |rrurcç|c|u||r c|a|rº, |cp|ca| |rrurc- rcdu|a|c|º ºuc| aº |r|(u|rcd, ard c]|c- ||re |uº|cr |c/|rº. 116 ally signihcant patteins ol cytoline se- cietion hy ¯ cells. ¯he ¯h1¯ suhset is uistinguisheu hy piouuction ol a high level ol lL-1¯, a nenhei ol a lanily ol ielateu cytolines (the othei nenheis aie lL-1¯B thiough l) that hau not yet heen iuentiheu vhen the ¯h1 anu ¯h2 suhsets veie hist uesciiheu. ¯h1¯ cells pionote inhannation, anu theie is con- sistent eviuence lion hunan autoin- nune uiseases anu nouse nouels ol these uiseases that lL-1¯piouucing cells aie ciitical ellectois in autoinnune uisease. 8 Anothei suhset ol ¯ cells lnovn as rcgu|ator, T .c||s (oi Trcg .c||s loi shoit) has eneigeu as a ciucial suh- set involveu in the naintenance ol pe- iipheial sell-toleiance. º ¯vo ol the nost uistinctive leatuies ol ¯ieg cells aie theii expiession ol the loxlo tiansciiption lactoi anu piouuction ol tiansloining giovth lactoi- (¯Cl- ), a cytoline that appeais to he ieguiieu loi ¯ieg cells to linit the excess activity ol the pio-inhannatoiy ¯-cell suhsets. 1O lL-1O nay also he ieguiieu loi the activity ol ¯ieg cells. Not only uo each ol these ¯- cell suhsets exhihit uistinctive patteins ol cytoline piouuction, cytolines aie ley lactois in inhuencing the uilleienti- ation ol naive ¯ cells into these suhsets. lL-12 is the ley ¯h1-pionoting lactoi, lL-4 is ieguiieu loi ¯h2 uilleientiation, anu hoth lL-2o anu ¯Cl- aie involveu in pionoting ¯h1¯ uevelopnent. S||uc|u|a| C|aºº||ca||cr c| C]|c||reº Not all uselul classihcations ol cytolines aie haseu solely on analysis ol cytoline lunction. Stiuctuial hiologists, aiueu hy inpioveu nethous ol geneiating honoge- nous piepaiations ol pioteins anu estah- lishnent ol nev analytical nethous (e.g., solution nagnetic iesonance spectios- copy) that conplenent the classical x-iay ciystallogiaphy technigue, have uetei- nineu the thiee-uinensional stiuctuie ol nany cytolines. ¯hese elloits have leu to the iuentihcation ol gioups ol cytolines that lolu to geneiate sinilai thiee-uinen- sional stiuctuies anu hinu to gioups ol cy- toline ieceptois that also shaie sinilai stiuctuial leatuies. loi exanple, nost ol the cytoline liganus that hinu to ieceptois ol the henatopoietin cytoline ieceptoi lanily aie nenheis ol the loui-helix hun- ule gioup ol pioteins. loui-helix hunule pioteins have a shaieu teitiaiy aichitec- tuie consisting ol loui antipaiallel -heli- cal stietches sepaiateu hy shoit connect- ing loops. ¯he noinal existence ol sone cytolines as oligoneis iathei than nono- neis vas uiscoveieu in pait as the iesult ol stiuctuial investigations. loi exanple, inteileion- (llN- ) is a loui-helix hunule cytoline that exists natuially as a nonco- valent uinei. ¯he hivalency ol the uinei enahles this liganu to hinu anu oligonei- ize tvo llN- ieceptoi conplexes, theiehy lacilitating signal tiansuuction. ¯Nl- anu ¯Nl- aie hoth tiineis that aie conposeu alnost exclusively ol - sheets lolueu into a °|elly ioll` stiuctuial notil. Liganu-inuuceu tiineiization ol ie- ceptois in the ¯Nl ieceptoi lanily is in- volveu in the initiation ol signaling. S|0\A| TRA\SDUCT|0\ PATHwA\S SHARED B\ C\T0||\ES ¯o acconplish theii ellects, cytolines nust hist hinu vith specihcity anu high alhnity to ieceptois on the cell suilaces ol iesponuing cells. íany aspects ol the pleiotiopisn anu ieuunuancy nanilesteu hy cytolines can he unueistoou thiough an appieciation ol shaieu nechanisns ol signal tiansuuction neuiateu hy cell sui- lace ieceptois loi cytolines. ln the eaily yeais ol the cytoline hiology eia, the en- phasis ol nost investigative voil vas the puiihcation anu eventual cloning ol nev cytolines anu a uesciiption ol theii lunctional capahilities, hoth in vitio anu in vivo. íost ol the cytoline ieceptois have nov heen cloneu, anu nany ol the signaling cascaues initiateu hy cytolines have heen uesciiheu in gieat uetail. ¯he vast na|oiity ol cytoline ieceptois can he classiheu into a ielatively snall nunhei ol lanilies anu supeilanilies (¯ahle 11-1), the nenheis ol vhich lunction in an ap- pioxinately sinilai lashion. ¯ahle 11-2 lists the cytolines ol paiticulai ielevance loi cutaneous hiology, incluuing the na- |oi souices, iesponsive cells, leatuies ol inteiest, anu clinical ielevance ol each cy- toline. íost cytolines senu signals to cells thiough pathvays that aie veiy sin- ilai to those useu hy othei cytolines hinuing to the sane class ol ieceptois. ln- uiviuual cytolines olten enploy seveial uovnstiean pathvays ol signal tians- uuction, vhich accounts in pait loi the pleiotiopic ellects ol these nolecules. Neveitheless, ve piopose heie that a lev na|oi signaling pathvays account loi nost ellects attiihutahle to cytolines. Cl paiticulaily cential inpoitance aie the Nl- B pathvay anu the [al/S¯A¯ path- vay, uesciiheu in the lolloving sections. \uc|ea| |ac|c| B, |r|||||c| c| B, ard P||ra|] C]|c||reº A na|oi nechanisn contiihuting to the extensive oveilap hetveen the hiologic F|608£ 11-1 C]|c||reº ccr||c| ||e de.e|cprer| c| ºpec||c CD4 |e|pe| T-ce|| ºu|ºe|º. T|e c]|c||re r|||eu a| ||e ||re c| ac||.a||cr c| ra|.e urd|||e|er||a|ed CD4 T ce||º |aº a p|c|curd |r1uerce cr ||e u|||ra|e pa||e|r c| c]|c||re ºec|e||cr adcp|ed |] |u||] d|||e|er||a|ed T ce||º. Su|ºe|º c| e||ec|c| CD4 T ce||º W||| de- |red pa||e|rº c| c]|c||re ºec|e||cr |rc|ude T |e|pe| 1 (T|1,, T|2, ard T|1/ ce||º. Reçu|a|c|] CD4 T ce||º (T|eç ce||º, e/p|eºº ||e |c/P8 ||arºc||p||cr |ac|c|, ard ||e|| e||ec|º a|e red|a|ed |r pa|| |] ||e|| p|cduc||cr c| ||arº|c|r|rç ç|cW|| |ac|c|- 1 (T0|- 1, ard/c| |r|e||eu||r 10 (||-10,. ||\ = |r|e||e|cr, |T = |]rp|c- |c/|r. (Adap|ed ||cr Ta|c C|, 0'S|ea JJ. w|a| dceº || rear |c |e juº| 1/´ Aat0rc 441.1oo, 200o., 0]tokiues iuflueuciug 0D4 developmeut Uudiffereutiated uaive 0D4 T cell ll-12 ll-4 T0F- 1 ll-28 ll-O T0F- 1 Th1 Th2 Th17 Treg T0F-  ll-10 ll-17 lFh- , lT- ll-4, ll-5, ll-18 0]tokiues made o] mature 0D4 T cells Foxp3 117 activities ol the piinaiy cytolines lL-1 anu ¯Nl is the shaieu use ol the Nl- B signal tiansuuction pathvay. lL-1 anu ¯Nl use conpletely uistinct cell suilace ieceptoi anu pioxinal signaling path- vays, hut these pathvays conveige at the activation ol the Nl- B tiansciiption lactoi. Nl- B is ol cential inpoitance in innune anu inhannatoiy piocesses he- cause a laige nunhei ol genes that elicit oi piopagate inhannation have Nl- B iecognition sites in theii pionoteis. 11 Nl- Biegulateu genes incluue cyto- lines, chenolines, auhesion nolecules, nitiic oxiue synthase, cyclooxygenase, anu phospholipase A2. ln unstinulateu cells, Nl- B het- eiouineis loineu lion p65 anu p5O suhunits aie inactive hecause they aie seguesteieu in the cytoplasn as a iesult ol tight hinuing to inhihitoi pioteins in the l B lanily (lig. 11-2). Signal tians- uuction pathvays that activate the Nl- Ik8L£ 11-2 0ytok|nas of Part|cu|ar 8a|avanca for 0utanaous 8|o|ogy 0YT0K|hF NAJ08 S0U80FS 8FSP0hS|VF 0FLLS FFATU8FS 0F |hTF8FST 0L|h|0AL 8FLFVAh0F ||-1 Ep|||e||a| ce||º |r||||a||rç |eu|cc]|eº Ac||.e |c|r º|c|ed |r |e|a||rcc]|eº ||-1Ra uºed |c ||ea| ||eura|c|d a|||||||º ||-1 |]e|c|d ce||º |r||||a||rç |eu|cc]|eº Caºpaºe 1 c|ea.açe |e(u||ed |c| ac||.a||cr ||-1Ra uºed |c ||ea| ||eura|c|d a|||||||º ||-2 Ac||.a|ed T ce||º Ac||.a|ed T ce||º, T|eç ce||º Au|cc||re |ac|c| |c| ac||.a|ed T ce||º ||-2 |uº|cr |c/|r |a|çe|º CTC| ||-4 Ac||.a|ed T|2 ce||º, \|T ce||º |]rp|cc]|eº, erdc||e||a| ce||º, |e|a||rcc]|eº Cauºeº B-ce|| c|aºº ºW||c||rç ard T|2 d|||e|er||a||cr - ||-o Ac||.a|ed T|2 ce||º, raº| ce||º B ce||º, ecº|rcp|||º Reçu|a|eº ecº|rcp||| |eºpcrºe |c pa|aº||eº Ar||-||-o dep|e|eº ecº|rcp|||º ||-o Ac||.a|ed r]e|c|d ce||º, |||c- ||aº|º, erdc||e||a| ce||º B ce||º, r]e|c|d ce||º, |epa|cc]|eº T||ççe|º acu|e-p|aºe |eºpcrºe, p|crc|eº |rrurcç|c|u||r º]r||eº|º - ||-10 T ce||º, \| ce||º |]e|c|d ard |]rp|c|d ce||º |r|||||º |rra|e ard ac(u||ed |rrure |eºpcrºeº - ||-12 Ac||.a|ed APCº T|1 ce||º P|crc|eº T|1 d|||e|er||a||cr, º|a|eº p40 ºu|ur|| W||| ||-28 Ar||-p40 |r|||||º C|c|r d|ºeaºe ard pºc||aº|º ||-18 Ac||.a|ed T|2 ce||º |crcc]|eº, |e|a||rcc]|eº, erdc||e||a| ce||º |ed|a|eº ||ººue |eºpcrºeº |c pa|aº||eº - ||-1/ Ac||.a|ed T|1/ ce||º |u|||p|e ce|| |]peº |ed|a|eº au|c|rrure d|ºeaºeº Pc|er||a| d|uç |a|çe| |r au|c|r- rure d|ºeaºe ||-28 Ac||.a|ed derd||||c ce||º |erc|] T ce||º, T|1/ ce||º D||ec|º T|1/ d|||e|er||a||cr, red|- a|eº au|c|rrure d|ºeaºe Ar||-p40 |r|||||º C|c|r d|ºeaºe ard pºc||aº|º T\|- Ac||.a|ed r]e|c|d, |]rp|c|d, ard ep|||e||a| ce||º |r||||a||rç |eu|cc]|eº |ed|a|eº |r1arra||cr Ar||-T\|- e||ec||.e |r pºc||aº|º ||\- ard ||\- P|aºrac]|c|d derd||||c ce||º |cº| ce|| |]peº |ajc| pa|| c| ar||.||a| |eºpcrºe E||c||ed |] |cp|ca| |r|(u|rcd app||ca||cr ||\- Ac||.a|ed T|1 ce||º, CD8 T ce||º, \| ce||º, derd||||c ce||º |ac|cp|açeº, derd||||c ce||º, ra|.e T ce||º |ac|cp|açe ac||.a||cr, ºpec||c |ºc- |]pe ºW||c||rç ||\- uºed |c ||ea| c||cr|c ç|aru|cra|cuº d|ºeaºe APC = ar||çer-p|eºer||rç ce||, CTC| = cu|arecuº T-ce|| |]rp|cra, ||\ = |r|e||e|cr, || = |r|e||eu||r, \| = ra|u|a| ||||e|, \|T = ra|u|a| ||||e| T ce||, T| = T |e|pe|, T\| = |urc| rec|cº|º |ac|c|, T|eç = T |eçu|a|c|]. Ik8L£ 11-1 Najor Fam|||as of 0ytok|na 8acaptors 8F0FPT08 FAN|LY FXANPLF NAJ08 S|0hAL T8AhS0U0T|0h PATHwAY(S} LFA0|h0 T0 8|0L00|0 FFFF0TS ||-1 |ecep|c| |ar||] ||-1R, |]pe | \|- B ac||.a||cr .|a TRA|o T\| |ecep|c| |ar||] T\|R1 \|- B ac||.a||cr |r.c|.|rç TRA|2 ard TRA|o Apcp|cº|º |rduc||cr .|a 'dea|| dcra|r' p|c|e|rº Hera|cpc|e||r |ecep|c| |ar||] (c|aºº | |ecep|c|º, ||-2R Ac||.a||cr c| Ja|/STAT pa||Wa] ||\/||-10 |ecep|c| |ar||] (c|aºº || |ecep|c|º, ||\- R Ac||.a||cr c| Ja|/STAT pa||Wa] |rrurcç|c|u||r ºupe||ar||] |-CS| R Ac||.a||cr c| |r|||rº|c |]|cº|re ||raºe T0|- |ecep|c| |ar||] T0|- R, |]peº | ard || Ac||.a||cr c| |r|||rº|c ºe||re/|||ecr|re ||raºe ccup|ed |c Srad p|c|e|rº C|erc||re |ecep|c| |ar||] CCRo Se.er ||arºrer||are |ecep|c|º ccup|ed |c 0 p|c|e|rº CCR = CC c|erc||re |ecep|c|, ||\ = |r|e||e|cr, || = |r|e||eu||r, Ja| = Jaruº ||raºe, |-CS| = rac|c- p|açe cc|cr]-º||ru|a||rç |ac|c|, \|- B = ruc|ea| |ac|c| B, STAT = º|çra| ||arºduce| ard ac||.a|c| c| ||arº- c||p||cr, T0| = ||arº|c|r|rç ç|cW|| |ac|c|, T\|= |urc| rec|cº|º |ac|c|, TRA| = |urc| rec|cº|º |ac|c| |ecep|c|-aººcc|a|ed |ac|c|. 118 B systen uo so thiough the activation ol an l B linase (lll) conplex consist- ing ol tvo linase suhunits (lll anu lll ) anu a iegulatoiy suhunit (lll ). ¯he lll conplex phosphoiylates l B anu l B on specihc seiine iesiuues, yieluing a taiget loi iecognition hy an lo uhiguitin ligase conplex. ¯he iesult- ing polyuhiguitination nails this l B loi iapiu uegiauation hy the 26S piotea- sone conplex in the cytoplasn. Cnce l B has heen uegiaueu, the liee Nl- B (vhich contains a nucleai localization signal) is ahle to pass into the nucleus anu inuuce expiession ol Nl- Bsensi- tive genes. ¯he piesence ol B iecogni- tion sites in cytoline pionoteis is veiy connon. Anong the genes iegulateu hy Nl- B aie lL-1 anu ¯Nl- . ¯his en- uovs lL-1 anu ¯Nl- vith the capac- ity to estahlish a positive iegulatoiy loop that lavois peisistent inhanna- tion. Cytolines hesiues lL-1 anu ¯Nl that activate the Nl- B pathvay as pait ol theii signal tiansuuction nechanisns incluue lL-1¯ anu lL-18. lio-inhannatoiy cytolines aie not the only stinuli that can activate the Nl- B pathvay. Bacteiial piouucts (e.g., lipo- polysacchaiiue, oi LlS), oxiuants, activa- tois ol piotein linase C (e.g., phoihol es- teis), viiuses, anu ultiaviolet (UV) iauiation aie othei stinuli that can stin- ulate Nl- B activity. ¯LR4 is a cell sui- lace ieceptoi loi the conplex ol LlS, LlS-hinuing piotein, anu CD14. ¯he cy- toplasnic uonain ol ¯LR4 is sinilai to that ol the inteileulin 1 ieceptoi type 1 (lL-1R1) anu othei lL-1R lanily nenheis anu is lnovn as the TlR uonain (loi ¯oll/lL-1 ieceptoi). 12 When liganu is hounu to a ¯lR uonaincontaining ie- ceptoi, one oi noie auaptei pioteins that also contain ¯lR uonains aie ieciuiteu to the conplex. íyD88 vas the hist ol these auapteis to he iuentiheu, the othei lnovn auapteis aie ¯lRAl (¯lR uo- naincontaining auaptei piotein), ¯Rll (¯lR uonaincontaining auaptei inuuc- ing llN- ), anu ¯RAí (¯Rll-ielateu auaptei nolecule). 1o lngagenent ol the auaptei, in tuin, activates one oi noie ol the lL-1Rassociateu linases (lRAl1 to lRAl4), vhich then signal thiough ¯RAl6, a nenhei ol the ¯RAl (¯Nl ie- ceptoiassociateu lactoi) lanily, anu ¯Al1 (¯Cl- activateu linase) to acti- vate the lll conplex. 14 Ja|/STAT Pa||Wa] A na|oi hiealthiough in the analysis ol cytoline-neuiateu signal tiansuuction vas the iuentihcation ol a connon cell suilace to nucleus pathvay useu hy the na|oiity ol cytolines. ¯his [al/S¯A¯ pathvay vas hist eluciuateu thiough caielul analysis ol signaling initiateu hy llN ieceptois (lig. 11-o) hut vas suhse- guently shovn to play a iole in signal- ing hy all cytolines that hinu to nen- heis ol the henatopoietin ieceptoi lanily. 15 ¯he [al/S¯A¯ pathvay opei- ates thiough the seguential action ol a lanily ol loui nonieceptoi tyiosine li- nases (the [als oi janus lanily kinases) anu a seiies ol latent cytosolic tiansciip- tion lactois lnovn as :TATs (signal tiansuuceis anu activatois ol tiansciip- tion). ¯he cytoplasnic poitions ol nany cytoline ieceptoi chains aie nonco- valently associateu vith one ol the loui [als |[al1, [al2, [alo, anu tyiosine li- nase 2 (¯yl2)]. ¯he activity ol the [al linases is up- iegulateu altei stinulation ol the cyto- line ieceptoi. Liganu hinuing to the cy- toline ieceptois leaus to the association ol tvo oi noie uistinct cytoline iecep- toi suhunits anu hiings the associateu [al linases into close pioxinity vith each othei. ¯his pionotes cioss-phos- phoiylation oi autophosphoiylation ie- actions that in tuin lully activate the li- nases. ¯yiosines in the cytoplasnic tail ol the cytoline ieceptoi as vell as ty- iosines on othei associateu anu nevly ieciuiteu pioteins aie also phosphoiy- F|608£ 11-2 Ac||.a||cr c| ruc|ea| |ac|c| B (\|- B,-|eçu|a|ed çereº a||e| º|çra||rç |] |ecep|c|º |c| p||ra|] c]|c||reº c| |] Tc||-|||e |ecep|c|º (T|Rº, erçaçed |] r|c|c||a| p|cduc|º. Urde| |eº||rç ccr- d|||crº, \|- B (a |e|e|cd|re| c| po0 ard poo ºu|ur||º, |º ||ç|||] |curd |c ar |r|||||c| ca||ed I 8 ||a| ºe- (ueº|e|º \|- B |r ||e c]|cp|aºr. Erçaçerer| c| cre c| ||e T|Rº c| ||e º|çra| ||arºduc|rç |ecep|c|º |c| |r|e||eu||r 1 (||-1, c| |urc| rec|cº|º |ac|c| (T\|, |ar||] rer|e|º |eadº |c |rduc||cr c| | B ||raºe ac||.- ||] ||a| p|cºp|c|]|a|eº | B cr c||||ca| ºe||re |eº|dueº. P|cºp|c|]|a|ed | B |eccreº a ºu|º||a|e |c| u||(- u|||ra||cr, W||c| |||ççe|º deç|ada||cr c| | B |] ||e 2oS p|c|eaºcre. |cºº c| | B |eºu||º |r |e|eaºe c| \|- B, W||c| pe|r||º || |c rc.e |c ||e ruc|euº ard ac||.a|e ||arºc||p||cr c| çereº W|cºe p|crc|e|º ccr|a|r B |eccçr|||cr º||eº. U| = u||(u|||r. 119 lateu. A suhset ol the nevly phosphoiy- lateu tyiosines can then seive as uocl- ing points loi attachnent ol auuitional signaling pioteins heaiing Sic honology 2 (SH2) uonains. Cytoplasnic S¯A¯s possess SH2 uonains anu aie ieciuiteu to the phosphoiylateu cytoline iecep- tois via this inteiaction. Honouineiic oi heteiouineiic S¯A¯ pioteins aie phosphoiylateu hy the [al linases anu suhseguently tianslocate to the nu- cleus. ln the nucleus they hinu iecogni- tion seguences in DNA anu stinulate tiansciiption ol specihc genes, olten in coopeiation vith othei tiansciiption lactois. ¯he sane S¯A¯ nolecules can he involveu in signaling hy nultiple uil- leient cytolines. ¯he specihcity ol the iesponse in these instances nay uepenu on the loination ol conplexes involv- ing S¯A¯s anu othei tiansciiption lac- tois that then selectively act on a spe- cihc set ol genes. |\TER|EU||\ 1 |A|||\ 0| C\T0||\ES (|\TER|EU||\S 1 , 1 , 18, 88, lL-1 is the piototype ol a cytoline that has heen uiscoveieu nany tines in nany uilleient hiologic assays. Distinct genes encoue the anu loins ol hu- nan lL-1, vith only 26 peicent honol- ogy at the anino aciu level. Both lL-1s aie tianslateu as o1-lu nolecules that lacl a signal peptiue, anu hoth iesiue in the cytoplasn. ¯his loin ol lL-1 is hi- ologically active, hut o1-lu lL-1 nust he cleaveu hy caspase 1 (initially teineu intcr|cukin-1 .onvcrting cn:,mc) to gen- eiate an active nolecule. ln geneial, lL-1 appeais to he the uoninant loin ol lL-1 piouuceu hy nonocytes, naciophages, Langeihans cells, anu uenuiitic cells, vheieas lL-1 pieuoninates in epithelial cells, incluuing leiatinocytes. ¯his is lilely to ielate to the lact that epithelial lL-1 is stoieu in the cytoplasn ol cells that conpiise an inteilace vith the exteinal enviionnent. Such cells, vhen in|uieu, ielease hiologi- cally active o1-lu lL-1 anu, hy uoing so, can initiate inhannation. 5 ll unin|uieu, hovevei, these cells vill uilleientiate anu ultinately ielease theii lL-1 contents into the enviionnent. Leulocytes, in- cluuing uenuiitic anu Langeihans cells, caiiy theii caigo ol lL-1 insiue the houy, vheie its uniegulateu ielease coulu cause signihcant tissue uanage. ¯hus, hiologi- cally active lL-1 ielease lion cells is contiolleu at seveial levels: lL-1 gene tiansciiption, caspase 1 gene tiansciip- tion, anu availahility ol the auaptei pio- teins ASC anu lpal that inteiact vith caspase 1 in the inhannasone to allov the geneiation ol natuie lL-1 . 16 ¯he iole ol lL-1 in the nigiation ol Langei- hans cells lion the epiueinis uuiing the initiation ol contact hypeisensitivity is a pivotal event in the egiess ol Langeihans cells lion the epiueinis anu the geneia- tion ol successlul sensitization. Stuuies ol nice uehcient in lL-1 anu lL-1 genes suggest that hoth nolecules aie inpoi- tant in contact hypeisensitivity hut that lL-1 is noie ciitical. Active loins ol lL-1 hinu to the lL-1R1 oi type 1 lL-1 ieceptoi. 12 ¯his is the sole signal-tiansuucing ieceptoi loi lL-1, anu its cytoplasnic uonain has little honol- ogy vith othei cytoline ieceptois, shoving gieatest honology vith the To|| gene piouuct iuentiheu in Droso¡hi|a. A seconu cell suilace piotein, the lL-1R ac- cessoiy piotein, oi lL-1RAcl, nust asso- ciate vith lL-1R1 loi signaling to occui. When lL-1 engages the lL-1R1/lL-1RAcl conplex, ieciuitnent ol the íyD88 auaptei occuis, lolloveu hy inteiactions vith one oi noie ol the lRAls. ¯hese li- nases in tuin associate vith ¯RAl6. Stepvise activation anu ieciuitnent ol auuitional signaling nolecules culninate in the inuuction ol lll activity. ¯he net iesult is the activation ol a seiies ol Nl- Biegulateu genes. A nolecule lnovn as the ll-1 rc.c¡tor antagonist, oi lL-1ia, can hinu to lL-1R1 hut uoes not inuuce signaling thiough the ieceptoi. ¯his lL-1ia exists in thiee alteinatively spliceu loins, anu an iso- loin piouuceu in nonocytes is the only liganu loi the lL-1R1 that hoth contains a signal peptiue anu is secieteu lion cells. ¯vo othei isoloins ol lL-1ia, hoth lacling signal peptiues, aie containeu vithin epithelial cells. ¯he lunction ol lL-1ia seens to he as a puie antagonist ol lL-1 liganu hinuing to lL-1R1, anu hinuing ol lL-1ia to lL-1R1 uoes not in- F|608£ 11-3 Pa|||c|pa||cr c| Ja| (Jaruº ||raºe, ard STAT (º|çra| ||arºduce| ard ac||.a|c| c| ||arº- c||p||cr, p|c|e|rº |r |r|e||e|cr- (||\- , º|çra||rç. B|rd|rç c| |urar ||\- (a d|re|, |c ||º |ecep|c| |||rçº a|cu| c||çcre||/a||cr c| |ecep|c| ccrp|e/eº ccrpcºed c| ard c|a|rº. T|e rcr|ecep|c| p|c|e|r |]- |cº|re ||raºeº Ja|1 ard Ja|2 a|e ac||.a|ed ard p|cºp|c|]|a|e c||||ca| |]|cº|re |eº|dueº |r ||e |ecep|c| ºuc| aº ||e |]|cº|re a| pcº|||cr 440 c| ||e c|a|r (\ 440 ,. STAT1 rc|ecu|eº a|e |ec|u||ed |c ||e ||\- |ecep|c| |aºed cr ||e a||r||] c| ||e|| S|c |crc|cç] 2 (SH2, dcra|rº |c| ||e p|cºp|cpep||de ºe(uerce a|curd \ 440 . Recep|c|-aººcc|a|ed STAT1 rc|ecu|eº ||er d|re||/e |||cuç| |ec|p|cca| SH2-p|cºp|c|]- |cº|re |r|e|ac||crº. T|e |eºu|||rç STAT1 d|re|º ||arº|cca|e |c ||e ruc|euº ard º||ru|a|e ||arºc||p||cr c| ||\- -|eçu|a|ed çereº. 120 uuce the nohilization ol lL-1RAcl. Conseguently, although hoth lL-1 / anu lL-1ia hinu vith eguivalent alhni- ties to lL-1R1, the association ol lL-1R1 vith lL-1RAcl incieases the alhnity loi lL-1 / nanylolu vhile not allecting the alhnity loi lL-1ia. ¯his is consistent vith the ohseivation that a vast nolai excess ol lL-1ia is ieguiieu to lully an- tagonize the ellects ol lL-1. ¯he hiologic iole ol lL-1ia is lilely to he in the guenching ol lL-1neuiateu inhanna- toiy iesponses, anu nice uehcient in lL- 1ia shov exaggeiateu anu peisistent in- hannatoiy iesponses. A seconu neans ol antagonizing lL-1 activity occuis via expiession ol a sec- onu ieceptoi loi lL-1, lL-1R2. ¯his ie- ceptoi has a shoit cytoplasnic uonain anu seives to hinu lL-1 / elhciently, hut not lL-1ia. ¯his 68-lu ieceptoi can he cleaveu lion the cell suilace hy an unlnovn piotease anu ieleaseu as a sta- hle, soluhle 45-lu nolecule that ietains aviu lL-1hinuing lunction. By hinuing the lunctional liganus loi lL-1R1, lL-1R2 seives to inhihit lL-1neuiateu ie- sponses. lt is lilely that lL-1R2 inhihits lL-1 activity in anothei vay, that is, hy associating vith lL-1RAcl at the cell suilace anu ienoving anu seguesteiing it lion the pool availahle to associate vith lL-1R1. ¯hus, soluhle lL-1R2 hinus to liee lL-1, vheieas cell suilace lL-1R2 seguesteis lL-1RAcl. lxpiession ol lL- 1R2 can he upiegulateu hy a nunhei ol stinuli, incluuing coiticosteioius anu lL- 4. Hovevei, lL-1R2 can also he inuuceu hy inhannatoiy cytolines, incluuing llN- anu lL-1, piohahly as a conpensa- toiy signal uesigneu to linit the scale anu uuiation ol the inhannatoiy ie- sponse. liouuction ol lL-1R2 seives to nale the piouucing cell anu suiiounu- ing cells iesistant to lL-1neuiateu acti- vation. lnteiestingly, sone ol the nost elhcient lL-1piouucing cells aie also the hest piouuceis ol the lL-1R2. lL-18 vas hist iuentiheu haseu on its capacity to inuuce llN- . Cne nane ini- tially pioposeu loi this cytoline vas lL- 1 , hecause ol its honology vith lL-1 anu lL-1 . Lile lL-1 , it is tianslateu as an inactive piecuisoi nolecule ol 2o lu anu is cleaveu to an active 18-lu species hy caspase 1. lt is piouuceu hy nultiple cell types in slin, incluuing leiatino- cytes, Langeihans cells, anu nonocytes. lL-18 inuuces piolileiation, cytotoxicity, anu cytoline piouuction hy ¯h1 anu nat- uial lillei (Nl) cells, nostly syneigisti- cally vith lL-12. ¯he lL-18 ieceptoi heais stiiling sinilaiity to the lL-1 ieceptoi. 12 ¯he hinuing chain (lL-18R) is an lL-1R1 honolog, oiiginally cloneu as lL-1Rip1. lL-18R alone is a lov-alhnity ieceptoi that nust ieciuit lL-18RAcl (a honolog ol lL-1RAcl). As loi lL-1, hoth chains ol the lL-18 ieceptoi aie ieguiieu loi signal tiansuuction. Although theie is no lL-18 honolog ol lL-1ia, a nolecule lnovn as ll-18|inding ¡rotcin hinus to soluhle na- tuie lL-18 anu pievents it lion hinuing to the lL-18R conplex. íoie iecently, it has hecone cleai that theie is a lanily ol ieceptois ho- nologous to the lL-1R1 anu lL-18R nol- ecules, 12 having in connon a ¯lR notil (lig. 11-4). All ol these shaie analogous signaling pathvays initiateu hy the íyD88 auaptei nolecule. Cne ol these ieceptois, oiiginally lnovn as :T`, vas initially chaiacteiizeu as a gene ex- piesseu hy ¯h2 cells, hut not hy ¯h1 cells. ¯he uesciiption ol a natuial liganu loi S¯2 uesignateu lL-oo has auueu a nev nenhei to the lL-1 lanily that shaies chaiacteiistic leatuies ol othei cytolines in the lanily, such as a ie- guiienent loi piocessing hy caspase 1 to ielease a natuie loin ol the liganu. lL-oo stinulation ol ¯h2 cells pionotes theii piouuction ol the chaiacteiistic ¯h2 cytolines lL-4, lL-5, anu lL-1O. lL- 1R1, lL-18R, lL-ooR (S¯2), the ¯LRs, anu theii liganus aie all hest vieveu as elenents ol the innate innune systen that signal the piesence ol uangei oi in- |uiy to the host. 1¯ When lL-1 piouuceu hy epiueinis vas oiiginally iuentiheu, it vas noteu that hoth intact epiueinis anu stiatun coi- neun containeu signihcant lL-1 activity, vhich leu to the concept that epiueinis vas a shielu ol seguesteieu lL-1 sui- iounuing the host, vaiting to he ieleaseu on in|uiy. íoie iecently, it vas ohseiveu that high levels ol the lL-1ia co-exist vithin leiatinocytes, hovevei, iepeateu expeiinents shov that in viitually all cases, the anount ol lL-1 piesent is sulh- cient to oveicone any potential loi inhi- hition neuiateu hy lL-1ia. Stuuies have nov shovn that nechanical stiess to le- iatinocytes peinits the ielease ol laige anounts ol lL-1 in the ahsence ol cell F|608£ 11-4 T|e |r|e||eu||r 1 |ecep|c| (||-1R, |ar||] ard Tc||-|||e |ecep|c|º (T|Rº, uºe a ccrrcr |r||ace||u|a| º|çra||rç pa||Wa]. Recep|c|º |c| c]|c||reº |r ||e ||-1 |ar||] (|]p||ed |] ||e ||-1 ard ||-18 |ecep|c|º, º|a|e a ccrrcr º|çra||rç dcra|r W||| ||e T|Rº (T|R1 |c T|R11, ca||ed ||e Tc!!/Il-1 rcccjtcr (TII; dcra|r. T|e T|R dcra|r |ecep|c|º |r|e|ac| W||| T|R dcra|r-ccr|a|r|rç adap|e| p|c|e|rº ºuc| aº |]D88 ||a| ccup|e ||çard ||rd|rç |c ac||.a||cr c| ||-1R-aººcc|a|ed ||raºe (|RA|, ard u|||ra|e|] ac||.a- ||cr c| ruc|ea| |ac|c| B (\|- B,. ||-1RAcP = ||-1R acceººc|] p|c|e|r, TRA| = |urc| rec|cº|º |ac|c| |e- cep|c|-aººcc|a|ed |ac|c|. 121 ueath. Release ol lL-1 inuuces expiession ol enuothelial auhesion nolecules, in- cluuing l-selectin, lCAí-1, anu VCAí- 1, as vell as chenotactic anu activating chenolines. ¯his attiacts not only nonocytes anu gianulocytes hut a spe- cihc suh-population ol nenoiy ¯ cells that heai cutaneous lynphocyte antigen on theii cell suilace. íenoiy ¯ cells pos- itive loi cutaneous lynphocyte antigen aie ahunuant in inhaneu slin, conpiis- ing the na|oiity ol ¯ cells piesent. ¯heie- loie, any in|uiy to the slin, no nattei hov tiivial, ieleases lL-1 anu attiacts this population ol nenoiy ¯ cells. ll they en- countei theii antigen in this nicioenvi- ionnent, theii activation anu suhseguent cytoline piouuction vill anplily the in- hannatoiy iesponse. ¯his has heen pio- poseu as the hasis ol the clinical ohseiva- tion ol inhannation in iesponse to tiauna, lnovn as the loc|ncr rca.tion. TU|0R \ECR0S|S |ACT0R. THE 0THER PR||AR\ C\T0||\E ¯Nl- is the piototype loi a lanily ol ie- lateu signaling nolecules that neuiate theii hiologic ellects thiough a lanily ol ielateu ieceptoi nolecules. ¯Nl- vas initially cloneu on the hasis ol its ahility to neuiate tvo inteiesting hiologic el- lects: (1) henoiihagic neciosis ol nalig- nant tunois, anu (2) inhannation-asso- ciateu cachexia. Although ¯Nl- exeits nany ol its hiologically inpoitant ellects as a soluhle neuiatoi, nevly synthesizeu ¯Nl- exists as a tiansnenhiane pio- tein on the cell suilace. A specihc netal- lopioteinase lnovn as T^l- .onvcrting cn:,mc (TACl; is iesponsihle loi nost ¯Nl- ielease hy ¯ cells anu nyeloiu cells. ¯he closest cousin ol ¯Nl- is ¯Nl- , also lnovn as |,m¡hotoxin (lT- ;. Cthei ielateu nolecules in the ¯Nl lanily incluue lynphotoxin (L¯- ), vhich conhines vith L¯- to loin the L¯- 1 2 heteiotiinei, las liganu (lasL), ¯Nl-ielateu apoptosis-inuucing liganu (¯RAlL), ¯Nl-ielateu activation-inuuceu cytoline (¯RANCl), anu CD4O liganu (CD154). Although sone ol these othei ¯Nl lanily nenheis have not heen tia- uitionally iegaiueu as cytolines, theii stiuctuie (all aie type ll nenhiane pio- teins vith an intiacellulai N-teininus anu an extiacellulai C-teininus) anu sig- naling nechanisns aie closely ielateu to those ol ¯Nl. ¯he soluhle loins ol ¯Nl- , L¯- anu lasL aie honotiineis, anu the pieuoninant loin ol L¯- is the nenhiane-hounu L¯- 1 2 heteiotiinei. ¯iineiization ol ¯Nl ieceptoi lanily nenheis hy theii tiineiic liganus ap- peais to he ieguiieu loi initiation ol sig- naling anu expiession ol hiologic activity. ¯he initial chaiacteiization ol ¯Nl ie- ceptois leu to the uiscoveiy ol tvo ie- ceptoi pioteins capahle ol hinuing ¯Nl- vith high alhnity. ¯he p55 ieceptoi loi ¯Nl (¯NlR1) is iesponsihle loi nost hiologic activities ol ¯Nl, hut the p¯5 ¯Nl ieceptoi (¯NlR2) is also capahle ol tiansuucing signals (unlile lL-1R2, vhich acts solely as a hiologic sinl loi lL-1). ¯NlR1 anu ¯NlR2 have suhstan- tial stietches ol close honology anu aie hoth piesent on nost types ol cells. Neveitheless, theie aie sone notahle uilleiences hetveen the tvo ¯NlRs. Unlile cytoline ieceptois lion sev- eial ol the othei laige lanilies, ¯Nl sig- naling uoes not involve the [al/S¯A¯ pathvay. ¯Nl- evoles tvo types ol iesponses in cells: (1) pio-inhannatoiy ellects, anu (2) inuuction ol apoptotic cell ueath (lig. 11-5). ¯he pio-inhanna- toiy ellects ol ¯Nl- , vhich incluue upiegulation ol auhesion nolecule ex- piession anu inuuction ol seconuaiy cy- tolines anu chenolines, sten in laige pait lion activation ol Nl- B anu can he tiansuuceu thiough hoth ¯NlR1 anu ¯NlR2. lnuuction ol apoptosis hy sig- naling thiough ¯NlR1 uepenus on a ie- gion lnovn as a dcath domain that is ah- sent in ¯NlR2, as vell as inteiactions vith auuitional pioteins vith ueath uo- nains vithin the ¯NlR1 signaling con- plex. Signaling initiateu hy liganu hinu- F|608£ 11-5 TWc ccr||aº||rç cu|ccreº c| º|çra||rç |||cuç| |urc| rec|cº|º |ac|c| |ecep|c| 1 (T\|R1,. Erçaçerer| c| T\|R1 |] |||re||c |urc| rec|cº|º |ac|c|- (T\|- , car |||ççe| apcp|cº|º ard/ c| ruc|ea| |ac|c| B (\|- B, ac||.a||cr. Bc|| p|cceººeº |r.c|.e ||e adap|e| p|c|e|r T\|R-aººcc|a|ed dea|| dcra|r (TRADD,, W||c| aººcc|a|eº W||| T\|R1 .|a |r|e|ac||crº |e|Weer 'dea|| dcra|rº' (D.D., cr |c|| p|c|e|rº. |c| \|- B ac||.a||cr, T\|R-aººcc|a|ed |ac|c| 2 (TRA|2, ard |ecep|c|-|r|e|ac||rç p|c|e|r (R|P, a|e |e(u||ed. |rduc||cr c| apcp|cº|º cccu|º W|er ||e dea|| dcra|r-ccr|a|r|rç p|c|e|r |aº-aººcc|- a|ed dea|| dcra|r p|c|e|r (|ADD, aººcc|a|eº W||| TRADD. |ADD a|ºc ccr|a|rº a 'dea|| e||ec|c| dcra|r' (D.E.D., ||a| |r|e|ac|º W||| caºpaºe 8 |c |r|||a|e ||e apcp|c||c p|cceºº. C]º = c]º|e|re. (Adap|ed ||cr \uar J. T|arºduc|rç º|çra|º c| |||e ard dea||. 00rr 0jir 0c!! 8ic! 9.24/, 199/, ard \aça|a S. Apcp|cº|º |] dea|| |ac|c|. 0c!! 88.8oo, 199/., 122 ing to ¯NlR1, las, oi othei ueath uonaincontaining ieceptois in the ¯Nl lanily eventually leaus to activa- tion ol caspase 8 oi 1O anu the nucleai changes anu DNA liagnentation chai- acteiistic ol apoptosis. At least tvo ¯NlR lanily nenheis (¯NlR1 anu the L¯- ieceptoi) also con- tiihute to the noinal anatonic uevelop- nent ol the lynphoiu systen. íice ue- hcient in ¯Nl- lacl geininal centeis anu lolliculai uenuiitic cells. ¯NlR1 nu- tant nice shov the sane ahnoinalities plus an ahsence ol leyei`s patches. íice vith null nutations in L¯- oi L¯- have luithei ahnoinalities in lynphoiu oiganogenesis anu lail to uevelop pe- iipheial lynph noues. ¯Nl- is an inpoitant neuiatoi ol cutaneous inhannation, anu its expies- sion is inuuceu in the couise ol alnost all inhannatoiy iesponses in slin. Noi- nal hunan leiatinocytes anu leiatino- cyte cell lines piouuce suhstantial anounts ol ¯Nl- altei stinulation vith LlS oi UV light. Cutaneous inhan- nation stinulateu hy iiiitants anu con- tact sensitizeis is associateu vith stiong inuuction ol ¯Nl- piouuction hy leiat- inocytes. lxposuie to ¯Nl- causes Langeihans cells to nigiate to uiaining lynph noues, vhich allovs loi sensiti- zation ol naive ¯ cells. Cne noleculai nechanisn that nay contiihute to ¯Nl- inuuceu nigiation ol Langeihans cells tovaiu lynph noues is ieuuceu expies- sion ol the l-cauheiin auhesion nole- cule altei exposuie to ¯Nl- . lnuuction ol CC chenoline ieceptoi ¯ on hoth epiueinal anu ueinal antigen-piesent- ing cells coiielates vith novenent into the uiaining lynphatics. ¯he pieuoni- nant ¯NlR expiesseu hy leiatinocytes is ¯NlR1. Autociine signaling loops in- volving leiatinocyte-ueiiveu ¯Nl- anu ¯NlR1 leau to leiatinocyte piouuc- tion ol a vaiiety ol ¯Nl-inuucihle sec- onuaiy cytolines. ¯he cential iole ol ¯Nl- in inhan- natoiy uiseases, incluuing iheunatoiu aithiitis anu psoiiasis, has hecone evi- uent lion clinical stuuies. Clinical uiugs that taiget the ¯Nl pathvay incluue the hunanizeu anti¯Nl- antihouy inhix- inah, the hunan anti¯Nl- antihouy aualuninah, anu the soluhle ¯Nl ie- ceptoi etaneicept. Diugs in this class aie U.S. loou anu Diug Auninistiation (lDA) appioveu loi the tieatnent ol seveial autoinnune anu inhannatoiy uiseases, incluuing Ciohn uisease anu iheunatoiu aithiitis. All ol these anti- ¯Nl uiugs aie also lDA appioveu loi the tieatnent ol psoiiatic aithiitis, anu etaneicept is appioveu loi use in tieat- ing chionic plague psoiiasis (see Chap. 2o5). ¯his class ol uiugs also has the po- tential to he valuahle in the tieatnent ol othei inhannatoiy ueinatoses. laia- uoxically, they aie not ellective against all autoinnune uiseasesnultiple scle- iosis appeais to voisen slightly altei tieatnent vith these agents. ¯he ¯Nl antagonists aie poveilul innunonou- ulating uiugs, anu appiopiiate caution is ieguiieu in theii use. Cases ol cutane- ous ¯-cell lynphona initially thought to iepiesent psoiiasis have iapiuly pio- giesseu to lulninant uisease altei tieat- nent vith ¯Nl antagonists. ¯Nl antag- onists can also allov the escape ol latent nycohacteiial inlections lion innune contiol, vith a potentially lethal out- cone loi the patient. ||0A\DS 0| THE C|ASS | (HE|AT0P0|ET|\ RECEPT0R, |A|||\ 0| C\T0||\E RECEPT0RS ¯he henatopoietin ieceptoi lanily (also lnovn as the .|ass l .,tokinc rc.c¡tor jam- i|,) is the laigest ol the cytoline ieceptoi lanilies anu conpiises a nunhei ol stiuctuially ielateu type l nenhiane- hounu glycopioteins. ¯he cytoplasnic uonains ol these ieceptois associate vith nonieceptoi tyiosine linase nole- cules, incluuing the [al linases anu sic lanily linases. Altei liganu hinuing anu ieceptoi oligoneiization, these associ- ateu nonieceptoi tyiosine linases phos- phoiylate intiacellulai suhstiates, vhich leaus to signal tiansuuction. íost ol the nultiple-chain ieceptois in the henato- poietin ieceptoi lanily consist ol a cy- toline-specihc chain suhunit paiieu vith one oi noie shaieu ieceptoi suh- units. live shaieu ieceptoi suhunits have heen uesciiheu to uate: the con- non chain ( c ), the connon chain shaieu hetveen the lL-2 anu lL-15 iecep- tois, a uistinct connon chain shaieu hetveen the gianulocyte-naciophage colony stinulating lactoi (Cí-CSl), lL-o, anu lL-5 ieceptois, the lL-12R 2 chain shaieu hy the lL-12 anu lL-2o ieceptois, anu hnally the glycopiotein 1oO (gp1oO) nolecule, vhich paiticipates in signal- ing hy lL-6 anu ielateu cytolines. C]|c||reº W||| Recep|c|º T|a| |rc|ude ||e c C|a|r ¯he ieceptoi conplexes using the c chain aie the lL-2, lL-4, lL-¯, lL-º, lL-1o, lL-15, anu lL-21 ieceptois. ¯vo ol these iecep- tois, lL-2R anu lL-15R, also use the lL- 2R c chain. ¯he c chain is physically asso- ciateu vith [alo, anu activation ol [alo is ciitical to nost signaling initiateu thiough this suhset ol cytoline ieceptois. 18 |hT£8L£0k|h 2 Ah0 |hT£8L£0k|h 15 l L- 2 anu lL-15 can each activate Nl cells anu stinulate piolileiation ol activateu ¯ cells. lL-2 is a piouuct ol activateu ¯ cells, anu lL-2R is laigely iestiicteu to lynphoiu cells. ¯he lL-15 gene is ex- piesseu hy nonlynphoiu tissues, anu its tiansciiption is inuuceu hy UVB ia- uiation in leiatinocytes anu hhiohlasts anu hy LlS in nonocytes anu uenuiitic cells. íultiple isoloins ol lL-15R aie lounu in vaiious henatopoietic anu non-henatopoietic cells. ¯he lL-2R anu lL-15R conplexes ol lynphocytes in- coipoiate up to thiee ieceptoi chains, vheieas nost othei cytoline ieceptoi conplexes have tvo. ¯he alhnities ol lL-2R anu lL-15R loi theii iespective li- ganus can he iegulateu, anu to sone ex- tent, lL-2 anu lL-15 conpete vith each othei. ¯he highest-alhnity ieceptoi conplexes loi each liganu (appioxi- nately 1O 11 /) consist ol the lL-2R c anu c chains, as vell as theii iespective chains (lL-2R , also lnovn as CD25, anu lL-15R ). c anu lL-2R c vithout the chains loin a lunctional lovei-al- hnity ieceptoi loi eithei liganu (1O 8 to 1O 1O /). Although hoth liganus tians- nit signals thiough the c chain, those signals elicit oveilapping hut uistinct ie- sponses in vaiious cells. Activation ol naive CD4 ¯ cells hy ¯-cell ieceptoi anu co-stinulatoiy nolecules inuuces ex- piession ol lL-2, lL-2R , anu lL-2R c , vhich leaus to vigoious piolileiation. liolongeu stinulation ol ¯-cell ieceptoi anu lL-2R leaus to expiession ol lasL anu activation-inuuceu cell ueath. Al- though lL-2 signaling lacilitates the ueath ol CD4 ¯ cells in iesponse to sus- taineu exposuie to antigen, lL-15 inhih- its lL-2neuiateu activation-inuuceu cell ueath as it stinulates giovth. Sini- laily, lL-15 pionotes piolileiation ol nenoiy CD8 ¯ cells, vheieas lL-2 in- hihits it. lL-15 is also involveu in the ho- neostatic suivival ol nenoiy CD8 ¯ cells, Nl cells, anu Nl ¯ cells. ¯hese contiasting hiologic ioles aie illustiateu hy nice uehcient in lL-2 oi lL-2R , vhich uevelop autoinnune uisoiueis, anu nice uehcient in lL-15 oi lL-15R , vhich have lynphopenia anu innune uehciencies. ¯hus lL-15 appeais to have an inpoitant iole in pionoting ellectoi lunctions ol antigen-specihc ¯ cells, vheieas lL-2 is involveu in ieining in autoieactive ¯ cells. 1º 123 |hT£8L£0k|h 4 Ah0 |hT£8L£0k|h 13 l L- 4 anu lL-1o aie piouucts ol activateu ¯h2 cells that shaie liniteu stiuctuial honol- ogy (appioxinately oO peicent) anu ovei- lapping hut uistinct hiologic activities. A specihc ieceptoi loi lL-4, vhich uoes not hinu lL-1o, is lounu on ¯ cells anu Nl cells. lt consists ol lL-4R (CD124) anu c anu tiansnits signals via [al1 anu [alo. A seconu ieceptoi conplex that can hinu eithei lL-4 oi lL-1o is lounu on leiatino- cytes, enuothelial cells, anu othei non- henatopoietic cells. lt consists ol lL- 1oR  (CD21oa1) anu lL-4R anu tians- nits signals via [al1 anu [al2. ¯hese ie- ceptois aie expiesseu at lov levels in iesting cells, anu theii expiession is in- cieaseu hy vaiious activating signals. Cu- iiously, exposuie ol nonocytes to lL-4 oi lL-1o suppiesses expiession ol lL-4R anu lL-1oR 1, vheieas the opposite el- lect is ohseiveu in leiatinocytes. Both signal tiansuuction pathvays appeai to conveige vith the activation ol S¯A¯6, vhich is hoth necessaiy anu sulhcient to uiive ¯h2 uilleientiation. Anothei cell suilace nolecule honologous to lL- 1oR  teineu ll-13R ` (CD21oa2), hinus specihcally to lL-1o hut is not lnovn to tiansnit any signals. 2O ¯he hiologic ellects ol engagenent ol the lL-4 ieceptoi vaiy uepenuing on the specihc cell type, hut nost peitain to its piincipal iole as a giovth anu uilleienti- ation lactoi loi ¯h2 cells. lxposuie ol naive ¯ cells to lL-4 stinulates then to piolileiate anu uilleientiate into ¯h2 cells, vhich piouuce noie lL-4, vhich in tuin leaus to autociine stinulation that piolongs ¯h2 iesponses. ¯hus the expiession ol lL-4 eaily in the innune iesponse can initiate a cascaue ol ¯h2 cell uevelopnent that iesults in a pie- uoninately ¯h2 iesponse. ¯he genes encouing lL-4 anu lL-1o aie locateu in a clustei vith lL-5 vhich unueigoes stiuc- tuial changes uuiing ¯h2 uilleientiation that aie associateu vith incieaseu ex- piession. Although naive ¯ cells can nale lov levels ol lL-4 vhen activateu, lL-4 is also piouuceu hy activateu Nl ¯ cells. íast cells anu hasophils also ie- lease pieloineu lL-4 lion secietoiy gianules in iesponse to lc Rl-neuiateu signals. A pioninent activity ol lL-4 is the stinulation ol class svitching ol the innunoglohulin genes ol B cells. As ciitical lactois in ¯h2 uilleientiation anu ellectoi lunction, lL-4 anu lL-1o aie ne- uiatois ol atopic innunity. ln auuition to contiolling the hehavioi ol ellectoi cells they also act uiiectly on iesiuent tissue cells, such as in inhannatoiy aii- vay ieactions. 21 |hT£8L£0k|h 9 Ah0 |hT£8L£0k|h 21 lL-º is a piouuct ol activateu ¯h2 cells that acts as an autociine giovth lactoi as vell as a neuiatoi ol inhannation. 22 lt is also pio- uuceu hy nast cells in iesponse to lL-1O oi sten cell lactoi. lt stinulates piolileiation ol ¯ anu B cells anu pionotes expiession ol innunoglohulin l hy B cells. lt also ex- eits pio-inhannatoiy ellects on nast cells anu eosinophils. lL-ºuehcient nice exhihit uehcits in nast cell anu gohlet cell uilleientiation. lL-21 is also a piouuct ol ¯h2 ¯ cells that signals thiough a ieceptoi conposeu ol a specihc chain (lL-21R) honologous to the lL-4R chain anu c . 2o Ahsence ol an intact lL-21 ieceptoi is as- sociateu vith inpaiieu ¯h2 iesponses. 24 lL-º anu lL-21 can he gioupeu togethei vith lL-4 anu lL-1o as cytolines that lunc- tion as ellectois ol alleigic inhannatoiy piocesses anu nay play an inpoitant iole in asthna anu alleigic uisoiueis. |hT£8L£0k|h 7 íutations ahiogating the lunction ol lL-¯, lL-¯R (CD12¯), c , oi [alo in nice oi hunans cause piolounu innunouehciency as a iesult ol ¯- anu Nl-cell uepletion. 18 ¯his is piincipally uue to the inuispensahle iole ol lL-¯ in pio- noting the expansion ol lynphocytes anu iegulating the ieaiiangenent ol theii anti- gen ieceptoi genes. lL-¯ is a potent nito- gen anu suivival lactoi loi innatuie lyn- phocytes in the hone naiiov anu thynus. ¯he seconu lunction ol lL-¯ is as a nouihei ol ellectoi cell lunctions in the ieactive phase ol ceitain innune ie- sponses. lL-¯ tiansnits activating signals to natuie ¯ cells anu ceitain activateu B cells. Lile lL-2, lL-¯ has heen shovn to stinulate piolileiation ol cytolytic ¯ cells anu lynpholine-activateu lillei cells in vitio anu to enhance theii activities in vivo. íonocytes exposeu to lL-¯ ielease lL-6, lL-1 , lL-1 , anu ¯Nl- anu exhihit enhanceu tunoiiciual activity in vitio. lL- ¯ is a paiticulaily signihcant cytoline loi lynphocytes in the slin anu othei epithe- lial tissues. lt is expiesseu hy leiatinocytes in a iegulateu lashion, anu this expiession is thought to he pait ol a iecipiocal signal- ing uialog hetveen uenuiitic epiueinal ¯ cells anu leiatinocytes in nuiine slin. le- iatinocytes ielease lL-¯ in iesponse to llN- , anu uenuiitic epiueinal ¯ cells seciete llN- in iesponse to lL-¯. An lL-¯ielateu cytoline using one chain ol the lL-¯ ieceptoi as pait ol its ie- ceptoi is thynic stional lynphopoietin (¯SLl). ¯SLl vas oiiginally iuentiheu as a novel cytoline piouuceu hy a thynic stio- nal cell line that coulu act as a giovth lac- toi loi B- anu ¯-lineage cells. ¯he ¯SLl ie- ceptoi consists ol the lL-¯ ieceptoi chain anu a seconu ieceptoi chain honologous to hut uistinct lion the c chain. ¯SLl has attiacteu inteiest hecause ol its ahility to piine uenuiitic cells to hecone stiongei stinulatois ol ¯h2 cells. ¯his activity nay peinit ¯SLl to lostei the uevelopnent ol sone types ol alleigic uiseases. 25 C]|c||reº W||| Recep|c|º Uº|rç ||e |r|e||eu||r 8 Recep|c| C|a|r ¯he ieceptois loi lL-o, lL-5, anu Cí-CSl consist ol unigue cytoline-specihc chains paiieu vith a connon chain lnovn as ll-3R oi . (CD1o1). lach ol these lactois acts on suhsets ol eaily he- natopoietic cells. 26 lL-o, vhich vas pievi- ously lnovn as mu|ti-|incagc .o|on,-stimu- |ating ja.tor, is piincipally a piouuct ol CD4 + ¯ cells anu causes piolileiation, uil- leientiation, anu colony loination ol vaii- ous nyeloiu cells lion hone naiiov. lL-5 is a piouuct ol ¯h2 CD4 + cells anu acti- vateu nast cells that conveys signals to B cells anu eosinophils. lL-5 has a co-stinu- latoiy ellect on B cells in that it enhances theii piolileiation anu innunoglohulin expiession vhen they encountei theii cognate antigen. ln con|unction vith an eosinophil-attiacting chenoline lnovn as cotaxin, lL-5 plays a cential iole in the accunulation ol eosinophils that accon- panies paiasitic inlections anu sone cuta- neous inhannatoiy piocesses. lL-5 ap- peais to he ieguiieu to geneiate a pool ol eosinophil piecuisois in hone naiiov that can he iapiuly nohilizeu to the hloou, vheieas eotaxin`s iole is locuseu on ieciuitnent ol these eosinophils lion hloou into specihc tissue sites. Cí-CSl is a giovth lactoi loi nyeloiu piogenitois piouuceu hy activateu ¯ cells, phago- cytes, leiatinocytes, hhiohlasts, anu vas- culai enuothelial cells. ln auuition to its iole in eaily henatopoiesis, Cí-CSl has potent ellects on naciophages anu uen- uiitic cells. ln vitio cultuie ol liesh Langei- hans cells in the piesence ol Cí-CSl pio- notes theii tiansloination into natuie uenuiitic cells vith naxinal innuno- stinulatoiy potential loi naive ¯ cells. ¯he ellects ol Cí-CSl on uenuiitic cells piohahly account loi the uianatic ahility ol Cí-CSl to evole theiapeutic antitu- noi innunity vhen tunoi cells aie engi- neeieu to expiess it. 2¯ |r|e||eu||r o ard 0||e| C]|c||reº W||| Recep|c|º Uº|rç 0|]ccp|c|e|r 180 Receptois loi a gioup ol cytolines in- cluuing lL-6, lL-11, lL-2¯, leulenia in- hihitoiy lactoi, oncostatin í, ciliaiy 124 neuiotiophic lactoi, anu caiuiotiophin-1 inteiact vith a henatopoietin ieceptoi lanily nenhei, gp1oO, that uoes not appeai to inteiact vith any liganu hy it- sell. ¯he gp1oO nolecule is ieciuiteu into signaling conplexes vith othei ie- ceptoi chains vhen they engage theii cognate liganus. lL-6 is the nost thoioughly chaiactei- izeu ol the cytolines that use gp1oO loi signaling anu seives as a paiauign loi uiscussion ol the hiologic ellects ol this lanily ol cytolines. lL-6 is yet anothei exanple ol a highly pleiotiopic cytoline vith nultiple ellects. A seiies ol uillei- ent nanes (incluuing ll^- `, 3-.c|| stimu- |ator, ja.tor `, ¡|asma.,toma grovth ja.tor, .,totoxi. T .c|| dijjcrcntiation ja.tor, anu hc¡ato.,tc-stimu|ating ja.tor) veie useu loi lL-6 heloie it vas iecognizeu that a sin- gle noleculai species accounts loi all ol these activities. lL-6 acts on a viue vaii- ety ol cells ol henatopoietic oiigin. lL-6 stinulates innunoglohulin secietion hy B cells anu has nitogenic ellects on B lin- eage cells anu plasnacytonas. lL-6 also pionotes natuiation ol negalaiyo- cytes anu uilleientiation ol nyeloiu cells. Not only uoes it paiticipate in henato- poietic uevelopnent anu ieactive in- nune iesponses, hut lL-6 is also a cential neuiatoi ol the systenic acute-phase ie- sponse. lncieases in ciiculating lL-6 levels stinulate hepatocytes to synthesize anu ielease acute-phase pioteins. ¯heie aie tvo uistinct signal tians- uuction pathvays tiiggeieu hy lL-6. ¯he hist ol these is neuiateu hy the gp1oO nolecule vhen it uineiizes on engage- nent hy the conplex ol lL-6 anu lL- 6R . Honouineiization ol gp1oO anu its associateu [al linases ([al1, [al2, ¯yl2) leaus to activation ol S¯A¯o. A seconu pathvay ol gp1oO signal tians- uuction involves Ras anu the nitogen- activateu piotein linase cascaue anu ie- sults in phosphoiylation anu activation ol a tiansciiption lactoi oiiginally uesig- nateu nu.|car ja.tor oj ll-o. lL-6 is an inpoitant cytoline loi slin anu is suh|ect to uysiegulation in seveial hunan uiseases, incluuing sone vith slin nanilestations. lL-6 is piouuceu in a iegulateu lashion hy leiatinocytes, h- hiohlasts, anu vasculai enuothelial cells as vell as hy leulocytes inhltiating the slin. lL-6 can stinulate the piolileiation ol hunan leiatinocytes unuei sone conuitions. lsoiiasis is one ol seveial in- hannatoiy slin uiseases in vhich ele- vateu expiession ol lL-6 has heen ue- sciiheu. Hunan heipesviius 8 piouuces a viial honolog ol lL-6 that nay he in- volveu in the pathogenesis ol hunan heipesviius 8associateu uiseases, in- cluuing laposi saicona anu houy cav- ityhaseu lynphonas. ¯he othei cytolines using gp1oO as a signal tiansuucei have uiveise hioactivi- ties. lL-11 inhihits piouuction ol inhan- natoiy cytolines anu has shovn sone theiapeutic activity in patients vith psoiiasis. lxogenous lL-11 also stinu- lates platelet piouuction anu has heen useu to tieat thionhocytopenia occui- iing altei chenotheiapy. lL-2¯ is uis- cusseu in the next section vith the lL-12 lanily ol cytolines. |r|e||eu||r 12, |r|e||eu||r 28, ard |r|e||eu||r 2/. P|.c|a| C]|c||reº |c| T He|pe| 1 ard T He|pe| 1/ Reºpcrºeº lL-12 is uilleient lion nost othei cyto- lines in that its active loin is a het- eiouinei ol tvo pioteins, po5 anu p4O. lL-12 is piincipally a piouuct ol antigen- piesenting cells such as uenuiitic cells, nonocytes, naciophages, anu ceitain B cells in iesponse to hacteiial conponents, Cí-CSl, anu llN- . Activateu leiatino- cytes aie an auuitional souice ol lL-12 in slin. Hunan leiatinocytes constitutively nale the po5 suhunit, vheieas expies- sion ol the p4O suhunit can he inuuceu hy stinuli incluuing contact alleigens, phoihol esteis, anu UV iauiation. lL-12 is a ciitical innunoiegulatoiy cytoline that is cential to the initiation anu naintenance ol ¯h1 iesponses. ¯h1 iesponses that aie uepenuent on lL-12 pioviue piotective innunity to intiacel- lulai hacteiial pathogens. lL-12 also has stinulatoiy ellects on Nl cells, pionot- ing theii piolileiation, cytotoxic lunc- tion, anu the piouuction ol cytolines, incluuing llN- . lL-12 has heen shovn to he active in stinulating piotective an- titunoi innunity in a nunhei ol ani- nal nouels. 2¯ ¯vo chains that aie pait ol the cell suilace ieceptoi loi lL-12 have heen cloneu. Both aie honologous to othei chains in the henatopoietin ieceptoi lanily anu aie uesignateu 1 anu 2. ¯he 1 chain is associateu vith ¯yl2 anu the 2 chain inteiacts uiiectly vith [al2. ¯he signaling conponent ol the lL-12R is the 2 chain. ¯he 2 chain is expiesseu in ¯h1 hut not ¯h2 cells anu appeais to he ciitical loi connitnent ol ¯ cells to piouuction ol type 1 cyto- lines. lL-12 signaling inuuces the phos- phoiylation ol S¯A¯1, S¯A¯o, anu S¯A¯4, hut it is S¯A¯4 that is essential loi inuuction ol a ¯h1 iesponse. lL-2o is a heteiouineiic cytoline in the lL-12 lanily that consists ol the p4O chain ol lL-12 in association vith a uis- tinct p1º chain. lL-2o has oveilapping activities vith lL-12 hut also inuuces piolileiation ol nenoiy ¯ cells. lnteiest in lL-2o has heen spaileu hy the ohsei- vation that lL-2o is involveu in the in- uuction ol ¯ cells piouucing lL-1¯ (¯h1¯ suhset). 28 ¯he lL-2o ieceptoi consists ol tvo chains: the lL-12R 1 chain that loins pait ol the lL-12 ieceptoi anu a specihc lL-2o ieceptoi encoueu hy a gene locateu neai the lL-12R 2 gene. 2º ¯he nevest nenhei ol the lL-12 lanily is lL-2¯. lL-2¯ is also a het- eiouinei anu consists ol a suhunit calleu l3l3 that is honologous to lL-12 p4O anu a seconu suhunit lnovn as ¡`8 that is honologous to lL-12 po5. lL-2¯ plays a iole in the eaily inuuction ol the ¯h1 iesponse. oO ¯he lL-2¯ ieceptoi con- sists ol a ieceptoi calleu \:X-1 that as- sociates vith the shaieu signal-tians- uucing nolecule gp1oO. o1 ¯he lL-12 lanily ol cytolines has eneigeu as a pionising nev taiget loi anti-cytoline phainacotheiapy. ¯he ap- pioach that has heen uevelopeu the lui- thest to uate is taigeting hoth lL-12 anu lL-2o vith nonoclonal antihouies ui- iecteu against the connon p4O suhunit. An antihunan p4O nonoclonal anti- houy (CN¯C 12¯5) vas iepoiteu to shov henehcial ellects in phase l tiials in psoiiasis patients. o2 A sinilai theiapeutic antihouy (AB¯-¯84) has uenonstiateu elhcacy in Ciohn uisease. oo ¯he uevelop- nent ol anti-p4O theiapies is seveial yeais hehinu anti¯Nl- uiugs, hut p4O is an attiactive taiget loi lutuie uiug ue- velopnent elloits loi sone types ol in- nune-neuiateu uiseases. ||0A\DS 0| THE C|ASS || |A|||\ 0| C\T0||\E RECEPT0RS A seconu na|oi class ol cytoline iecep- tois vith connon leatuies incluues tvo types ol ieceptois loi llNs, lL-1OR, anu the ieceptois loi auuitional lL-1O ielateu cytolines incluuing lL-1º, lL-2O, lL-22, anu lL-24. |r|e||e|crº. P|c|c|]peº c| C]|c||reº S|çra||rç T||cuç| a Ja|/STAT Pa||Wa] llNs veie one ol the hist lanilies ol cy- tolines to he chaiacteiizeu in uetail. ¯he llNs veie initially suhuiviueu into thiee classes: llN- (the leulocyte llNs), llN- (hhiohlast llN), anu llN- 125 (innune llN). ¯he anu llNs aie col- lectively calleu t,¡c l ll^s, anu all ol these nolecules signal thiough the sane tvo-chain ieceptoi (the llN- iecep- toi). o4 ¯he seconu llN ieceptoi is a uis- tinct tvo-chain ieceptoi specihc loi llN- . Both ol these llN ieceptois aie piesent on nany cell types vithin slin as vell as in othei tissues. lach ol the chains conpiising the tvo llN iecep- tois is associateu vith one ol the [al li- nases (¯yl2 anu [al1 loi the llN- R anu [al1 anu [al2 loi the llN- R). Cnly in the piesence ol hoth chains anu tvo lunctional [al linases vill ellective sig- nal tiansuuction occui altei llN hinuing. A nev class ol llNs lnovn as ll^- oi t,¡c lll ll^s has nov heen iuentiheu that has a lov uegiee ol honology vith hoth type l llNs anu lL-1O. o5 ¯he cui- ient nenheis ol this class aie lL-28A, lL-28B, anu lL-2º. Although the ellects ol these cytolines aie sinilai to those ol the type l llNs, they aie less potent. ¯hese type lll llNs use a shaieu iecep- toi that consists ol the chain ol the lL- 1O ieceptoi associateu vith an lL-28 ie- ceptoi chain. Viiuses, uouhle-stianueu RNA, anu hacteiial piouucts aie anong the stinuli that elicit ielease ol the type l llNs lion cells. llasnacytoiu uenuiitic cells have eneigeu as a paiticulaily potent cellulai souice ol type l llNs. íany ol the el- lects ol the type l llNs uiiectly oi inui- iectly inciease host iesistance to the spieau ol viial inlection. Auuitional el- lects neuiateu thiough llN- R aie incieaseu expiession ol na|oi histo- conpatihility conplex (íHC) class l nolecules anu stinulation ol Nl cell ac- tivity. Not only uoes it have vell- lnovn antiviial ellects, hut llN- also can nouulate ¯-cell iesponses hy lavoi- ing the uevelopnent ol a ¯h1 type ol ¯- cell iesponse. linally, the type l llNs also inhihit the piolileiation ol a vaiiety ol cell types, vhich pioviues a iationale loi theii use in the tieatnent ol sone types ol cancei. loins ol llN- en|oy consiueiahle use clinically loi inuica- tions ianging lion haiiy cell leulenia, vaiious cutaneous nalignancies, anu papillonaviius inlections (see Chap. 1º6). Sone ol the sane conuitions that iesponu to theiapy vith type l llNs also iesponu to topical innunonouulatoiy agents lile iniguinou. ¯his synthetic iniuazoguinoline uiug is an agonist loi the ¯LR¯ ieceptoi, vhose natuial liganu is single-stianueu RNA. lniguinou stinulation ol cells expiessing ¯LR¯ elicits local ielease ol laige anounts ol type l llNs lion plasnacytoiu uenuiitic cells, vhich can tiiggei clinically uselul antiviial anu tunoi inhihitoiy ellects against genital vaits, supeihcial hasal cell caicinona, anu actinic leiatoses. Resiguinou is a ielateu synthetic con- pounu that activates hoth ¯LR¯ anu ¯LR8, eliciting a slightly uilleient spec- tiun ol cytolines. o6 liouuction ol llN- is iestiicteu to Nl cells, CD8 ¯ cells, anu ¯h1 CD4 ¯ cells. ¯h1 cells piouuce llN- altei engage- nent ol the ¯-cell ieceptoi, anu lL-12 can pioviue a stiong co-stinulatoiy sig- nal loi ¯-cell llN- piouuction. Nl cells piouuce llN- in iesponse to cytolines ieleaseu hy naciophages, incluuing ¯Nl- , lL-12, anu lL-18. llN- has anti- viial activity, hut it is a less potent neui- atoi than the type l llNs loi inuuction ol these ellects. ¯he na|oi physiologic iole ol llN- is its capacity to nouulate in- nune iesponses. llN- inuuces synthesis ol nultiple pioteins that play essential ioles in antigen piesentation to ¯ cells, incluuing íHC class l anu class ll glyco- pioteins, invaiiant chain, the Lnp2 anu Lnp¯ conponents ol the pioteasone, anu the ¯Al1 anu ¯Al2 intiacellulai peptiue tianspoiteis. ¯hese changes in- ciease the elhciency ol antigen piesenta- tion to CD4 anu CD8 ¯ cells. llN- is also ieguiieu loi activation ol nacio- phages to theii lull antiniciohial poten- tial, enahling then to elininate niciooi- ganisns capahle ol intiacellulai giovth. Lile type l llNs, llN- also has stiong antipiolileiative ellects on sone cell types. linally, llN- is also an inuucei ol selecteu chenolines (CXC chenoline liganus º to 11) anu an inuucei ol enuo- thelial cell auhesion nolecules (e.g., lCAí-1 anu VCAí-1). Because ol the hieauth ol llN- `s activities, it cones the closest ol the ¯-cell cytolines to hehav- ing as a piinaiy cytoline. |r|e||eu||r 10. Ar 'Ar||- |r1arra|c|]' C]|c||re lL-1O is one ol seveial cytolines that piinaiily exeit iegulatoiy iathei than stinulatoiy ellects on innune ie- sponses. o¯ lL-1O vas hist iuentiheu as a cytoline piouuceu hy ¯h2 ¯ cells that inhihiteu cytoline piouuction altei acti- vation ol ¯ cells hy antigen anu antigen- piesenting cells. lL-1O exeits its action thiough a cell suilace ieceptoi lounu on naciophages, uenuiitic cells, neutio- phils, B cells, ¯ cells, anu Nl cells. ¯he liganu-hinuing chain ol the ieceptoi is honologous to the ieceptois loi llN- / anu llN- , anu signaling events neui- ateu thiough the lL-1O ieceptoi use a [al/S¯A¯ pathvay. lL-1O hinuing to its ieceptoi activates the [al1 anu ¯yl2 li- nases anu leaus to the activation ol S¯A¯1 anu S¯A¯o. ¯he ellects ol lL-1O on antigen-piesenting cells such as nonocytes, naciophages, anu uen- uiitic cells incluue inhihition ol expies- sion ol class ll íHC anu co-stinulatoiy nolecules (e.g., B¯-1, B¯-2) anu ue- cieaseu piouuction ol ¯ cellstinulating cytolines (e.g., lL-1, lL-6, anu lL-12). At least loui viial genones haihoi viial ho- nologues ol lL-1O that tiansnit sinilai signals hy hinuing to the lL-1OR. A na|oi souice ol lL-1O vithin slin is epiueinal leiatinocytes. leiatinocyte lL-1O piouuction is upiegulateu altei ac- tivation, one ol the hest-chaiacteiizeu activating stinuli loi leiatinocytes is UV iiiauiation. UV iauiationinuuceu leiatinocyte lL-1O piouuction leaus to local anu systenic ellects on innunity. Sone ol the vell-uocunenteu innuno- suppiessive ellects that occui altei UV light exposuie aie the iesult ol the lihei- ation ol leiatinocyte-ueiiveu lL-1O into the systenic ciiculation. lL-1O also plays a uanpening iole in othei types ol cuta- neous innune anu inhannatoiy ie- sponses, hecause the ahsence ol lL-1O pieuisposes nice to exaggeiateu iiiitant anu contact sensitivity iesponses. \c.e| |r|e||eu||r 10-Re|a|ed C]|c||reº. |r|e||eu||rº 19, 20, 22, ard 24 A seiies ol cytolines ielateu to lL-1O have heen iuentiheu anu shovn to en- gage a nunhei ol ieceptoi conplexes vith shaieu chains. o8 lL-1º, lL-2O, anu lL-24 tiansnit signals via a conplex consisting ol lL-2OR anu lL-2OR . ¯iansgenic nice oveiexpiessing lL-2O uevelop seveie cutaneous inhannation anu alteieu epiueinal piolileiation anu uilleientiation. lxpiession ol the lL-2OR chains is stiongly inuuceu vhen they aie tiiggeieu, anu they aie only uetecteu on leiatinocytes, enuothelial cells, anu ceitain nonocytes in association vith inhannatoiy conuitions such as psoiia- sis. oº lL-22 activates a ieceptoi consist- ing ol lL-22R anu lL-1OR , vheieas lL- 2O anu lL-24 also engage a conplex in- coipoiating lL-2OR anu lL-22R. 4O,41 ¯he piolounu ellects ol lL-2O expies- sion in tiansgenic nice anu the associa- tion ol lL-2OR expiession vith psoiiasis point tovaiu a signihcant iole loi these cytolines in the epiueinal changes as- sociateu vith cutaneous inhannation. 126 TRA\S|0R||\0 0R0wTH |ACT0R- |A|||\ A\D |TS RECEPT0RS ¯Cl- 1 vas hist isolateu as a secieteu piouuct ol viially tiansloineu tunoi cells capahle ol inuucing noinal cells in vitio to shov phenotypic chaiacteiistics associ- ateu vith tiansloination. Cvei oO auui- tional nenheis ol the ¯Cl- lanily have nov heen iuentiheu. ¯hey can he gioupeu into seveial lanilies: the piototypic ¯Cl- s (¯Cl- 1 to ¯Cl- o), the hone noipho- genetic pioteins, the giovth/uilleientia- tion lactois, anu the activins. ¯he ¯Cl nane loi this lanily ol nolecules is sone- vhat ol a nisnonei, hecause ¯Cl- has antipiolileiative iathei than piolileiative ellects on nost cell types. íany ol the ¯Cl- lanily nenheis play an inpoitant iole in uevelopnent, inhuencing the uil- leientiation ol unconnitteu cells into spe- cihc lineages. ¯Cl- lanily nenheis aie naue as piecuisoi pioteins that aie hio- logically inactive until a laige pio-uonain is cleaveu. íononeis ol the natuie uo- nain ol ¯Cl- lanily nenheis aie uisul- hue linleu to loin uineis that stiongly ie- sist uenatuiation. laiticipation ol at least tvo cell suilace ieceptois (type l anu type ll) vith seiine/ thieonine linase activity is ieguiieu loi hiologic ellects ol ¯Cl- . 42 Liganu hinu- ing hy the type ll ieceptoi (the tiue li- ganu-hinuing ieceptoi) is associateu vith the loination ol conplexes ol type l anu type ll ieceptois. ¯his allovs the type ll ieceptoi to phosphoiylate anu activate the type l ieceptoi, a °tiansuucei` nole- cule that is iesponsihle loi uovnstiean signal tiansuuction. Dovnstiean signal tiansnission lion the nenhiane-hounu ieceptois in the ¯Cl- ieceptoi lanily to the nucleus is piinaiily neuiateu hy a lanily ol cytoplasnic Snau pioteins that tianslocate to the nucleus anu iegulate tiansciiption ol taiget genes. ¯Cl- has a piolounu inhuence on sev- eial types ol innune anu inhannatoiy piocesses. An innunoiegulatoiy iole loi ¯Cl- 1 vas iuentiheu in pait thiough analysis ol ¯Cl- 1 lnoclout nice that ue- velop a vasting uisease at 2O uays ol age associateu vith a nixeu inhannatoiy cell inhltiate involving nany inteinal oigans. ¯his phenotype is nov appieciateu to he a iesult in pait ol the conpioniseu uevelop- nent ol iegulatoiy ¯ cells vhen ¯Cl- 1 is not availahle. Developnent ol cells in the uenuiitic cell lineage is also peituiheu in the ¯Cl- 1uehcient nice, as eviuenceu hy an ahsence ol epiueinal Langeihans cells anu specihc suh-populations ol lynph noue uenuiitic cells. A conhination ol el- lects ol ¯Cl- on hhiohlast lunction nale it one ol the nost hhiogenic ol all cyto- lines stuuieu. 4o ¯Cl- tieateu hhiohlasts uisplay enhanceu piouuction ol collagen anu othei extiacellulai natiix nolecules. ln auuition, ¯Cl- inhihits the piouuction ol netallopioteinases hy hhiohlasts anu stinulates the piouuction ol inhihitois ol the sane netallopioteinases (tissue inhihi- tois ol netallopioteinase, oi ¯líls). ¯Cl- ellects on hhiohlasts nay he inpoitant in pionoting vounu healing. CHE|0||\ES. SEC0\DAR\ C\T0||\ES CE\TRA| T0 |EU|0C\TE |0B|||ZAT|0\ Chenolines aie a laige supeilanily ol snall cytolines that have tvo na|oi lunctions. liist, they guiue leulocytes via chenotactic giauients in tissue. ¯ypi- cally, this is to hiing an ellectoi cell to vheie its activities aie ieguiieu. Seconu, a suhset ol chenolines has the capacity to inciease the hinuing ol leulocytes via theii integiins to liganus at the enuothe- lial cell suilace, vhich lacilitates hin au- hesion anu extiavasation ol leulocytes in tissue. ¯he activities ol this inpoitant class ol cytolines aie sulhciently con- plex that they aie the suh|ect ol a sepa- iate chaptei (Chap. 12). C\T0||\E \ETw0R|- THERAPEUT|C ||P||CAT|0\S A\D APP||CAT|0\S ¯his chaptei has attenpteu to hiing sone uegiee ol oiuei anu logic to the analysis ol a helu ol hunan hiology that continues to giov at a iapiu iate. Although nany things nay change in the voilu ol cyto- lines, ceitain ley concepts have stoou the test ol tine. liincipal anong then is the iuea that cytolines aie eneigency nolecules, uesigneu to he ieleaseu locally anu tiansiently in tissue nicioenviion- nents. When cytolines aie ieleaseu pei- sistently, the iesult is typically chionic uisease. Cne potential vay to tieat such uiseases is vith cytoline antagonists oi othei uiugs that taiget cytolines oi cyto- line-neuiateu pathvays. Cytolines anu cytoline antagonists aie heing useu theiapeutically hy clinicians, anu uevelopnent ol auuitional agents con- tinues. With ceitain notahle exceptions, systenic cytoline theiapy has heen uisap- pointing anu is olten acconpanieu hy suh- stantial noihiuity. ln contiast, local anu tiansient auninistiation ol cytolines nay yielu noie pionising iesults. An exanple ol this appioach is the tiansuuction ol tunoi cells to expiess lactois such as Cí-CSl (CVAX vaccines) oi lL-12 lanily nenheis to enhance antitunoi innune iesponses. 44 Conveisely, agents that spe- cihcally hlocl cytoline activity aie also he- ing uevelopeu. Antihouies anu ¯Nl iecep- toilc lusion pioteins aie lDA-appioveu antagonists ol ¯Nl- activity that aie highly ellective at inuucing uuiahle ienis- sions in psoiiasis (see Chaps. 18, 2o5, anu 2o6). Antihouies against the p4O suhunit shaieu hy lL-12 anu lL-2o aie also active in tieating psoiiasis. Analinia is a loinula- tion ol ieconhinant lL-1Ra appioveu hy the lDA as au|unct theiapy oi seconu-line nonotheiapy loi the tieatnent ol auult iheunatoiu aithiitis anu has heen shovn to he veiy ellective in patients vith neona- tal-onset nultisystenic inhannatoiy uis- ease (see Chap. 1o4). Cthei cytolines that have pieuoninantly anti-inhannatoiy el- lects, such as lL-1O anu lL-11, shov sone inhihitoiy activity in psoiiasis, hut aie not cuiiently heing uevelopeu luithei loi this inuication. A class ol phainacologic agents that inhihits the piouuction ol nul- tiple ¯ cellueiiveu cytolines is the cal- cineuiin inhihitois. ¯aciolinus anu pine- ciolinus hoth hinu to the innunophilin ll-5O6 hinuing piotein-12 (llBl-12), pio- uucing conplexes that hinu to calcineuiin, a calciun-uepenuent phosphatase that acts on pioteins in the nucleai lactoi ol activateu ¯ cells` lanily to pionote theii nucleai tianslocation anu activation ol cy- toline genes (incluuing lL-2, lL-4, anu llN- ) 45 (see Chap. 221). linally, lusion toxins linleu to cytolines, such as the lL-2 lusion piotein uenileulin uiltitox, exploit the cel- lulai specihcity ol ceitain cytoline-iecep- toi inteiactions to lill taiget cells (see Chap. 2o5). Denileulin uiltitox is lDA ap- pioveu loi the tieatnent ol cutaneous ¯- cell lynphona anu has also shovn theia- peutic activity in psoiiasis. 46 lach ol the aloienentioneu appioaches is still iela- tively nev anu open to consiueiahle lutuie uevelopnent. An unueistanuing ol cyto- lines hy clinicians ol the lutuie is lilely to he cential to ellective patient caie. |E\ RE|ERE\CES T|e |u|| |e|e|erce ||º| |c| a|| c|ap|e|º |º a.a||a||e a| WWW.d|çr/.ccr. 1. Cppenhein [[: Cytolines: last, piesent, anu lutuie. lnt j Hcmato| 74:o, 2OO1 o. Lugei ¯A et al: lpiueinal cell (leiatino- cyte)-ueiiveu thynocyte-activating lac- toi (l¯Al). j lmmuno| 127:14ºo, 1º81 4. luppei ¯S: ¯he activateu leiatinocyte: A nouel loi inuucihle cytoline piouuction hy nonhone naiiovueiiveu cells in cutaneous inhannatoiy anu innune iesponses. j lnvcst Dcrmato| º4:146S, 1ººO 5. luppei ¯S: lnnune anu inhannatoiy piocesses in cutaneous tissues. íecha- nisns anu speculations. j C|in lnvcst 86:1¯8o, 1ººO 127 C H A P T E R 1 2 0hemok|oes Sar T. HWarç ¯he slin is an oigan in vhich the nigia- tion, inhux, anu egiess ol leulocytes oc- cuis in hoth honeostatic anu inhanna- toiy piocesses. Chenolines anu theii ieceptois aie accepteu as vital neuiatois ol cellulai tialhcling. Since the uiscoveiy ol the hist chenoattiactant cytoline, oi chenoline, in 1º¯¯, 5O auuitional nev chenolines anu 1¯ chenoline iecep- tois have heen uiscoveieu. íost che- nolines aie snall pioteins vith nolec- ulai veights in the 8 to 1O lu iange anu aie synthesizeu constitutively in sone cells anu can he inuuceu in nany cell types hy cytolines. lnitially associateu only vith ieciuitnent ol leulocyte suh- sets to inhannatoiy sites, 1 it has he- cone cleai that chenolines play ioles in angiogenesis, neuial uevelopnent, cancei netastasis, henatopoiesis, anu inlectious uiseases. ¯his chaptei locuses piinaiily on the lunction ol chenolines in inhannatoiy conuitions, hut also touches on the iole ol these nolecules in othei settings as vell. STRUCTURE 0| CHE|0||\ES Chenolines aie gioupeu into loui suh- lanilies haseu on the spacing ol anino ac- ius hetveen the hist tvo cysteines. ¯he CXC chenolines (also calleu -.hcmo- kincs) shov a C-X-C notil vith one non- conseiveu anino aciu hetveen the tvo cysteines. ¯he othei na|oi suhlanily ol chenolines (calleu -chenolines) lacls the auuitional anino aciu anu is teineu the CC su|jami|,. ¯he tvo ienaining suh- lanilies contain only one nenhei each: the C suhlanily is iepiesenteu hy lyn- photactin, anu liactalline is the only nenhei ol the CXXXC (oi CXoC) suh- lanily. Chenolines can also he assigneu to one ol tvo hioau anu, peihaps, ovei- lapping lunctional gioups. Cne gioup |e.g., iegulateu on activation noinal ¯- cell expiesseu anu secieteu (RAN¯lS), naciophage inhannatoiy piotein 1 / , livei anu activation-iegulateu chenoline (LARC)] neuiates the attiaction anu ie- ciuitnent ol innune cells to sites ol ac- tive inhannation, vheieas otheis |e.g., seconuaiy lynphoiu-oigan chenoline (SLC) anu stional cellueiiveu lactoi-1 (SDl-1)] appeai to play a iole in constitu- tive oi honeostatic nigiation pathvays. 2 ¯he conplexity anu ieuunuancy in the nonenclatuie ol chenolines have leu to the pioposal loi a systenatic no- nenclatuie loi chenolines haseu on the type ol chenoline (C, CXC, CXoC, oi CC) anu a nunhei haseu on the oiuei ol uiscoveiy as pioposeu hy Zlotnil anu Yoshie. 2 loi exanple, SDl-1, a CXC chenoline, has the systenatic nane CXCL12. Because hoth nonenclatuies aie still in viue use, the oiiginal nanes (ahhieviateu in nost cases) as vell as systenatic nanes aie useu inteichange- ahly thioughout the chaptei. ¯ahle 12-1 pioviues a list ol chenoline ieceptois ol inteiest in slin that aie uiscusseu in this chaptei as vell as the na|oi cheno- line liganus that hinu to then. Chenolines aie highly conseiveu anu have sinilai seconuaiy anu teitiaiy stiuc- tuie. Baseu on ciystallogiaphy stuuies, a uisoiueieu anino teininus lolloveu hy thiee conseiveu antipaiallel -pleateu sheets is a connon stiuctuial leatuie ol chenolines. liactalline is unigue in that the chenoline uonain sits atop a nucin-lile stall tetheieu to the plasna nenhiane via a tiansnenhiane uo- nain anu shoit cytoplasnic tail. o Al- though CXC anu CC chenolines loin nultineiic stiuctuies unuei conuitions ieguiieu loi stiuctuial stuuies, these as- sociations nay he ielevant only vhen chenolines associate vith cell-suilace conponents such as glycosaninogly- cans (CACs) oi pioteoglycans. Because nost chenolines have a net positive chaige, these pioteins tenu to hinu to negatively chaigeu caihohyuiates piesent on CACs. lnueeu, the ahility ol posi- tively chaigeu chenolines to hinu to CACs is thought to enahle chenolines to pieleientially associate vith the lu- nenal suilace ol hloou vessels uespite the piesence ol sheai loices lion the hloou that voulu otheivise vash the chenolines avay. CHE|0||\E RECEPT0RS A\D S|0\A| TRA\SDUCT|0\ Chenoline ieceptois aie seven tians- nenhiane spanning nenhiane pio- teins that couple to intiacellulai heteio- tiineiic C pioteins containing , , anu suhunits. 2 ¯hey iepiesent a pait ol a laige lanily ol C piotein coupleu iecep- tois (ClCRs), incluuing ihouopsin, that have ciitical hiologic lunctions. Leulo- cytes expiess seveial C piotein suh- types: s, i, anu g, vheieas the anu suhunits each have 5 anu 11 lnovn suhtypes, iespectively. ¯his conplexity in the loination ol the heteiotiineiic C piotein nay account loi specihcity in the action ol ceitain chenoline iecep- tois. Noinally, C pioteins aie inactive vhen guanosine uiphosphate (CDl) is hounu, hut they aie activateu vhen the CDl is exchangeu loi guanosine tii- phosphate (C¯l) (lig. 12-1). Altei hinu- ing to liganu, chenoline ieceptois iap- iuly associate vith C pioteins, vhich in tuin incieases the exchange ol C¯l loi CDl. leitussis toxin is a connonly useu inhihitoi ol ClCR that iiieveisihly auenosine uiphosphate-iihosylates C suhunits ol the i class anu suhse- guently pievents nost chenoline ie- ceptoineuiateu signaling. Activation ol C pioteins leaus to the uissociation ol the C anu C suhunits (see lig. 12-1). ¯he C suhunit has heen ohseiveu to activate piotein tyiosine li- nases anu nitogen activateu piotein li- nase, leauing to cytosleletal changes anu gene tiansciiption. ¯he C suhunit ie- tains C¯l, vhich is slovly hyuiolyzeu hy the guanosine tiiphosphatase (C¯lase) activity ol this suhunit. ¯his C¯lase ac- tivity is hoth positively anu negatively iegulateu hy C¯lase-activating pioteins CHE|0||\ES AT A 0|A\CE C|erc||reº ard ||e|| |ecep|c|º a|e .||a| red|a|c|º c| ce||u|a| ||a||c||rç. |cº| c|erc||reº a|e ºra|| p|c|e|rº W||| rc|ecu|a| We|ç||º |r ||e 8- |c 10-|d |arçe. C|erc||reº a|e º]r||eº|/ed ccrº|||u- ||.e|] |r ºcre ce||º ard car |e |rduced |r rar] ce|| |]peº |] c]|c||reº. C|erc||reº p|a] |c|eº |r |r1arra||cr, arç|cçereº|º, reu|a| de.e|cprer|, car- ce| re|aº|aº|º, |era|cpc|eº|º, ard |r|ec- ||cuº d|ºeaºe. |r º||r, c|erc||reº p|a] |rpc||ar| |c|eº |r a|cp|c de|ra||||º, pºc||aº|º, re|arcra, re|arcra re|aº|aº|º, ard ºcre .||a| (|rc|ud|rç |e||c.||a|, |r|ec||crº. P|cr|º|rç ||e|apeu||c app||ca||crº c| c|erc||reº |rc|ude ||e p|e.er||cr c| T- ce|| a||eº| cr ac||.a|ed erdc||e||ur c| ||cc||rç |r|ec||cr c| T ce||º |] |urar |rrurcde|c|erc] .||uº 1 uº|rç CC c|e- rc||re |ecep|c| o ara|cçueº. 128 (also lnovn as rcgu|ator oj C ¡rotcin sig- na|ing ¡rotcins). ¯he C uinei initiates ciitical signaling events in iegaiu to che- notaxis anu cell auhesion. lt activates phospholipase C, 4 leauing to loination ol uiacylglyceiol anu inositol tiiphos- phate |lns(1,4,5)l o ]. lns(1,4,5)l o stinu- lates Ca 2+ entiy into the cytosol, vhich along vith uiacylglyceiol, activates pio- tein linase C isoloins. Although the C suhunits have heen shovn to he ciitical loi chenotaxis, the C i suhunit has no lnovn iole in chenotactic nigia- tion. ¯heie is also eviuence that hinuing ol chenoline ieceptois iesults in the ac- tivation ol othei intiacellulai ellectois in- cluuing Ras anu Rho, phosphatiuylinosi- tol-o-linase. 5 RhoA anu piotein linase C appeai to play a iole in integiin alhnity changes, vheieas phosphatiuylinositol-o-linase nay he ciitical loi changes in the aviu- ity state ol lynphocyte lunctionassoci- ateu antigen 1. Cthei pioteins have heen lounu that iegulate the synthesis, expiession, oi uegiauation ol ClCRs. loi exanple, ieceptoi-activity-nouily- ing pioteins act as chapeiones ol seven tiansnenhiane spanning ieceptois anu iegulate suilace expiession as vell as Ik8L£ 12-1 0hamok|na 8acaptors |n Sk|n 8|o|ogy 0HFN0K|hF 8F0FPT08 (008} 0HFN0K|hF L|0Ah0 (00L} FXP8FSS|0h PATTF8h 00NNFhTS 8FFF8Fh0FS CCR1 ||P-1 (CC|8,, RA\TES (CC|o,, |CP-8 (CC|/, T, |c, DCº, \|, B ||ç|a||cr c| DCº ard |c, º||crç|] up|eçu|a|ed |r T |] ||-2 82 CCR2 |CP-1 (CC|2,, -8, -4 (CC|18, T, |c ||ç|a||cr c| T |c |r1ared º||eº, |ep|er|º| |arçe|- |arº ce|| p|ecu|ºc|º |r ep|de|r|º, |r.c|.ed |r º||r |||cº|º .|a |CP-1 82, o8, 82 CCR8 Ec|a/|r (CC|11, > RA\TES, |CP-2 (CC|8,, 8, 4 Ecº|rcp|||º, |aºcp|||º, T|2, \| ||ç|a||cr c| T|2, T, ard 'a||e|ç|c' |rrure ce||º 22, 91 CCR4 TARC (CC|1/,, rac|cp|açe- de||.ed c|erc||re (CC|22, T (|er|çr ard ra||ç- rar|, E/p|eºº|cr |r T|2 > T|1 ce||º, ||ç||] e/p|eººed cr C|A+ rerc|] T, TARC e/p|eºº|cr |] |e|a||rcc]|eº ra] |e |rpc||ar| |r a|cp|c de|ra||||º, ra] çu|de ||a||c||rç c| ra||çrar| aº We|| aº |er|çr |r1arra- |c|] T 10, 21, 44, /8, 92 CCRo RA\TES, ||P-1 (CC|8, 4, T, |c, DCº |a||e| |c| T|1 ce||º, r|ç|a||cr |c acu|e|] |r1ared º||eº, ra] |e |r.c|.ed |r ||arºr|ç|a||cr c| T |||cuç| erdc||e||ur, rajc| H|V-1 |uº|cr cc-|ecep|c| 14, 82 CCRo ||.e| ard ac||.a||cr-|eçu|a|ed c|erc||re (CC|20, T, DCº, B E/p|eººed |] rerc|], rc| ra|.e, T, pcºº|||] |r.c|.ed |r a||eº| c| rerc|] T |c ac||.a|ed erdc||e- ||ur ard |ec|u||rer| c| T |c ep|de|r|º |r pºc||aº|º o4, oo, 98 CCR/ Seccrda|] |]rp|c|d-c|çar c|e- rc||re (CC|21,, Epº|e|r-Ba|| .||uº-|rduced rc|ecu|e-1 ||çard c|erc||re (CC|19, T, DCº, B, re|arcra ce||º C||||ca| |c| r|ç|a||cr c| ra|.e T ard 'cer||a| rer- c|]' T |c ºeccrda|] |]rp|c|d c|çarº, |e(u||ed |c| ra|u|e DCº |c er|e| |]rp|a||cº ard |cca||/e |c |]rp| rcdeº, |ac||||a|eº rcda| re|aº|aº|º 1o, 84, 88, /4, 94 CCR9 T|]ruº-e/p|eººed c|erc||re (CC|2o, T, re|arcra ce||º Aººcc|a|ed W||| re|arcra ºra|| |cWe| re|aº|aºeº /o CCR10 CTAC| (CC|2/, T (|er|çr ard ra||ç- rar|,, re|arcra ce||º P|e|e|er||a| |eºpcrºe c| C|A + T |c CTAC| |r .|||c, ra] |e |r.c|.ed |r T (|er|çr aº We|| aº ra||çrar|, |cr|rç |c ep|de|r|º, W|e|e CTAC| |º e/p|eººed, ºu|.|.a| c| re|arcra |r º||r 9, 2/, /o, 80 C/CR1, 2 ||-8 (C/C|8,, |0SA/0R0 (C/C|1,, E\A-/8 (C/C|o, \eu||cp|||º, \|, Er, re|arcra ce||º Rec|u||rer| c| reu||cp|||º (e.ç., ep|de|r|º |r pºc||- aº|º,, ra] |e |r.c|.ed |r arç|cçereº|º, re|arcra ç|cW|| |ac|c| o1, 9o, 9/ C/CR8 |r|e||e|cr-|rduc|||e p|c|e|r 10 (C/C|10,, rcrc||re |rduced |] |r|e||e|cr- (C/C|9,, |r|e||e|cr- |rduc|||e T ce|| c|erca|||ac- |ar| (C/C|11, T |a||e| |c| T|1 ce||º ard ra] |e |r.c|.ed |r T |ec|u||rer| |c ep|de|r|º |r cu|arecuº T-ce|| |]r- p|cra, |rduceº a||eº| c| ac||.a|ed T cr º||ru|a|ed erdc||e||ur 18, 2o C/CR4 S||cra| ce||-de||.ed |ac|c|-1 , (C/C|12, T, DCº, Er, re|arcra ce||º |ajc| H|V-1 |uº|cr cc-|ecep|c|, |r.c|.ed |r .aºcu|a| |c|ra||cr, |r.c|.ed |r re|arcra re|aº|aº|º /8, 82 C/8CR1 ||ac|a|||re (C/8C|1, T, |c, raº| ce||º, \| |a] |e |r.c|.ed |r ad|eº|cr cr ac||.a|ed T, |c, ard \| ce||º |c ac||.a|ed erdc||e||ur 8, 9/ B = B ce||º, C|A = cu|arecuº |]rp|cc]|e-aººcc|a|ed ar||çer, CTAC| = cu|arecuº T ce||-a|||ac||rç c|erc||re, DCº = derd||||c ce||º, Er = erdc||e||a| ce||º, H|V-1 = |urar |rrurcde|c|erc] .||uº 1, || = |r|e||eu||r, |CP = rac|cp|açe c|erca|||ac|ar| p|c|e|r, ||P = rac|cp|açe |r1arra|c|] p|c|e|r, |c = rcrcc]|eº, \| = ra|u|a| ||||e| ce||º, RA\TES = |eçu|a|ed cr ac||.a||cr rc|ra| T-ce|| e/p|eººed ard ºec|e|ed, T = T ce||º, TARC = ||]ruº ard ac||.a||cr-|eçu|a|ed c|erc||re, T| = T |e|pe|. 129 the liganu specihcity ol chenoline ie- ceptois (see lig. 12-1). lnpoitantly, altei chenoline ieceptois aie exposeu to ap- piopiiate liganus, they aie lieguently in- teinalizeu, leauing to an inahility ol the chenoline ieceptoi to neuiate luithei signaling. ¯his uovniegulation ol che- noline lunction, vhich has heen teineu dcscnsiti:ation, occuis hecause ol phosphoiylation ol Sei/¯hi iesiuues in the C-teininal tail hy pioteins teineu ClCR kinascs anu suhseguent inteinal- ization ol the ieceptoi (see lig. 12-1). Desensitization nay he an inpoitant nechanisn loi iegulating the lunction ol chenoline ieceptois hy inhihiting cell nigiation as leulocytes aiiive at the piinaiy site ol inhannation. CHE|0||\ES A\D CUTA\E0US |EU|0C\TE TRA|||C||\0 Ceneially spealing, chenolines aie thought to play at least thiee uilleient ioles in the ieciuitnent ol host uelense cells, pieuoninantly leulocytes, to sites ol inhannation. 6 liist, they pioviue the signal oi signals ieguiieu to cause leulo- cytes to cone to a conplete stop (i.e., ai- iest) in hloou vessels at inhaneu sites such as slin. Seconu, chenolines have heen shovn to have a iole in the tians- nigiation ol leulocytes lion the lune- nal siue ol the hloou vessel to the ahlu- nenal siue. ¯hiiu, chenolines attiact leulocytes to sites ol inhannation in the ueinis oi epiueinis altei tiansni- giation. leiatinocytes anu enuothelial cells aie a iich souice ol chenolines vhen stinulateu hy appiopiiate cyto- lines. ln auuition, chenolines anu theii ieceptois aie lnovn to play ciitical ioles in the enigiation ol iesiuent slin uen- uiitic cells (DCs) |i.e., Langeihans cells (LCs) anu ueinal DCs] lion the slin to uiaining lynph noues (LNs) via alleient lynphatic vessels, a piocess that is es- sential loi the uevelopnent ol acguiieu innune iesponses (see Chap. 1O). ¯his section is uiviueu into thiee suh- sections. ¯he hist intiouuces hasic con- cepts ol hov all leulocytes aiiest in inllaneu hloou vessels heloie tiansni- giation hy intiouucing the nultistep nouel ol leulocyte ieciuitnent. ¯he seconu uetails nechanisns ol ¯-cell ni- giation, anu the hnal suhsection locuses on the nechanisns hy vhich cheno- lines neuiate the physiologic nigiation ol DCs lion the slin to iegional LNs. |u|||º|ep |cde| c| |eu|cc]|e Rec|u||rer| loi leulocytes to auheie anu nigiate to peiipheial tissues, they nust oveicone the pushing loice ol the vasculai hloou stiean as they hinu to activateu enuo- thelial cells at local sites ol inhanna- tion. Accoiuing to the nultistep oi cas- caue nouel ol leulocyte ieciuitnent (lig. 12-2), one set ol honologous auhe- sion nolecules teineu sc|c.tins neuiates the tiansient attachnent ol leulocytes to enuothelial cells vhile anothei set ol auhesion nolecules teineu intcgrins anu theii ieceptois (innunoglohulin supei- lanily nenheis) neuiates stiongei hinuing (i.e., aiiest) anu tiansnigiation. ¯ ¯he selectins (l-, L-, anu l-selectin) aie nenheis ol a laigei lanily ol caihohy- uiate-hinuing pioteins teineu |c.tins. ¯he selectins hinu theii iespective cai- hohyuiate liganus locateu on piotein scallolus anu thus neuiate the tiansient hinuing oi °iolling` ol leulocytes on en- uothelial cells. ¯he slin-associateu vasculai selectin lnovn as l-sc|c.tin is upiegulateu on en- uothelial cells hy inhannatoiy cyto- lines such as tunoi neciosis lactoi (¯Nl)- anu hinus to sialyl Levis X haseu caihohyuiates. l-selectin liganus loin uistinct epitopes lnovn as the .utancous |,m¡ho.,tcasso.iatcd antigcn (CLA). CLA is expiesseu hy 1O peicent to 4O peicent ol nenoiy ¯ cells anu has heen suggesteu as a nailei loi slin- honing ¯ cells. 8 At least tvo cheno- line ieceptois |CC chenoline ieceptoi 1O (CCR1O) anu CCR4] shov pieleien- tial expiession in CLA + nenoiy ¯ F|608£ 12-1 C|erc||re |ecep|c|-red|a|ed º|çra||rç pa||Wa]º. C| = c|erc||re, ER = erdcp|aºr|c |e||cu|ur, 0DP = çuarcº|re d|p|cºp|a|e, 0R| = 0 p|c|e|r ccup|ed |ecep|c| ||raºe, 0TP = çuarcº|re |||p|cºp|a|e, |aP| = r||cçer-ac||.a|ed p|c|e|r ||raºe, P|C = p|c|e|r ||raºe C, P|C = p|cºp|c||paºe C, PT| = p|c|e|r |]|cº|re ||raºe(º,, PT/ = pe||uºº|º |c/|r, RA|P = |ecep|c|-ac||.||]-rcd||]|rç p|c|e|r, R0S = |eçu|a|c| c| 0 p|c|e|r º|çra||rç p|c|e|r. 130 cells. º,1O Wheieas l-selectin is lilely to he an inpoitant conponent ol slin- selective honing, theie is also eviuence to suggest that L-selectin is involveu in ¯-cell nigiation to slin. 11,12 ln the seconu phase ol this nouel, leulocyte integiins such as those ol the 2 lanily nust he °tuineu on` oi acti- vateu lion theii iesting state to hinu to theii countei-ieceptois such as inteicel- lulai auhesion nolecule 1 that aie ex- piesseu hy enuothelial cells. A vast ai- iay ol uata suggest that the hinuing ol chenolines to leulocyte chenoline ie- ceptois plays a ciitical iole in activating hoth 1 anu 2 integiins. 5,1o Activation ol chenoline ieceptois leaus to a con- plex signaling cascaue (see lig. 12-1) that causes a conloinational change in inuiviuual integiins that leaus to in- cieases in the alhnity anu aviuity ol in- uiviuual leulocyte integiins loi theii li- ganus. luitheinoie, latei steps ol nigiation (i.e., tiansnigiation oi uiape- uesis) have heen shovn to he uepen- uent on chenolines as vell in selective cases. 14 ln the case ol neutiophils, theii ahility to ioll on inhaneu hloou vessels lilely uepenus on theii expiession ol L- selectin anu l-selectin liganus vheieas theii aiiest on activateu enuothelia lilely uepenus on theii expiession ol CXCR1 anu CXCR2 as uesciiheu helov loi vounu healing (see Chap. 16o). lnte- giin activation via chenoline-neuiateu signals appeais to he noie conplex in ¯ cells, vhich appeai to use nultiple che- noline ieceptois, anu is uesciiheu in noie uetail in the lolloving section. C|erc||re-|ed|a|ed ||ç|a||cr c| T Ce||º Antigen-inexpeiienceu ¯ cells aie teineu naivc anu can he iuentiheu hy expies- sion thiee cell suilace pioteins: CD45RA (an isoloin ol the pan-leulocyte nailei), L-selectin, anu the chenoline ieceptoi CCR¯. ¯hese ¯ cells nigiate elhciently to seconuaiy LNs, vheie they nay nale contact vith antigen-heaiing DCs lion the peiipheiy. Cnce activateu hy DCs piesenting antigen, ¯ cells then ex- piess CD45RC, aie teineu mcmor, ¯ cells, anu appeai to expiess a vaiiety ol auhesion nolecules anu chenoline ie- ceptois vhich lacilitate theii extiava- sation lion hloou vessels to inhaneu peiipheial tissue. A specihc suhset ol CCR¯ , L-selectin nenoiy ¯ cells, has heen pioposeu to iepiesent an ellectoi nenoiy ¯-cell suhset that is ieauy loi iapiu ueploynent at peiipheial sites in teins ol theii cytotoxic activity anu ahility to nohilize cytolines. 15 Although chenolines aie hoth se- cieteu anu soluhle, the net positive chaige on nost chenolines allovs then to hinu to negatively chaigeu pio- teoglycans such as hepaiin sullate that aie piesent on the lunenal suilace ol enuothelial cells, thus alloving then to he piesenteu to ¯ cells as they ioll along the lunenal suilace (see lig. 12-2). Altei liganu hinuing, chenoline ieceptois senu intiacellulai signals that leau to in- cieases in the alhnity anu aviuity ol ¯- cell integiins such as lynphocyte lunc- tionassociateu antigen 1 anu veiy late antigen 4 loi theii enuothelial ieceptois inteicellulai auhesion nolecule 1 anu vasculai cell auhesion nolecule-1, ie- spectively. 16 Cnly a lev chenoline ie- ceptois (CXCR4, CCR¯, CCR4, anu CCR6) aie expiesseu at sulhcient levels on iesting peiipheial hloou ¯ cells to neuiate this tiansition. With activation anu inteileulin (lL)-2 stinulation, in- cieaseu nunheis ol chenoline iecep- tois (e.g., CXCRo) aie expiesseu on acti- vateu ¯ cells, naling then noie lilely to iesponu to othei chenolines. ln sev- eial uilleient systens, inhihition ol spe- cihc chenolines piouuceu hy enuothe- lial cells oi chenoline ieceptois lounu on ¯ cells uianatically inhuences ¯-cell aiiest in vivo anu in vitio. 1¯ CXCRo seives as a ieceptoi loi che- noline liganus íig (nonoline inuuceu hy inteileion- ), inteileion-inuucihle pio- tein 1O (ll-1O), anu inteileion-inuucihle ¯ cell chenoattiactant. All thiee ol these chenolines aie uistinguisheu lion othei chenolines hy heing highly upiegulateu hy inteileion- . Resting ¯ cells uo not expiess lunctional levels ol CXCRo, hut upiegulate this ieceptoi vith activation anu cytolines such as lL-2. Cnce expiesseu on ¯ cells, CXCRo is capahle ol neuiating aiiest ol nen- oiy ¯ cells on activateu enuothelial cells. 18 ¯he expiession ol its chenoline liganus is stiongly inhuenceu hy the cytoline inteileion- , vhich syneigisti- cally voils vith pioinhannatoiy cyto- lines such as ¯Nl- to inciease ex- piession ol these liganus hy activateu enuothelial cells 18 anu epithelial cells. ln geneial, activation ol ¯ cells hy cy- tolines such as lL-2 is associateu vith the enhanceu expiession ol CCR1, CCR2, CCR5, anu CXCRo. [ust as ¯ helpei 1 (¯h1) anu ¯h2 (¯ cell) suhsets have uilleient lunctional ioles, it night F|608£ 12-2 |u|||º|ep rcde| c| |eu|cc]|e |ec|u||rer|. |eu|cc]|eº, puº|ed |] ||e ||ccd º||ear, |||º| ||arº|er||] ||rd c| '|c||' cr ||e ºu||ace c| ac||.a|ed erdc||e||a| ce||º .|a |ap|d |r|e|ac||crº W||| P-, E-, c| |-ºe|ec||r. C|erc||reº a|e ºec|e|ed |] erdc||e||a| ce||º ard ||rd |c p|c|ecç|]carº ||a| p|eºer| ||e c|e- rc||re rc|ecu|eº |c c|erc||re |ecep|c|º cr ||e ºu||ace c| ||e |eu|cc]|e. A||e| c|erc||re |ecep|c| ||- ça||cr, |r||ace||u|a| º|çra||rç e.er|º |ead |c a c|arçe |r ||e ccr|c|ra||cr c| |r|eç||rº ard c|arçeº |r ||e|| d|º||||u||cr cr ||e p|aºra rer||are, |eºu|||rç |r |r|eç||r ac||.a||cr. T|eºe c|arçeº |eºu|| |r ||ç| a||r||]/a.|d||] ||rd|rç c| |r|eç||rº |c erdc||e||a| ce|| |r|e|ce||u|a| ad|eº|cr rc|ecu|eº (|CA|º, ard .aºcu- |a| ce|| ad|eº|cr rc|ecu|e (VCA|,-1 |r a º|ep |e|red |rr acIcsicr, W||c| |º ||er |c||cWed |] ||arºr|- ç|a||cr c| ||e |eu|cc]|e |e|Weer erdc||e||a| ce||º ard |r|c ||ººue. C|A = cu|arecuº |]rp|cc]|e-aººcc|- a|ed ar||çer, |ç = |rrurcç|c|u||r, PS0|-1 = P-ºe|ec||r ç|]ccp|c|e|r ||çard 1. 131 have heen pieuicteu that these tvo suh- sets ol ¯ cells voulu expiess uilleient chenoline ieceptois. lnueeu, CCR4 1º21 anu CCRo 22 aie associateu vith ¯h2 cells in vitio, vheieas ¯h1 cells aie as- sociateu vith CCR5 anu CXCRo. 2o ln sone instances, chenoline iecep- tois nay he iegaiueu as lunctional naileis that iuentily ¯h1- veisus ¯h2- type lynphocytes vhile also pionoting theii ieciuitnent to inhannatoiy sites chaiacteiizeu hy °alleigic` oi °cell- neuiateu` innunity, iespectively. When ¯ cells aie activateu in vitio in the piesence ol ¯h1-pionoting cytolines, CXCRo anu CCR5 appeai to he highly expiesseu, vheieas in the piesence ol ¯h2-pionoting cytolines, CCR4, CCR8, anu CCRo expiession pieuoninates. ln iheunatoiu aithiitis, a ¯h1-pieuoni- nant uisease, nany inhltiating ¯ cells expiess CCR5 anu CXCRo 24 vheieas, in atopic uisease, CCR4 expiessing ¯ cells nay he noie lieguent. 21 ¯heie is lilely to he oveilap as uenonstiateu un- uei sone conuitions in vhich hoth ¯h1 anu ¯h2 type ¯ cells can expiess CCR4. 2O ¯he epiueinis is a paiticulaily iich souice ol chenolines, incluuing RAN¯lS, naciophage chenoattiactant piotein-1 (íCl-1), ll-1O, lL-8, LARC, anu thy- nus anu activation-iegulateu cheno- line (¯ARC), vhich lilely contiihute to epiueinal ¯-cell nigiation. leiatino- cytes lion patients vith uistinctive slin uiseases appeai to expiess unigue che- noline expiession piohles. loi in- stance, leiatinocytes ueiiveu lion pa- tients vith atopic ueinatis (see Chap. 14) synthesizeu nessengei RNA loi RAN¯lS at consiueiahly eailiei tine points in iesponse to lL-4 anu ¯Nl- in conpaiison to unallecteu anu psoiiatic patients. 25 leiatinocytes ueiiveu lion psoiiatic patients (see Chap. 18) synthe- sizeu highei levels ol ll-1O vith cyto- line stinulation as vell as highei con- stitutive levels ol lL-8, 25 a chenoline lnovn to ieciuit neutiophils. lL-8 nay contiihute to the laige nunheis ol neu- tiophils that localize to the supiahasal anu coiniheu layeis ol the epiueinis in psoiiasis. ll-1O nay seive to ieciuit acti- vateu ¯ cells ol the ¯h1 helpei pheno- type to the epiueinis anu has heen pos- tulateu to have a iole in the ieciuitnent ol nalignant ¯ cells to the slin in cutaneous ¯-cell lynphonas. 26 Cutaneous ¯ cellattiacting cheno- line (C¯ACl)/CC chenoline liganu 2¯ (CCL2¯) is selectively anu constitutively expiesseu in the epiueinis, anu its ex- piession is only naiginally incieaseu unuei inhannatoiy conuitions. 2¯ lntei- estingly, C¯ACl has heen iepoiteu to pieleientially attiact CLA + nenoiy ¯ cells in vitio 2¯ anu has heen uenon- stiateu to play a iole in the ieciuitnent anu lunction ol slin-honing ¯ cells in inhannatoiy uisease nouels. 28,2º C|erc||reº |r ||e T|a||c||rç c| Derd||||c Ce||º ||cr S||r |c Reç|cra| |]rp| \cdeº Antigen-piesenting cells, incluuing DCs ol the slin, aie ciitical initiatois ol in- nune iesponses anu theii tialhcling patteins aie thought to inhuence innu- nologic outcones. ¯heii nission in- cluues taling up antigen at sites ol in- lection oi in|uiy anu hiinging these antigens to iegional LNs vheie they hoth piesent antigen anu iegulate the iesponses ol ¯ anu B cells. Slin-iesiuent DCs aie initially ueiiveu lion henato- poietic hone naiiov piogenitois oO anu nigiate to slin uuiing the late pienatal anu nevhoin peiious ol lile. Unuei iest- ing (steauy state) conuitions, honeo- static piouuction hy leiatinocytes ol CXCL14 (ieceptoi unlnovn) nay he involveu in attiacting CD14 + DC pie- cuisois to the hasal layei ol the epiuei- nis. o1 Unuei inhannatoiy conuitions, vhen slin-iesiuent DC anu LC leave the slin in laige nunheis, leiatinocytes ielease a vaiiety ol chenolines, incluu- ing CCL2 anu CCL¯ (via CCR2) o2 anu CCL2O (via CCR6), oo vhich nay attiact nonocyte-lile DC piecuisois to the epi- ueinis to ieplenish the LC population. When activateu hy inhannatoiy cy- tolines (e.g., ¯Nl- , anu lL-1 , lipo- polysacchaiiue, oi in|uiy, slin DCs, in- cluuing LCs, leave the epiueinis, entei alleient lynphatic vessels, anu nigiate to uiaining iegional LNs vheie they en- countei hoth naive anu nenoiy ¯ cells. Chenolines guiue the DC on this |oui- ney. Activateu DC specihcally upiegu- late expiession ol CCR¯, vhich hinus to seconuaiy lynphoiu tissue chenoline (SLC/CCL21), a chenoline expiesseu constitutively hy lynphatic enuothelial cells (see elig. 12-2.1 in on-line eui- tion). o4,o5 SLC guiues DCs into ueinal lynphatic vessels anu helps ietain then in SLC-iich iegional uiaining LNs (lig. 12-o). o6 lnteiestingly, naive ¯ cells also stiongly expiess CCR¯ anu use this ie- ceptoi to aiiest on high enuothelial venules. o¯ ¯he inpoitance ol the CCR¯ pathvay is uenonstiateu hy LCs lion CCR¯ lnoclout nouse that uenon- stiate pooi nigiation lion the slin to iegional LNs o8 anu hy the ohseivation that antihouies to SLC hlocl nigiation ol DCs lion the peiipheiy to LNs. o4 ¯hus, CCR¯ anu its liganus lacilitate the ieciuitnent ol at least tvo uilleient linus ol cellsnaive ¯ cells anu DCs to the LNs thiough tvo uilleient ioutes unuei hoth inhannatoiy o8 anu iesting conuitions. o6 Altei DCs ieach the LN, they nust inteiact vith ¯ cells to loin a so-calleu immuno|ogi. s,na¡sc that is ciitical loi ¯- cell activation. Activateu DCs seciete a nunhei ol chenolines, incluuing nac- iophage-ueiiveu chenoline, oº vhich attiacts ¯ cells to the vicinity ol DCs anu pionotes auhesion hetveen the tvo cell types. 4O,41 CCR5 (via CCLo/4) has also heen iuentiheu as neuiating ie- ciuitnent ol naive CD8 + ¯ cells to ag- giegates ol antigen-specihc CD4 + ¯ cells anu DCs. 42 ¯heieloie, chenolines oi- chestiate a conplex seiies ol nigiation patteins, hiinging hoth DCs anu ¯ cells to the conhnes ol the LN, vheie expies- sion ol chenolines hy DCs thenselves appeais to he a uiiect signal loi hinuing ol the ¯ cell (see lig. 12-o). CHE|0||\ES |\ D|SEASE A|cp|c De|ra||||º (See Chap. 14) Atopic ueinatitis is a piototypical ¯h2- neuiateu, alleigic slin uisease (see Chap. 14) in vhich chenolines nay play pathogenic ioles. 4o ¯he nechanisn ol lynphocyte honing to slin in the set- ting ol atopic ueinatitis has heen eluci- uateu hy clinical uata lion hunans as vell as expeiinental uata in the NC/Nga nouse nouel ol atopic ueinatitis, vhich suggest that the ¯h2-associateu chenoline ieceptoi, CCR4, in con|unc- tion vith its liganu, ¯ARC/CCL1¯, nay play a iole in ieciuiting ¯ cells to atopic slin. ln hunan patients vith atopic uei- natitis, CLA + CCR4 + lynphocytes veie lounu to he incieaseu in the peiipheial hloou ol atopic ueinatitis patients con- paieu to contiols. 21 íoieovei, seiun lev- els ol ¯ARC in atopic ueinatitis patients veie 1O-lolu highei than concentiations lounu in unallecteu inuiviuuals anu coi- ielateu vith uisease seveiity, vheieas psoiiatics shoveu only a nininal eleva- tion ol ¯ARC in the seiun. 44 lnteiest- ingly, anothei chenoline, CCL18, vhose ieceptoi is cuiiently unlnovn, is pio- uuceu hy LC (as vell as othei antigen- piesenting cells) anu shovs selective expiession in atopic slin ielative to pso- iiatic slin. Sinilai to ¯ARC, CCL18 at- 132 tiacts CLA + nenoiy ¯ cells. 45 leihaps ol physiologic conseguence, CCL18 ex- piession is eliciteu in volunteei slin altei topical challenge vith uust nite alleigen anu staphylococcal supeiantigen. 46 ¯he ieciuitnent ol eosinophils to slin is a lieguently ohseiveu hnuing in alleigic slin uiseases, incluuing atopic ueinatitis anu cutaneous uiug ieac- tions, anu lilely is neuiateu hy cheno- lines. lotaxin/CCL11 vas initially iso- lateu lion the hionchoalveolai huiu ol guinea pigs altei expeiinental alleigic inhannation anu hinus piinaiily to CCRo, a ieceptoi expiesseu hy eosino- phils, 4¯ hasophils, anu ¯h2 cells. 22 ln|ec- tion ol eotaxin into the slin pionotes the ieciuitnent ol eosinophils vheieas anti-eotaxin antihouies uelay the ueinal ieciuitnent ol eosinophils in the late- phase alleigic ieaction in nouse slin. 48 lnnunoieactivity anu nessengei RNA expiession ol eotaxin anu CCRo aie hoth incieaseu in lesional slin anu se- iun ol patients vith atopic ueinatitis, hut not in nonatopic contiols. 4º,5O lo- taxin has also heen shovn to inciease piolileiation ol CCRo-expiessing leiati- nocytes in vitio. 51 linally, expiession ol eotaxin (anu RAN¯lS) hy ueinal enuo- thelial cells has heen coiielateu vith the appeaiance ol eosinophils in the ueinis in patients vith onchoceiciasis that ex- peiience alleigic ieactions altei tieat- nent vith iveinectin. 52 ¯hese ohseiva- tions suggest that piouuction ol eotaxin anu CCRo nay contiihute to the ie- ciuitnent ol eosinophils anu ¯h2 lyn- phocytes in auuition to stinulating le- iatinocyte piolileiation. Pºc||aº|º (See Chap. 18) lsoiiasis, an inhannatoiy slin uisoi- uei chaiacteiizeu hy thicleneu, piuiitic plagues, uoes not have a cleai etiology, although it is consiueieu a ¯h1-neui- ateu, autoinnune uisease. As shovn in lig. 12-4 anu ievieveu hy otheis, 5o theie aie nultiple potential tialhcling pathvays that nay he neuiateu hy chenolines in psoiiasis. Chenolines, incluuing LARC/CCL2O 54 anu ¯ARC/ CCL1¯, 1O that aie expiesseu hy vasculai enuothelial cells neuiate the aiiest ol ellectoi nenoiy ¯ cells on enuothelial cells. 55 ln auuition, hoth CCL1¯ anu CCL2O can he synthesizeu hy leiatino- cytes, possihly contiihuting to ¯-cell ni- giation to the epiueinis. Although the CCL1¯ ieceptoi, CCR4, has heen asso- ciateu vith ¯h2-type ¯ cells, 1º theie is also eviuence suggesting that ¯h1-type ¯ cells can expiess this ieceptoi. 2O Neutiophils lounu in the epiueinis ol psoiiatic slin aie lilely to he attiacteu theie hy high levels ol lL-8, vhich voulu act via CXCR1 anu CXCR2. ln auuition to attiacting neutiophils, lL-8 is an lLR + CXC chenoline that is lnovn to he angiogenic, anu it nay also attiact enuothelial cells. ¯his nay leau to the loination ol the long toituous capillaiy hloou vessels in the papillaiy ueinis that aie chaiacteiistic ol psoiiasis. íoie- ovei, leiatinocytes also expiess CXCR2 anu thus nay he auto-iegulateu hy the expiession ol CXCR2 liganus in the slin. Cl note, an lL-8/CXCL8piouuc- ing population ol nenoiy ¯ cells that expiess CCR6 has heen isolateu lion patients vith acute geneializeu exan- thenatous pustulosis, a conuition in- uuceu nost connonly hy uiugs (e.g., aninopenicillins) anu chaiacteiizeu hy snall intiaepiueinal oi suhcoineal stei- ile pustules (see Chap. 4O). 56 Sinilai ¯ cells have heen isolateu lion patients vith Behçet uisease anu pustulai psoiia- sis. 5¯ lt is possihle that this suhpopula- tion ol ¯ cells contiihutes to neutiophil accunulation in the stiatun coineun (íunio ahscesses) in psoiiasis anu othei inhannatoiy slin uisoiueis chaiactei- izeu hy neutiophil-iich inhltiates in the ahsence ol lianl inlection. F|608£ 12-3 T|a||c||rç c| ep|- de|ra| |arçe||arº ce||º (|Cº, |c |eç|cra| |]rp| rcdeº. |Cº a|e ac||- .a|ed |] a .a||e|] c| º||ru||, |rc|ud- |rç |rju|], |r|ec||cuº açer|º, ard c]- |c||reº ºuc| aº |r|e||eu||r-1 ard |urc| rec|cº|º |ac|c|- . Ha.|rç ºarp|ed ar||çerº, ||e ac||.a|ed |Cº dcWr|eçu|a|e E-cad|e||r ard º||crç|] up|eçu|a|e CC c|erc||re |ecep|c| / (CCR/,. Serº|rç ||e CCR/-||çard, ºeccrda|] |]rp|c|d- c|çar c|erc||re (S|C, ,, p|c- duced |] |]rp|a||c erdc||e||a| ce||º, ||e |Cº r|ç|a|e |r|c |]r- p|a||c .eººe|º, paºº|.e|] 1cW |c ||e |]rp| rcdeº, ard º|cp |r ||e T-ce|| /creº (TCZº, ||a| a|e ||c| |r |Wc CCR/ ||çardº, S|C ard Epº|e|r- Ba|| .||uº-|rduced rc|ecu|e-1 ||çard c|erc||re (E|C,. \c|e ||a| c|erc- ||reº a|ºc ccr||||u|e |c ||e |ec|u||- rer| c| |Cº urde| |c|| |eº||rç ard |r1arra|c|] ccrd|||crº. BCZ = B- ce|| /cre, CC| = CC c|erc||re ||- çard, C/C| = C/C c|erc||re ||- çard. 133 Although the aloienentioneu cheno- lines have heen shovn to he expiesseu in psoiiatic epiueinis, they nay also he lounu in a vaiiety ol slin uiseases, in- cluuing cutaneous ¯-cell lynphona anu atopic ueinatitis. lt is heconing appai- ent that nultiple, iathei than single, chenolines anu theii ieceptois lilely contiihute to the hne-tuning ol ¯-cell nigiation in the slin. Carce| Chenolines nay play a iole in tunoi loination anu innunity in seveial uis- tinct vays, incluuing the contiol ol an- giogenesis anu the inuuction ol tunoi innune iesponses. 58 CXC chenolines that expiess a thiee anino aciu notil consisting ol glu-leu-aig (lLR) inneui- ately pieceuing the CXC signatuie aie angiogenic, vheieas nost non-lLR CXC chenolines, except SDl-1, aie an- giostatic. lnteiestingly, it is not cleai that lLR chenolines actually hinu to chenoline ieceptois to ieuuce angio- genesis. lt has heen pioposeu that they act hy uisplacing giovth lactois lion pioteoglycans. ln any event, the halance hetveen lLR + veisus lLR chenolines is thought to contiihute to the conplex iegulation ol angiogenesis at tunoi sites. lL-8, a piototypical lLR + cheno- line, can he secieteu hy nelanona cells anu has heen uetecteu in con|unction vith netastatic uissenination ol this cancei. 5º lL-8 nay also act as an auto- ciine giovth lactoi loi nelanona 6O as vell as seveial othei types ol cancei. Al- though CXCR1 anu CXCR2 hinu lL-8 in connon, seveial othei lLR + CXC che- nolines, incluuing giovth iegulateu oncogene anu epithelial-neutiophil activating peptiue-¯8, hinu piinaiily to CXCR2. CXCR2 appeais, in nost in- stances, to he associateu vith hoth the angiogenic anu giovth iegulatoiy piop- eities ol tunois. 61 ¯unois, incluuing nelanona, have long heen lnovn to seciete chenolines that can attiact a vaiiety ol leulocytes. ¯he guestion aiises as to vhy this is not ueleteiious to the tunoi itsell. Bieast canceis, loi instance, aie lnovn to se- ciete íCl-1, a chenoline that attiacts naciophages thiough CCR2. Highei tis- sue levels ol íCl-1 coiielate vith in- cieasing nunheis ol naciophages vithin the tissue. Although chenolines secieteu hy tunoi cells uo leau to ie- ciuitnent ol innune cells, this uoes not necessaiily leau to incieaseu cleaiance ol the tunoi. 62 lnhannatoiy cells such as nacio- phages nay actually play a ciitical iole in cancei invasion anu netastasis. liist, íCl-1 nay inciease expiession ol naciophage lL-4 thiough an autociine leeuhacl loop anu possihly slev the in- nune iesponse lion ¯h1 to ¯h2. lntei- estingly, íCl-1uehcient nice shov naileuly ieuuceu ueinal hhiosis altei ueinal challenge vith hleonycin, a hnu- ing ol possihle ielevance to the pathogen- esis ol conuitions such as scleioueina. 6o Seconuly, naciophages nay pionote tu- noi invasion anu netastasis. 64 ¯he anti- tunoi ellects ol specihc chenolines nay occui hy a vaiiety ol nechanisns. lLR CXCRo liganus such as ll-1O aie potently anti-angiogenic anu nay act as uovn- stiean ellectois ol lL-12inuuceu, natuial lillei celluepenuent angiostasis. 65 Cl note, sone cancei cells can synthesize F|608£ 12-4 Pcºº|||e º||eº c| ac||crº c| c|erc||reº |r pºc||aº|º. C|erc||reº a|||ac| |c|| reu||cp|||º (|c |c|r |ur|c a|ºceººeº, ard |]rp|cc]|eº .|a a|- |ac|rer| |c erdc||e||a| ce||º ard ||er r|ç|a|e |c ||e ep|de|r|º (ep|de|rc||cp|ºr,. Spec||c c|erc||reº |erd |c a|||ac| e|||e| reu||cp|||º c| |]rp|cc]|eº, |u| çer- e|a||] rc| |c||. A reW|] |der|||ed ºu|ºe| c| T ce||º car ºec|e|e |r|e||eu||r-8 ard a|||ac| reu||cp|||º |r ccrd|||crº ºuc| aº acu|e çere|a||/ed e/ar||era|cuº puº|u- |cº|º. o8 Derd||||c ce||º ra] a|ºc ºec|e|e c|erc||reº, a|||ac| T ce||º, ard º||ru|a|e ccrjuça|e |c|ra||cr ||a| ac||.a|eº T ce||º. CCR = CC c|erc||re |ecep|c|, CTAC| = cu|arecuº T ce||-a|||ac||rç c|erc||re, C/CR = C/C c|erc||re |ecep|c|, ||-8 = |r|e||eu||r 8, |-TAC = |r|e||e|cr-|rduc|||e T ce|| c|erca|||ac|ar|, |ARC = ||.e| ard ac||.a||cr-|eçu|a|ed c|erc||re, |CP-1 = rac|cp|açe c|erca|||ac|ar| p|c|e|r-1, |DC = rac|cp|açe-de||.ed c|erc||re, ||ç = rcrc||re |rduced |] |r|e||e|cr- , RA\TES = |eçu|a|ed cr ac||.a||cr rc|ra| T-ce|| e/p|eººed ard ºec|e|ed, TARC = ||]ruº ard ac||.a||cr-|eçu|a|ed c|erc||re. kerat|oocytes Nuuro aoscess Activatiou £odothe||a| ce||s Nig TAR0 ND0 l-TA0 lAR0 0TA0K luitial adhesiou of leukoc]tes to eudothelium 0R0 ll-8 0TA0K RAhTE8 lAR0 N0P-1 heutrophils Nuuro aoscesses T cells epidermotropism ll-8 heutrophils (0X0R1/2} l]mphoc]tes (00R2, 00RO, 0X0R8, 00R10, 00R4} Deudritic cells (with autigeu} 134 LARC, attiacting innatuie DCs that ex- piess CCR6. 66 lxpeiinentally, LARC has heen tiansuuceu into nuiine tunois, vheie it attiacts DCs in nice anu sup- piesses tunoi giovth in expeiinental systens. 6¯ Last, chenolines piouuceu hy tunoi cells nay attiact CD4 + CD25 + ¯ iegulatoiy cells that suppiess host anti-tu- noi cytolytic ¯ cells. 68 ¯unoi netastasis is the nost con- non souice ol noitality anu noihiuity in cancei. With slin canceis such as nelanona, theie is a piopensity loi spe- cihc sites such as hiain, lung, anu livei, as vell as uistant slin sites. Canceis nay also netastasize via alleient lyn- phatics anu eventually ieach iegional uiaining LNs. ¯he uiscoveiy ol noual netastasis olten poitenus a pooi piog- nosis loi the patient. ln lact, the pies- ence ol noual netastases is one ol the nost poveilul negative pieuictois ol suivival in nelanona. 6º Chenolines nay play an inpoitant iole in the site-specihc netastases ol canceis ol the hieast anu ol nelanona (lig. 12-5). ¯O Hunan hieast cancei as vell as nelanona lines expiesseu the chenoline ieceptois CXCR4 anu CCR¯, vheieas noinal hieast epithelial cells anu nelanocytes uo not appeai to ex- piess these ieceptois. ¯1 CXCR4 is ex- piesseu in ovei 2o uilleient soliu anu henatopoietic canceis. Bioau expies- sion ol this ieceptoi nay he uue to its iegulation hy hypoxia, a conuition con- non to gioving tunois, via the hy- poxia inuucihle lactoi-1 tiansciiption lactoi. ¯2 ln seveial uilleient aninals ol hieast cancei ¯1 anu nelanona netasta- sis, ¯o inhihition ol CXCR4 vith anti- houies oi peptiues iesulteu in uianati- cally ieuuceu netastases to uistant oigans. lxpiession ol CCR¯ hy cancei cells, incluuing gastiic caicinona anu nelanona, appeais to he ciitical loi in- vasion ol alleient lynphatics anu LN netastasis. CCR¯-tianslecteu B16 nu- iine nelanona cells veie lounu to ne- tastasize vith nuch highei elhciency to iegional LNs conpaieu to contiol B16 cells altei inoculation into the lootpau ol nice. ¯4 CCRº nay also play a iole in nelanona netastasis to the snall hovel, vhich shovs high expiession ol the CCRº liganu, CCL25. ¯5 CCR1O is highly expiesseu hy nela- nona piinaiy tunois ¯6 anu is coiie- lateu vith noual netastasis in nela- nona patients ¯¯ anu in expeiinental aninal nouels (see elig. 12-5.1 in on- line euition). ¯6 lngagenent ol CCR1O hy C¯ACl iesults in activation (via phosphoiylation) ol the phosphatiuyl- inositol o-linase anu Alt signaling path- vays, leauing to anti-apoptotic ellects in nelanona cells. ¯6 Because C¯ACl is constitutively piouuceu hy leiatino- cytes, it nay act as a suivival lactoi loi hoth piinaiy as vell as seconuaiy (netastatic) nelanona tunois that ex- piess CCR1O. ln lact, CCR1O-activateu nelanona cells hecone iesistant to lilling hy nelanona antigen-specihc ¯ cells. ¯6 lnteiestingly, CCR4 ¯8 anu CCR1O ¯º,8O have heen inplicateu in the tialhcling anu/oi suivival ol nalignant ¯ (lynphona) cells to slin. ¯hus, a lin- iteu nunhei ol specihc chenoline ie- ceptois appeai to play uistinct, non- ieuunuant ioles, in lacilitating cancei piogiession anu netastasis (sunna- iizeu in lig. 12-5). |r|ec||cuº D|ºeaºeº Although chenolines anu chenoline ieceptois nay have evolveu as a host ie- sponse to inlectious agents, iecent uata suggest inlectious oiganisns nay have co-opteu chenoline- oi chenoline ie- ceptoilile nolecules to theii ovn au- vantage in selecteu instances. A vaiiety ol niciooiganisns expiess chenoline ieceptois, incluuing US28 hy cytonega- loviius (see Chap. 1ºo) anu laposi sai- cona heipesviius (oi hunan heipesvi- ius-8) ClCR. ln the case ol laposi saicona heipesviius ClCR, this iecep- toi is ahle to pioniscuously hinu seveial chenolines. íoie inpoitant, it is con- stitutively active anu nay voil as a giovth pionotei in laposi saicona (see Chap. 128). 81 Hunan innunouehciency viius 1 (HlV-1), the causative agent ol acguiieu innunouehciency synuione, is an en- velopeu ietioviius that enteis cells via ieceptoi-uepenuent nenhiane lusion (see Chap. 1º8). CD4 is the piinaiy lu- sion ieceptoi loi all stiains ol HlV-1 anu hinus to HlV-1 pioteins, gp12O anu gp41. Hovevei, uilleient stiains ol HlV- 1 have eneigeu that pieleientially use CXCR4 (¯-tiopic) oi CCR5 (í-tiopic) oi eithei chenoline ieceptoi as a co- ieceptoi loi entiy. Although othei che- noline co-ieceptois can potentially seive as co-ieceptois, nost clinical HlV-1 stiains aie piinaiily uual-tiopic loi ei- thei CCR5 oi CXCR4. 82 ¯he uiscoveiy ol a o2hase paii uele- tion ( o2) in CCR5 in sone inuiviuuals that leaus to lov levels ol CCR5 expies- sion in ¯ cells anu DCs anu coiielates vith a uianatic iesistance to HlV-1 in- lection uenonstiateu a cleai iole loi CCR5 in the pathogenesis ol HlV-1 in- F|608£ 12-5 C|erc||re |ecep|c|º |r re|arcra p|cç|eºº|cr ard re|aº|aº|º. C|erc||re |ecep|c|º p|a] d|º||rc| |c|eº |r re|arcra re|aº|aº|º. /1 CC c|erc||re |ecep|c| 10 (CCR10, ra] er|arce ºu|.|.a| c| p||ra|] re|arcra |urc|º ard º||r re|aº|aºeº. CCR/, CCR10, ard, pcºº|||], C/C c|erc||re |ecep- |c| 4 (C/CR4, ra] ccr||||u|e |c |]rp| rcde re|aº|aº|º. C/CR4 appea|º |c |e |r.c|.ed |r p||ra|] |urc| de.e|cprer| ard re|aº|aº|º a| d|º|ar| c|çar º||eº ºuc| aº ||e |urçº. CCR9 |aº |eer |rp||ca|ed |r re|- arcra ºra|| |cWe| re|aº|aº|º |r pa||er|º. 135 lection. 8o lnteiestingly, the lieguency ol o2 nutations in hunans is suipiisingly high, anu the conplete ahsence ol CCR5 in honozygotes has only heen associateu vith a noie clinically seveie loin ol saicoiuosis. Ctheivise, these inuiviuuals aie healthy. ln lact, theie is an association ol less seveie autoin- nune uisease vith this nutation. 84 LCs iesiue in laige nunheis in the geni- tal nucosa anu nay he one ol the hist ini- tial taigets ol HlV-1 inlection. 85 Because inlecteu (activateu) LCs lilely entei uei- nal lynphatic vessels anu then localize to iegional LNs, the physiologic nigiatoiy pathvay ol LCs nay also coinciuentally leau to the tiansnission ol HlV-1 to ¯ cells vithin seconuaiy lynphoiu oigans. CCR5 is expiesseu hy innatuie oi iest- ing LCs in the epiueinis anu is the taiget ol CCR5 analogues ol RAN¯lS that hlocl HlV inlection, 86 suggesting possihle theia- peutic stiategies in the tieatnent oi pie- vention ol HlV-1 uisease. 8¯ CXCR4 antag- onists nay also he ol clinical utility vith ¯- oi uual-tiopic viiuses. 88 A nevly uesciiheu autosonal uoni- nant genetic synuione conpiiseu ol vaits (hunan papillona viiusassoci- ateu), hypogannaglohulinenia, inlec- tions, anu nyelolathexis is the iesult ol an activating nutation (ueletion) in the cytoplasnic tail ol the CXCR4 ieceptoi oi in yet uniuentiheu uovnstiean iegulatois ol CXCR4 lunction. 8º,ºO Bacteiial inlec- tions aie connon hecause nyelolathexis is associateu vith neutiopenia anu ahnoi- nal neutiophil noiphology. ¯he neaily univeisal piesence ol hunan papillona viius inlections associateu vith this syn- uione can involve nultiple connon, as vell as genital, vait suhtypes (see elig. 12-5.2 in on-line euition) anu suggest a ciitical iole loi noinal CXCR4 lunction in innunologic uelense against this con- non hunan pathogen. ¯hus, the slin is iich in cells (leiati- nocytes, hhiohlasts, enuothelial cells, anu innune cells) that aie ahle to pio- uuce chenolines. Chenolines not only oichestiate the nigiation ol inhanna- toiy cells, hut also play ioles in angio- genesis, cancei netastasis, anu cellulai piolileiation. Cthei unanticipateu hio- logic ioles nay ultinately he uiscov- eieu. [ust tvo ol the pionising theia- peutic applications ol chenolines (oi nolecules that ninic chenolines) nay he in (1) pieventing unuesiiahle nigia- tion into the slin hy pieventing aiiest ol ¯ cells oi othei inhannatoiy cells on activateu enuotheliun anu (2) hlocling the inlection ol DCs anu ¯ cells hy HlV- 1 viius using CCR5 analogues. Signaling pathvays aie |ust heginning to he un- ueistoou, anu luithei voil neeus to he uone to unueistanu the iegulation ol these ieceptois, the specihcity ol intia- cellulai activities, anu the nechanisn hy vhich chenoline ieceptois voil in the lace ol nultiple chenolines piesent in nany inhannatoiy sites. |E\ RE|ERE\CES T|e |u|| |e|e|erce ||º| |c| a|| c|ap|e|º |º a.a||a||e a| WWW.d|çr/.ccr. 1. Chaio ll, Ransoholl Rí: ¯he nany ioles ol chenolines anu chenoline ieceptois in inhannation. ^ lng| j /cd 354:61O, 2OO6 2. Zlotnil A, Yoshie C: Chenolines: A nev classihcation systen anu theii iole in innunity. lmmunit, 12:121, 2OOO 6. Honey B: Chenolines anu inhanna- toiy slin uiseases. Adv Dcrmato| 21:251, 2OO5 o6. Chl L et al: CCR¯ goveins slin uen- uiitic cell nigiation unuei inhannatoiy anu steauy-state conuitions. lmmunit, 21:2¯º, 2OO4 ¯¯. Sinonetti C et al: lotential iole ol CCL2¯ anu CCR1O expiession in nela- nona piogiession anu innune escape. lur j Can.cr 42:1181, 2OO6 ºO. Diaz CA, Culino AV: WHlí synuione: A uelect in CXCR4 signaling. Curr A||crg, Asthma Rc¡ 5:o5O, 2OO5 C H A P T E R 1 8 A||erg|c 0ootct 0ermt|t|s Da.|d E. Cc|er S|a|cr E. Jacc| As the piinaiy inteilace vith the envi- ionnent, the slin is placeu in the pie- caiious position ol ioutine exposuie anu assault lion exogenous chenicals anu physical agents. loitunately, nost ol these exposuies iesult in no clinically appaient uisease. Hovevei, in sone cii- cunstances, a panoply ol innunologic events iesults in the sensitization anu suhseguent elicitation ol alleigic contact ueinatitis (ACD). ¯he classic inteipietation ol the slin as a sinple haiiiei to penetiation hy exoge- nous agents unueiestinates the innu- nologic capacity ol the integunent. íouein concepts have uivulgeu the hnely oichestiateu inteiplay ol host ue- lenses that cope vith these onslaughts. ln the 1º5Os, Lanusteinei anu Chase 1 hinly estahlisheu ACD as a loin ol cell- neuiateu hypeisensitivity. lt vas not un- til the lattei hall ol the tventieth centuiy, hovevei, that the lunuanental iole ol in- tact lynphatic systens, cellulai elenents (Langeihans cells, leiatinocytes, anu lynphoiu cells), anu specihc cytolines in the sensitization anu elicitation phases ol ACD hecane iecognizeu (see Chap. 1O). 1 ¯ouay ve unueistanu that these con- plex ¯-cellneuiateu events aie specih- cally anu sensitively taigeteu to one oi noie chenical entities. When the level ol exposuie exceeus the thiesholus ol sensitization anu elicitation, innuno- logic nenoiy ol the event is geneiateu. ¯hat heing saiu, the lieguent lacl ol an ohvious causative culpiit oi tenpoial ie- lationship hetveen the alleigen anu uei- natitis leaus to an intense uetective anu analytic exeicise ol ueteinining anu suhseguently avoiuing the ollenuing chenical entity. EP|DE||0|00\ íuch ol the epiueniologic uata iegaiu- ing ACD has heen extiapolateu oi in- leiieu lion goveinnent iepoits on the pievalence anu econonic inpact ol oc- cupational slin uiseases. A hasic as- sunption in nany stuuies is that nost occupational ueinatitis is iiiitant in na- tuie. íoie iecent eviuence, hovevei, suggests that theie is a laigei piopoition ol alleigic occupational ueinatosis than pieviously thought. Cl the 58oº pa- tients patch-testeu loi contact ueinati- tis hy the Noith Aneiican Contact Dei- natitis Cioup hetveen 1ºº8 anu 2OOO, 1Oº¯ (1º peicent) veie ueeneu to have occupationally ielateu uisease. ln this occupational cohoit, 6O peicent ol cases veie ol alleigic anu o2 peicent veie ol iiiitant oiigin. Cl note, the hanus veie piinaiily allecteu in tvo-thiius ol allei- gic occupational cases anu loui-hlths ol iiiitant occupational cases 2 (lig. 1o-1, see Chap. 211). ln 2OO1, 4¯14 cases ol occupational ueinatitis veie iepoiteu to the Buieau 136 ol Lahoi Statistics, uovn 5O peicent lion the º4¯2 cases iegisteieu |ust 1O yeais eailiei. ¯he suhstantial uiop ovei that ue- caue in hoth the iate anu ahsolute nun- hei ol cases ol occupational ueinatitis nay iehect inpioveu voil conuitions anu nay explain the ohseiveu ielative ueciease in iiiitant contact ueinatitis (lCD) anu piopoitional inciease in ACD. lt is inpoitant to note that the pieva- lence ol ACD in the geneial population is olten extiapolateu lion the uata gleaneu lion occupational ueinatitis stuuies oi lion centeis anu gioups that patch-test patients vho alieauy have ueinatitis. Because lev cioss-sectional geneial population-haseu stuuies iegaiuing the pievalence anu inciuence ol ACD have evei heen peiloineu, the ienainuei ol availahle epiueniologic uata is genei- ally ohtaineu lion ietiospective stuuies ievieving specihc houy sites ol in- volvenent. ¯hese uata aie naiieu to vaiying extents hy the selection hias in- heient in ieleiial to a patch test centei anu nay not he iepiesentative ol the geneial population. Neveitheless, such uata peinit iecognition ol alleigens vith high sensitizing potential anu stiategies loi theii ieplacenent hy suh- stances vith lov sensitizing potential. ¯ahle 1o-1 lists nany connon allei- gens that eliciteu positive test iesults in a gioup ol inuiviuuals vho veie patch- C0\TACT DER|AT|T|S AT A 0|A\CE A||e|ç|c ccr|ac| de|ra||||º (ACD, |º ||e c|aºº|c p|eºer|a||cr c| de|a]ed-|]pe |]pe|ºerº|||.||] |eºpcrºeº |c e/cçercuº açer|º. 0.e| 8/00 a||e|çerº |a.e |eer |epc||ed |c cauºe ACD |r |urarº. ACD ra] c||r|ca||] p|eºer| acu|e|] a||e| a||e|çer e/pcºu|e ard |r|||a| ºerº|||/a||cr c| a||e| e||c||a||cr |r a p|e.|cuº|] ºerº|- ||/ed |rd|.|dua|. T|e acu|e p|aºe |º c|a|ac|e||/ed |] ||e de.e|cprer| c| e|]||era|cuº, |rdu|a|ed, ºca|] p|a(ueº, W||| ºe.e|e caºeº dercr- º||a||rç .eº|cu|a||cr ard |u||ae |r e/pcºed a|eaº. A||ec|ed º||eº c||er r|r|c ||e pa||e|r c| e/pcºu|e ard ra] p|c.|de |rº|ç|| |r|c ||e a||e|çer ºcu|ce ard e||c|- |c| c| d|ºeaºe. Repea|ed c| ccr||rucuº e/pcºu|e c| ºerº|- ||/ed |rd|.|dua| |c a||e|çerº |eºu||º |r c||cr|c d|ºeaºe, W||c| |º uºua||] ra||ed |] ||c|er||ed e|]||era|cuº p|a(ueº W||| .a||- a||e |]pe||e|a|cº|º, ºca|e, ard |ººu||rç. T|e |ardº, |ee|, e]e||dº, ard ||pº, W||c| ccrrcr|] ccre |r ccr|ac| W||| ||e er.|- |crrer|, a|e |||e|] º||eº |c| ACD. H|º|cpa||c|cç|c p|eºer|a||cr ccrº|º|º c| ep|de|ra| ºpcrç|cº|º W||| a ºupe||c|a|, pe||.aºcu|a|, |]rp|c||º||cc]||c de|ra| |r||||a|e. F|608£ 13-1 A||e|ç|c ccr|ac| de|ra||||º |c epc/]. T||º pa||er| Waº cccupa||cra||] e/pcºed. Ik8L£ 13-1 Prava|anca/Parcantaga of Subjacts Show|ng Pos|t|va 8aact|ons to A||argans Tastad by tha horth Amar|can 0ontact 0armat|t|s 0roup 1. h|cke| s0|Ite (2.5%) a 16.7 81. EU/|| |eº|r (o°, 2.8 2. heomyc|o (20%) 11.6 32. Loo||o (30%) 2.2 3. 8|sm oI Per0 (25%) 11.6 33. p-tert-80ty|pheoo| Iorm|de- hyde res|o (1%) 1.9 4. Frgroce m|x (8%) 10.4 5. Th|meros| (0.1%) | 10.2 84. 0|]ce|]| |||cç|]cc|a|e (1°, 1.9 o. Scd|ur çc|d |||cºu||a|e (0.o°, a 10.2 35. 8eozoc|oe (5%) 1.7 7. 00tero|0m-15 (2%) | 9.3 8o. Tc|º]|ar|de |c|ra|de|]de |eº|r (10°, 1.o 8. Form|dehyde (1% gs) | 8.4 8/. |e||]| re||ac|]|a|e (2°, 1.4 9. Bac|||ac|r (20°, /.9 88. 0|u|a|a|de|]de (1°, | 1.4 10. 0ob|t ch|or|de (1%) a 7.4 89. E||]| ac|]|a|e (0.1°, 1.8 11. |D0\/PE (2.o°, | o.8 40. d|- -Tcccp|e|c| 1.1 12. 0rb m|x (30%) c 4.9 41. Budeºcr|de (0.1°, 1.1 13. Pr-pheoy|eoed|m|oe (1%) 4.8 42. D|DHEU (4.o° a(º, 1.1 14. Th|0rm (1%) c 4.5 48. \|arç-]|arç c|| (2°, 1.1 15. Potss|0m d|chromte (0.25%) a 4.3 44. 8|ck r0bber m|x (6%) c 1.0 1o. Ber/a||cr|ur c||c||de (1° a(º, | 4.8 4o. Ccrpcº||ae r|/ (o°, 1.0 1/. P|cp]|ere ç|]cc| (80° a(º, 4.2 46. Nercptobeozoth|zo|e (1%) c 0.9 18. 2-B|crc-2-r|||cp|cpare-1,8-d|c| (0.o°, | 8.8 4/. D||uca|re (2.o°, 0.9 48. T||cu|eaº (1°, 0.8 19. D|a/c||d|r]|u|ea (1° a(º, | 8.2 49. Jaºr|re a|ºc|u|e (2°, 0./ 20. |r|da/c||d|r]|u|ea (2°, | 8.0 50. Nercpto m|x (1%) c 0.7 21. T|/ccc||c|-21-p|.a|a|e (1°, 8.0 o1. ||dcca|re (1o°, 0./ 22. D|ºpe|ºe B|ue 10o (1°, 8.0 52. Prbeo m|x (1%) | 0.6 23. £thy|eoed|m|oe d|hydro- ch|or|de (1%) 2.8 o8. Seº(u||e|pere |ac|cre (0.1°, 0.o o4. Ber/cp|ercre (8°, 0.o 24. D|D| |]dar|c|r (1°, | 2.8 oo. PC|/ (1°, | 0.o 2o. Cccar|dcp|cp]| |e|a|re (1° a(º, 2.8 oo. Te||aca|re (1°, 0.o 2o. |D0\/PE (4°, | 2./ o/. H]d|ccc|||ºcre-1/-|u|]|a|e (1°, 0.o 27. 0o|ophooy (20%) 2.6 o8. d|- -Tcccp|e|c| ace|a|e 0.o 28. £poxy res|o (1%) 2.3 o9. |PBC (0.1°, 0.8 29. N0|lN| (100 ppm gs) | 2.3 o0. PE (1°, | 0.2 80. Ar|dcar|re (0.1° a(º, 2.8 o1. P|||cca|re (2.o°, 0.1 a(º = a(uecuº, D|DHEU = d|re||]|c|d||]d|c/]e||]|ereu|ea, D|D| = d|re||]|c|-d|re||]|, EU/|| = e||]- |ereu|ea/re|ar|re |c|ra|de|]de, |PBC = |cdcp|cp]r]| |u|]| ca||ara|e, |C|/|| = re||]|c||c|c|ºc|||a/c||- rcre/re||]||ºc|||a/c||rcre, |D0\ = re||]|d|||crc ç|u|a|cr|||||e, PC|/ = pa|ac||c|cre|a/]|erc|, PE = p|erc/]e||arc|. a |e|a| a||e|çer. | B|cc|deº/p|eºe|.a||.eº. c Ru||e| add|||.e. Bc|d |rd|ca|eº ccrpcrer|º c| T.R.U.E. (T||r-|a]e| Rap|d Uºe Ep|cu|arecuº, Teº|. (T.R.U.E. Teº| uºeº ca|re r|/ |rº|ead c| |er/cca|re., \c||| Are||car Ccr|ac| De|ra||||º 0|cup. /r J 0crtact 0crratc! 15.1/o, 2004. 137 testeu hy the Noith Aneiican Contact Deinatitis Cioup. ln tvo cioss-sectional stuuies, ¯6º ianuonly selecteu 15- to 41-yeai-olu pa- tients lion the vestein pait ol Copen- hagen County, Dennail, veie patch- testeu in 1ººO anu 1ºº8 to evaluate the point pievalence ol ACD in this popula- tion. ¯he iate ol positive ieactions to at least one alleigen vas 15.º peicent anu 18.6 peicent, iespectively. Niclel vas the nost connon alleigen. luithei- noie, the investigatois noteu a statisti- cally signihcant inciease in alleigy to cosnetic agents ovei the tine inteival hetveen stuuies. o ¯hese sane investigatois conpleteu anothei cioss-sectional stuuy in those sane yeais. ¯hey ianuonly patch- testeu 56¯ patients ageu 15 to 6º yeais lion vestein Copenhagen in 1ººO. ln 1ºº8, they ie-testeu o65 ol the sane pa- tients in an elloit to ohseive inciuent cases. Cl the inuiviuuals vho pievi- ously hau negative patch test iesults in 1ººO, 12 peicent shoveu one oi noie positive patch test iesults (inciuent con- tact alleigy). Notahly, 6 peicent anu 8 peicent ol the ie-testeu patients vho pieviously hau negative patch test ie- sults uevelopeu inciuent alleigy to niclel anu haptens othei than niclel, ie- spectively. lenale genuei, young age, anu piioi eai pieicing (heloie 1ººO) veie iisl lactois loi the uevelopnent ol niclel alleigy. 4 ln a Uniteu Stateshaseu stuuy, ¯en- plet, Hall, anu Belsito noteu that hanu ueinatitis vas one ol the nost lie- guently citeu ieasons loi ieleiial to a patch-testing centei. Cl the 1Oo4 pa- tients vho hau heen patch-testeu ovei an 8-yeai peiiou, o2 peicent hau hanu ueinatitis, 54 peicent veie uiagnoseu vith ACD, vheieas only 2¯ peicent ie- ceiveu a uiagnosis ol lCD. A genuei uil- leience vas seen: the peal pievalence in nen vas in the hlth uecaue, vheieas no specihc peal vas seen in vonen. 5 Anothei Uniteu Stateshaseu stuuy lounu that 1¯ peicent ol a U.S. nanageu caie insuieu population expeiienceu hanu ueinatitis, vith one in six allecteu patients not seeling neuical attention. ¯he ellect ol chionic hanu uisease vas estinateu to inciease total neuical costs hy 25 peicent oi S¯O pei nonth haseu on neuical caie ueliveiy anu piesciip- tion costs. 6 With the high inciuence ol hanu anu lace exposuie to the enviionnent, one voulu anticipate a conpaiahle pieva- lence ol hanu anu lace ueinatitis. Ahso- lute pievalence uata on lacial anu eyeliu ueinatitis in the geneial population is not availahle, hovevei. Rathei, scant pievalence uata aie availahle lion tei- tiaiy caie ieleiial centeis, vhich iepie- sent only appioxinately 1¯ peicent ol all patch-testeu inuiviuuals. Cl the inui- viuuals vith eyeliu ueinatitis ieleiieu loi patch testing, appioxinately 5O pei- cent to ¯5 peicent veie iepoiteu to have at least one positive patch test ie- action. ¯,8 lev uata aie availahle loi souice-haseu epiueniology. U.S. popu- lation stuuies ol cosnetic alleigy pieva- lence aie neaily 2O yeais olu anu, given the uynanic natuie ol piouuct uevelop- nent, no longei pioviue the uata accu- iacy they once uiu. Cne stuuy in lnuia uenonstiateu a 66 peicent iate ol posi- tive ieactions to cosnetics in patch test- ing. ¯he alleigic inuiviuuals tenueu to he young (nean age, 2¯.5 yeais), vith ueinatitis allecting the lace, necl, anu scalp. liagiances, pieseivatives, anu paia-phenyleneuianine (llD) veie the nost connon piovocative agents. º Açe Although the suh|ect ol ACD in peuiatiic patients has ieceiveu suhstantial atten- tion in luiope, it has not en|oyeu the sane level ol attention in Noith Anei- ica. Despite this, anple eviuence sug- gests that even young chiluien have iathei suhstantial pievalence iates vhen they aie patch-testeu unuei appiopiiate conuitions 1O (lig. 1o-2). ln ltaly, ol 1Oº4 consecutively patch-testeu chiluien, 5¯O pioveu to he alleigic (52.1 peicent). ln this cohoit ol chiluien youngei than 12 yeais ol age, the highest sensitization iate vas ohseiveu in those ¯ nonths to o yeais ol age (6o.4 peicent alleigic). íet- als, neicuiy ueiivatives (thineiosal anu netallic neicuiy), neonycin, vool alco- hols, nethylchloioisothiazolone-nethyl- isothiazolinone (lathon CC), anu lia- giance nix veie the nost lieguent contact alleigens. Ciils shoveu a gieatei piopensity loi niclel alleigy than hoys. ¯he necl anu antecuhital/popliteal los- sae veie noie lieguently involveu in in- uiviuuals alleigic to niclel anu lathon CC, anu sensitization vas noie lie- guently seen in atopic than in non-atopic patients. 11 Clinically, inuiviuuals oluei than 65 yeais have vaiious uelects in the inuuc- tion anu/oi elicitation ol ACD. 1o ln stuu- ies ol Rhus ieactivity, youngei inuiviuuals (18 to 25 yeais) hau a noie iapiu onset anu iesolution ol the ueinatitis than uiu oluei peisons. When sensitization iates to stanuaiu alleigens veie analyzeu as a lunction ol age, inciuence iates veie lounu to he signihcantly lovei in inuiviu- uals oluei than ¯O yeais. 14 When 1444 el- ueily suh|ects vith suspecteu ACD veie conpaieu to a contiol gioup ageu 2O to 4O yeais, the pievalence ol alleigic ieactivity vas lounu to he signihcantly lovei in the elueily gioup conpaieu vith youngei auult patients (4O.¯ peicent vs. 4¯.8 pei- cent, p < O.OOO1). ¯he clinical ielevance ol this uilleience is uehatahle, hovevei, anu nay iehect a neeu to nouily the alleigens selecteu in leeping vith age-appiopiiate exposuies oi to allov a longei tine he- tveen patch ienoval anu the uelayeu ieauing. Alleigens useu vith gieatei lie- guency in this population, such as neo- nycin, lanolin alcohols, paiahen nix, anu nethyl uihionoglutaionitiile/phenoxy- ethanol (luxyl l4OO) shoveu a highei sensitization iate in elueily patients than in youngei auult patients 15 (lig. 1o-o). 0erde| ard Race Cenuei uilleiences in the uevelopnent ol ACD aie laigely unlnovn, hecause lev stuuies have looleu at inuuction ol sensitization in nen anu vonen unuei contiolleu ciicunstances. When the hu- nan iepeat-insult patch-testing nethou vas useu to assess inuuction iates loi 1O connon alleigens, vonen veie lounu to he noie olten sensitizeu to ¯ ol the F|608£ 13-2 T||º pa||er| Waº |curd |c |a.e c||r|ca||] |e|e.ar| pcº|||.e |eac||crº |c |a|ºar c| Pe|u ard ||crcr|- ||cp|cpare. 138 1O alleigens stuuieu. 16 ln naxinization stuuies that looleu at alleigens ol uillei- ent potencies, vonen ieacteu noie lie- guently to the vealest sensitizeis. 1¯ ¯he iole ol iace, il any, in the uevelop- nent ol ACD to potent alleigens such as uinitiochloiohenzene paiaphenyleneui- anine ienains contioveisial. 18,1º Coh lounu no uilleiences in the inciuence ol ACD anong the inuigenous (íalay, Chi- nese, anu lnuian) suh-populations in Sin- gapoie. 2O Liniteu stuuies suggest lovei sensitization iates to niclel anu neony- cin in Aliican Aneiicans than in Cauca- sians. 14 ln auuition, eiythena evaluation hecones incieasingly uilhcult vith as- cenuing oiuei in litzpatiicl`s slin typing, vhich nales this evaluation vaiiahle anu ieguiies that gieatei inpoitance he given to changes in euena anu inuuia- tion. Auuitional stuuies evaluating iacial inhuences on innunologic anu nonin- nunologic (e.g., haiiiei lunction) lactois anu ethnic inhuences allecting ACD ue- velopnent aie neeueu. ET|0|00\ A\D PATH00E\ES|S ACD iepiesents a uelayeu (type lV) hy- peisensitivity ieaction to the ovei o¯OO exogenous chenicals that have heen ue- sciiheu to piovole this ieaction. 21 Be- cause this iepiesents a tiue alleigy vith innunologic seguelae, only ninute guan- tities ol a given chenical aie necessaiy to elicit oveit alleigic ieactions. lviuence uating hacl to the 1º4Os inuicates that the ahility to he sensitizeu to specihc agents has a genetic conponent. Reseaich has nov linleu the piesence ol specihc hu- nan leulocyte antigen alleles to alleigy to niclel, chioniun, anu cohalt. 22,2o ¯o nount an innune ieaction to an alleigen, the inuiviuual nust he geneti- cally susceptihle, have sulhcient contact vith a sensitizing chenical, anu then have iepeateu contact vith the suh- stance latei. ¯his is in uistinction to lCD, in vhich no innunologic ieaction tales place anu the intensity ol the ieaction is piopoitional to the uose ol the chenical applieu (vhich is uiiectly ielateu to chenical concentiation, uuiation ol ex- posuie, anu geneial slin integiity). ¯hus ACD is a systenic uisease ue- hneu hy hapten-specihc ¯ cellneuiateu slin inhannation anu chaiacteiizeu hy thiee phases: sensitization, elicitation, anu iesolution. 24 ln the sensitization phase, lov-noleculai-veight electiophilic oi hy- uiophilic hapten chenicals (usually less than 5OO to 1OOO u) penetiate the slin anu loin hapten-piotein conplexes vith epi- ueinal caiiiei pioteins, vhich piouuces a conplete alleigen. ¯hese hinuing pio- teins aie lilely cell suilace nolecules on the Langeihans cell, such as class l anu ll na|oi histoconpatilihility conplex nole- cules. loi a uetaileu uesciiption ol the nechanisns involveu in the geneiation anu peipetuation ol ACD, see Chap. 1O. ¯he linlage hetveen haptens anu epi- ueinal pioteins is usually covalent, al- though netallic haptens nay loin stahle noncovalent linlages vith caiiiei pio- teins, such as cohalt in vitanin B 12 . 25 Sone ol these hapten chenicals aie not inheiently alleigenic (pio-haptens) anu nust unueigo netaholic hiotiansloina- tion to he ahle to paiticipate in an alleigic iesponse. 26 Because the slin has suhstan- tial netaholic capahilities, incluuing nany phase l anu phase ll enzynes, such hiotiansloination nay occui in the slin at the site ol contact vith the chenical. ¯he inpoitance ol the ielationship he- tveen the caiiiei anu the hapten cannot he unueiestinateu, hecause potent con- tact sensitizeis, vhen conplexeu to non- innunogenic caiiieis, can inuuce tolei- ance iathei than sensitization. C||\|CA| APPR0ACH An algoiithnic appioach to the patient is uesciiheu in the lolloving sections. Ccrº|de|a||cr c| ||e D|açrcº|º ACD shoulu he consiueieu in the uillei- ential uiagnosis ol a viue iange ol ec- zenatous ueinatoses (Box 1o-1). loi exanple, a patient vho has a geonetiic oi pattein-specihc ueinatitis altei an exposuie to an exogenous agent shoulu he suspecteu ol having ACD. ln auui- tion, the uiagnosis shoulu he consiueieu in inuiviuuals vhose ueinatitis is pei- sistent uespite appiopiiate stanuaiu theiapies. ¯his also peitains to patients vith conlounuing slin uisoiueis, such as atopic ueinatitis anu psoiiasis, vho have classic piesentations. Ccrº||uc||cr c| ||e E/pcºu|e |cr|açe Sensitization anu suhseguent elicitation ol a ueinatitis aie a uiiect conseguence ol exposuie to a specihc chenical in a susceptihle peison. ¯heie aie nany vaii- ahles that lactoi into the susceptihility ol a given inuiviuual. loi exanple, an altei- ation in the inheient slin haiiiei lunction oi iepaii nechanisn, vhich nay he al- lecteu hy genetics, age, genuei, custons, anu psychosocial inhuences, can inciease the pieuisposition. ¯he geogiaphic loca- tion in vhich the patient iesiues nay also he inpoitant, hecause it nay, loi exan- ple, inciease the piohahility ol encountei- ing iegion-specihc hotanical alleigens. li- nally, inciuental ianuon exposuies nust he consiueieu, loi instance, a lloiiuian lanily`s excuision to poison ivylauen lennsylvania. ¯hus, it nay he consiueieu that loi eveiy chenical theie is a pieue- teinineu uose (thiesholu ol sensitization) in eveiy peison that unuei optinal cii- cunstances coulu potentially iesult in sensitization anu the suhseguent clinical outcone ol ACD. H|º|c|] Ta||rç ¯he paiauox ol patch testing is the ue- ceptive sinplicity ol application veisus the ieguiieu expeitise necessaiy loi al- leigen selection anu inteipietation anu iecognition ol clinical signihcance. 2¯ lx- peitise in patch testing staits vith oh- taining a conpiehensive nulti-yeai his- toiy lion the patient iegaiuing the piesent illness. An algoiithnic appioach is again necessaiy. lnloination iegaiu- ing the patient`s uenogiaphic chaiactei- istics, peisonal anu lanily neuical his- toiies, anu occupational anu hone enviionnent, as vell as a ueinatitis- specihc histoiy incluuing piioi use ol ovei-the-countei anu piesciiption neui- cations nust he ohtaineu (¯ahle 1o-2). |r.eº||ça||cr c| E/pcºu|e Pa||e|rº latteins ol exposuie uiiect the physi- cian to the lilely cause(s) ol the eiup- F|608£ 13-3 A||e|ç|c ccr|ac| de|ra||||º |c ar|rcç|]ccº|de ar||||c||cº. T|e pa||er| uºed a recr]c|r-ccr|a|r|rç |cp|ca| ar||||c||c ard a |c- ||ar]c|r-ccr|a|r|rç e]ed|cp. 139 tion. Cne nust not only consiuei the potential exposuie vaiiahles loi each pa- tient hut also nust cioss-ieleience these alleigen exposuies to aiiive at the nost lilely suspect alleigen list loi that inui- viuual. As a case in point, a patient vith a peisistent posthaii uye haiiline anu eyeliu ueinatitis shoulu he investigateu loi cuiient use ol haii uye piouucts, hlacl henna tattoo piepaiations, paia- aninohenzoic aciuhaseu sunscieens, estei anesthetics, anu cioss-ieacting neuications (e.g., hyuiochloiothiaziue, sullonyluieas, anu cyclooxygenase 2 in- hihitois). luitheinoie, a 2-yeai-olu vith conconitant hanu anu lacial uei- natitis voulu noie lilely he sensitizeu to halsan ol leiuhaseu liagiances oi pieseivatives in hahy vashes anu uiapei halns. lt is inpoitant to locus on the nost lilely suhstances hut also to in- cluue high-piohahility alteinatives. Cl note, each algoiithn is as specihc to the patient as the patient`s enviionnent is to hin oi hei. lotential nev alleigens aie lieguently enteiing the inuiviuual`s in- neuiate anu glohal enviionnent. loi ex- anple, hetaine ueteigent technology vas hist incoipoiateu into peisonal caie anu hygiene piouucts (e.g., lov-iiiitancy hahy shanpoo) in the late 1º6Os. ln 1º8o, the hist case ol cocaniuopiopyl hetaine al- leigy vas noteu, since then theie has heen an upvaiu tienu tovaiu its evei- incieasing inclusion in peisonal caie piouucts. 28 Alnost tvo uecaues latei, the incieasing inciuence ol cocaniuopiopyl hetaine alleigy leu to the inclusion ol this alleigen in conpiehensive stanuaiu scieening tiays anu the uesignation ol co- caniuopiopyl hetaine as alleigen ol the yeai hy the Aneiican Contact Deinatitis Society. Although theie aie inheient lini- tations anu hiases in the uata tiacleu hy the nenheis ol teitiaiy ieleiial gioups that iepoit epiueniologic uata, the in- poitance ol these uata cannot he oveien- phasizeu, hecause they also inciease avaieness ol iising chenical alleigies pieviously thought to he iaie (e.g., to coi- ticosteioius, golu, anu aniue anesthetics). C||\|CA| |A\||ESTAT|0\S Cu|arecuº ||rd|rçº Civen the viue aiiay ol potential allei- gens anu the inheient unigueness ol ev- eiy peison`s slin, it stanus to ieason that theie shoulu he an egually viue vaiiation in the clinical piesentation ol ACD. Hovevei, ceitain aspects aie less vaiiahle anu tenu to lollov iathei iepio- uucihle patteins. ln geneial, once sensi- tization has heen estahlisheu, acute ACD piogiesses lion eiythena to euena to papulovesiculation, vith esca- lating iesponses (see ligs. 1o-2 anu 1o-o). Cne exception nay he the aieas ol thin slin vith highei ahsoiption coelhcients, such as the eyelius, nucosal suilaces, anu genitalia. ¯hese aieas nay guiclly hecone euenatous, vhich leaus the in- uiviuual to avoiu hehaviois oi to seel neuical attention, anu thus the noie uevelopeu stage nay he inteiiupteu. Seconu, ACD usually occuis in the uis- tiihution ol the contactant. loi exanple, an ain that has hiusheu against poison ivy nay uenonstiate a lineai vesiculai euenatous plague. ln situations in Ik8L£ 13-2 H|story Tak|ng |n A||arg|c 0ontact 0armat|t|s Dercç|ap||cº ard cccupa- ||cra| ||º|c|] Açe, çerde|, |ace, e||r|c- ||], |e||ç|cr, ºcc|a| aºpec|º (ra|||a| º|a|uº,, jc| ||||e, jc| deºc||p||cr, |eçu|a| ard cccaº|cra| c|er|ca| e/pcºu|eº ard ºcu|ceº, |cca||cr c| erp|c]rer|, ||re a| cu||er| jc|, p|e.|- cuº cccupa||crº |ar||] red|ca| ||º|c|] 0ere||c |ac|c|º, p|ed|º- pcº|||crº Pe|ºcra| red|- ca| ||º|c|] D|uç a||e|ç|eº, ccrccr|- |ar| d|ºeaºeº, red|ca- ||crº, ºu|çe||eº De|ra||||º- ºpec||c ||º|c|] 0rºe|, |cca||cr, |erpc- |a| aººcc|a||crº (Wa/|rçº/ War|rçº,, ||ea|rer|º 8ox 13-1 0|ffarant|a| 0|agnos|s of tha Fczamatous 0armatosas 0|FF£8£hT|AL 0|A6h0S|S 6£068APh|0-N08Ph0L06|0 0|ST8|80T|0h 0|A6h0ST|0 0L0£S A||e|ç|c ccr|ac| de|ra||||º Ec/era|cuº, ºca|] edera|cuº p|a(ueº W||| .eº|cu|a||cr P||ra|] |eº|crº |r d|º||||u||cr c| ccr|ac|ar|, p|u|||uº Aº|ec||c de|ra||||º C|ac||ed pa|c|rer|-|||e pa|c|eº, a|ºer| edera ard .eº|cu|a||cr |cWe| |eçº A|cp|c de|ra||||º Ec/era|cuº, |cre]-c|uº|ed, ºca|ed p|a(ueº, c||cr|c |eº|crº ra] |e ||c|er||ed ||e/u|a| a|eaº |r c|||d|er ard rec| p|edcr|rarce Au|cºerº|||/a||cr |eac||cr Ec/era|cuº, pcc||] de|red pa|c|eº c| .eº|cu|a||cr H|º|c|] c| c||cr|c de|ra||||º c| |r|ec||cr W||| reW W|deºp|ead, |eºº-de|red pa|c|eº D]º||d|c||c ec/era Deep-ºea|ed papu|c.eº|c|eº cr pa|ra|-p|ar|a| ºu||aceº ard .c|a| edçeº Pa|r ard ºc|e |]p|ca||] dc|ºa| |r.c|.erer| |||||ar| ccr|ac| de|ra||||º S|a|p|] dera|ca|ed racu|a| e|]||era, |]pe||e|a|cº|º, a|ºerce c| .eº|cu|a||cr Bu|r|rç e/ceedº ||c||rç |]ccº|º |urçc|deº (pa|c| |c p|a(ue º|açe, Pcc||] dera|ca|ed, a||cp||c, ºca|] p|r| pa|c|eº ard p|a(ueº Tc|ºc p|edcr|rarce \urru|a| de|ra||||º Cc|r-º|aped, We|| dera|ca|ed p|a(ueº W||| ºca|e ard .eº|cu- |a||cr, .a||a||] e/uda||.e |eçº, dc|ºa| |ardº, e/|erºc| ºu||aceº Pºc||aº|º S|a|p|] dera|ca|ed papu- |cº(uarcuº p|a(ueº W||| rc .eº|cu|a||cr Sca|p, |e||c-au||cu|a| a|ea, e||cWº, |reeº, çer||a||a, ra||º, p|edcr|rarce |r a|eaº c| ||aura (|ce|re||/a||cr,, puº- |u|eº ra] |e acu|e|] p|eºer|, pa|||cu|a||] cr pa|rº ard ºc|eº, ccrccr||ar| a|||||||º Se|c|||e|c de|ra||||º Papu|cº(uarcuº ç|eaº], ºca|] p|a(ueº Ha||-|ea||rç |eç|crº, ç|a|e||a, ard raºc|a||a| |c|dº S|aº|º de|ra||||º Papu|cº(uarcuº p|a(ueº W||| d]ºc||cr|a S||rº ard red|a| ºu||aceº, |cWe| |eçº, ccrccr||ar| .a||- ccº|||eº ||cr R|e|ºc|e| R|. C|ueº |c ar accu|a|e d|açrcº|º c| ccr|ac| de|ra||||º. 0crratc! TIcr 17.224, 2004. 140 vhich the alleigen exposuie is peisis- tent, hovevei, lichenihcation anu scale pieuoninate. Concuiient vith this evo- lution cones the possihility ol noie viuespieau eiuptions in non-uistinct patteins. Civen this, eaily uiagnosis is ol utnost inpoitance. |c|p|c|cç|c App|cac| Cnce a conpiehensive histoiy has heen ohtaineu, the seconu step is a conplete ueinatologic assessnent ol the patient. ¯his is especially helplul hecause the patient nay he avaie ol only the nost pioninent site ol ueinatitis, anu a con- cuiient ueinatitis at a ienote site nay pioviue integial clues to the uiagnosis. lnovleuge ol the shape, chaiactei, anu location ol the ueinatitis heightens the piohahility that the culpiit alleigen vill he accuiately chosen loi testing. Reç|cra| De|ra||||º A|çc||||r S0ALP Despite the gieat potential loi al- leigen exposuie, the scalp ienains iela- tively iesistant to alleigic ueinatitis. lossihle ieasons loi this uecieaseu ieac- tivity nay he incieaseu slin thiclness, alteiations in cellulai nilieu hecause ol the lolliculai haii units, vaiiations in vasculaiity, anu uilutional ellects ol pei- spiiation. Clten alleigens that aie ap- plieu the scalp anu haii, loi exanple, haii uye (llD) anu shanpoos (lia- giances, pieseivatives, anu suilactants), nay elicit ueinatitis in the au|acent ai- eas, such as the haiiline, eyelius, anu postauiiculai aieas. ln the patient vith scalp ueinatitis, consiueiation shoulu he given to alteinative uiagnoses such as sehoiiheic ueinatitis anu lCD. FA0£ Ah0 £Y£L|0S ¯he lace is alvays exposeu to a gieat nunhei ol potential alleigens (see ligs. 1o-2 anu 1o-o). lnci- uental exposuies to aeioalleigens can leau to seveie conseguences, loi exan- ple, hlisteiing ueinatitis altei lall huin- ing ol leaves acciuentally contaninateu vith poison ivy oi chionic photo con- tact ueinatitis lion leveilev oi othei sesguiteipene lactonecontaining plants. luitheinoie, inauveitent tiansnission lion the hanus is lieguent to this aiea, anu ueinatitis can he seen uespite lacl ol any eviuence ol alleigy on the hanus (ectopic contact ueinatitis). Because the lace is the nost lilely aiea to en- countei a nyiiau ol giooning tools such as eyelash cuileis, naleup sponges, anu toothhiushes (iuhhei auuitives) anu peisonal hygiene piouucts anu cosnet- ics (liagiances, enulsiheis, pieseiva- tives), a viue iange ol alleigens nust he consiueieu. Vehicle-haseu pieseiva- tives aie a signihcant souice ol lacial ueinatitis. h£0k Lile the lace, the necl is suh|ect to nuneious uiiect enviionnental en- counteis as vell as inuiiect exposuie lion the hanus. Civen the iepeateu in- sult lion a viue vaiiety ol liagiance- haseu chenicals (peilune, eau ue toi- lette, scents), the necl anu viists aie especially pione to anu nay eventually uevelop a |cr|oquc ueinatitis (|cr|oquc is liench loi °tiinlet-lile,` anu ieleis to the penuant-lile pignentation seen on the necl anu chest). íetal alleigy nay nanilest as chionic ueinatitis lion ex- posuie to necllaces anu |eveliy clasps that contain niclel oi cohalt. T08S0 ¯he ielatively piotecteu conui- tion ol the toiso alteis the list ol poten- tial alleigen souices. Although it also encounteis the liagiances, pieseiva- tives, anu ueteigents ol uaily peisonal hygiene piouucts (houy vashes, soaps, lotions), it is also susceptihle to textile alleigens (uyes anu loinaluehyue ies- ins.) ¯he nost signihcant textile-associ- ateu alleigens aie the uispeise uyes (azoanilines) anu uiea loinaluehyue iesins (in viinlle-iesistant, coloilast clothing). Specihcally, the heat, huniu- ity, anu liiction ol the houy lolu (peiiax- illaiy anu peiiciuial) aieas nay contiih- ute to the leaching ol the textile iesins anu uyes anu the ohseiveu ueinatitis accentuation in these aieas. 2º AX|LLA£ ¯he axillaiy conpaitnent is suh|ect to nany ol the sane exposuies as the tiunl, vith one na|oi uistinction heing the use ol ueouoiants anu antipei- spiiants (lig. 1o-4). ¯he loinulations ol these piouucts use a viue vaiiety ol constituents, such as liagiances |halsan ol leiu, Lyial (hyuioxyisohexyl o-cyclo- hexene caihoxaluehyue)], pieseivatives (loinaluehyue ieleaseis, paiahens), anu othei excipients (lichen extiact, vitanin l, piopylene glycol). A connonly oh- seiveu ellect is the spaiing ol the vault, seconuaiy to the peispiiational uilution ol the alleigens. luitheinoie, aeio- solizeu exposuie ol the alleigens nay leau to a scatteiing aiiay pattein vith satellite papules. hAh0S Ah0 F££T ¯he high inciuence ol hanu ueinatitis (see lpiueniology) is a uiiect conseguence ol the lact that the hanus aie oui nost inpoitant tools in oui inteiactions vith the enviionnent. ln lact, hanu ueinatitis can account loi as nuch as 8O peicent ol the occupationally ielateu slin uiseases, especially in ceitain °vet voil` occupations (health caie, loou hanuling, cosnetology, etc.). oO Caie- lul consiueiation shoulu he given to occu- pation-specihc exposuies in the evalua- tion ol hanu ueinatitis. loi exanple, a constiuction voilei nay he sensitizeu to chioniun lion cenent exposuie, vheieas a haiiuiessei nay he alleigic to paiaphenyleneuianine (uyes), cocani- uopiopyl hetaine (suilactant-ueteigent), oi glyceiol nonothioglycolate (peina- nent vave anu stiaightening solutions). ¯he nultilactoiial etiology ol hanu ueinatitis auus to the conplexity ol hoth the uiagnosis anu tieatnent (see lig. 1o-1). o1 Co-existent uisoiueis, such as atopy, uyshiuiosis, psoiiasis, anu uei- natophytosis, nay he encounteieu in these patients. At tines, an unueilying enuogenous ueinatosis nay even he- cone unnasleu oi voiseneu hy a sec- onuaiy contact ueinatitis (eithei alleigic oi iiiitant). loi exanple, cases ol iatio- genic contact ueinatitis to eithei the iuh- hei auuitive in gloves (thiuian, caiha- nate) oi topical theiapeutics (pieseivatives anu coiticosteioius) nay he encounteieu. Clinical clues that the physician shoulu have a highei inuex ol suspicion ol ACD incluue involvenent ol the hngei veh spaces anu uoisal hanus, anu piuiitus. As aie the palns, the volai loot suilaces aie ielatively iesistant to uevelopnent ol ACD, anu the investigatoi nust consiuei co-noihiuities anu the possihility ol con- lounuing uisoiueis (psoiiasis, uyshiuio- sis, |uvenile plantai ueinatosis, etc.) to F|608£ 13-4 A||e|ç|c ccr|ac| de|ra||||º |c ae|cºc| decdc|ar|. T||º pa||er| Waº a||e|ç|c |c |]|a|. 141 conpiehensively evaluate the patient vith such nanilestations. ¯he uoisun ol the loot, on the othei hanu, is lieguently involveu. Conplete evaluation shoulu in- cluue testing vith the piincipal alleigens geneially associateu vith loot ueinatitis, incluuing iuhhei acceleiatois (piesent in iuhhei-haseu lineis anu/oi glues), isocya- nates (in loan iuhhei), ¡-teit-hutylphenol loinaluehyue iesin (in glue), potassiun uichionate (in tanneu leathei), antihiotic cieans anu topical coiticosteioius (lion piesciiption anu ovei-the-countei sell- tieatnent), in auuition to suspect souice conponent testing using a 81O nn punch hiopsy svatch ol the shoe. Clten, extenueu contact vith the shoe conpo- nent is necessaiy to elicit a ieaction. Pe||c|a| ard Pe||ara| |uccºa| E/pcºu|eº íucosal ACD, such as aphthae anu lin- gual eiosions causeu hy contact vith alleigens in toothpaste, is a iaie hut peihaps unuei-iepoiteu phenonenon. íoie connonly, patients have peisis- tent peiioial ueinatitis iathei than in- tia-oial lesions. llavoiants, ueteigents (cocaniuopiopyl hetaine), anu vhiten- eis (peioxiues) aie lieguently encoun- teieu in uental hygiene piouucts. loitu- nately, only iaiely uo inuiviuuals ieact to uental analgan netals (niclel, co- halt, neicuiy, anu golu) vith oial lichen planuslile ueinatoses, stonatitis, oi systenatic synptons. ¯he lov ieaction iates nay iehect a uilutional ellect ol the nucosal secietions oi inheient uil- leiences in nucosal innunity. luithei- noie, stuuies have shovn that piinaiy nucosal exposuie to an alleigen nay leau to toleiance. loi exanple, the lie- guency ol niclel sensitivity is lovei in inuiviuuals vho unueigo oithouontic tieatnent heloie eai pieicing. o2 With an incieasing nunhei ol oluei peisons (oluei than 65 yeai ol age) in oui society, age-associateu changes such as nucosal uiyness, incontinence, anu in- ahility to cleanse piopeily have iesulteu in incieasing use ol genital anu peiianal hygiene piouucts anu exposuie to ielateu alleigens, such as noisteneu toilet tissue (nethylchloioisothiazolinone anu neth- yluihionoglutaionitiile) anu supposito- iies (liagiances anu paiahens). Although lovei oi slovei ieactivity is iepoiteu in the ageu population, stuuies suggest that ACD continues to occui in this popula- tion. ooo5 ¯hus, incieaseu vigilance vill he ieguiieu to uiscovei nev alleigen as- sociations involving these anu othei piouucts useu hy this population. Pa|adc/|ca| De|ra|cºeº ¯he guintessential alleigen inuucing a paiauoxical ueinatitis is golu. lt is in- poitant to note that alleigic ieactions to golu veiy iaiely involve the contact site ol the ollenuing |eveliy, such as a vatch oi a iing. Reactions nay he seen on the eyelius, cheels, oi hiiuge ol the nose, hovevei, vheie golu (e.g., in glasses) has cone into contact vith a haiuei netal such as titaniun uioxiue oi zinc oxiue in a sunscieen, cosnetic ciean, oi lounuation. o6 Seveial othei alleigens (e.g., lanolin anu paiahen) aie also noteu loi theii paiauox- ical inuuction ol ACD hecause they aie too veal to elicit a iesponse on intact slin hut nay give iise to ACD vhen they aie applieu to a uanageu epiueinis (e.g., atopy, stasis ueinatitis)thus the teins ¡ara|cn ¡aradox anu |ano|in ¡aradox. o¯ lui- theinoie, coiticosteioius, vhich veie uesignateu the alleigens ol the yeai in 2OO5 hy the Aneiican Contact Deinati- tis Society, hecause ol theii intiinsic anti- inhannatoiy piopeities, ieguiie a ue- layeu patch test ieauing (at º6 houis) to captuie alleigic ieactions. ln cases ol tieatnent-iesistant ueinatitis oi cases in vhich clinical piogiession occuis uespite the use ol incieasingly potent coiticostei- oius, coiticosteioiu alleigy shoulu he sus- pecteu. Cne nust he avaie ol the hve stiuctuial classes ol coiticosteioius (A, B, C, D1, anu D2, see Chap. 216) anu the in- heient potential cioss-ieactivities he- tveen the classes. o8 S]º|er|c |ar||eº|a||crº ard 0ere|a||/ed De|ra||||º Systenic contact ueinatitis is a iela- tively unconnon anu pooily unuei- stoou aspect ol ACD that highlights the potential loi long-lasting innunologic nenoiy in pieviously sensitizeu aieas ol slin. ¯his phenonenon occuis pii- naiily in inuiviuuals vho aie initially sensitizeu topically to an alleigen anu then suhseguently exposeu systeni- cally, vhich iesults in a viue aiiay ol outcones, lion a iecall ieaction (uei- natitis at the site ol oiiginal sensitiza- tion) to extensive, hizaiie-appeaiing ueinatitis anu eiythioueina. ¯he noie uhiguitous the alleigen in natuie anu the patient`s enviionnent, the less ohvious the tenpoial associa- tions vill he hetveen the exposuies anu the ueinatitis. Cne paiticulaily notoii- ous alleigen is halsan ol leiu, ueiiveu lion the post-vounuing exuuates ol the hail ol the ll Salvauoian /,rox,|on ¡crcirac tiee (see ligs. 1o-2, 1o-5). oº lt is encounteieu in eaily inlancy in hahy vashes anu uiapei salves anu again uaily in auulthoou a viue iange ol suh- stances lion liagianceu peisonal hy- giene piouucts to uentuie auhesives. luitheinoie, the halsan itselloi, noie typically, nouiheu liactions ol itaie lieguently useu as liagiance anu havoiing auuitives (e.g., in lozenges, cough syiups, chiluien`s antihiotic sus- pensions, anu colas). lnpoitantly, he- cause these chenicals (cinnanic aciu, cinnanyl cinnanate, henzyl henzoate, henzoic aciu, anu henzyl alcohol anu es- teiiheu polyneis ol conileiyl alcohol) aie natuially ueiiveu, they have a nun- hei ol natuial cioss-ieactants (cinna- non, clove, eugenol). ln one iepoit spe- cial analyses pioveu that tonatoes containeu cinnanic alcohol anu co- nileiyl alcohol, tvo nain alleigens in the halsan ol leiu nixtuie. 4O Con- sunption ol these alleigens nay iesult in a iecall ieaction topically at othei sites vheie sinilai chenicals veie pie- viously applieu oi in a systenic haie (see lig. 1o-5). Cl note, 4¯ peicent ol patients alleigic to halsan ol leiu anu/ oi othei liagiance agents ieguiieu ui- etaiy nouihcation to contiol theii uei- natitis, 18 peicent ol patients vho laileu to nouily theii uiets hau peisis- tent uisease, anu only o6 peicent in- pioveu vithout sone loin ol uietaiy nouihcation. oº ¯he netals aie a gioup ol lieguently encounteieu uhiguitous alleigens (niclel, cohalt, anu chioniun). ¯hey aie piesent in a viue iange ol netallic oh|ects (|ev- eliy, tveezeis, clothing snaps, papeiclips, anu coins) in auuition to unexpecteu souices such as cigaiette snole, vita- nins, vatei, anu looustulls. Anothei lieguently anu unexpect- euly encounteieu alleigen is loinalue- F|608£ 13-5 A||e|ç|c ccr|ac| de|ra||||º |c ||a- ç|arceº. T||º pa||er| |ad a º]º|er|c 1a|e |eac||cr. 142 hyue. lt has a vaiiety ol inuustiial appli- cations, incluuing in plastics anu glues, anu is connonly useu as a hioau-spec- tiun hiociue. ¯hus souices ol exposuie can iange lion insulation nateiials, shoe glues, papei piouucts, nail haiuen- eis, clothing iesins, anu cigaiette snole to connonly useu peisonal hygiene piouucts anu neuical cieans. ¯he loi- naluehyue-ieleasing pieseivatives (lRls) incluue guateiniun-15 (Dovicil), iniua- zoliuinyl uiea (Ceinal l), uiazoliuinyl uiea (Ceinal ll), 2-hiono-2-nitiopio- pane-1,o-uiol (Bionopol), uinethylol- uinethyl hyuantoin (Clyuant), anu tris- (hyuioxy-nethyl)-nitio-nethane (¯iis Nitio). A staggeiing nunhei ol leave on anu vash on/vash oll cosnetics anu cieans incluue these connon alleigenic pieseivatives. Cl note, sone topical steioiu piepaiations contain laiily high anounts ol lRls, anu lailuie to inpiove vaiiants patch testing vith hoth coiti- costeioiu anu pieseivatives. luithei- noie, coiticosteioius containing lRls shoulu not he useu hy patients hypei- sensitive to loinaluehyue. 41 loi nany patients, the uiagnosis ol iuhhei alleigy cones vith a cunhei- sone list ol suhstances to avoiu, he- cause hoth natuial anu synthetic iuhhei chenicals aie uhiguitous. lieguent sites ol alleigen contact anu suhseguent ieac- tion aie the lace (naleup sponges), eai canals (eaiplugs, eai phones), peiioculai aiea (goggles, eyelash cuileis), hiassieie anu/oi vaistline aieas (elasticizeu un- ueigainents), genital aieas (conuons, uiaphiagns, pessaiies), hanus (gloves, iuhhei hanus), leet (shoes), anu/oi |oints (oithopeuic hiaces). lt is inpoitant to note that loi eveiy 1OO lh ol iuhhei, theie aie 4 to 5 lh ol iuhhei auuitives (ºO peicent ol vhich constitute the ac- celeiatois anu antiuegiauants), anu these auuitives aie iesponsihle loi a na- |oiity ol the ieactions. 42 Sensitization is typical to eithei the acceleiants (thi- uians, caihanates, guaniuines, anu/oi henzothiazoles) oi the antioxiuants (hlacl iuhhei nix/llD ueiivatives) that aie lounu in hoth natuial anu synthetic iuhhei, vith thiuian nix (62 peicent) anu hlacl iuhhei nix (o8 peicent) heing the nost connon ollenueis. 4o h0h£0I£NAT00S VA8|AhTS 0F ALL£86|0 00hTA0T 0£8NAT|T|S ACD, lile syphi- lis, is a gieat niniclei vith nultiple noneczenatous vaiiants, incluuing hut not liniteu to lichenoiu contact ueina- titis, eiythena nultiloine (lí), celluli- tis-appeaiing ueinal contact hypeisen- sitivity, contact leuloueina, contact puipuia, anu eiythena uyschionicun peistans. 44 Cl these, the lichenoiu anu lí-lile vaiiants aie nost connon. Lichenoiu alleigic contact ieactions aie usually seconuaiy to exposuie anu sensi- tization to netals, suhstituteu llD coloi uevelopeis, anu havoiing agents. íetals, in paiticulai, have heen linleu to oial li- chen planus. íany uiugs can also cause a systenic lichenoiu hypeisensitivity, the nost notoiious heing the guinine ueiiva- tives, hyuioxyuiea, angiotensin-conveit- ing enzyne inhihitois, hlocleis, anu anti-epileptic agents. lí-lile ACD ieac- tions aie nost lieguently seen altei con- tact vith exotic voous, connon plants, anu topical neuications. ¯he othei non- eczenatous vaiiants ol ACD aie guite iaie. Cl note, nost cases ol contact leu- loueina aie uue to eithei post-inhan- natoiy hypopignentation oi uiiect chenical toxicity (e.g., hyuioguinones, catechols, phenols, neicaptoanines). 45 Cianulonatous ueinatitis has heen ie- poiteu in iesponse to netals, incluuing neicuiy, chionates, cohalt, heiylliun, golu, anu pallauiun (lig. 1o-6). ALL£86|0 00hTA0T 08T|0A8|A Alleigic con- tact uiticaiia (ACU) iepiesents one ol the least connon loins ol contact uei- natitis. ACU is an innunoglohulin l neuiateu inneuiate-type hypeisensi- tivity ieaction that is uistinct lion the ¯ cellneuiateu type lV hypeisensitivity ieaction ol ACD. lnpoitantly, ACU has heen iepoiteu in iesponse to a nunhei oi agents that aie also capahle ol elicit- ing a type lV ieaction, loi exanple, hac- itiacin (antihiotic), neicaptohenzothia- zole (iuhhei acceleiatoi), anu colophony (auhesive). ¯he nost notoiious alleigen to cause ACU voiluviue is natuial iuhhei latex. ¯he inciuence in the Uniteu States is laigely unlnovn, hovevei, estinates sug- gest that less than 1 peicent to 2 peicent ol the geneial population is allecteu. 46 Anong hospital voileis nost lilely to he exposeu to natuial iuhhei latex gloves, the iate ol latex ACU has heen iepoiteu to iange lion a lov ol 5.5 peicent 4¯ to as high as o8 peicent. 48 luitheinoie, co- noihiu conuitions ieguiiing hospitaliza- tions anu neuical caie in eaily lile, such as noueiate to seveie atopic ueinatitis, spina hihua, oi neningonyelocele, pieuis- pose to the uevelopnent ol ACU, as uoes nucosal exposuie to latex. ACU lion latex nay piesent as in- neuiate synptons (such as huining, stinging, oi itching vith oi vithout lo- calizeu uiticaiia on contact vith latex pioteins) oi, vith aeiosolization expo- suie, nay incluue uisseninateu uiti- caiia, alleigic ihinitis, anu/oi anaphy- laxis. Latex-alleigic patients nay also uevelop a type lV uelayeu hypeisensi- tivity ieaction to nonlatex conponents ol the gloves, usually on the uoisal as- pect ol the hanus, loi exanple, to a iuh- hei auuitive (thiuian) that nay he lounu in latex, nitiile, anu vinyl gloves. ln contiast to ACD, ACU in iesponse to latex gloves nay piesent vith palnai involvenent, vhich nay ielate to solu- hilization ol the latex pioteins oi the lipiu content ol the hypeileiatotic volai suilace causeu hy noinal hiuiosis. Although theie aie ovei 25O sepaiate natuial iuhhei latex pioteins, only ap- pioxinately 25 peicent shov ieactivity vith innunoglohulin l autoantihou- ies. 46 As ol 2OOo, the lnteinational Union ol lnnunological Societies Con- nittee on Nonenclatuie listeu 1o Hcvca |rasi|icnsis (Hev h) piotein alleigens. Sig- nihcant auvances in DNA technology anu cloning have alloveu loi puiihca- tion anu chaiacteiization ol these allei- gens. lt is nov lnovn that the nost in- poitant Hev h alleigens aie Hev h 1 to o F|608£ 13-6 0|aru|cra|cuº ccr|ac| de|ra- ||||º |r a pa||er| W||| pa||ad|ur a||e|ç]. A pa||a- d|ur-ccr|a|r|rç der|a| pcº| Waº |rp|ar|ed cr ||e a||ec|ed º|de juº| |e|c|e ||e crºe| c| ||e e|up||cr. |rp|c.erer| Waº e||ec|ed |] ||º |erc.a|. 143 loi chiluien vith spina hihua anu Hev h 2 anu 5 to ¯ loi health caie voileis. 46 A uiagnosis ol latex alleigy shoulu he consiueieu in any patient vith a histoiy ol uiticaiia oi angioeuena vhen uonning conuons oi gloves, oi inhating halloons. ln vitio iauioalleigosoihent testing anu en- zyne-linleu innunosoihent assay aie conneicially availahle anu shoulu he pei- loineu as the initial uiagnostic step. ¯hiee in vitio seiologic assays have U.S. loou anu Diug Auninistiation (lDA) appioval loi uiagnostic puiposes: lnnunoCAl (lhainacia-Up|ohn, Uppsala, Sveuen), AlaS¯A¯ lllA (Diagnostic liouucts Coip., Los Angeles, CA), anu HY-¯lC llA (Hy- coi Bioneuical, lnc., Caiuen Ciove, CA). Although slin piicl testing is the golu stanuaiu, it shoulu he noteu that theie is cuiiently no lDA-appioveu, connei- cially availahle, stanuaiuizeu latex allei- gen piepaiation. ¯he stahility piohle anu guality contiollahility ol non-annoniateu latex nale it the cuiient top canuiuate loi lDA licensuie. 46 Cuiiently, extenpoiane- ous extiacts oi elutes naue hy soaling high-alleigen gloves in vatei at ioon tenpeiatuie aie useu. 4º ln nost hut not all cases, these ciuue eluates aie sulhcient to allov piicl test conhination ol ACU. lt nust he enphasizeu that in vivo testing can potentiate anaphylactic ieactions. |AB0RAT0R\ ||\D|\0S |r V|.c Pa|c| Teº| ¯he golu stanuaiu nethou loi the uiag- nosis ol ACD ienains the patch test. De- tails on the patch test pioceuuie aie he- yonu the scope ol this chaptei hut nay he lounu in a nunhei ol stanuaiu texts. 5O lt nust he noteu that only 2o connei- cially piepaieu alleigens aie cuiiently lDA appioveu in the Uniteu States loi use in a pieloaueu systen. A peiusal ol ¯ahle 1o-1 nales it appaient that neaily hall ol the top 25 alleigens in Noith Aneiica aie not availahle on the con- neicially naue tiays in the Uniteu States. ¯he ¯.R.U.l. (¯hin-layei Rapiu Use lpicutaneous) ¯est has 2 panel tiays. ¯hus, investigatois vho intenu to lully evaluate theii patients nust piepaie al- leigen tiays vith voiluviue stanuaiu- izeu conneicially availahle alleigens anu auu patient-specihc test nateiials loi conpleteness. Conpounuing ieleience texts outlining appiopiiate alleigen con- centiations anu vehicles aie availahle. 5O T80£-P0S|T|V£ Ah0 T80£-h£6AT|V£ 8£- S0LTS ¯he iuentihcation ol tiue-posi- tive ieactions vith clinical ielevance is the piinaiy goal ol the patch test anu is hest achieveu vith a high pie-test pioh- ahility. 51 ¯hat heing saiu, one na|oi challenge in patch testing is ohtaining a tiue-positive iesult (tiue sensitization) vith no clinical ielevance to the pa- tient`s cuiient ueinatologic piohlen anu assuning they aie ielateu. Attenpts to assign ielevance to such an alleigen nay leau to conseguences that aie cun- heisone anu uistiessing to hoth the physician anu the patient. Assigning clinical ielevance to a tiue-positive patch test iesult ieguiies coiielation he- tveen the involveu aieas ol slin anu the patient`s enviionnental exposuies, anu notation ol signihcant inpiovenent on avoiuance ol the alleigen oi iecuiience vith its ieintiouuction. ¯he Noith Aneiican Contact Deina- titis Cioup lieguently iepoits theii pievalence uata vith ielevance assign- nents, anu continueu lailuie ol iele- vance nails the alleigen loi ienoval lion the stanuaiu scieening seiies. A goou exanple ol this is thineiosal. íany patients vith positive patch test iesults to thineiosal have heen sensi- tizeu hy vaccines hut aie asynpto- natic. 52 lt shoulu he noteu that lacl ol ielevance uoes not nean the patient is not alleigic to the chenical in guestion, hut noie specihcally that this chenical is not the causal agent loi the ueinatitis cuiiently heing evaluateu. ¯iue-negative iesults aie an egually inpoitant conponent ol the patch test, hecause they pioviue sone assuiance that a chenical in guestion is not caus- ing the ueinatitis. ll a guestion aiises as to vhethei a tiue-negative iesult is tiuly iiielevant, piovocative iepeat open ap- plication testing can he an invaluahle ui- agnostic tool. ¯he patient is taught to iepeateuly apply the conneicial piou- uct to intact noinal slin (sane site) sev- eial tines uaily loi 1 to 2 veels to elicit a ieaction. FALS£-P0S|T|V£ Ah0 FALS£-h£6AT|V£ 8£- S0LTS No in vivo test is inlallihle, anu in- vestigative patch testeis nust alvays tale into consiueiation the possihility ol lalse- positive anu lalse-negative ieactions vhen peiloining the patch test. Because theie aie noie than o¯OO potential hunan alleigens, anu hecause ol the ohvious linitation ol the con- neicially availahle scieening tiays such as ¯.R.U.l. ¯est (lahi lhainacia Sei- vice A/S, Hilleiou, Dennail) anu Allei- gen latch ¯est lit (Heinal Lahoiato- iies, Delnai, NYAneiican Acaueny ol Deinatology), it stanus to ieason that a high nunhei ol clinically iele- vant alleigens go uniuentiheu. ln an analysis ol the Noith Aneiican Con- tact Deinatitis Cioup uata loi 1ºº4 to 1ºº6 on o12O patients 5o it vas lounu that 62 peicent hau at least one posi- tive ieaction to an alleigen piesent on the ¯.R.U.l. ¯est, ol vhich 45 peicent veie ielevant to the cuiient ueinatitis. ln theii stuuy ol ¯o2 patients ovei 5.5 yeais, Cohen et al. 54 lounu that only 2o peicent ol patients ieacteu exclusively to alleigen(s) in the Alleigen latch ¯est stanuaiu seiies, o¯ peicent ieacteu to alleigens in hoth the stanuaiu seiies anu othei supplenentaiy tests, anu 4O peicent ieacteu only to supplenentaiy alleigens. |r V|||c Teº|º |c| A||e|ç|c Ccr|ac| De|ra||||º ln vitio anu aninal tests loi the uiagnosis ol ACD such as the lynphocyte tiansloi- nation anu naciophage nigiation inhi- hition tests have heen in uevelopnent loi the last uecaue. Cne na|oi ohstacle in ueveloping in vitio systens is the lacl ol specihcity to uetect the antigenic noiety ol a paiticulai chenical. Lynphocyte tiansloination tests peiloineu on hloou cells lion patients vho hau a positive patch test ieaction to thiuian nix anu/oi shoveu sensitization to tetianethyl- thiuian nonosulhue oi to tetianethyl- thiuian nonosulhue anu tetianethylthi- uian uisulhue uenonstiateu signihcant piolileiation ol peiipheial hloou nono- nucleai cells in iesponse to hapten- piotein con|ugates, vheieas cells lion patients vith negative patch test ieac- tions to thiuian anu contiol uonois vith no histoiy ol ACD laileu to nount a sig- nihcant iesponse. 58 ¯he local lynph noue assay, vhich uses a nouse nouel, allovs guantitative assessnent ol the sensitizing potency ol alleigens. 5º Hov- evei, patch testing ienains the only ieli- ahle hioassay to asceitain sensitization to exogenous chenicals. D|||ERE\T|A| D|A0\0S|S Ec/era|cuº De|ra|cºeº ¯he uilleiential uiagnosis ol ACD in- cluues a viue iange ol inhannatoiy slin uisoiueis (see Box 1o-1). ¯he piesence ol eosinophilic spongiosis anu nultinucle- ate ueinal uenuiitic hhiohistiocytic cells is especially suggestive ol ACD vhen encounteieu in the piesence ol acantho- sis, lynphocytic inhltiate, ueinal eosin- ophils, anu hypeileiatosis. 6O 144 \crec/era|cuº Va||ar|º ¯he pathologic hnuings ol the nonec- zenatous vaiiants ol ACD nay he neaily iuentical to those ol the uiseases they sinulate. Lichenoiu ACD uoes have sone leatuies that help to uistin- guish it lion iuiopathic lichen planus, incluuing a less intense lichenoiu inhl- tiate vith noie eosinophils anu neutio- phils, less epiueinal hypeiplasia vith levei neciotic leiatinocytes, anu sone uegiee ol epiueinal spongiosis. 61 ln contiast, lí-lile ACD has no epiuei- nal spongiosis, anu the hnuings aie in- uistinguishahle lion those ol lí lion othei causes. Deinal contact hypeisen- sitivity also lacls spongiosis hut has the chaiacteiistic lynphohistiocytic, peii- vasculai inhltiate that olten goes ueepei in the ueinis (niu-ueinal) than eczen- atous ACD. ¯he histopathologic lea- tuies ol acute alleigic contact leulo- ueina have not heen stuuieu. ln the hest-uocunenteu cases, eczenatous patch test ieactions to llD suhseguently ue- pignenteu, at vhich tine the hiopsy specinen vas inuistinguishahle lion that loi chenically inuuceu vitiligo. Al- leigic contact puipuia is pathologically sinilai to the eczenatous vaiiant ol ACD hut vith a capillaiitis that iesults in extiavasation ol ieu hloou cells. 62 lt is uilhcult to sepaiate lion the othei pig- nenteu puipuiic ueinatoses. ln all ol the noneczenatous anu ec- zenatous vaiiants ol ACD, patch testing is the only neans loi accuiate uiagnosis. ¯he histoiy, physical exanination, anu/ oi pathology aie usually not uiagnostic. C0|P||CAT|0\S Ccrp||ca||crº c| \c| Pa|c| Teº||rç ln 2OO4 the Aneiican Acaueny ol Dei- natology anu the Society loi lnvestiga- tive Deinatology ueteinineu that ¯2 nillion Aneiicans veie living vith con- tact ueinatitis anu that it vas the thiiu nost connon ieason loi patients to seel consultation vith the ueinatolo- gist. lt accounteu loi º.2 nillion visits that yeai, at a cost ol S1.º hillion. 6o ln 1º8º, Rietschel ueteinineu that patch testing the 5.¯ nillion peisons estinateu to have ueinatitis/eczena tianslateu into a positive cost-heneht iatio ol S4O nillion to SºO nillion pei yeai, vhen the expense ol patch testing vas con- paieu vith the cost ol tieatnent. 64 lui- theinoie, Van Dei Vall, Devos, anu Coeniaaus iepoiteu that patch testing vas even noie cost ellective vhen the test vas peiloineu on patients loi vhon theie vas a high inuex ol suspi- cion loi the uiagnosis ol ACD, hecause incieaseu lilelihoou ol uetecting a clini- cally ielevant alleigen coiielates vith a signihcantly hettei clinical outcone. 65 Ccrp||ca||crº c| Pa|c| Teº||rç latient uisappointnent is a signihcant piohlen vith patch testing, hecause theie is no guaiantee ol uetection ol a clinically ielevant alleigen oi ol suhse- guent slin inpiovenent vith avoiu- ance ol a given alleigen. ¯hese out- cones aie anticipateu anu expecteu, hut not guaianteeu. luitheinoie, theie aie snall iisls ol causing a haie ol the uei- natitis anu, although ienote, ol inuuc- ing sensitization to one ol the alleigens. latients shoulu he naue avaie that positive test ieactions nay peisist loi seveial veels, anu in the case ol golu, sonetines longei. lost-inhannatoiy hypeipignentation oi hypopignenta- tion nay occui at positive patch test ie- action sites. PR00\0S|S lt is uilhcult to assess the actual piogno- sis ol ACD, hecause theie is no stan- uaiuizeu instiunent loi such an eval- uation. Cuality-ol-lile guestionnaiies (vhich neasuie synpton, enotional, anu lunctional paianeteis), nunhei ol outpatient ueinatology visits, anu suh- |ective evaluations have all heen useu. ln lact, nuch ol the inloination on piognosis is extiapolateu lion uata on occupational contact ueinatitis, he- cause ol the inpoitant inplications loi voilei`s conpensation. lt is inpoitant to note that these uata aie suh|ect to se- lection hias, hecause nost stuuies aie investigating patients vho aie heing evaluateu at a teitiaiy caie contact uei- natitis ieleiial clinic. 6¯ Alnost tvo uecaues ago, the piogno- sis loi occupational contact ueinatitis vas ielatively pooi, vith only oO peicent to 5O peicent ol patients uenonstiating inpiovenent. 68 loitunately, noie iecent ievievs uenonstiate that vith eaily in- teivention anu appiopiiate nanagenent ovei ¯5 peicent ol patients iecovei vith- out peinanent inpaiinent. 6º ¯his up- vaiu tienu tovaiu a positive piognosis nay ielate to hettei iuentihcation ol al- leigens, inpioveu stanuaiuization ol the uiagnostic tools, incieaseu pieventive el- loits, anu patient euucation. ¯O Cahill et al. peiloineu an extensive ie- viev ol the liteiatuie to iuentily connon vaiiahles that inhuence piognosis. ¯1 ¯hey specihcally looleu at the ellects ol age, sex, atopy, patient lnovleuge, uisease etiology, uuiation ol synptons, anu change ol vocation anu lounu no uillei- ences ielateu to these lactois. Change ol voil conuitions is not alvays associateu vith an inpioveu piognosis, hecause pa- tients nay still not appiopiiately avoiu the inuucing alleigen. luitheinoie, change ol enploynent, although it nay inpiove ACD, nay have a uiiect nega- tive inpact on guality ol lile. ¯2 Although assessnent ol the patient`s lnovleuge hase is a uilhcult tasl, it is geneially accepteu that gieatei lnovl- euge coiielates vith hettei clinical out- cones. ln a lollov-up stuuy hy Agnei, llyvholn, anu íenne, patients uiag- noseu vith loinaluehyue alleigy veie iigoiously inloineu ahout theii uiagnosis anu the culpiit alleigen, anu given an ex- posuie assessnent loi theii piouucts. At 1- anu 5-yeai postpatch test lollov-up, the patients veie inteivieveu anu exan- ineu hy the ueinatologist, anu given lui- thei exposuie assessnent loi theii cui- ient piouucts. As expecteu, patients vho iepoiteu not paying attention to theii al- leigens vhen huying oi using consunei piouucts veie exposeu to loinaluehyue in theii cuiient piouucts. luitheinoie, patients vho iepoiteuly paiu attention to avoiuing theii alleigens hau statistically levei haies ol theii ueinatitis. ¯o Use ol the Contact Alleigen Replace- nent Datahase tool alloveu loi a lovei nean counseling tine anu highei levels ol patient satislaction, although no statis- tically signihcant uilleiences veie noteu on clinical neasuies ol uisease activity. ¯4 Nielsen et al. peiloineu a cioss- sectional stuuy on a ianuon sanple ol 56¯ peisons (ageu 15 to 6º yeais) anu a suhseguent iepeat patch stuuy on o65 (68 peicent) ol the oiiginal population. losi- tive patch test iesults veie ie-conhineu in ¯1 peicent ol the suh|ects (o¯ out ol 52) 8 yeais altei the haseline stuuy. Niclel piovoleu the highest lieguency ol positive ieactions at ¯º peicent (1º out ol 24 suh|ects), vheieas cosnetic ingieuients piouuceu the lovest lie- guency, 5O peicent (5 out ol 1O suh- |ects). Cl note, 6O peicent (21 out ol o5 suh|ects) hau a positive patch test ieac- tion to one oi noie alleigens. ¯his stuuy conhineu the continueu neeu loi alleigen avoiuance to pievent elicitation ol ACD. ¯5 Unloitunately, theie aie lac- tois that aie heyonu the ahility ol the patient to contiol to hecone synpton liee. ¯hese incluue the natuie (uhiguity) ol the alleigen itsell oi the inahility to 145 shielu the slin lion the enviionnent (e.g., the lace anu hanus aie alvays ex- poseu). Repoits inuicate that sensitiza- tion to niclel, chioniun, anu epoxy aie specihcally associateu vith a less lavoi- ahle piognosis, especially il contact is occupationally ielateu, even vhen con- tinueu exposuie ceases. ¯6,¯¯ íeuing, Wiangs|o, anu [aivholn eval- uateu the long-tein couise, occupational ielevance, anu neuico-social inplica- tions ol hanu ueinatitis in patients ui- agnoseu thiough a piioi population- haseu stuuy. ¯8 latients veie evaluateu using tvo guestionnaiies, one auninis- teieu at haseline anu one auninisteieu 15 yeais latei. Cl the patients vho con- pleteu hoth guestionnaiies, 66 peicent iepoiteu peiiouic exaceihations ol theii chionic hanu eczena (44 peicent ol vhich hau heen vithin the pievious yeai), vheieas 12 peicent expeiienceu continuous synptons. ¯hese hnuings unueiscoie the oveivhelning chionic- ity ol nost hanu ueinatitis cases. lie- uictive lactois loi hanu eczena seveiity veie also assesseu using a logistic ie- giession nouel. ¯º ¯he nost inpoitant pieuictive lactois loi peisistence ol uis- ease veie a histoiy ol chiluhoou ec- zena, a gieatei extent ol eczena in- volvenent at initial piesentation, anu an age youngei than 2O yeais at onset ol the hanu eczena. ln auuition they lounu that hanu ueinatitis vas associ- ateu vith consiueiahle alteiation ol psy- chosocial lunction, loi exanple, sleep uistuihances (o6 peicent) anu han- peieu leisuie activities (¯2 peicent). ln the o peicent ol patients vho iepoiteu a necessaiy occupational change seconu- aiy to theii hanu ueinatitis, this change uiu coiielate vith clinical inpiovenent. TREAT|E\T ¯he lunuanental nanagenent ol pa- tients vith ACD ielies on hoth tieatnent ol synptons anu avoiuance ol auuitional encounteis vith alleigic contactants. P|a|racc|cç|c |r|e|.er||cr ln the lace ol acute oi synptonatic chionic contact ueinatitis, phainaco- logic inteivention is necessaiy to alleviate the synptons anu physical linitations inposeu hy the eiuption. ¯he inpact ol the ueinatitis on the activities ol uaily living anu the ahility to peiloin voil lunctions nust not he unueiestinateu. Acute vesiculai, veeping eiuptions nay heneht lion the use ol uiying agents such as topical aluninun sullate/ calciun acetate. Chionic, licheniheu eiuptions aie hest tieateu vith enol- lients. liuiitus can he contiolleu vith topical antipiuiitics oi oial antihista- nines, hut topical antihistanines anu anesthetics aie hest avoiueu hecause ol the iisl ol inuucing a seconuaiy alleigy in alieauy ueinatitic slin. Despite the uiavhacls associateu vith theii long-tein use, coiticosteioius ie- nain the golu stanuaiu anu the nainstay loi alleviating synptons anu hastening the iecoveiy lion ACD (see Chap. 216). ¯opical coiticosteioius (uiviueu into hve steieochenical stiuctuial classes, each vith sinilaily hioau nechanisns ol ac- tion anu ellectiveness o8 ) have heen shovn in a nunhei ol nouels to ieuuce the signs anu synptons ol ACD. 8O luitheinoie, they aie geneially vell toleiateu vhen useu shoit tein. Long-tein anu viue- spieau use ol topical steioius, hovevei, can iesult in cutaneous atiophy, hiisutisn, hypopignentation, lolliculitis, acne, anu systenic ahsoiption. ¯he use ol systenic coiticosteioius, on the othei hanu, is vai- ianteu only in noueiate to seveie acute cases anu in cases ol ieliactoiy ACD. ln the past uecaue, calcineuiin inhihi- tois have heen useu as tieatnent op- tions loi nany inhannatoiy slin uisoi- ueis. ¯heii nechanisn ol action is elahoiateu in Chap. 221. Cial cyclo- spoiine anu topical taciolinus anu pineciolinus have uenonstiateu elh- cacy in the tieatnent ol eczenatous ueinatitiues, incluuing atopic ueinati- tis pieuoninantly, as vell as contact ueinatitis. Cyclospoiine has heen useu oially to tieat ACD, hut liniteu penetia- tion has hinueieu its topical use. ln au- uition, taciolinus anu pineciolinus (vhich shaie a naciolactan stiuctuie) have pioveu elhcacious as topical anti- inhannatoiy uiugs. P|c|c||e|ap] lhototheiapy has heen ieseiveu loi pa- tients vith ieliactoiy ACD vho aie unie- sponsive to coiticosteioius anu loi patients vho aie unahle to avoiu all piovoling lac- tois in theii uaily enviionnent. Seveial stuuies have uenonstiateu the ellective- ness ol ultiaviolet light (oial psoialen plus ultiaviolet A photochenotheiapy, anu theiapy vith shoitvave ultiaviolet B light), uue to its intiinsic innunosuppies- sive piopeities, in the tieatnent ol hoth chionic ACD anu lCD ol the hanus. lui- theinoie, ultiaviolet B light theiapy vas saiu to piouuce an excellent ellect in ¯ ol 1O patients vith hanu ACD. 81 Notahly, the tieatnent uuiation vas lengthy (5 nonths), naintenance theiapy vas ie- guiieu, anu contiols veie not peiloineu. PREVE\T|0\ lievention iests on the avoiuance ol alleigens. At tines, the sensitization to alleigens such as niclel anu liagiance chenicals lile halsan ol leiu can inuuce non-local- izeu ieactions thiough theii systenic ah- soiption (¯ahle 1o-o). ln sone ciicun- stances, the avoiuance ol these alleigens in the uiet can iesult in clinical inpiove- nent. ln any event, the tieatnent ol ACD is sinply alleigen avoiuance. lt is the piocess ol eluciuating anu inple- nenting this tieatnent plan that can he so aiuuous. ¯his concept is ieinloiceu hy the iesults ol one stuuy ol 2oO voileis, 82 in vhich only one-thiiu ol stuuy paitici- pants accuiately iecalleu theii uiagnoses anu tieatnent ieginens, anu peisistent ueinatitis vas thiee tines noie lilely in those voileis vho coulu not ienenhei this inloination than in those vho uiu. ¯he heneht ol alleigen avoiuance anu the conseguences ol not uoing so aie uis- cusseu in the liognosis section. loi ceitain alleigens lounu in topical piepaiations (e.g., vehicles, pieseiva- tives, stahilizeis, anu enulsiheis), it is inpoitant to inpiess upon patients the Ik8L£ 13-3 Foods and Top|ca| |tams 8aportad to Provoka 8aact|ons |n Parsons A||arg|c to Fragranca and 8a|sam of Paru º Tcra|ceº º ||a.c|ed |eaº, cc|- |ee, ard |c|accc º C|||uº ||u||º º Sp|ceº ºuc| aº c|r- rarcr, c|c.eº, .a- r|||a, ru|reç, cu||], a||ºp|ce, pap|||a, ar|ºe, ard ç|rçe| º Decdc|ar|º º A||e|-º|a.e |c||crº º Ccr|ec||cra|] º T|rc|u|e c| |er/c|r º Cc|aº ard c||e| ºc|| d||r|º º C|ccc|a|e º C|||| º wcurd ºp|a] º Bee| ard W|re º |ed|c|ra| c|earº º V|reça| º Ca|ar|re |c||cr º Da||] p|cduc|º º Ba|] pcWde| º Cc||ee º Der|a| cerer| º Ba|ed çccdº º Surºc|eerº º Herc|||c|da| ºuppcº||c||eº º Ccuç| red|c|re º |c/erçeº º ||aç|arced pe|- ºcra| |]ç|ere p|cd- uc|º ard ccºre||cº º Sur|ar |c||crº º ||p p|epa|a||crº Da|a ||cr S||.aº|a.a D, C|arç \T, |ura| S, Cc|er DE. |der|||ca||cr c| ||e ccrº|||uer|º c| |a|ºar c| Pe|u |r |cra|ceº. 0crratitis 16.091, 200o. 0|a| p|eºer|a||cr, a|º||ac|, ard Sa|ar T\, |cW|e| J|. Ba|ºar-|e|a|ed º]º|er|c ccr|ac| de|ra||||º J /r /cac 0crratc! 45.8//, 2001. 146 neeu to ieau lahels. ln auuition, a peii- ouically upuateu electionic uatahase ol ingieuients in cosnetics anu ovei-the- countei anu piesciiption topical piepa- iations (Contact Alleigen Replacenent Datahase) is availahle on the lnteinet (http://vvv.contactuein.oig) anu al- lovs piactitioneis to geneiate a unigue list ol topical piepaiations appiopiiate loi the inuiviuual vith specihc alleigies. latients vith alleigies to pieseivatives (e.g., nethylchloioisothiazolone) nust he avaie that these nateiials can he lounu in any vatei-haseu loinulation, such as la- tex paint. luitheinoie, the nane given a chenical useu in a cosnetic oi phaina- ceutical piouuct is lieguently changeu vhen it is useu in an inuustiial piouuct. loi instance, the cosnetic pieseivative guateiniun-15, vhen useu in inuustiy, is ieleiieu to as Dovicil 1OO oi Dovicil 2OO. liactitioneis guiuing patients thiough the synonynic |ungle ol these chenicals aie auviseu to consult stanuaiu texts on the suh|ect. Unloitunately loi patients anu physi- cians alile, the alleigenic conponents ol nany nateiials vill lail to he laheleu (e.g., iuhhei-, textile-, anu netal-ielateu alleigens, to nane a lev). ln counseling patients vith ieactions to these nateii- als, the physician nust pioviue inloina- tion ahout vhat linus ol piouucts aie lilely to contain the alleigens, as vell as appiopiiate ieplacenents. Such inloi- nation can he lounu in stanuaiu texts. 5O luitheinoie, sone alleigens nay he in- conpletely laheleu, loi exanple, given the piopiietaiy natuie ol a liagiance loi- nulation, inuiviuual liagiances con- hineu in a piouuct nay go unlisteu. la- tients vith an alleigic ieaction to a liagiance shoulu he auviseu to use lia- giance-liee nateiials, vhich incluue not only topical piepaiations hut also a vaii- ety ol othei piouucts such as toilet pa- pei, sanitaiy naplins, anu uiapeis. Because nany alleigens shaie connon antigenic noieties, the patient neeus to he instiucteu not only ahout the lnovn allei- gen hut also ahout possihle cioss-ieacting alleigens. loi exanple, the inuiviuual al- leigic to henzocaine nust he avaie ol the nany potentially cioss-ieacting suh- stances, vhich incluue agents as uiveise as othei estei anesthetics (e.g., piocaine), ceitain neuications (e.g., sullonaniues), haii uyes (e.g., llD), textile uyes (e.g., aniline uyes), sone sunscieens (e.g., paia- aninohenzoic aciu), anu othei piouucts. ¯o uate, hyposensitization oi tolei- ance inuuction has ienaineu an elusive nethou loi coping vith ACD. |E\ RE|ERE\CES T|e |u|| |e|e|erce ||º| |c| a|| c|ap|e|º |º a.a||a||e a| WWW.d|çr/.ccr. 4. Nielsen NH et al: lnciuence ol alleigic contact sensitization in Danish auults hetveen 1ººO anu 1ºº8, the Copen- hagen Alleigy Stuuy, Dennail. 3r j Dcrmato| 147:48¯, 2OO2 12. Heine C et al: lieguency ol contact alleigy in Ceinan chiluien anu auoles- cents patch testeu hetveen 1ºº52OO2: Results lion the lnloination Netvoils ol the Depaitnents ol Deinatology anu the Ceinan Contact Deinatitis Reseaich Cioup. Conta.t Dcrmatitis 51:111, 2OO4 21. ue Cioot AC: lat.h tcsting: Tcst Con- .cntrations and Vchi.|cs jor 3700 A||cr- gcns, 2nu eu. Ansteiuan, llseviei, 1ºº4 o8. [acoh Sl, Steele ¯: Coiticosteioiu classes: A guicl ieleience guiue incluu- ing patch test suhstances anu cioss ieactivity. j Am A.ad Dcrmato| 54:¯2o, 2OO6 oº. Veien Nl: lngesteu loou in systenic alleigic contact ueinatitis. C|in Dcrmato| 15:54¯, 1ºº¯ 44. Belsito DV: ¯he uiagnostic evaluation, tieatnent, anu pievention ol alleigic contact ueinatitis in the nev nillen- niun. j A||crg, C|in lmmuno| 105:4Oº, 2OOO 46. ¯ayloi [S, lilel l: Latex alleigy: Diag- nosis anu nanagenent. Dcrmato| Thcr 7:28º, 2OO4 5o. Noith Aneiican Contact Deinatitis Cioup patch test iesults loi the uetec- tion ol uelayeu-type hypeisensitivity to topical alleigens. Am j Conta.t Dcrmato| 15:1¯6, 2OO4 54. Cohen Dl et al: Utility ol a stanuaiu alleigen seiies alone in the evaluation ol alleigic contact ueinatitis: A ietiospec- tive stuuy ol ¯o2 patients. j Am A.ad Dcrmato| 36:º14, 1ºº¯ ¯4. list [í et al: ¯he Contact Alleigen Replacenent Datahase anu tieatnent ol alleigic contact ueinatitis. Ar.h Dcr- mato| 140:1448, 2OO4 C H A P T E R 1 4 Atop|c 0ermt|t|s (Atop|c £czem) Dcra|d \. |. |eurç |aW|erce |. E|c|er|e|d |a|| Bcçur|eW|c/ Atopic ueinatitis (AD) is a chionically ielapsing slin uisease that occuis nost connonly uuiing eaily inlancy anu chiluhoou. lt is lieguently associateu vith ahnoinalities in slin haiiiei lunc- tion anu alleigen sensitization. ¯heie is no single uistinguishing leatuie ol AD oi a uiagnostic lahoiatoiy test. ¯hus, the uiagnosis is haseu on the constellation ol clinical hnuings uesciiheu hy Hanihn anu Ra|la 1 anu listeu in ¯ahle 14-1. EP|DE||0|00\ Since the 1º6Os, theie has heen a gieatei than thieelolu inciease in the pieva- lence ol AD. 2 lnueeu, the nost iecent estinates inuicate that AD is a na|oi puhlic health piohlen voiluviue, vith a pievalence in chiluien ol 1O peicent to 2O peicent in the Uniteu States, noith- ein anu vestein luiope, uihan Aliica, [apan, Austialia, anu othei inuustiial- izeu countiies. o ¯he pievalence ol AD in auults is appioxinately 1 peicent to o peicent. lnteiestingly, the pievalence ol AD is nuch lovei in agiicultuial coun- tiies such as China anu in lastein lu- iope, iuial Aliica, anu Cential Asia. ¯heie is also a lenale pieponueiance loi AD, vith an oveiall lenale/nale ia- tio ol 1.o:1.O. ¯he hasis loi this incieaseu pieva- lence ol AD is not vell unueistoou. Hovevei, viue vaiiations in pievalence have heen ohseiveu vithin countiies in- hahiteu hy sinilai ethnic gioups, sug- gesting that enviionnental lactois aie ciitical in ueteinining uisease expies- sion. 4 Sone ol the potential iisl lactois that have ieceiveu attention as heing as- sociateu vith the iise in atopic uisease incluue snall lanily size, incieaseu in- cone anu euucation hoth in vhites anu hlacls, nigiation lion iuial to uihan enviionnents, anu incieaseu use ol anti- hiotics, that is, the so-calleu \cstcrn |ijc- st,|c. 5,6 ¯his has iesulteu in the °hygiene hypothesis` that alleigic uiseases night he pieventeu hy °inlection in eaily chilu- hoou tiansnitteu hy unhygienic contact vith oluei sihlings.` ¯ ET|0|00\ A\D PATH00E\ES|S AD is a highly piuiitic inhannatoiy slin uisease that iesults lion conplex intei- actions hetveen genetic susceptihility genes iesulting in a uelective slin haiiiei, uelects in the innate innune systen, 147 anu heighteneu innunologic iesponses to alleigens anu niciohial antigens. 8 Dec|eaºed S||r Ba|||e| |urc||cr AD is associateu vith a naileu ue- ciease in slin haiiiei lunction uue to the uovniegulation ol coiniheu envelope genes (hlaggiin anu loiiciin), ieuuceu cei- aniue levels, incieaseu levels ol enuoge- nous pioteolytic enzynes, anu en- hanceu tians-epiueinal vatei loss. º,1O Auuition ol soap anu ueteigents to the slin iaises its pH, theiehy incieasing ac- tivity ol enuogenous pioteases, leauing to luithei hiealuovn ol epiueinal hai- iiei lunction. ¯he epiueinal haiiiei nay also he uanageu hy exposuie to exoge- nous pioteases lion house uust nites anu :ta¡h,|o.o..us aurcus. ¯his is vois- eneu hy the lacl ol ceitain enuogenous piotease inhihitois in atopic slin. ¯hese epiueinal changes lilely contiihute to incieaseu alleigen ahsoiption into the slin anu niciohial colonization. Be- cause epicutaneous, as conpaieu to sys- tenic oi aiivay, sensitization to allei- gen iesults in highei level alleigic innune iesponses, uecieaseu slin hai- iiei lunction coulu act as a site loi allei- gen sensitization anu pieuispose such chiluien to the uevelopnent ol iespiia- toiy alleigy latei in lile. 11 |rrurcpa||c|cç] c| A|cp|c De|ra||||º Clinically unallecteu slin ol AD patients nanilests nilu epiueinal hypeiplasia anu a spaise peiivasculai ¯-cell inhltiate. 8 Acute eczenatous slin lesions aie chai- acteiizeu hy naileu inteicellulai euena (spongiosis) ol the epiueinis. Denuiitic antigen-piesenting cells |e.g., Langei- hans cells (LCs), naciophages] in lesional anu, to a lessei extent, in nonlesional slin ol AD exhihit suilace-hounu innuno- glohulin l (lgl) nolecules. A spaise epi- ueinal inhltiate consisting piinaiily ol ¯ lynphocytes is also lieguently ohseiveu. ln the ueinis ol the acute lesion, theie is an inhux ol ¯ cells vith occasional nonocyte-naciophages. ¯he lynpho- cytic inhltiate consists pieuoninantly ol activateu nenoiy ¯ cells heaiing CDo, CD4, anu CD45 RC (suggesting pievious encountei vith antigen). losinophils aie iaiely piesent in acute AD. íast cells aie lounu in noinal nunheis in uilleient stages ol uegianulation. Chionic licheniheu lesions aie chaiac- teiizeu hy a hypeiplastic epiueinis vith elongation ol the iete iiuges, pioninent hypeileiatosis, anu nininal spongiosis. ¯heie is an incieaseu nunhei ol lgl- heaiing LCs in the epiueinis, anu nac- iophages uoninate the ueinal nono- nucleai cell inhltiate. íast cells aie incieaseu in nunhei hut aie geneially lully gianulateu. Neutiophils aie ahsent in AD slin lesions even in the setting ol incieaseu :. aurcus colonization anu in- lection. lncieaseu nunheis ol eosinophils aie ohseiveu in chionic AD slin lesions. ¯hese eosinophils unueigo cytolysis vith ielease ol gianule piotein contents into the uppei ueinis ol lesional slin. losino- phil-ueiiveu extiacellulai na|oi hasic piotein can he uetecteu in a hhiillai pat- tein associateu vith the uistiihution ol elastic hheis thioughout the uppei uei- nis. losinophils aie thought to contiih- ute to alleigic inhannation hy the secie- tion ol cytolines anu neuiatois that augnent alleigic inhannation anu in- uuce tissue in|uiy in AD thiough the pio- uuction ol ieactive oxygen inteineui- ates anu ielease ol toxic gianule pioteins. C]|c||reº ard C|erc||reº Atopic slin inhannation is oichestiateu hy the local expiession ol pio-inhanna- toiy cytolines anu chenolines. 12 Cyto- lines such as tunoi neciosis lactoi- (¯Nl- ) anu inteileulin 1 (lL-1) lion ies- iuent cells |leiatinocytes, nast cells, uen- uiitic cells (DCs)] hinu to ieceptois on the vasculai enuotheliun, activating cel- lulai signaling pathvays, vhich leaus to the inuuction ol vasculai enuothelial cell auhesion nolecules. ¯hese events ini- tiate the piocess ol tetheiing, activation, anu auhesion to vasculai enuotheliun lolloveu hy extiavasation ol inhanna- toiy cells into the slin. Cnce inhanna- toiy cells have inhltiateu into the slin, they iesponu to chenotactic giauients estahlisheu hy chenolines vhich ena- nate lion sites ol in|uiy oi inlection. Acute AD is associateu vith the pio- uuction ol ¯ helpei 2 type (¯h2) cyto- lines, notahly lL-4 anu lL-1o, 1o vhich neuiate innunoglohulin isotype svitch- AT0P|C DER|AT|T|S AT A 0|A\CE P|e.a|erce pea| c| 1o pe|cer| |c 20 pe|- cer| |r ea||] c|||d|ccd |r |rduº|||a||/ed ccur|||eº. A c||cr|c c| c||cr|ca||] |e|apº|rç d|ºc|- de| W||| rajc| |ea|u|eº c|. P|u|||uº Ec/era|cuº de|ra||||º (acu|e, ºu|- acu|e, c| c||cr|c, W||| |]p|ca| rc|- p|c|cç] ard açe-ºpec||c pa||e|rº |ac|a| ard e/|erºc| |r.c|.erer| |r |r|arc] ||e/u|a| ec/era/||c|er||ca||cr |r c|||- d|er ard adu||º. Ccrrcr|] aººcc|a|ed W|||. Pe|ºcra| c| |ar||] ||º|c|] c| a|cp] (a||e|ç|c |||r|||º, aº||ra, a|cp|c de|- ra||||º, /e|cº|º/º||r |a|||e| d]º|urc||cr |rrurcç|c|u||r E |eac||.||]. 0ere||c |aº|º |r1uerced |] er.||crrer|a| |ac|c|º W||| a||e|a||crº |r |rrurc|cç|c |eºpcrºeº |r T ce||º, ar||çer p|cceºº|rç, |r1arra|c|] c]|c||reº, |cº| de|erºe p|c- |e|rº, a||e|çer ºerº|||.||], ard |r|ec||cr. Ik8L£ 14-1 Faaturas of Atop|c 0armat|t|s º |ajc| |ea|u|eº º P|u|||uº º Raº| cr |ace ard/c| e/|erºc|º |r |r|ar|º ard ]curç c|||d|er º ||c|er||ca||cr |r 1e/u|a| a|eaº |r c|de| c|||d|er º Terderc] |cWa|d c||cr|c c| c||cr|ca||] |e|apº|rç de|ra||||º º Pe|ºcra| c| |ar||] ||º|c|] c| a|cp|c d|º- eaºe. aº||ra, a||e|ç|c |||r|||º, a|cp|c de|ra||||º º 0||e| ccrrcr |rd|rçº º D|]reºº º Derr|e-|c|çar |c|dº (accer|ua|ed ||reº c| ç|cc.eº |e|cW ||e ra|ç|r c| ||e |cWe| e]e||d, º A||e|ç|c º||re|º (da||er|rç |erea|| ||e e]eº, º |ac|a| pa||c| º P||]||aº|º a||a º |e|a|cº|º p||a||º º |c|||]cº|º .u|ça||º º H]pe|||rea|||] c| pa|rº ard ºc|eº º w|||e de|ra|cç|ap||ºr (W|||e ||re appea|º cr º||r W||||r 1 r|ru|e c| |e|rç º||c|ed W||| ||ur| |rº||urer|, º Ccrjurc||.|||º º |e|a|cccruº º Ar|e||c| ºu|capºu|a| ca|a|ac|º º E|e.a|ed ºe|ur |rrurcç|c|u||r E º |rred|a|e º||r |eº| |eac||.||] 148 ing to lgl synthesis, anu upiegulate ex- piession ol auhesion nolecules on en- uothelial cells. ln contiast, lL-5, is involveu in eosinophil uevelopnent anu suivival, anu pieuoninates in chionic AD. 1o ¯he inpoitant iole that ¯h2 cyto- lines play in the slin`s inhannatoiy ie- sponse is suppoiteu hy the ohseivation that tiansgenic nice genetically engi- neeieu to oveiexpiess lL-4 in theii slin uevelop inhannatoiy piuiitic slin le- sions sinilai to AD, suggesting that lo- cal slin expiession ol ¯h2 cytolines plays a ciitical iole in AD. 14 Alleigen- sensitizeu slin lion lL-5uehcient nice has heen lounu to have no uetect- ahle eosinophils anu exhihits uecieaseu thiclening, vheieas slin lion lL-4 uehcient nice uisplays noinal thiclen- ing ol the slin layeis, hut has a ieuuction in eosinophils. 15 lncieaseu piouuction ol gianulocyte naciophage colony-stinu- lating lactoi in AD is iepoiteu to inhihit apoptosis ol nonocytes, theiehy con- tiihuting to the peisistence ol AD. 16 ¯he naintenance ol chionic AD also in- volves piouuction ol the ¯h1-lile cyto- lines lL-12 anu lL-18, as vell as seveial ienoueling-associateu cytolines, in- cluuing lL-11 anu tiansloining giovth lactoi- 1. 1¯ ¯he slin-specihc chenoline, cutane- ous ¯ cellattiacting chenoline |C¯ACl, CC chenoline liganu 2¯ (CCL2¯)], is highly upiegulateu in AD anu pieleien- tially attiacts slin honing cutaneous lyn- phoiu antigen (CLA) + CC chenoline ie- ceptoi 1O + (CCR1O + ) ¯ cells into the slin. 12 CCR4 expiesseu on slin honing CLA + ¯ cells can also hinu to CCL1¯ on the vasculai enuotheliun ol cutaneous venules. Selective ieciuitnent ol CCR4- expiessing ¯h2 cells is neuiateu hy nac- iophage-ueiiveu chenoline anu thynus anu activation-iegulateu cytoline, hoth ol vhich aie incieaseu in AD. Seveiity ol AD has heen linleu to the nagnituue ol thynus anu activation-iegulateu cyto- line levels. ln auuition, chenolines such as liactalline, inteileion (llN)- inuuc- ihle piotein 1O, anu nonoline inuuceu hy llN- aie stiongly upiegulateu in leiatino- cytes anu iesult in ¯h1-cell nigiation to- vaiu epiueinis, paiticulaily in chionic AD. lncieaseu expiession ol the CC chenolines, naciophage chenoattiac- tant piotein-4, eotaxin, anu RAN¯lS (ieg- ulateu on activation noinal ¯-cell ex- piesseu anu secieteu) contiihute to inhltiation ol naciophages, eosinophils, anu ¯ cells into hoth acute anu chionic AD slin lesions. See Chaps. 11 anu 12 loi a noie uetaileu ieviev ol cytolines anu chenolines in slin inhannation. |e] Ce|| T]peº |r A|cp|c De|ra||||º S||r AhT|6£h-P8£S£hT|h6 0£LLS AD slin contains tvo types ol high-alhnity, lgl- ieceptoiheaiing nyeloiu DCs: (1) LCs anu (2) inhannatoiy uenuiitic epiuei- nal cells (lDlCs), lgl-heaiing LCs that appeai to play an inpoitant iole in cuta- neous alleigen piesentation to lL-4pio- uucing ¯h2 cells. 18 ln this iegaiu, lgl- heaiing LCs lion AD slin lesions, hut not LCs that lacl suilace lgl, aie capa- hle ol piesenting inhalant alleigens to ¯ cells. ¯hese iesults suggest that cell- hounu lgl on LCs lacilitates captuie anu inteinalization ol alleigens into LCs he- loie theii piocessing anu antigen pie- sentation to ¯ cells. lgl-heaiing LCs that have captuieu alleigen lilely acti- vate nenoiy ¯h2 cells in atopic slin, hut they nay also nigiate to the lynph noues to stinulate naive ¯ cells theie to luithei expanu the pool ol systenic ¯h2 cells. Stinulation ol lc Rl on the suilace ol LCs hy alleigens inuuces the ielease ol chenotactic signals anu ieciuitnent ol piecuisoi cells ol lDlCs anu ¯ cells in vitio. Stinulation ol lc Rl on lDlCs leaus to the ielease ol high anounts ol pio-inhannatoiy signals, vhich con- tiihute to the anplihcation ol alleigic innune iesponse. ln contiast to othei inhannatoiy slin uiseases, such as alleigic contact ueinatitis oi psoiiasis vulgaiis, veiy lov nunheis ol plasnacytoiu DCs (pDCs), vhich play an inpoitant iole in host uelense against viial inlections, can he uetecteu vithin the AD slin le- sion. 1º pDCs in the peiipheial hloou ol patients vith AD have heen shovn to heai the tiineiic vaiiant ol lc Rl on theii cell suilace, vhich is occupieu hy lgl nolecules. ¯he nouiheu innune lunction ol pDCs ol patients vith AD altei lc Rl-neuiateu alleigen stinula- tion night contiihute to a local ueh- ciency ol type l llNs, theiehy contiih- uting to incieaseu susceptihility ol AD patients tovaiu viial slin inlections such as eczena heipeticun. 2O T 0£LLS Slin honing nenoiy ¯ cells play an inpoitant iole in the pathogene- sis ol AD, paiticulaily uuiing the acute phase ol illness. ¯his concept is sup- poiteu hy the ohseivation that piinaiy ¯-cell innunouehciency uisoiueis aie lieguently associateu vith eczenatous slin lesions that cleai altei successlul hone naiiov tiansplantation. 21 luithei- noie, in aninal nouels ol AD, the ec- zenatous iash uoes not occui in the ah- sence ol ¯ cells. 15 ln auuition, tieatnent vith topical calcineuiin inhihitois, vhich specihcally taiget activateu ¯ cells, sig- nihcantly ieuuces the clinical slin iash ol AD. 22 Seveial stuuies have uenonstiateu, in acute AD, the piesence ol ¯h2-lile ¯ cells that piouuce cytolines that en- hance alleigic slin inhannation. Dui- ing the chionic phase ol AD, theie is a svitch to ¯h1-lile cells vhich piinaiily piouuce llN- . ¯hese ¯h2-lile cells in- uuce the activation anu apoptosis ol le- iatinocytes. 2o Recently, ¯ iegulatoiy (¯ieg) cells have heen uesciiheu as a lui- thei suhtype ol ¯ cells that have innu- nosuppiessive lunction anu cytoline piohles uistinct lion eithei ¯h1 anu ¯h2 cells. 24 ¯ieg cells aie ahle to inhihit the uevelopnent ol hoth ¯h1 anu ¯h2 iesponses. íutations in a nucleai lactoi expiesseu in ¯ieg cells, loxlo, iesult in lllX (innune uysiegulation, ¡olyenuo- ciinopathy, cnteiopathy, X-linleu) syn- uione chaiacteiizeu hy elevateu seiun lgl, loou alleigy, anu eczena. 25 lnteiest- ingly, staphylococcal supeiantigens suh- veit ¯ieg cell lunction anu nay theiehy augnent slin inhannation. 26 k£8AT|h00YT£S leiatinocytes play a ciitical iole in the augnentation ol atopic slin inhannation. AD leiatino- cytes seciete a unigue piohle ol cheno- lines anu cytolines altei exposuie to pio-inhannatoiy cytolines. ¯his in- cluues high levels ol RAN¯lS altei stinulation vith ¯Nl- anu llN- . 2¯ ¯hey aie also an inpoitant souice ol thynic stional lynphopoietin (¯SLl), vhich activates DCs to piine naive ¯ cells to piouuce lL-4 anu lL-1o (i.e., ¯h2 cell uilleientiation). 28 ¯he inpoitance ol ¯SLl in AD pathogenesis is sup- poiteu hy the ohseivation that nice ge- netically nanipulateu to oveiexpies- sion ¯SLl in the slin uevelop AD-lile slin inhannation. leiatinocytes also play a ley iole in the slin`s innate innune iesponses via the expiession ol ¯oll-lile ieceptois, piouuction ol pio-inhannatoiy cyto- lines anu antiniciohial peptiues (such as hunan uelensins anu catheliciuins) in iesponse to tissue in|uiy oi invauing niciohes. 2º Seveial stuuies have nov uenonstiateu that AD leiatinocytes piouuce ieuuceu anounts ol antinicio- hial peptiues anu this nay pieuispose such inuiviuuals to slin colonization anu inlection vith :. aurcus, viiuses, anu lungi. ¯his uelect, hovevei, appeais to he acguiieu as the iesult ol ¯h2-cytoline (lL-4, lL-1O, anu lL-1o)neuiateu inhihi- 149 tion ol ¯Nl- anu llN- inuuceu antini- ciohial peptiue geneiation. 0ere||cº AD is lanilially tiansnitteu vith a stiong nateinal inhuence. Cenone scieens ol lanilies vith AD have inpli- cateu chionosonal iegions that oveilap vith othei inhannatoiy slin uiseases such as psoiiasis. ¯ogethei vith canui- uate gene stuuies, these have pioviueu inteiesting insights into the pathogene- sis ol AD. Although nany genes aie lilely to he involveu in the uevelopnent ol AD, theie has heen paiticulai inteiest in the potential iole ol slin haiiiei/epi- ueinal uilleientiation genes anu in- nune iesponse/host uelense genes. Loss-ol-lunction nutations ol the epi- ueinal haiiiei piotein, hlaggiin, have heen uenonstiateu to he a na|oi pieuis- posing lactoi loi AD oO as vell as ichthy- osis vulgaiis, a connon leiatinizing uis- oiuei associateu vith AD. Cl note, the hlaggiin gene is lounu on chionosone 1g21 vhich contains genes (incluuing loiiciin anu S1OO calciun hinuing pio- teins) in the epiueinal uilleientiation conplex, vhich aie lnovn to he ex- piesseu uuiing teininal uilleientiation ol the epiueinis. DNA nicioaiiay anal- yses have uenonstiateu upiegulation ol S1OO calciun hinuing pioteins anu uovniegulation ol loiiciin anu hlaggiin in AD. Canuiuate gene appioaches have also inplicateu vaiiants in the :ll^l5 gene, vhich is expiesseu in the uppei- nost epiueinis vheie its piouuct, Lll¯1, inhihits tvo seiine pioteases in- volveu in uesguanation anu inhanna- tion (stiatun coineun tiyptic enzyne anu stiatun coineun chynotiyptic en- zyne). Stiatun coineun tiyptic enzyne anu stiatun coineun tiyptic enzyne expiession is incieaseu in AD, suggest- ing that an inhalance ol piotease veisus piotease inhihitoi activity nay contiih- ute to atopic slin inhannation. ¯hese ohseivations estahlish a ley iole loi in- paiieu slin haiiiei lunction in the patho- genesis ol AD, as inpaiieu slin haiiiei loination allovs incieaseu tiansepiuei- nal vatei loss anu, inpoitantly, in- cieaseu entiy ol alleigens, antigens, anu chenicals lion the enviionnent iesult- ing in slin inhannatoiy iesponses. lt is inpoitant to note that these hlaggiin nutations, anu lilely othei nutations allecting the slin haiiiei, can occui in unallecteu inuiviuuals, patients vith ichthyosis vulgaiis vho uo not have AD, anu that the na|oiity ol patients vith AD outgiov theii inhannatoiy slin uisease. ¯hus, othei gene piouucts nust also he involveu in AD pathology. Chionosone 5go1-oo contains a clusteieu lanily ol lunctionally ielateu cytoline geneslL-o, lL-4, lL-5, lL-1o, anu gianulocyte naciophage colony- stinulating lactoivhich aie expiesseu hy ¯h2 cells. A case contiol conpaiison has suggesteu a genotypic association hetveen the ¯ allele ol the 5ºOC/¯ polynoiphisn ol the lL-4 gene pio- notei iegion vith AD. Because the ¯ al- lele is associateu vith incieaseu lL-4 gene pionotei activity vhen conpaieu to the C allele, this suggests that genetic uilleiences in tiansciiptional activity ol the lL-4 gene inhuence AD pieuisposi- tion. ln auuition, an association ol AD vith a gain-ol-lunction nutation in the suhunit ol the lL-4 ieceptoi has heen iepoiteu, pioviuing luithei suppoit ol the concept that lL-4 gene expiession plays a iole in AD. lunctional nutations in the pionotei iegion ol the C-C che- nolines, RAN¯lS anu eotaxin, as vell as vaiiants in lL-1o, the suhunit ol the high alhnity cell suilace ieceptoi loi lgl (lc R1) lounu on hasophils anu nast cells suggest an oveilapping genetic hasis vith othei atopic uiseases. ¯he in- volvenent ol ¯-cell innunoglohulin- anu nucin-uonaincontaining nole- cule-1 anu lL-18 genes suppoit the iole ol CD4 + ¯ cells anu uysiegulation ol ¯h1 genes in the pathophysiology ol AD. As vell, iepoits ol AD association vith polynoiphisns ol the NCD1 gene, vhich encoues cytosolic pathogen iecognition ieceptoi anu ¯oll-lile iecep- tois, suggest an inpoitant iole loi host uelense genes in the pathogenesis ol AD. ¯he ieauei is ieleiieu to Chap. 8 anu ieleience o1 loi a uetaileu uiscus- sion ol the genetics ol AD. Rc|e c| P|u|||uº |r A|cp|c De|ra||||º liuiitus is a pioninent leatuie ol AD, nanilesteu as cutaneous hypeiieactiv- ity anu sciatching lolloving exposuie to alleigens, changes in huniuity, excessive sveating, anu lov concentiations ol iiii- tants. o2 Contiol ol piuiitus is inpoitant hecause nechanical in|uiy lion sciatch- ing can inuuce pio-inhannatoiy cyto- line anu chenoline ielease, leauing to a vicious sciatch-itch cycle peipetuating the AD slin iash. ¯he nechanisns ol piuiitus in AD aie pooily unueistoou. Alleigen-inuuceu ielease ol histanine lion slin nast cells is not an exclusive cause ol piuiitus in AD, hecause antihis- tanines aie not ellective in contiolling the itch ol AD. oo ¯he ohseivation that tieatnent vith topical coiticosteioius anu calcineuiin inhihitois is ellective at ieuucing piuiitus suggests that the in- hannatoiy cells play an inpoitant iole in piuiitus. o4,o5 íolecules that have heen inplicateu in piuiitus incluue ¯-cell ueiiveu cytolines such as lL-o1, stiess- inuuceu neuiopeptiues, pioteases such as pioteases vhich can act on piotease- activateu ieceptois, eicosanoius, anu eosinophil-ueiiveu pioteins. o6o8 ¯he ieauei is ieleiieu to Chap. 1O2 loi a ue- taileu uiscussion ol the pathophysiology ol piuiitus. C||\|CA| ||\D|\0S ¯he uiagnosis ol AD is haseu on the con- stellation ol clinical leatuies sunnaiizeu in ¯ahle 14-1. AD typically hegins uuiing inlancy. Appioxinately 5O peicent ol pa- tients uevelop this illness hy the hist yeai ol lile anu an auuitional oO peicent he- tveen the ages ol 1 anu 5 yeais. Betveen 5O peicent anu 8O peicent ol patients vith AD uevelop alleigic ihinitis oi as- thna latei in chiluhoou. íany ol these patients outgiov theii AD as they aie ueveloping iespiiatoiy alleigy. Cu|arecuº |eº|crº lntense piuiitus anu cutaneous ieactiv- ity aie caiuinal leatuies ol AD. liuiitus nay he inteinittent thioughout the uay hut is usually voise in the eaily evening anu night. lts conseguences aie sciatch- ing, piuiigo papules (lig. 14-1), lichenih- cation (lig. 14-2), anu eczenatous slin lesions. Acute slin lesions aie chaiactei- izeu hy intensely piuiitic, eiythenatous papules associateu vith excoiiation, vesicles ovei eiythenatous slin, anu se- ious exuuate (lig. 14-o). Suhacute uei- natitis is chaiacteiizeu hy eiythena- tous, excoiiateu, scaling papules (lig. F|608£ 14-1 P|u||çc papu|eº |r a pa||er| W||| a|cp|c de|ra||||º. 150 14-4). Chionic AD is chaiacteiizeu hy thicleneu plagues ol slin, accentuateu slin nailings (lichenihcation), anu h- hiotic papules (piuiigo nouulaiis, lig. 14-5). ln chionic AD, all thiee stages ol slin ieactions lieguently co-exist in the sane inuiviuual. At all stages ol AD, pa- tients usually have uiy, lacllustei slin (lig. 14-6). ¯he uistiihution anu slin ieaction pat- tein vaiy accoiuing to the patient`s age anu uisease activity. Duiing inlancy, the AD is geneially noie acute anu piinai- ily involves the lace, scalp, anu the ex- tensoi suilaces ol the extienities (lig. 14-¯). ¯he uiapei aiea is usually spaieu. ln oluei chiluien, anu in those vho have long-stanuing slin uisease, the patient uevelops the chionic loin ol AD vith li- chenihcation anu localization ol the iash to the hexuial lolus ol the extienities (lig. 14-8). AD olten suhsiues as the pa- tient giovs oluei, leaving an auult vith slin that is pione to itching anu inhan- nation vhen exposeu to exogenous iiii- tants. Chionic hanu eczena nay he the piinaiy nanilestation ol nany auults vith AD (lig. 14-º). Cthei associateu leatuies ol AD aie listeu in ¯ahle 14-1. |a|c|a|c|] Teº|º Lahoiatoiy testing is not neeueu in the ioutine evaluation anu tieatnent ol un- conplicateu AD. Seiun lgl levels aie el- evateu in appioxinately ¯O peicent to 8O peicent ol AD patients. ¯his is associateu vith sensitization against inhalant anu loou alleigens anu/oi conconitant allei- gic ihinitis anu asthna. oº,4O ln contiast, 2O peicent to oO peicent ol AD patients have noinal seiun lgl levels. ¯his suh- type ol AD has a lacl ol lgl sensitization against inhalant oi loou alleigens. Hov- evei, sone ol these patients nay possess lgl sensitization against niciohial anti- gens such as :. aurcus toxins, anu Can- dida a||i.ans oi /a|assc:ia s,m¡odia|is can he uetecteu. As vell, sone ol these pa- tients shov positive ieactions using the atopy patch test uespite negative inne- uiate slin tests. ¯he na|oiity ol patients vith AD also have peiipheial hloou eosinophilia. latients vith AD have incieaseu spon- taneous histanine ielease lion haso- F|608£ 14-2 ||c|er||ca||cr c| ||e rec| ard º|cu|de|º |r ar adu|| W||| a|cp|c de|ra||||º. F|608£ 14-4 E|]||era|cuº papu|eº |r a pa- ||er| W||| ºu|acu|e a|cp|c de|ra||||º. F|608£ 14-5 Se.e|e ||c|er||ca||cr ard |]- pe|p|çrer|ed p|u||çc papu|eº ºeer |r a pa||er| W||| c||cr|c a|cp|c de|ra||||º. F|608£ 14-3 A. P|crcurced Weep|rç ard c|uº||rç c| ec/era- |cuº |eº|crº |r c|||d|ccd a|cp|c de|ra||||º. 8. E/cc||a|ed papu|eº ard c|uº||rç |r ar acu|e 1a|e c| a|cp|c de|ra||||º. A 8 151 phils. ¯hese hnuings lilely iehect a sys- tenic ¯h2 innune iesponse in AD especially those patients vho have ele- vateu seiun lgl levels. lnpoitantly, the peiipheial hloou slin honing CLA + ¯ cells in AD expiessing eithei CD4 oi CD8 spontaneously seciete lL-5 anu lL- 1o, vhich lunctionally piolong eosino- phil suivival anu inuuce lgl synthesis. D|A0\0S|S A\D D|||ERE\T|A| D|A0\0S|S ¯ahle 14-1 lists the clinical leatuies ol AD. Cl the na|oi leatuies, piuiitus anu chionic oi ienitting eczenatous ueina- titis vith typical noiphology anu uistii- hution aie essential loi uiagnosis. Cthei leatuies, incluuing exogenous alleigy oi elevateu lgl, aie vaiiahle, anu sone ol the °associateu leatuies` in the tahle nay not he uselul uisciininatois ol in- uiviuuals vith AD lion the unallecteu geneial population. Vaiious uiagnostic ciiteiia have heen pioposeu to assist vith clinical uiagnosis, uehnition ol pa- tients loi clinical stuuies, anu epiuenio- logic population stuuies. 41 A iehneu list ol uiagnostic ciiteiia suitahle loi epiue- niologic stuuies has heen ueiiveu anu valiuateu hy voileis in the Uniteu linguon. 42 Box 14-1 lists a nunhei ol inhanna- toiy slin uiseases, innunouehciencies, slin nalignancies, genetic uisoiueis, in- lectious uiseases, anu inlestations that shaie synptons anu signs vith AD. ¯hese shoulu he consiueieu anu iuleu out heloie a uiagnosis ol AD is naue. lnlants piesenting in the hist yeai ol lile vith lailuie to thiive, uiaiihea, a genei- alizeu scaling eiythenatous iash, anu iecuiient cutaneous anu/oi systenic in- lections shoulu he evaluateu loi seveie conhineu innunouehciency synuione. Wislott-Aluiich synuione is an X- linleu iecessive uisoiuei chaiacteiizeu hy cutaneous hnuings alnost inuistin- guishahle lion AD. lt is associateu vith thionhocytopenia, vaiiahle ahnoinali- ties in hunoial anu cellulai innunity, anu iecuiient seveie hacteiial inlec- tions. ¯he hypei-lgl synuione is chai- acteiizeu hy elevateu seiun lgl levels, uelective ¯-cell lunction, iecuiient ueep-seateu hacteiial inlections, in- cluuing cutaneous ahscesses uue to :. aurcus anu/oi piuiitic slin uisease uue to :. aurcus pustulosis, oi hy iecalci- tiant ueinatophytosis. A papulopustu- lai eiuption ol the lace anu scalp nay he seen in eaily lile. 4o Although :. au- rcus is an inpoitant pathogen in this uisoiuei, inlection vith othei hacteiia, viiuses, anu lungi nay occui, paiticu- laily vhen patients aie on chionic anti- staphylococcal antihiotic piophylaxis. Cthei leatuies ol hypei-lgl synuione incluue pneunonia vith pneunato- cele loination, uental anonalies vith ietaineu piinaiy teeth, hone liactuies, anu osteopenia. lt is inpoitant to iecognize that an auult vho piesents vith an eczenatous ueinatitis vith no histoiy ol chiluhoou eczena, iespiiatoiy alleigy, oi atopic lanily histoiy nay have alleigic contact ueinatitis. A contact alleigen shoulu he consiueieu in any patient vhose AD uoes not iesponu to appiopiiate thei- apy. Cl note, contact alleigy to topical glucocoiticoius anu topical calcineuiin inhihitois has heen iepoiteu in patients vith chionic ueinatitis. ln auuition, cu- taneous ¯-cell lynphona nust he iuleu out in any auult piesenting vith chionic ueinatitis pooily iesponsive to topical glucocoiticoiu theiapy. lueally, hiopsies shoulu he ohtaineu lion thiee sepaiate sites, hecause the histology nay shov spongiosis anu cellulai inhltiate sinilai to AD. lczenatous ueinatitis has heen also iepoiteu vith hunan innunoueh- ciency viius as vell as vith a vaiiety ol inlestations such as scahies. Cthei con- uitions that can he conluseu vith AD incluue psoiiasis, ichthyoses, anu sehoi- iheic ueinatitis. F|608£ 14-6 |r||||a|ed, e|]||era|cuº |ac|a| º||r W||| ºca||reºº |r ar adc|eºcer| W||| a|cp|c de|ra||||º. \c|e |a|e|a| |||rr|rç c| e]e||cWº ard |r||a-ccu|a| (Derr|e-|c|çar, |c|d. F|608£ 14-7 ||c||rç |r|ar| W||| a|cp|c de|ra- ||||º. (Uºed W||| pe|r|ºº|cr ||cr 0|c|r |a|ºer, |D., F|608£ 14-8 C|||d|ccd a|cp|c de|ra||||º W||| ||c|er||ca||cr c| ar|ecu|||a| |cººae ard çere|a||/ed ºe.e|e|] p|u||||c ec/era|cuº p|a(ueº. F|608£ 14-9 T]p|ca| papu|eº, .eº|c|eº, ard e|cº|crº ºeer |r a|cp|c |ard de|ra||||º. 152 C0|P||CAT|0\S 0cu|a| P|c||erº lye conplications associateu vith se- veie AD can leau to signihcant noihiu- ity. lyeliu ueinatitis anu chionic hleph- aiitis aie connonly associateu vith AD anu nay iesult in visual inpaiinent lion coineal scaiiing. Atopic leiatocon- |unctivitis is usually hilateial anu can have uisahling synptons that incluue itching, huining, teaiing, anu copious nucoiu uischaige. Veinal con|unctivitis is a seveie hilateial iecuiient chionic in- hannatoiy piocess associateu vith papillaiy hypeitiophy, oi cohhlestoning ol the uppei eyeliu con|unctiva. lt usu- ally occuis in youngei patients anu has a naileu seasonal inciuence, olten in the spiing. ¯he associateu intense piuiitus is exaceihateu hy exposuie to iiiitants, light, oi sveating. leiatoconus is a con- ical ueloinity ol the coinea helieveu to iesult lion chionic iuhhing ol the eyes in patients vith AD anu alleigic ihinitis. Cataiacts veie iepoiteu in the eaily lit- eiatuie to occui in up to 21 peicent ol patients vith seveie AD. Hovevei, it is uncleai vhethei this vas a piinaiy nanilestation ol AD oi the iesult ol the extensive use ol systenic anu topical glucocoiticoius, paiticulaily aiounu the eyes. lnueeu, noie iecent stuuies sug- gest that ioutine scieening loi cataiacts in patients vith AD nay not he piouuc- tive unless theie is concein ahout poten- tial siue ellects lion steioiu theiapy. |r|ec||crº AD can he conplicateu hy iecuiient viial slin inlections that nay iehect local ue- lects in ¯-cell lunction. ¯he nost seiious viial inlection is heipes sinplex (see Chap. 1ºo), vhich can allect patients ol all ages, iesulting in laposi vaiicelliloin eiuption oi eczena heipeticun. Altei an incuhation peiiou ol 5 to 12 uays, nulti- ple, itchy, vesiculopustulai lesions eiupt in a uisseninateu pattein, vesiculai lesions aie unhilicateu, tenu to ciop, anu olten hecone henoiihagic anu ciusteu (lig. 14-1O). luncheu out anu extienely pain- lul eiosions iesult. ¯hese lesions nay coa- lesce to laige, uenuueu, anu hleeuing aieas that can extenu ovei the entiie houy. Although snallpox inlections have heen eiauicateu voiluviue since the late 1º¯Os, thieats ol hioteiioiisn (vith snallpox anu othei inlectious agents) have naue nations ieconsiuei theii poli- cies tovaiu initiating vaccination pio- gians. ln AD patients, snallpox vaccina- tion (oi even exposuie to vaccinateu inuiviuuals) (see Chap. 1º5) nay cause a seveie viuespieau eiuption (calleu c.- :cma va..inatum) that appeais veiy sinilai to eczena heipeticun. ¯hus, in patients vith AD, vaccination is contiainuicateu unless theie is a cleai iisl ol snallpox. ln auuition, uecisions iegaiuing vaccination ol lanily nenheis shoulu tale into con- siueiation the potential ol eczena vacci- natun in householu contacts. Supeihcial lungal inlections aie also noie connon in atopic inuiviuuals anu nay contiihute to the exaceihation ol AD. latients vith AD have an incieaseu pievalence ol Tri.ho¡h,ton ru|rum inlec- tions conpaieu to nonatopic contiols. ¯heie has heen paiticulai inteiest in the iole ol /. jurjur (lit,ros¡orum ova|c oi l. or|i.u|arc) in AD. /. jurjur is a lipophilic yeast (see Chap. 18º) connonly piesent in the sehoiiheic aieas ol the slin. lgl antihouies against /. jurjur aie connonly lounu in AD patients anu nost lieguently in patients vith heau anu necl ueinatitis. ln contiast, lgl sensitization to /. jurjur is iaiely oh- seiveu in noinal contiols oi asthnatics. lositive alleigen patch test ieactions to this yeast have also heen uenonstiateu. ¯he potential inpoitance ol /. jurjur as vell as othei ueinatophyte inlections is luithei suppoiteu hy the ieuuction ol AD slin seveiity in such patients altei tieatnent vith antilungal agents. :. aurcus is lounu in noie than ºO pei- cent ol AD slin lesions. Honey-coloieu ciusting, lolliculitis, anu pyoueina aie inuicatois ol seconuaiy hacteiial slin in- lection, usually uue to :. aurcus. that ie- guiies antihiotic theiapy. Regional lyn- phauenopathy is connon in such patients. ¯he inpoitance ol :. aurcus in AD is suppoiteu hy the ohseivation that patients vith seveie AD, even those vithout oveit inlection, can shov clini- 8ox 14-1 0|ffarant|a| 0|agnos|s of Atop|c 0armat|t|s Mcst LikeIy L£SS 00NN0hl8A8£ 0|S080£8S P8£00N|hAhTLY |h |hFAhTSl0h|L08£h Ccr|ac| de|ra||||º (a||e|ç|c ard |||||ar|, Se|c|||e|c de|ra||||º |e|a|c||c/ru|||||cra| Sca||eº º P|er]||e|cru||a Pºc||aº|º º P|c||daºe de|c|erc] |c|||]cº|º .u|ça||º º |u|||p|e ca||c/]|aºe de|c|erc] |e|a|cº|º p||a||º º Z|rc de|c|erc] (ac|cde|ra||||º er|e|c- pa|||ca, p|era|u|||], de|c|er| ||eaº| r||| /|rc, c]º||c |||cº|º, De|ra|cp|]|cº|º 0cnsider º 0||e|º. ||c||r, eººer||a| |a||] ac|dº, c|çar|c ac|du||aº Aº|ea|c||c ec/era ||c|er º|rp|e/ c||cr|cuº P||ra|] |rrurcde|c|erc] d|ºc|de|º \urru|a| de|ra||||º º Se.e|e ccr||red |rrurcde|c|erc] d|ºc|de| Ju.er||e pa|ra|-p|ar|a| de|ra|cº|º |rpe||çc º D|0ec|çe º]rd|cre D|uç e|up||crº º H]pcçarraç|c|u||rer|a Pe||c|a| de|ra||||º º Açarraç|c|u||rer|a P||]||aº|º a||a º w|º|c||-A|d||c| º]rd|cre P|c|cºerº|||.||] d|ºc|de|º (|]d|ca .acc|r||c|re, pc|]rc|p|cuº ||ç|| e|up||cr, pc|p|]||aº, º A|a/|a-|e|arç|ec|aº|a º H]pe||rrurcç|c|u||r E º]rd|cre |c||uºcur de|ra||||º º C||cr|c rucccu|arecuº card|d|aº|º º 0rerr º]rd|cre L£SS 00NN0hl8A8£ 0|S080£8S P8£00N|hAhTLY |h A00L£S0£hTS Ah0 A00LTS 0ere||c º]rd|creº º \e||e||cr º]rd|cre º Hu||e| º]rd|cre Cu|arecuº T-ce|| |]rp|cra (r]ccº|º |urçc|deº c| Se/a|] º]rd|cre, |r1arra|c|], au|c|rrure d|ºc|de|º º Ecº|rcp||||c çaº||cer|e||||º Hurar |rrurcde|c|erc] .||uº-aººcc|a|ed de|ra|cºeº º 0|u|er-ºerº|||.e er|e|cpa||] º \ecra|a| |upuº e|]||era|cºuº |upuº e|]||era|cºuº P|c|||e|a||.e d|ºc|de|º De|ra|cr]cº|||º º |arçe||arº ce|| ||º||cc]|cº|º 0|a||-.e|ºuº-|cº| d|ºeaºe Perp||çuº |c||aceuº De|ra||||º |e|pe|||c|r|º P|c|cºerº|||.||] d|ºc|de|º (|]d|ca .acc|r||c|re, pc|]rc|p|cuº ||ç|| e|up||cr, pc|p|]||aº, 153 cal iesponse to conhineu tieatnent vith antistaphylococcal antihiotics anu topical glucocoiticoius. Although iecui- ient staphylococcal pustulosis can he a signihcant piohlen in AD, ueep-seateu :. aurcus inlections occui iaiely anu shoulu iaise the possihility ol an innu- nouehciency synuione such as hypei- lgl synuione. íethicillin-iesistant staph- ylococcus nay he an inpoitant pathogen in sone patients. Hard De|ra||||º latients vith AD olten uevelop non- specihc, iiiitant hanu ueinatitis. lt is lieguently aggiavateu hy iepeateu vetting anu hy vashing ol the hanus vith haish soaps, ueteigents, anu uis- inlectants. Atopic inuiviuuals vith oc- cupations involving vet voil aie pione to uevelop an intiactahle hanu ueinatitis in the occupational setting. ¯his is a connon cause ol occupa- tional uisahility. E/|c||a||.e De|ra||||º latients vith extensive slin involvenent nay uevelop exloliative ueinatitis (see Chap. 2o). ¯his is associateu vith genei- alizeu ieuness, scaling, veeping, ciusting, systenic toxicity, lynphauenopathy, anu levei. Although this conplication is iaie, it is potentially lile thieatening. lt is usu- ally uue to supeiinlection, loi exanple, vith toxin-piouucing :. aurcus oi heipes sinplex inlection, continueu iiiitation ol the slin, oi inappiopiiate theiapy. ln sone cases, the vithuiaval ol systenic glucocoiticoius useu to contiol seveie AD nay he a piecipitating lactoi loi exlolia- tive eiythioueina. PR00\0S|S A\D C||\|CA| C0URSE ¯he natuial histoiy ol AD is not con- pletely lnovn hecause stuuies have heen haveu in teins ol inaueguate sanple size, an uncleai uehnition ol ie- nission, inaueguate length ol lollov up, selection hias in the initial cohoit, anu excessive loss ol patients to lollov up. Neveitheless, although the outcone ol AD nay he uilhcult to pieuict in any given inuiviuual, the uisease geneially tenus to he noie seveie anu peisistent in young chiluien. leiious ol ienission appeai noie lieguently as the patient giovs oluei. Spontaneous iesolution ol AD has heen iepoiteu to occui altei age 5 yeais in 4O peicent to 6O peicent ol patients allecteu uuiing inlancy, paiticu- laily il theii uisease is nilu. Although eailiei stuuies suggesteu that appioxi- nately 84 peicent ol chiluien outgiov theii AD hy auolescence, noie iecent stuuies have iepoiteu that AD uisap- peais in appioxinately 2O peicent ol chiluien lolloveu lion inlancy until au- olescence, hut hecones less seveie in 65 peicent. ln auuition, noie than one-hall ol auolescents tieateu loi nilu ueinati- tis nay expeiience a ielapse ol uisease as auults. lnpoitantly loi occupational counsel- ing, auults vhose chiluhoou AD has heen in ienission loi a nunhei ol yeais nay piesent vith hanu ueinatitis, espe- cially il uaily activities ieguiie iepeateu hanu vetting. ¯he lolloving pieuictive lactois coiielate vith a pooi piognosis loi AD: viuespieau AD in chiluhoou, as- sociateu alleigic ihinitis anu asthna, lan- ily histoiy ol AD in paients oi sihlings, eaily age at onset ol AD, heing an only chilu, anu veiy high seiun lgl levels. TREAT|E\T Successlul tieatnent ol AD ieguiies a systenatic, nultipiongeu appioach that incoipoiates slin hyuiation, phainaco- logic theiapy, anu the iuentihcation anu elinination ol haie lactois such as iiii- tants, alleigens, inlectious agents, anu enotional stiessois (lig. 14-11). 44 íany lactois leau to the synpton conplex chaiacteiizing AD. ¯hus, tieatnent plans shoulu he inuiviuualizeu to au- uiess each patient`s slin uisease ieac- tion pattein, incluuing the acuity ol the iash, anu the tiiggei lactois that aie unigue to the paiticulai patient. ln pa- tients ieliactoiy to conventional loins ol theiapy, alteinative anti-inhanna- toiy anu innunonouulatoiy agents nay he necessaiy. Tcp|ca| T|e|ap] 00TAh£00S hY08AT|0h latients vith AD have ieuuceu slin haiiiei lunction anu uiy slin (xeiosis) contiihuting to uisease noihiuity hy the uevelopnent ol ni- ciohssuies anu ciacls in the slin, vhich seive as poitals ol entiy loi slin patho- gens, iiiitants, anu alleigens. ¯his pioh- len can hecone aggiavateu uuiing the uiy vintei nonths anu in ceitain voil enviionnents. Lulevain soaling haths loi at least 2O ninutes lolloveu hy the application ol an occlusive enollient to ietain noistuie can give such patients ex- cellent synptonatic ieliel. Use ol an el- lective enollient conhineu vith hyuia- tion theiapy helps to iestoie anu pieseive the stiatun coineun haiiiei, anu nay ueciease the neeu loi topical glucocoiticoius. íoistuiizeis aie avail- ahle in the loin ol lotions, cieans, oi ointnents. Sone lotions anu cieans nay he iiiitating uue to auueu pieseivatives, soluhilizeis, anu liagiances. Lotions con- taining vatei nay he uiying uue to an evapoiative ellect. Hyuiophilic oint- nents can he ohtaineu in vaiying uegiees ol viscosity accoiuing to the patient`s pieleience. Ccclusive ointnents aie sone- tines not vell toleiateu hecause ol intei- leience vith the lunction ol the ecciine sveat uucts anu the inuuction ol lollicu- litis. ln these patients, less occlusive agents shoulu he useu. ¯opical theiapy to ieplace ahnoinal epiueinal lipius, inpiove slin hyuia- tion, anu ueciease slin haiiiei uyslunc- tion nay he uselul theiapeutically. Stuu- ies have shovn henehts ol topical piepaiations vith uistinct conposi- tions ol lipius anu ceianiues, as vell as a nonsteioiual ciean containing palni- taniue ílA, an essential latty aciu, anu F|608£ 14-10 Ec/era |e|pe||cur. T]p|ca| .eº|c|eº ard c|uº||rç |r a pa||er| W||| d|ººer|ra|ed d|ºeaºe. 154 a hyuiolipiuic ciean vith glycyiihetinic aciu (íASO6oADl). 45,46 luithei clinical stuuies to uehne the henehts ielative to tiauitional noistuiizeis anu topical anti- inhannatoiy agents vill he helplul. Hyuiation, hy haths oi vet uiessings, pionotes tiansepiueinal penetiation ol topical glucocoiticoius. Diessings nay also seive as an ellective haiiiei against peisistent sciatching, alloving noie iapiu healing ol excoiiateu lesions. Wet uiessings aie ieconnenueu loi use on seveiely allecteu oi chionically involveu aieas ol ueinatitis ieliactoiy to theiapy. Hovevei, oveiuse ol vet uiessings nay iesult in naceiation ol the slin conpli- cateu hy seconuaiy inlection. Wet uiess- ings oi haths also have the potential to pionote uiying anu hssuiing ol the slin il not lolloveu hy topical enollient use. ¯hus, vet uiessing theiapy is ieseiveu loi pooily contiolleu AD anu shoulu he closely nonitoieu hy a physician. T0P|0AL 6L000008T|00|0 Th£8APY ¯opi- cal glucocoiticoius aie the coineistone ol tieatnent loi anti-inhannatoiy eczena- tous slin lesions. Because ol potential siue ellects, nost physicians use topical glucocoiticoius only to contiol acute ex- F|608£ 14-11 App|cac| |c pa||er| W||| a|cp|c de|ra||||º (AD,. a See Ta||e 14-1. | Seccrd-||re ||e|ap] pe| ||ac| |c/ Wa|r|rç. Patieut preseuts with histor] of pruritic dermatitis Patieut meets Hauifiu aud Rajka criteria for diaguosis of AD a 0eueral skiu care measures. º educatiou º appropriate skiu h]dratiou aud use of emollieuts/skiu oarrier repair measures º avoidauce of irritauts º ideutificatiou aud avoidauce of  allergeus º auti-iuflammator] therap] (topical steroids, topical calciueuriu iuhioitors o } º autipruritic iuterveutious (sedatiug autihistamiues, oehavioral modificatiou} º ideutificatiou aud treatmeut of complicatiug oacterial, viral, or fuugal iufectious º treatmeut of ps]chosocial aspects of disease S0ccessI0| o0tcome? Titratiou of topical therap], usiug emollieuts/oarrier repair measures topical steroids or topical calciueuriu iuhioitors as ueeded iutermitteutl] º Re-assess diaguosis of AD º 0ousider role of uurecoguized iufectious ageuts, allergeus; etc. º 0ousider poor uuderstaudiug or uou-adhereuce with treatmeut plau S0ccessI0| o0tcome? º 0ousultatiou with AD specialist º 0ousider skiu oiops] º 0ousider hospitalizatiou º 0ousider c]closporiu A, ultraviolet therap] etc. £va|0ate Ior other cood|t|oos + - + - + - 155 aceihations ol AD. Hovevei, iecent stuuies suggest that once contiol ol AD is achieveu vith a uaily ieginen ol topical glucocoiticoiu, long-tein contiol can he naintaineu in a suhset ol patients vith tvice veelly applications ol topical hu- ticasone to aieas that have healeu hut aie pione to ueveloping eczena. 4¯ latients shoulu he caielully instiucteu in the use ol topical glucocoiticoius to avoiu potential siue ellects. ¯he potent huoiinateu glucocoiticoius shoulu he avoiueu on the lace, the genitalia, anu the inteitiiginous aieas. A lov-potency glucocoiticoiu piepaiation is geneially ieconnenueu loi these aieas. latients shoulu he instiucteu to apply topical glu- cocoiticoius to theii slin lesions anu to use enollients ovei uninvolveu slin. lail- uie ol a patient to iesponu to topical glu- cocoiticoius is sonetines uue in pait to an inaueguate supply. lt is inpoitant to ienenhei that it tales appioxinately oO g ol ciean oi ointnent to covei the en- tiie slin suilace ol an auult once. ¯o tieat the entiie houy tvice uaily loi 2 veels ieguiies appioxinately 84O g (2 lh) ol topical glucocoiticoius. ¯heie aie seven classes ol topical glu- cocoiticoius, ianleu accoiuing to theii potency haseu on vasoconstiictoi assays. Because ol theii potential siue ellects, the ultiahigh-potency glucocoiticoius shoulu he useu only loi veiy shoit peiious ol tine anu in aieas that aie licheniheu hut not on the lace oi inteitiiginous aieas. ¯he goal is to use enollients to enhance slin hyuiation anu lov-potency gluco- coiticoius loi naintenance theiapy. íiu- potency glucocoiticoius can he useu loi longei peiious ol tine to tieat chionic AD involving the tiunl anu extienities. Clucocoiticoius in gels aie olten in a pio- pylene glycol hase anu nay he iiiitating to the slin in auuition to pionoting uiy- ness, thus liniting theii use to the scalp anu heaiu aieas. lactois vhich inhuence topical gluco- coiticoiu potency anu siue ellects incluue the noleculai stiuctuie ol the conpounu, the vehicle, the anount ol neuication applieu, the uuiation ol application, oc- clusion, as vell as host lactois, incluuing age, houy suilace aiea anu veight, slin inhannation, anatonic location ol tieateu slin, anu inuiviuual uilleiences in cutaneous oi systenic netaholisn. Siue ellects lion topical glucocoiticoius aie uiiectly ielateu to the potency ianling ol the conpounu anu the length ol use, so it is incunhent on the clinician to halance the neeu loi a noie potent steioiu vith the potential loi siue ellects. ln auuition, ointnents have a gieatei potential to oc- cluue the epiueinis, iesulting in en- hanceu systenic ahsoiption vhen con- paieu to cieans. Siue ellects lion topical glucocoiticoius can he uiviueu into local siue ellects anu systenic siue ellects ie- sulting lion suppiession ol the hypotha- lanic-pituitaiy-auienal axis. Local siue ellects incluue the uevelopnent ol stiiae, slin atiophy, peiioial ueinatitis, anu acne iosacea. ¯he potential loi potent topical glucocoiticoiu to cause auienal suppiession is gieatest in inlants anu young chiluien. Cl note, a stuuy ol chil- uien as young as o nonths ol age lounu that huticasone piopionate O.O5 peicent ciean, a niupotency loinulation, vas sale anu ellective even vhen applieu on the lace anu ovei signihcant aieas ol the houy loi up to 1 nonth 48 anu huticasone O.O5 peicent ciean has heen appioveu loi use in chiluien as young as o nonths loi up to 4 veels vith huticasone lotion appioveu loi use in chiluien 12 nonths anu oluei. íonetasone ciean anu oint- nent aie appioveu loi chiluien ages 2 yeais anu oluei. Because noinal-appeaiing slin in AD shovs eviuence ol innunologic uysieg- ulation, the use ol topical coiticostei- oius as naintenance theiapy has heen iepoiteu in seveial contiolleu stuuies. 4º Cnce contiol ol AD vith a once uaily ieginen vas achieveu, long-tein con- tiol coulu he naintaineu vith tvice veelly application ol huticasone to pie- viously involveu aieas. T0P|0AL 0AL0|h£08|h |hh|8|T08S ¯opical taciolinus anu pineciolinus have heen uevelopeu as nonsteioiual innunonou- ulatois. 5O ¯aciolinus ointnent O.Oo pei- cent has heen appioveu loi inteinittent tieatnent ol noueiate to seveie AD in chiluien ageu 2 yeais anu oluei, vith taciolinus ointnent O.1 peicent ap- pioveu loi use in auults, vheieas pine- ciolinus ciean 1 peicent is appioveu loi tieatnent ol patients ageu 2 yeais anu oluei vith nilu-noueiate AD. Both uiugs have pioven to he ellective vith a goou salety piohle loi tieatnent up to 4 yeais vith taciolinus ointnent 51 anu up to 2 yeais vith pineciolinus ciean. 52 A lieguently ohseiveu siue ellect vith top- ical calcineuiin inhihitois is a tiansient huining sensation ol the slin. lnpoi- tantly, tieatnent vith topical calcineuiin inhihitois is not associateu vith slin at- iophy, 5o thus they aie paiticulaily uselul loi the tieatnent ol aieas such as the lace anu inteitiiginous iegions. Cngoing suiveillance anu iecent iepoits have not shovn a tienu loi incieaseu lieguency ol viial supeiinlections especially ec- zena heipeticun. 54 ¯he long-tein salety ol topical calcineuiin inhihitois has not heen estahlisheu. Raie cases ol slin nalignancy anu lynphona have heen iepoiteu vith topical taciolinus, though the level ol uata guality anu ap- plicahility ol these iepoits vas |uugeu lov in the iepoit ol a scientihc consen- sus conleience. 55 |der|||ca||cr ard E||r|ra||cr c| T||ççe||rç |ac|c|º 6£h£8AL 00hS|0£8AT|0hS latients vith AD aie noie susceptihle to iiiitants than aie unallecteu inuiviuuals. ¯hus, it is inpoitant to iuentily anu elininate aggiavating lactois that tiiggei the itch- sciatch cycle. ¯hese incluue soaps oi ueteigents, contact vith chenicals, snole, ahiasive clothing, anu exposuie to extienes ol tenpeiatuie anu huniu- ity. Alcohol anu astiingents lounu in toi- letiies aie uiying. When soaps aie useu, they shoulu have nininal uelatting ac- tivity anu a neutial pH. Nev clothing nay he launueieu heloie veaiing to ue- ciease levels ol loinaluehyue anu othei auueu chenicals. Resiuual launuiy ue- teigent in clothing nay he iiiitating. Us- ing a liguiu iathei than povuei uetei- gent anu auuing a seconu iinse cycle lacilitates ienoval ol the ueteigent. Reconnenuations iegaiuing enviion- nental living conuitions shoulu incluue tenpeiatuie anu huniuity contiol to avoiu piohlens ielateu to heat, huniu- ity, anu peispiiation. lveiy attenpt shoulu he naue to allov chiluien to he as noinally active as possihle. Ceitain spoits, such as svinning, nay he het- tei toleiateu than othei spoits involving intense peispiiation, physical contact, oi heavy clothing anu eguipnent, hut chloiine shoulu he iinseu oll inneui- ately altei svinning anu the slin luhii- cateu. Although ultiaviolet (UV) light nay he henehcial to sone patients vith AD, sunscieens shoulu he useu to avoiu sunhuin. Hovevei, hecause sunscieens can he iiiitants, caie shoulu he useu to iuentily a noniiiitating piouuct. SP£0|F|0 ALL£86£hS loous anu aeioallei- gens such as uust nites, aninal uanueis, nolus, anu pollens have heen uenon- stiateu to exaceihate AD. lotential al- leigens can he iuentiheu hy taling a caielul histoiy anu caiiying out selec- tive slin-piicl tests oi specihc seiun lgl levels. Negative slin tests oi seiun tests loi alleigen-specihc lgl have a high pieuictive value loi iuling out suspecteu alleigens. A noinal total seiun lgl 156 level, hovevei, uoes not iule out the possihility ol alleigen-specihc lgl heing piesent. lositive slin oi in vitio tests, paiticulaily to loous, olten uo not coiie- late vith clinical synptons anu shoulu he conhineu vith contiolleu loou chal- lenges anu elinination uiets. Avoiuance ol loous inplicateu in contiolleu chal- lenges iesults in clinical inpiovenent. lxtensive elinination uiets, vhich in sone cases can he nutiitionally ueh- cient, aie iaiely, il evei, ieguiieu, he- cause even vith nultiple positive slin tests, the na|oiity ol patients ieact to thiee oi levei loous on contiolleu chal- lenge. ln uust nitealleigic patients vith AD, piolongeu avoiuance ol uust nites has heen lounu to iesult in in- piovenent ol theii slin uisease. Avoiu- ance neasuies incluue use ol uust nite piool encasings on pillovs, nattiesses, anu hox spiings, vashing heuuing in hot vatei veelly, ienoval ol heuioon caipeting, anu uecieasing inuooi huniu- ity levels vith aii conuitioning. Because theie aie nany tiiggeis contiihuting to the haies ol AD, attention shoulu he lo- cuseu on iuentilying anu contiolling the haie lactois that aie inpoitant to the in- uiviuual patient. lnlants anu young chil- uien aie noie lilely to have loou allei- gies, vheieas oluei chiluien anu auults aie noie lilely to he sensitive to envi- ionnental aeioalleigens. £N0T|0hAL ST8£SS08S Although eno- tional stiess uoes not cause AD, it olten exaceihates the illness. AD patients ol- ten iesponu to liustiation, enhaiiass- nent, oi othei stiesslul events vith in- cieaseu piuiitus anu sciatching. ln sone instances, sciatching is sinply hahitual anu less connonly associateu vith sig- nihcant seconuaiy gain. lsychological evaluation oi counseling shoulu he con- siueieu in patients vho have uilhculty vith enotional tiiggeis oi psychological piohlens, contiihuting to uilhculty in nanaging theii uisease. lt nay he espe- cially uselul in auolescents anu young auults vho consiuei theii slin uisease uishguiing. Relaxation, hehavioial nou- ihcation, oi hioleeuhacl nay he helplul in patients vith hahitual sciatching. |hF£0T|00S A6£hTS Anti-staphylococ- cal antihiotics aie veiy helplul in the tieatnent ol patients vho aie heavily colonizeu oi inlecteu vith :. aurcus. 56 Cephalospoiins oi penicillinase-iesis- tant penicillins (uicloxacillin, oxacillin, oi cloxacillin) aie usually henehcial loi patients vho aie not colonizeu vith iesistant :. aurcus stiains. Because eiyth- ionycin-iesistant staphylococci aie con- non, eiythionycin anu nevei nacio- liue antihiotics aie usually ol liniteu utility. ¯opical nupiiocin olleis sone utility in the tieatnent ol inpetiginizeu lesions, hovevei, in patients vith exten- sive supeiinlection, a couise ol systenic antihiotics is nost piactical. íethicillin- iesistant staphylococci nay ieguiie cul- tuie anu sensitivity testing to assist in appiopiiate antihiotic selection. Heipes sinplex can piovole iecuiient ueinatitis anu nay he nisuiagnoseu as :. aurcus inlection. ¯he piesence ol puncheu-out eiosions, vesicles, anu/oi in- lecteu slin lesions that uo not iesponu to oial antihiotics shoulu initiate a seaich loi heipes sinplex. ¯his can he uiagnoseu hy a Ciensa-staineu ¯zancl sneai ol cells sciapeu lion the vesicle hase, uiiect innunohuoiescence assay, polyneiase chain ieaction iuentihcation ol heipes ge- netic nateiial, oi hy viial cultuie. loi in- lection suspecteu to he causeu hy heipes sinplex, topical anti-inhannatoiy agents night he uiscontinueu, at least tenpo- iaiily. Antiviial tieatnent loi cutaneous heipes sinplex inlections is ol ciitical in- poitance in the patient vith viuespieau AD hecause lile-thieatening uissenina- tion has heen iepoiteu. Acyclovii, 4OO ng thiee tines uaily loi 1O uays oi 2OO ng loui tines uaily loi 1O uays hy oial au- ninistiation (oi an eguivalent uosage ol one ol the nevei antiheipetic neuica- tions), is uselul in auults vith heipes sin- plex conhneu to the slin. lntiavenous tieatnent nay he necessaiy loi seveie uisseninateu eczena heipeticun. ¯he uosage shoulu he au|usteu accoiuing to veight in chiluien. Deinatophyte inlections can conpli- cate AD anu nay contiihute to exaceiha- tion ol uisease activity. latients vith uei- natophyte inlection oi lgl antihouies to /a|assc:ia nay heneht lion a tiial ol topical oi systenic antilungal theiapy. P808|T0S ¯he tieatnent ol piuiitus in AD shoulu he uiiecteu piinaiily at the unueilying causes. Reuuction ol slin in- hannation anu uiyness vith topical glu- cocoiticoius anu slin hyuiation, iespec- tively, olten synptonatically ieuuce piuiitus. lnhaleu anu ingesteu alleigens shoulu he elininateu il uocunenteu to cause slin iash in contiolleu challenges. Systenic antihistanines act piinaiily hy hlocling the H 1 ieceptois in the ueinis, theiehy anelioiating histanine-inuuceu piuiitus. Hovevei, histanine is only one ol nany neuiatois that can inuuce piuii- tus ol the slin. ¯heieloie, ceitain pa- tients nay ueiive nininal heneht lion antihistaninic theiapy. Sone antihista- nines aie also nilu anxiolytics anu nay ollei synptonatic ieliel thiough tian- guilizing anu seuative ellects. Stuuies ol nevei, non-seuating antihistanines shov vaiiahle iesults in the ellectiveness ol contiolling piuiitus in AD, although they nay he uselul in the suhset ol AD pa- tients vith conconitant uiticaiia oi con- cuiient alleigic ihinitis. Because piuiitus is usually voise at night, the seuating antihistanines, loi exanple, hyuioxyzine oi uiphenhyuia- nine, nay ollei an auvantage vith theii sopoiihc siue ellects vhen useu at heu- tine. Doxepin hyuiochloiiue has hoth tiicyclic antiuepiessant anu H 1 - anu H 2 - histanine ieceptoihlocling ellects. lt can he useu in uoses ol 1O to ¯5 ng oially at night oi up to ¯5 ng hiu in auult patients. ll noctuinal piuiitus ienains se- veie, shoit-tein use ol a seuative to al- lov aueguate iest nay he appiopiiate. ¯ieatnent ol AD vith topical antihista- nines is geneially not ieconnenueu he- cause ol potential cutaneous sensitiza- tion. Hovevei, shoit-tein (1 veel) application ol topical 5 peicent uoxepin ciean has heen iepoiteu to ieuuce piuii- tus vithout sensitization. Cl note, seua- tion is a siue ellect ol viuespieau appli- cation ol uoxepin ciean, anu alleigic contact ueinatitis has heen iepoiteu. Ta| P|epa|a||crº Coal tai piepaiations nay have antipiu- iitic anu anti-inhannatoiy ellects on the slin although usually not as pionounceu as those ol topical glucocoiticoius. 5¯ ¯ai piepaiations nay he uselul in ieuucing the potency ol topical glucocoiticoius ie- guiieu in chionic naintenance theiapy ol AD. Nevei coal tai piouucts have heen uevelopeu that aie noie acceptahle vith iespect to ouoi anu staining ol clothes than sone oluei piouucts. ¯ai shanpoos can he henehcial loi scalp ueinatitis anu aie olten helplul in ieuucing the concen- tiation anu lieguency ol topical gluco- coiticoiu applications. ¯ai piepaiations shoulu not he useu on acutely inhaneu slin, hecause this olten iesults in slin ii- iitation. Siue ellects associateu vith tais incluue lolliculitis anu photosensitivity. ¯heie is a theoietic iisl ol tai heing a cai- cinogen haseu on ohseivational stuuies ol voileis using tai conponents in theii occupations. P|c|c||e|ap] Natuial sunlight is lieguently henehcial to patients vith AD. Hovevei, il the 157 sunlight occuis in the setting ol high heat oi huniuity, theiehy tiiggeiing sveating anu piuiitus, it nay he uelete- iious to patients. Bioauhanu UVB, hioauhanu UVA, naiiovhanu UVB (o11 nn), UVA-1 (o4O to 4OO nn), anu con- hineu UVA-B phototheiapy can he use- lul au|uncts in the tieatnent ol AD. ln- vestigation ol the photoinnunologic nechanisns iesponsihle loi theiapeutic ellectiveness inuicates that epiueinal LCs anu eosinophils nay he taigets ol UVA phototheiapy vith anu vithout psoialen, vheieas UVB exeits innuno- suppiessive ellects via hlocling ol lunc- tion ol antigen-piesenting LCs anu al- teieu leiatinocyte cytoline piouuction. lhotochenotheiapy vith psoialen anu UVA light nay he inuicateu in patients vith seveie, viuespieau AD, although stuuies conpaiing it vith othei noues ol phototheiapy aie liniteu. Shoit-tein auveise ellects vith phototheiapy nay incluue eiythena, slin pain, piuiitus, anu pignentation. Long-tein auveise ellects incluue pienatuie slin aging anu cutaneous nalignancies (see Chaps. 2o8 anu 2oº loi uetaileu uiscussion ol pho- totheiapy anu photochenotheiapy). Hcºp||a||/a||cr AD patients vho appeai eiythioueinic oi vho have viuespieau seveie slin uisease iesistant to outpatient theiapy shoulu he hospitalizeu heloie consiuei- ing systenic alteinative theiapies (see Systenic ¯heiapy). ln nany cases, ie- noving the patient lion enviionnental alleigens oi enotional stiesses, intense patient euucation, anu assuiance ol conpliance vith theiapy iesults in a sustaineu inpiovenent in theii AD. Cleaiing ol the patient`s slin uuiing hospitalization also allovs the patient to unueigo alleigen slin testing anu ap- piopiiately contiolleu piovocative chal- lenges to coiiectly iuentily oi iule out potential alleigens. S]º|er|c T|e|ap] SYST£N|0 6L000008T|00|0S ¯he use ol systenic glucocoiticoius, such as oial pieunisone, is iaiely inuicateu in the tieatnent ol chionic AD. Sone patients anu physicians pielei the use ol sys- tenic glucocoiticoius to avoiu the tine- consuning slin caie involving hyuiation anu topical theiapy. Hovevei, the uia- natic clinical inpiovenent that nay occui vith systenic glucocoiticoius is lieguently associateu vith a seveie ie- hounu haie ol AD altei the uiscontinua- tion ol systenic glucocoiticoius. Shoit couises ol oial glucocoiticoius nay he appiopiiate loi an acute exaceihation ol AD vheieas othei tieatnent neasuies aie heing instituteu. ll a shoit couise ol oial glucocoiticoius is given, it is inpoi- tant to tapei the uosage anu to hegin in- tensiheu slin caie, paiticulaily vith topi- cal glucocoiticoius anu lieguent hathing lolloveu hy application ol enollients, to pievent iehounu haiing ol AD. 0Y0L0SP08|h£ Cyclospoiine is a potent innunosuppiessive uiug that acts pii- naiily on ¯ cells hy suppiessing cyto- line tiansciiption. ¯he uiug hinus to cy- clophilin, an intiacellulai piotein, anu this conplex, in tuin, inhihits cal- cineuiin, a nolecule ieguiieu loi initia- tion ol cytoline gene tiansciiption. íultiple stuuies uenonstiate that hoth chiluien anu auults vith seveie AD, ie- liactoiy to conventional tieatnent, can heneht lion shoit-tein cyclospoiine tieatnent. Vaiious oial-uosing ieginens have heen ieconnenueu: 5 ng/lg has geneially heen useu vith success in shoit-tein anu long-tein (1 yeai) use, vheieas sone authoiities auvocate houy-veightinuepenuent uaily uosing ol auults vith 15O ng (lov uose) oi oOO ng (high uose) uaily ol cyclospoiine ni- cioenulsion. ¯ieatnent vith cyclospoi- ine is associateu vith ieuuceu slin uis- ease anu an inpioveu guality ol lile (see Chap. 2o4 loi luithei uiscussion). Dis- continuation ol tieatnent nay iesult in iapiu ielapse ol slin uisease, although sone patients nay have sustaineu ie- nission. llevateu seiun cieatinine oi noie signihcant ienal inpaiinent anu hypeitension aie specihc siue ellects ol concein vith cyclospoiine use. AhT|N£TA80L|T£S íycophenolate no- letil is a puiine hiosynthesis inhihitoi useu as an innunosuppiessant in oigan tiansplantation, that has heen useu loi tieatnent ol ieliactoiy inhannatoiy slin uisoiueis (see Chap. 228). Cpen- lahel stuuies iepoit that shoit-tein oial nycophenolate noletil, 2 g uaily, as nonotheiapy iesults in cleaiing ol slin lesions in auults vith AD iesistant to othei tieatnent, incluuing topical anu oial steioius anu psoialen anu UVA light. ¯he uiug has geneially heen vell toleiateu vith the exception ol one pa- tient ueveloping heipes ietinitis that nay have heen seconuaiy to this innu- nosuppiessive agent. Dose-ielateu hone naiiov suppiession has also heen oh- seiveu. Sinilai iesults veie pieviously iepoiteu in anothei open stuuy ol ten patients vith a nean ieuuction in the SCCRAD (SCCRing Atopic Deinati- tis) inuex ol 68 peicent in all ten pa- tients. Cl note, not all patients heneht lion tieatnent. ¯heieloie the neuica- tion shoulu he uiscontinueu il patients uo not iesponu vithin loui to eight veels. Dose hnuing anu vell-contiolleu stuuies aie neeueu loi this uiug. íethotiexate is an antinetaholite vith potent inhihitoiy ellects on inhan- natoiy cytoline synthesis anu cell che- notaxis. íethotiexate has heen useu loi AD patients vith iecalcitiant uis- ease, although contiolleu tiials aie lacl- ing. Dosing is noie lieguent than the veelly uosing useu loi psoiiasis. Aza- thiopiine is a puiine analog vith anti-in- hannatoiy anu antipiolileiative ellects, azathiopiine has heen useu loi seveie AD, although no contiolleu tiials have heen iepoiteu. íyelosuppiession is a signihcant auveise ellect, anu thio- puiinenethyl tiansleiase levels nay pieuict inuiviuuals at iisl. Urp|c.er T|e|ap|eº |hT£8F£80h- llN- is lnovn to sup- piess lgl iesponses anu uovniegulate ¯h2 cell piolileiation anu lunction. Sev- eial stuuies ol patients vith AD, incluu- ing a nulticentei, uouhle-hlinu, placeho- contiolleu tiial 58 anu tvo long-tein open tiials, 5º,6O have uenonstiateu that tieat- nent vith ieconhinant hunan llN- ie- sults in clinical inpiovenent. Reuuction in clinical seveiity ol AD coiielateu vith the ahility ol llN- to ueciease total cii- culating eosinophil counts. lnhuenza-lile synptons aie connonly ohseiveu siue ellects eaily in the tieatnent couise. 0NAL|I0NA8 ¯ieatnent ol patients vith seveie AD anu elevateu seiun lgl levels vith nonoclonal anti-lgl has shovn lacl ol elhcacy in thiee auult patients 61 anu signihcant inpiovenent in thiee auolescent patients. 62 ALL£86£h |NN0h0Th£8APY Unlile allei- gic ihinitis anu extiinsic asthna, innu- notheiapy vith aeioalleigens has not pioven to he elhcacious in the tieatnent ol AD. ¯heie aie anecuotal iepoits ol hoth uisease exaceihation anu inpiove- nent. A iecent stuuy ol specihc innu- notheiapy ovei 12 nonths in auults vith AD sensitizeu to uust nite alleigen shoveu inpiovenent in SCCRAD as vell as ieuuction in topical steioiu use. 6o Hovevei, vell-contiolleu stuuies aie still ieguiieu to ueteinine the iole loi innu- notheiapy vith this uisease. 158 £XT8A008P08£AL Ph0T0Ph£8£S|S lxtia- coipoieal photopheiesis consists ol the passage ol psoialen-tieateu leulocytes thiough an extiacoipoieal UVA light systen. Clinical inpiovenent in slin le- sions associateu vith ieuuceu lgl levels has heen iepoiteu in a lev patients vith seveie, iesistant AD vho veie tieateu vith extiacoipoieal photopheiesis anu topical glucocoiticoius. P808|0T|0S leiinatal auninistiation ol the piohiotic la.to|a.i||us rhamnosus stiain CC vas shovn to ieuuce the inci- uence ol AD in at-iisl chiluien uuiing the hist 2 yeais ol lile. 64 íotheis veie given eithei placeho oi lactohacillus CC uaily loi 4 veels heloie ueliveiy anu then eithei the nothei (il hieast leeuing) oi the inlant continueu vith uaily thei- apy loi 6 nonths. ln a lollov-up stuuy, the sane gioup assesseu the peisistence ol potential to pievent AD at 4 yeais. 65 ¯he iesults suggest that the pieventive ellect ol la.to|a.i||us CC on AD coulu extenu heyonu inlancy. ln a seconu stuuy, chiluien vith AD tieateu vith tvo la.to|a.i||us stiains loi 6 veels ex- peiienceu inpiovenent ol theii eczena conpaieu to placeho tieateu patients, al- though theii SCCRAD inuex uiu not change signihcantly. 66 ¯he tieatnent ie- sponse vas lounu to he noie pio- nounceu in patients vith positive slin- piicl tests anu elevateu lgl levels. An- othei stuuy ol chiluien vith noueiate to seveie AD tieateu loi 8 veels vith l. jcrmcntum in a placeho-contiolleu stuuy shoveu peisistent inpiovenent in SCCRAD at 16 veels. 6¯ ¯hese stuuies suggest that piohiotics, oi at least sone lactohacillus stiains, nay have pieventa- tive, lasting ellects on the inciuence ol AD in a suhset ol patients. íoie ieseaich into suhgioups ol iesponueis, optinal theiapy |ioute (i.e., uiiectly to inlant oi via nothei`s nill), length ol tieatnent, stiain ol lactohacillus], as vell as necha- nisns involveu is cleaily neeueu. 68 0h|h£S£ h£88AL N£0|0AT|0hS Seveial placeho-contiolleu clinical tiials have suggesteu that patients vith seveie AD nay heneht lion tieatnent vith tiaui- tional Chinese heihal theiapy (see Chap. 242). ¯hey hau signihcantly ie- uuceu slin uisease anu uecieaseu piuii- tus. ¯he henehcial iesponse ol Chinese heihal theiapy, hovevei, is olten ten- poiaiy, anu ellectiveness nay veai oll uespite continueu tieatnent. ¯he possi- hility ol hepatic toxicity, caiuiac siue el- lects, oi iuiosynciatic ieactions ienains a concein. ¯he specihc ingieuients ol the heihs also ienain to he eluciuateu anu sone piepaiations have heen lounu to he contaninateu vith coiticostei- oius. At piesent, Chinese heihal theiapy loi AD is consiueieu investigational. |E\ RE|ERE\CES T|e |u|| |e|e|erce ||º| |c| a|| c|ap|e|º |º a.a||a||e a| WWW.d|çr/.ccr. 1. Hanihn [í, Ral|a C: Diagnostic lea- tuies ol atopic ueinatitis. A.ta Dcrm Vcncrco| º2:44, 1º8O 8. Leung DY et al: Nev insights into atopic ueinatitis. j C|in lnvcst 113:651, 2OO4 º. Coil í[ et al: Nev peispectives on epi- ueinal haiiiei uyslunction in atopic ueinatitis: Cene-enviionnent inteiac- tions. j A||crg, C|in lmmuno| 118:o, 2OO6 1O. Sugiuia H et al: Laige-scale DNA nicioaiiay analysis ol atopic slin lesions shovs oveiexpiession ol an epi- ueinal uilleientiation gene clustei in the alteinative pathvay anu lacl ol pio- tective gene expiession in the coiniheu envelope. 3r j Dcrmato| 152:146, 2OO5 12. Honey B et al: Cytolines anu cheno- lines oichestiate atopic slin inhanna- tion. j A||crg, C|in lmmuno| 118:1¯8, 2OO6 2º. ícCiit LY, Becl LA: lnnate innune uelects in atopic ueinatitis. j A||crg, C|in lmmuno| 118:2O2, 2OO6 o1. íoiai N et al: ¯he genetics ol atopic ueinatitis. j A||crg, C|in lmmuno| 118:¯, 2OO6 o2. Leung DY, Biehei ¯: Atopic ueinatitis. lan.ct 361:151, 2OOo o4. lichenhelu Ll et al: Salety anu elhcacy ol pineciolinus (ASí º81) ciean 1" in the tieatnent ol nilu anu noueiate atopic ueinatitis in chiluien anu auoles- cents. j Am A.ad Dcrmato| 46:4º5, 2OO2 o5. Van Dei íeei [B et al: ¯he nanage- nent ol noueiate to seveie atopic uei- natitis in auults vith topical huticasone piopionate. ¯he Netheilanus Auult Atopic Deinatitis Stuuy Cioup. 3r j Dcrmato| 140:1114, 1ººº o¯. Bilshoiough [ et al: lL-o1 is associateu vith cutaneous lynphocyte antigen- positive slin honing ¯ cells in patients vith atopic ueinatitis. j A||crg, C|in lmmuno| 117:418, 2OO6 o8. Sonloly l et al: lL-o1: A nev linl hetveen ¯ cells anu piuiitus in atopic slin inhannation. j A||crg, C|in lmmu- no| 117:411, 2OO6 44. Hoaie C, Li Wan lo A, Willians H: Sys- tenatic ieviev ol tieatnents loi atopic eczena. Hca|th Tc.hno| Asscss 4:1, 2OOO 55. Beigei ¯C et al: ¯he use ol topical cal- cineuiin inhihitois in ueinatology: salety conceins. Repoit ol the Aneiican Acaueny ol Deinatology Association ¯asl loice. j Am A.ad Dcrmato| 54:818, 2OO6 C H A P T E R 1 o h0mm0|r £czem od L|cheo S|mp|ex 0hroo|c0slPr0r|go hod0|r|s Suºar Bu|ç|r \U||U|AR ECZE|A Ep|der|c|cç] Nunnulai eczena (also nunnulai ueinatitis) is pieuoninantly a uisease ol auulthoou. íen aie noie lieguently allecteu than vonen. ¯he peal inci- uence in hoth nales anu lenales is aiounu 5O to 65 yeais ol age. ¯heie is a seconu peal in vonen aiounu 15 to 25 yeais ol age. Nunnulai eczena is iaie in inlancy anu chiluhoou. ¯he peal age ol onset in chiluhoou is 5 yeais. 1 E||c|cç] ard Pa||cçereº|º ¯he pathogenesis ol nunnulai ec- zena is unlnovn. ¯he vast na|oiity ol patients vith nunnulai eczena uo not have a peisonal oi lanily histoiy ol atopy, 2,o although nunnulai plagues nay he seen in atopic eczena. Nu- neious lactois have heen inplicateu as causal. ¯he state ol hyuiation ol the slin in elueily patients has heen shovn to he uecieaseu. 4 ¯he iole ol inlection pieviously ieceiveu nuch at- tention in the liteiatuie. An inteinal locus ol inlection, incluuing teeth, up- pei iespiiatoiy tiact, anu lovei iespi- iatoiy tiact, vas lounu in 68 peicent ol patients in one stuuy. 5 A iole loi enviionnental alleigens, such as the house uust nite anu Candida a||i.ans has also heen touteu. 4 Nunnulai ec- zena has heen iepoiteu uuiing thei- apy vith isotietinoin anu golu. 6,¯ Ceneializeu nunnulai eczena is seen in patients vith hepatitis C unueigo- ing conhination theiapy vith intei- leion- 2h anu iihaviiin. 8,º íeicuiy analgan vas inplicateu as a cause in tvo patients. 1O 159 C||r|ca| ||rd|rçº Well-uenaicateu, coin-shapeu plagues loin lion coalescing papules anu pap- ulovesicles. linpoint oozing anu ciust- ing eventuate anu aie uistinctive (lig. 15-1). Ciust nay hovevei covei the entiie suilace (lig. 15-2). llagues iange lion 1 to o cn in size. ¯he suiiounuing slin is geneially noinal, hut nay he xeiotic. liuiitus vaiies lion nininal to seveie. Cential iesolution nay occui, leauing to annulai loins. Chionic plagues aie uiy, scaly, anu licheniheu. ¯he classic uistiihution ol lesions is the extensoi aspects ol the extienities. ln vonen, the uppei extienities, incluu- ing the uoisal aspects ol the hanus, aie noie lieguently allecteu than the lovei extienities. 2 lxuuative uiscoiu anu lichenoiu ueinatitis ol Sulzheigei- Caihe nay iepiesent a vaiiant ol nun- nulai eczena. 11 |a|c|a|c|] Teº|º latch testing nay he uselul in chionic iecalcitiant cases to iule out a supeiin- poseu contact ueinatitis. ln a seiies lion lnuia, |ust unuei one-hall ol 5O pa- tients hau positive patch tests to coloph- ony, nitioluiazone, neonycin sullate, anu niclel sullate. 12 Seiun innuno- glohulin l levels aie noinal. Spec|a| Teº|º Histopathologic changes aie iehective ol the stage at vhich the hiopsy is pei- loineu. Acutely, theie is spongiosis, vith oi vithout spongiotic niciovesi- cles. ln suhacute plagues, theie is paia- leiatosis, scale-ciust, epiueinal hypei- plasia, anu spongiosis ol the epiueinis (lig. 15-o). ¯heie is a nixeu cell inhl- tiate in the ueinis. Chionic lesions nay iesenhle lichen sinplex chionicus nicioscopically. D|||e|er||a| D|açrcº|º See Box 15-1. Ccrp||ca||crº Nunnulai eczena nay he conplicateu hy seconuaiy hacteiial inlection. P|cçrcº|º ard C||r|ca| Ccu|ºe ¯he couise is usually chionic. Recui- ience at piioi sites ol involvenent is a leatuie ol the uisease. 5 T|ea|rer| ¯opical steioius in the niu- to high- potency iange aie the nainstay ol tieat- nent. ¯he calcineuiin inhihitois, tac- \U||U|AR ECZE|A AT A 0|A\CE A|ºc |rcWr aº cisccic cczcra. A c||cr|c d|ºc|de| c| ur|rcWr e||c|cç]. Papu|eº ard papu|c.eº|c|eº cca|eºce |c |c|r rurru|a| p|a(ueº W||| cc/|rç, c|uº|, ard ºca|e. |cº| ccrrcr º||eº c| |r.c|.erer| a|e uppe| e/||er|||eº, |rc|ud|rç ||e dc|ºa| |ardº |r Wcrer, ard ||e |cWe| e/||er|- ||eº |r rer. Pa||c|cç] ra] º|cW acu|e, ºu|acu|e, c| c||cr|c ec/era. F|608£ 15-1 \urru|a| ec/era. Cc|r-º|aped p|a(ueº W||| p|rpc|r| e|cº|crº ard e/cc||a||crº. (|r- açe ||cr D|.|º|cr c| De|ra|c|cç], Ur|.e|º||] c| ||e w||Wa|e|º|ard, Jc|arreº|u|ç, Scu|| A|||ca, W||| pe|r|ºº|cr ||cr P|c|eººc| D. |cd|., F|608£ 15-2 \urru|a| ec/era |r a c|||d. C|uº|ed p|a(ueº. (Uºed W||| pe|r|ºº|cr ||cr P. ||c, |.D., Be|| |º|ae| Deaccreºº |ed|ca| Cer|e|, Bcº|cr, |aººac|uºe||º., F|608£ 15-3 H|º|cpa||c|cç] c| rurru|a| ec/era. Pa|a|e|a|cº|º ccr|a|r|rç p|aºra ard reu||cp|||º (ºca|e-c|uº|, ard pºc||aº||c|r ep|de|- ra| |]pe|p|aº|a W||| ºpcrç|cº|º a|e p|eºer|, W||| a ºupe||c|a| de|ra| pe||.aºcu|a| |r||||a|e c| |]r- p|cc]|eº, rac|cp|açeº, ard ecº|rcp|||º. 8ox 15-1 0|ffarant|a| 0|agnos|s of hummu|ar Fczama Mcst LikeIy A||e|ç|c ccr|ac| de|ra||||º S|aº|º de|ra||||º A|cp|c de|ra||||º T|rea cc|pc||º 0cnsider |rpe||çc Pºc||aº|º (|crç-º|ard|rç p|a(ueº, |]ccº|º |urçc|deº (|crç-º|ard|rç p|a(