NONSPECIEIC HOST DEFENSE MEC HANISMS Nonspecific host defense mechanisms ae gener Nonsre poteet the body against many him ai stances. One of the nonspecific host defenses the ied was inhi er inborn, resistance observed among sore specis oy Terps to desto : finals and some persons who have a natural resin substances that are foreign t0 it, certain diseases. Innate or inherited characteristics, aid Jnchuding pathogens. The third these people and animals more resistant to some dieu line of defense, the immune re= sponse, is very specific. In third line of defense (or sped bast defense mechanisms), proteins called antibodies are in response to the pres foreign substances ine of Tinie FIGURE 15-2, Categories of host defense repens: mechanisms.CHAPTER 15 «© Nonspecific Host Defense Mechanisen sors that produce this innate eer derstood, Dut are probably re- ot eee ae and temperature differ- eo pre ere as the general state of 7 chee SPE. ofthe person and environ et Me ce HO oer o Ss gs ally unawae oft, oUF bodies are or nee sf defending us against miro- Sythe Pee eer pathogens and potential "We neo day of our fi tiles. WES per day, every day of our lives. ga gocesfally war off or destroy the Mali ee ecific host defense mecha- (ser chapter include mechanical and So ion chemical eto, microbial (eer pgenos miro, eve, the i by o¥F PN Galammation), and phagocytic ist ot TI chagocytes) a INE OF DEFENSE AFP qucous Membranes wa Barriers ns skin that Intact skin and membranes nonspecific nro represents 2 fdefense mech- risers 354 PS eet ical barrier ine ew pathogens sense inact sin. al Pein helminth it Sete hoern ne c a Pa As iis only perature of the inhibit colonization nd cronth of vathogens: perspiration, in Fushes them away Se aliesstscocy inectons. Phagocyes i inhibits colonivation by many pathogens Als, the acidity (p11 5.0) and temperature (87°C) ofthe skin inhibit che growth of pathogens. The oily sebum thats pro ed by sebaceous glands in the skin contains fatty acids, which are toxie to some pathogens. host defense | walls by degrading < 3. Lactafer is a protein that binds iron, | tineral that is required by all pathogens. Because they re unable to compete with lactoferrin for free iron, ‘the pathogens are deprived of this essential nutrient Lacroperaidaseis an enzyme that produces superoxide rad- ical, highly reacdve forms of oxygen, which are toxic to bacter Because mucosal cells are among the most rapidly dividing cells inthe body, they are constantly being pro- duced and released from mucous membranes. Bacteria forthe hair, mucous mem- upward toward the Bg irene haben emma nose that serve to trap swallowed or expelled. ‘much of the inhaled. debris Also, the cilia (mucociliary covering) present on epithe lial cells ofthe posterior nasal membranes, nasal sinuses, ‘bronchi, and trachea sweep the tripped dust and mi robes upward toward the throat, where they are swab lowed or expelled by sneezing and coughing. Damage to these ciliated epithelial cells (eg., damage caused by “smoking, other pollutants, bacterial or viral respiratory Infections) can increase a person's susceptibility to bacte- the mucous ‘membranes may also be involved in his mucociliary ‘clearance mechanism. Lysozyme and other enzymes that lyse or destroy bacteria are present in nasal secretion, saliva, and tears. Even the swallowing of saliva can be thought of as a non- specific host defense mechanism, because thousands ofmaby of the indigenes nara ante following facony Abn o hey ACTION vit # Paton onspecific host defense mec Iceni ar revved ram the oa ine ve eae eal apresnatey | 4 the» Competition for colonin tees Pathogens entering , iu, % sein xen, i ewan Capen om : Feige. factrs_yrnect the GEOG ras oy prediction of substances thay eet ought at the ie pte dons iro. of he AME = saeercral cavity, Upper respira, umber of fy ofan a thereto ce Specific ont defense mea eg} wy tract, and colon play yg tng role 4 nonspectnc nt yg ies mechan preset pug tan ing pathogens and potental opps grag pathogens from coloniang rear these sites. The effectiveness of ig microbial antagonisin is fre decreased after ly p19) + Digestive enzym ‘Ackiny ofthe stomach (approximate «Alkalinity of the intestines Bi which sxe Peal ioe iver ty the sll see 0 fn Hehe rte peers fo te ine sc che ct an wa Sitges ie acer cll ls respecte sn embraes tha make reared. Ave res of te combina arse cst an the pi ow a 8 oe een lf mesane ell oe of aceti ny voding mornin ae oped in % 0 wre trace, where they. sticky, mucous Fining of the digestive may be destroyed by bactericidal enzymes and Gjtes. Peristalsis and the expulsion of Feces serve 10 f move bacteria from the intestine. Bacteria, sna about 50% of feces. “The urinary tact is usually Th sterile in healthy persons, with fu the exception of indigenous col microorganisms that colonize the distal urethra (that part of the urethra furthest from the “Microorganisms are continually fl thra by frequent urination and secretions. Many urinary bladder in infrequent urination, including th after Intercourse. Conditions that (eg, benign prosatc hyperplea the chances of developing eyrit Th ral id sualy ib clon pathogens. However, women bral coneroceptives re perica Fe infections because ee, neon ten fetes of date lly destroyed by nonspe- Microbial Antagonism See nae . “sponses, collectively referred bed cease? in Chay to as the second ine of de- a yen resident microby fense. A complex sequence of indigenous mnicroflg eas develops volving duction of fever, production of in Pevstalsis and urination colonization by né particular anaton the complement system, infla phagocytosis. Each of these this chapter.efense Mech sec ‘Twmane 2 eit ae + Digi cach appre eo sted peristalsis and urination anges sa nem irereria easier ofstomach ai, ete small inte ero al of he comin tw oF CON” wget of bacteria. to digest Jacively free of bacter bile salts, ve digestive tract isl enzymes end phogo- jon of feces serve 10 FE re, Bacteria make P SEE, ow ning seri i an he ep Bow 50% oF ee ny the ay of anal sterile in healthy persons, with id ‘coal ines on of indigenous colonization 0! ie she acetone elon aga by patooe: eres. hat the i te fm the urinary add) “Microorganisms are continually flushed roe ¢ je wre thra by frequent urination and expulsion o| = secretions. Many urinary bladder infections result from infrequent urination, including the failure to urinate after intercourse. Conditions that obstruct urine flow (eg. benign prostatic hyperplasia [BPH)) also increase the chances of developing cystitis. The low pH of vagi- nal fluid usually inhibits colonization of the vagina by pathogens. However, women who are taking certain oral contraceptives are particularly susceptible to some infections because the contraceptives increase the PH of the vagina. Microbial Antagonism ‘As mentioned in Chapter 10, When indigenous when resident microbes of the microflora prevent the indigenous microflora prevent establishment of colonization by new arrivals to arriving pathogens, it aparticular anatomical site, it isis known as microbial, known as microbial antagonism. antagonism. This is another example of a ronspecific host defense mech, werability of the indigenays Pt ta the following facta wed ion for colonization + Co 1 Competition for nutrients 1 production of substances Prowl that kt It is thought that the jn. roflora of the they digenous shen iy upper reps seed caon pi, Mona a Ply ne a = vigor role asa NONSPeCIFIc hone Sete mechanism by preven £2 an ov ing, pathogens and potential Spagens from colonizing PPO Ise ates. The effectiveness ee’ tg microbial antagonism is Tre« supe Ad oo decreed fer pro reese a iiinged administration of broadespeg, . Anois reduce oF eliminate ee hig Gigenous microflora (eg. the vag Em | flor leading eo overgrowth by feet mg resent 0 the, ambitic®) being 4 fing | overgrowth oF “population expos, Siting called nprnfectin sapere fag in the vagina may lead to the conding” C&ee vaginitis. A superinfection of Clam Hwy fey Creer lead co Citas aa anuion- associated diarrhea (AAD) ang sag nous colitis PMO). Psu, Some bacteria produce pro- ae teins that kill other bacteri collectively, these antibacte substances are known as bac. riocins. An example is. colicin, Which is produced by certain serains of Bihorichia coli. Similar antbaceri are produced by some strains of Preudomart species as well as by certain other bacteria pet have a narrower range of activity than do ange ™8 they are more potent than antibiotics. as Coen a @ bacteriog, Proteins ae Some baer other batters ‘oy OF DEFENSE SE Pathogens able to penetrat the firs line of delenee are ae usually destroyed by nonspe- complement syst cific cellular and chemical re- ‘nfemnationeaaae sponses, collectively referred phagocytosis ae alt to as the second line of de- part of the seconde fense. A complex sequence of of defense, events develops involving pro- duction of fever, production of interferons, acivainé the complement system, inflammation, chemo phagocytosis. Each of these responses is disuse! this chapter.Sibu oy 18 ion of isjand sed in CHAPTER 15 © Nonspecific Hist Defense Mechanim 1 Transferrin serves as en ost defense hen mechanism by depriving) mor pathogens of fon, i ut CE Neg, eransfertin serves as a a al pecan DY seawetrng ee een ofthis essential nutrient ie Hg pale ferrin levels im the blood estan peo meni baer Se : e uc. ubstances that ecrure OT) stimlate the production oF fever are called pyagens or pyrogenic Be empeacre TET rant sine ss Ne eal MBE: OF Preis iS ter oie ore ioe rage Ye the body include pathogens fromoutpatances that they produce or Fe a cen com Voie: Maced within the body (Let (ea PO tes epee The eligi dy rete coed tobe 3 nonaec ho fon, he bois defects fo the felling ers pring wie lod ells shoes) to deploy soma vades ee Ee pla ion, which inthe Trt nen ta eg ron fo eplion Saxe con of IL-1, which causes the se Rion, and action of mpho- tee amnologc response ¥ tempera- A fever can slow down Bie Wo tera of the rte of grnth of en pathogens certain pathogens and oho er come espe- can even Kil some heen pthogers. expect fastidious ling scenario OS. srs one way in. which eden daring an infectious disease 1A tae has sepricemia caused by Gram-negative ies ire Grama wp) ec fo Cher 13 that sepiceia sa serious disease dhmceied by chs, fever,prostron, and the pesne of bacteria or their toxins in the blood: 2. The bacteria telease endotoxin into the patients Wn de a {ure of Gram-negative bacteria tis the lipid compo nent of lipopolysaceharide.) " " hagoeytes ingest (phagocytic) the endetoin The ingested endotoxin stimulates the phagocytes to Broduce IL-1 an endogenous pyrogn. Hel po «, {Me rinaiy by macrophages les the ahaa pa of he in refered to as the body's thermostat) to produce Prostaglandins, , =< Once metabolized, the prostaglandins cavse the hypo thalamic thermostat tobe seta higher level ‘Theincreased thermostatic reading ends ot signals co the nerves surounding peripheral blood ves. This ass the vesels to contract, thus conserving heat 8. The increased body heat, resulting from vasoconstric- tion, continues until the temperature ofthe blood supplying the hypothalamus matches the elevated thermostat reading. The thermostat can be reset €0 the normal body temperature when the concentration of endogenous pyrogen decreases There are, of course, detrimental aspects of fever— especially protonged high fevers. These incivde in- creased heart rate, increased metabolic rate, increased caloric demand, and mild yo severe dehydration. Interferons Interferons are small, antiviral Interferons ate Sally proteins produced by virus- antiviral proteins infected cells. They are called produced by incrferons because they “in- virus-infected cells) terfere” with viral replication. They interfere with ‘The three known types of in- viral replication. terferon, referred to a alpha (4), beta (8), and gamma (1) interferons, ae induced by diferent stimuli including viruses, tumors, bacteria, and other foreign cells. The diferent types of interferons are produced by different type of cells. a-Interferon is produced by B lymphocytes (B cells), monocytes, and ‘macrophages; Brinterferon, by fibroblasts and other virus-infected cells; and -interferon, by activated T Iymn- phocytes CT cells) and natural killer cells (NK cells). ‘The interferons produced by a virus-infected cell are tunable to save that cell from destruction, but once they are released from that cell, they attach to the membranes of surrounding cells and prevent vieal replication from ‘occurring in those cell. Thus, the spread ofthe infection is inhibited, allowing other body defenses to fight the dis- ‘ease more effectively. In this way, many viral diseases (eg, colds influenza, and measles) are limited in dura tion. Similarly, the acute phase of herpes simplex cold sores is of limited duration. The herpesvirus then enters a Tatent phase and hides in nerve ganglion cells where it js protected until che person's defenses are down; the cycle of disease and latency is repeated over and over,256 coe ae nt vis Hate at cer they are virus-specific, but they specific, meaning tat 7 i ae bost-specific. fictive agaist 2 variety of vinises, not just the particular steno ‘of vino that sdanblated their production; Inte ae pe however, meatng da they are fe the nly an the species of animal that produced them. ‘Thug rabbi interferons are ony effective in rabbis and TNT ot be used to treat viral infections in humans. Ftuman inrerferons are industrially produced by gencti- tally engincered bacteria (bacteria into which human sprcferon genes have been inserted) and are wsed experi telly to ceat cern val ineton vars herpes areas hepatitis B and C) and cancers (eg, leukemias, simples Berns acon pens wth aod = aoneefciency syndrome or acquired immunodeficiency verome [AIDS). In addition to interfering with viral a eaton, mterfrons av actvate cera Iympho- PC ENK cells) to il virus-infected cell, NK cells are discussed in Chapter 16. - cn akon tothe beneficial aspects of the interferons produced in response to certain viral infections, they aetally cause the nonspecific lulike symproms {imalase, myalgia, chills, fever) that are associated with ‘many vial infections. that are The Complement System Complement is not a single The proteins of the cencity, but rather a. group of complement system approximately 30 different pro- (collectively refered to res (including nine proteins as complement designated as C1 through C9) components) interact that are found in normal blood with each other in a plasma. These proteins make up stepwise manner, known that is called “the complement as the complement system’—so named because itis cascade—a nonspecific plementary to che action of ‘host defense mechanism the immune system. The pro- that assists in the teins ofthe complement system, destruction of many sometimes collectively referred. different pathogens. to as complement components, interact with each other in a stepwise manner, known as the complement cascade. A discussion of the somewhat complex steps in the complement cascade is beyond the scope of this book. What is of primary importance is that activation of the complement system is considered a non- specific host defense mechanism; it assists in the destruc- ‘on of many different pathogens. The major consequences of complement activation are listed here: * Initiation and amplification of inflammation * Attraction of phagocytes to sites where they are needed (chemotaxis; to be discussed later) * Activation of leukocytes + Lysis of bacteria and other foreign cells * Increased phagocytosis by phagocytic cells (op- sonization) ‘Mechanisms SECTION VIL = Pathogenesis and Host Defense M See this book's CD-ROM for Complement System." ‘Opsonization is process Opsonieay by which phagogoss fc proces gO tte by the deposion of op- phage sonins, such a antibodies or facings? erain complement fragmens, deposition Cals Insome coms phages ete Fn some cases Pages certain ane are unable co ingest certain ar- Fragments) geet ticles or cells (e.g, encapsulated. surace sp, the bacteris) until opsonization cele, Pes occurs. One of the products formed ring the complement cascade, ele opsonin. es deposited om the uric of es Neutrophils and macrophages possess surface "™iny (ecepton) that can recogize and bind wo Cay Complement fragments C3a, Cia, ase ina cel m degra and reese Ht 20 ineressed vasalor permeability and aE Cormac we ase ea ak a ay Semon Chote a neutrophils and macrophages. Chemoattra fe cussed ater inthe cupten Me, ‘There area variety of hereditary compl cies that interfere with acts of the compl ‘aq Closer 1 tein. Some ofthese inherited deficiencies se et with defect in activation of the classical ina ciency of C3 lead toa defetin action of sia and ternative pathways. Defece of proper yoo impair activation ofthe alternative pathy” defect lends to incensed siscepbliy to mee producing) stahylococal and streptococcal infetege Acute-Phase Proteins Plasma levels of molecules collectively referred toa an phar pai nae sty eee ae flammation, and tissue injury. They serve as how defy mechanisms by enhancing resistance to infeson and pret rmoting the repair of damaged tissu. Acute-phase protng clude C-reactive protein (which is used as a smarker for, oF indication of inflammation), serum angle A protein, protease inhibitors, and coagulation protin Cytokines Cytokines are chemical me- Cytokines are chemizal diators that are released from mediators that are many different types of cells released from many in the human body. They en- different types of cls able cells to communicate in the human body. with cach other. They act as. They act as chemical chemical messengers both messengers, enabling within the immune system cells to communicate (discussed in Chapter 16) and with each other. As plained on the CD-ROM, the complement system can be a= vated by any of three pathways: the caical (or asc) pea, he kerma pathway, an the lecia pathway.CHAPTER AS» ny Nonspecific he immune Stem and other g Host Defense Mechanism save sale 10 “Sense” the presence tHE "357 Presence of three major ye 18 appropriate surface recent Fg ¥en in acute inflam whe Mare the CFTOKINe, The eyeo nc ts that * ANincreasein the 7 mn are: a of response in Ine mediates —_ which increases tate of capil . 2 eine cytokines et able to * There shed ow wo hee Maton, a sence. SOIE cytokines are ches > ased permeabi pee ef reac aeh ecaag amen Spe fa ny he pl oa here they ae needed Orne MaEM RES to * Escape of la ke incerfer. cumulation OMS Fe petra ASEUSEA), hake a dee role fee he site oF nj | The pri q | fee the inte, PPS Of Therma | joflamarma® ig. 15-4), ‘sponse ofthe inlammaeog” pea injury itrtation, mi- in acute inflammation * Localize an infection an infection, prevent © | sai imasion, oF bacterial are vasodilation, * Pleven the spread of micro. a4 of microbial atta comples series of increased permenbitty bil invaden invades, neutralize coin alecvely referred co ofthe capita, ind Neutralize any toxins being “O52 odin the si ion or the inflam escape of eukocytes _, Proteed atthe sitet of damages | asnfat ose Fig 15-3). The rom the capers Aid inthe esi of damaged" TISSUE INJURY ‘© An intammetory esponse ms hemor Sg ey 8983 by phy ie ns latory sponge to bata intr penetotee he Si 7 | coca ooo |B rncoovrosis Progocye staches to bacterium *pdtnguit by endocytosis. CHEMOTAXIS © Netrophtsané macrophages move to ‘Site of injury in eponse t estar EXUDATE INCREASED PERMEABILITY ivvich exudate containing “oglovuine ana comperant| moves ina ilured ares GG ewicnanow oF teuKocrres 1 Neutrophis ana macrophages ashore 0 Cpdotre cei ot eopaanes BB vssoon a0» | © promaes increased devety of plana Protas. neutropis ane poagocyes © Leukocytes squeeze through gaps created by coitaction of enh! ces FIGURE 15-3. Sequence of events in inflammation. (From Harvey RA, Champe RA, es. Lippincott strated Reviews: Microbiology. Philadelphia: Lippincott Williams & Wilkin, 2001.) | |8 SECTION VI « Pi | \ Sper Tolocaize f ‘and healing Togostoy and Tosigamogere’* —aotoutypatiogers FIGURE 15-4. The purposes of inflammation. cardinal During the infarmnaeny Te prose ny noes iin sand alm meio Som Then imerrcd pty: inammation re Pe ctom rsltm the oor redness, beat swe ect fm sgn ad yp (edema), and pa tome of infammason rednes, ISTe Selig (edema and pain There is often pus ‘ettadon al ccastonally aos of fncon ofthe dame tgelare (eg. an nfamed elbow rnighe prevent bending ofthe rm) " "Xcompex series of physio Naolation=an logit cron oecurs immed Hore the Can deli aer the inal damage oof caplaies-leadsto the tisue. One of the inal rednes, heat and ents isvasodilion atthe site edema Of injury, mediated by vasoac~ tive agents (eg., histamine and prostaglandins) released from damaged cells. Vasodilation allows more blood to flow to the site, bringing redness and heat. Additional heat results from increased metabolic activities in the tis- sue cells at the site. Vasodilation causes the endothelial cells that line the capillaries to stretch and separate, re- sulting in increased permeability. Plasma escapes from the capillaries into the surrounding area, causing the site to become edematous (swollen). Sometimes the swelling is severe enough to interfere with the bending of a par- ticular joint (eg, knuckle, elbow, knee, ankle), leading to a Joss of function. A variety of chemotactic agents (to be discussed later) are produced at the site of inflammation, leading to an influx of phagocytes. The pain or tenderness that accompanies inflammation may result from actual dam- age of the nerve fibers because of the injury, irritation by microbial toxins or other cellular secretions (such as prostaglandins), or increased pressure on nerve endings because of the edema © In his writen work, De Medicine (On Meds), Aukes Cornelis CCelsus, a Roman encyclopedist who lived and ded before the time of Christ, described the cardinal signs of inflammation using the Latin terms ror (rednes), calor (warmth) dlr (pain, and remor(swellng). These Latin tern are sometimes taught in Physiology courses a | huhogencss and Host Defense Mechanisns The accumolation of fad, cat wc clade oe eee maton sit i eered to. tengo 2 an inflammatory ecadae. I be, the nie ka ree yellow cg live and dead leukocytes itis known a in tc or pr Hoeven a ifacae oC such as anbris or pancreatitis, there 0 are o imading miroorgansns, When robes (it rodacing mci), sac pA and streptococci, ae present, additonal pur ca, 25 a result of the kiling effect of bac Puce Dhagocytesand sue cll: Akhough moar 28 Yellow, the exudate is often Bhish grea ss SEE. cae by Prados. is ish green pigment (cle para) peck mie ‘rooenin) Produced by When the inflammatory response is over body has won the battle, phagocytes clear ® ihe the and help to restore order. The eels and tana repair the damage and begin to function none in homecsati (equilibrated) ste, although a Iman mage nd searing may rl Pe 1¢Iymphatiesystem— Te primay func including mph (he Gl com OF the yan ponent of the Ipmphatic sys ince ring fem), Iymphatic vessels, lymph creulatng inte nodes an mph organs Tus fen thn (onsils, spleen, and. thymus ‘transporting tees role in defending the body system tothe bane aginst imadere The primary tenor rea ig fonctions ofthis system include and microbes for draining and circulating iter- lymph, and podese® cellular Aus ftom the tsacs antibodies ant and transporting digested fats factors to ad inthe from the digestive system to destruction and the blood. Also, macrophages, detoxication of ay Beell and T ceils in the lymph invading microbes nodes Serve to filter the Iymph by removing foreign matter and microbes, and by prod: ing antibodies and other factors toad inthe degree, and detoxification of any invading microbes ‘The body continually wages war against damage, in- jury, malfunction, and microbial invasion. The outome of eich bade depends on the person's age, hormonal ba, ance, genetic resistance, and overall state of physical and ‘mental health, as well asthe virulence of the pathogens involved, Se U3 sopra | Beware of Similar Sounding Terms Pyrogenic substances (pyrogens) are fever-producing substances. Pyogenic means pus-producing; thus, pyo- ( genic microbes are pus-producing microbes. 3CHAPTER 15 * Nonspecific Host Defense Mechanism pagoeytosis feel clement 0 ond. Te te maj jen in. Figure. 15-5. categories of leukocytes ae hot Chapter 13 that the found in blood are Reclaer categorise of leuko- menace, ‘ae fund in blood ae mono- lympho, and Se hmphoges and grano-_anuloctes, Goes The three ope: of Fizlogtes are neuropil, eosinophils, and basophil hagas white blood cells The two'mast important see led phagocytes, and_ groups of phagocytes in ‘procs by which phagocytes the human body— ‘and. engulf inges) sometimes refered to favin material iscalled phago- as “professional gross. The to most impor- phagocytes’—are Tegroups of phagocytes in the macrophages and funan body are macrophages neutrophis, and neutrophils; chey ae some- tines ile “professional phagocytes,” because phagocyto- ‘isis their major function.* Macrophages serve as a “clean- tparew" to rid the body’ of unwanted and often harmful stances, such as dead clls, unused celular secretions, debs, nd microorganisms. “Merphages and neoropbils are not te only body cll capable of hagyons, but they are the most importane phapocyuc ells 29 FIGURE 15-5, Cellular elements of the blood, as seen ina Wright’s-stained peripheral blood smear. Wright’ stain con- tains two dyes: eosin (a reddish orange acidic dye, which stains basic substances) and methylene blue (a dark blue dye, which stains acidic substances). Eosinophil gran- les stain reddish orange because their contents are basic and, there- fore, attract the acidic dye. Basophil granules stain dark blue because °\ their contents are acidic and, therefore, attract the basic dye. The contents of neutrophil granules ate neutral (neither basic nor acidic) and, therefore atract neither the acidic dye nar the basic dye. (From McCall RE, Tankersley CM. Phiebotomy Essentials, 2nd ed. Philadelphia: Lippincott-Raven Publishers, 1998.) og rimulocytes are name Granuloytesinelide for the prominent cytoplasmic basophils, eosinophils granules that they possess. and neutrophils. Phssonc“panuloyes neutrophils and eosinophils. Neutrophils (also ‘own 8 plymorphonuce el pos and PMI) ae toch more efficent at phagocytosis than eosinophils An abnormally high mumber of eosinophils in the peripheral » ime z Gellular Elements of Blood Exythrocytes (red blood cells) ‘Thrombocytes(plateles) Leukocytes (white blood cells) Tells Helper T cells (Tz cells) Cytotoxic T cells (Te cells) ‘Natural killer cells (NK cells)bodes incon t pe og vote n aller a sin pages phil gran ae a Pechercherical mediators: Hap are farther newaed in Chapter 16 “Macrophages. sieveop (Wandering macrophages from "3 type of lokocyte_letve the Woodsen, fled momacytes during the and migrate to sites matory response to n= infection and other "Those that leave the areas where they ar Feeded, Fired fee Ioodsirea and migrate 0 infected areas are called wan macrophages rem dering. macrophages. Fixed within tissues and organs. macrophages (also known as Iotacyres oF biticyen) remain within tissues and organs and serve to trap foreign de- iris: Macrophages are extremely efficient phagocytes They are found in tsaues ofthe reticuloendodhelial system (RES). This nonspecific defensive system in- Glades cols inthe liver (oper eel), spleen, yep totes, and bone marrow 25 well = the lings GWeolar or dust cell), Blood esc intestines, and brain (i= rogia). The principal funtion of the entire RES is the engulfnent and removal of foreign and wselesspar= ticles, living or dead, such as excess elllar secretions, dead and dying levkocytes, erythrocytes, and cssue Cells as well 2: foreign debris and microorganisms that fain entrance to the body. “ “The four steps in phagocytosis are chemotaxis, at- tachment, ingestion, and digestion. They are discussed next and are summarized in Table 15-1 Chemotaxis Phagocytosis begins phagocytes move to the site where they are needed. This directed migration is called chemotaxis and isthe result of a5 chemotactic agents, when The directed migration ‘of phagocytes is called chemotaxis. [tis caused by chemicals referred to om, BRIEF DESCRIPTION STEP 1. Chemotaxis Phagocytes are attracted by chemotactic agents to the site where they are needed 2 Attachment A phagocyte attaches to an object 3. Ingestion Pseudopodia suround the object, and itis taken into the cell 4. Digestion The object fs broken down and dissolved by digestive enzymes and other mechanisms ical atractans relerred (0 48 chey Pace 3 oN see by various cel of the home 2 seein” Chemotactic opener etoile: conde and tenets rermans pong acncyaion ren, ete agents to the area of highest ereea™ ten of highese concentration ithe Tiemnucde ages oe being prods ‘often the site of inflammation. Ths, the 2 "lene sted tothe ate where they arc tee type of chemoracic AEER arc dierent IPotoeyeesy sme attract monocytes oe eT™ Oye tid il echers eosinophil oat Zi nt Ly ‘Ton oaet mp ke phepoeys eeacinen of he papoote pce ea Side nies ee leer ae Sots SMS Ge eened meena Phagocytes can only ingest ob- oF antiboie ™29# Pe abich they re snack Saeed mtd oti tees essary to enable phagocytes t0 attach to certain et Gp capeienl tach in opcnage bbecomes coated with opsonins (ether compiene Pate momar antibodies). Beause she pera a fei cee de dnd anodic the phapoge cannes act Bae ticle (Fig. 15-6). reach 0 the pa The phagocytes then saround AR the objeee with prcedopodia, partie been wich fe gsher acd Se eee pt is ngeeed (6 pegory” (inate tized or phagocytosed) (Fig. membrane-bound ,Phgoeesnone pe ‘ecaed ana GF en the pce ingrtogwntevial roe omits acl. Win plasm of the phagocyte, the object is contained nq Inembrane-bound vesicle called’ sphagoosrnes 2 Digestion The phagosome next fuses with The Risin of aig 4 nearby Iysosome to form a and a phagosome rele digestive vacuole (phagolyso- in a phagolysoome, some), within which killing within which the and digestion occur Fig. 15-8). ingested parce i Recall from Chapter 3 that digested. * Various sypes of ells within the human body incaling cok of immune syste, communicate with each ether. They do soy mer chemical messages—proteins known as otokines. Ifthe eyokie chemotactic agens, ataeting leukocytes to areas where thy it ceed they ate refered to as chemolinet,¢ 6. opsonization. (A) The phagocyte shown gure a“ ach to the ‘encapsulated bacterium Bere are no molecules (receptors) onthe surface - that can recognize or attach to the ride capsule. (B) Complement fragments (rep- arine ambolC’) Mave been deposited eatere recat the capsule. (In this example, the opsonins are amt actvium because there are receptors (represented by the Whe phagocyte’s surface that can recognize and gan Pmonert ogments. (C) Antibodies (they vd molecules) have attached to the capsule, (In this ‘ape, the opsonins ae antibodies.) Now the phago- fe ean attach to the bacterium because there are recep- tas (represented by B®) on the phagocyte's surface that tprecognize and bind to the Fe region of antibody mo tals, (See text for additional details.) N, nucleus. ea Iyosomes are membrane-bound vesicles containing digestive enzymes, Digestive enzymes found within lys somes include lysozyme, B-lysin, lipases, proteases, pep- tdwes, DNASes, and RNases, which degrade carbohy- drt, lipids, proteins, and nucleic acids, Other mechanisms also participate in the destruction of phagocytized microorganisms. In neutrophils, for ex- ample, membrane-bound enzyme called nicotinamide CHAPTER AS » Nop Host Detense Mechanivm Mlenine dinucleotide ph cs on per robe Figures 15-7 and 15-10 dep ¢ lepict Gard lambs pho zoites being phagacytized by ae at leukocytes. G. lembler (also known as Giardia intertinatny ee 2am parsite that camer y darth na Siardiass. These pheromicronrarh micro BSraphe were taken during laboratory rescaeh ae involving opsonization of G Giardia trophowontes Mechanisms by which Path Destruction by Phagocyte During the initial phases of infection, capsules serve an an tiphagocytic function, protect ing encapsulated bacteria from being phagocytized, Some bacteria produce an exoenzyme (referred to as a toxin by Some scientists) called Jeutocidin, which kills phage eytes. As mentioned in Chapter 14, not all bacteria engulfed by phagocytes are destroyed within phagolyso- somes. For example, wanes in the cell wall of Mycobacterium tuberculosis protect the organist from di ‘gestion. The bacteria are even able to multiply within the phagocytes and are transported within them to ‘other parts of the body. Other pathogens that are able © survive within phagocytes include bacteria such as Rickettsia ricketttiy Legionella pnenmopbila, Brucella abortus, Coxiella burnetii, Listeria monnytogenes, and Salmonella spp. as well as Protozoan parasites such as Toxoplasma gondii, Trypanosoma crt Some bacteria and protozoa are able to Survive within phagocytes, and Leishmania spp. The mechanism by which each pathogen evades digestion by lysosomal enzymes differs from one Pathogen to another; in some cases, the mechanisin is ‘ot yet understood. These pathogens may remain dor. mane within phagocytes for months or years before they escape to cause disease, Thus, these types of virulent Pathogens usually win the battle with phagocytes. Unless antibodies or complement fragments are present to aid in the destruction of these pathogens, the infec tion may progress unchecked. Ehrlichia and Anaplasma spp., closely related to rick- exsias, are obligate, intracellu- Jar, Gram-negative bacteria that live within leukocytes (ie, they are intraleukocytic pathogens) ‘These organisms cause two endemic, ickborne diseases in the United States. Ehrlichia spp. cause human monocytic Ehitichia and Anoplasma’ pp. ate intraleukocytic bacteria, able to live and multiply within leukocytes, (26 gern i «Pago an Del 5-7. Tre Ingestion phase of BT a) A papocyte Nas paneer» bacterial co.) Psewdopodi® ached to ee acecl ca (TM sma meet and 48 Cet Foy eect ol, HOS Orme snow inside the Phage The membrane: Do tontaiin the ingested bacte agosome, M, oucleus rgune phagocytor at el scaled @ FIGURE 15-8. The digestion phase of Ph: mn phase of phago- ytosis. (A) A bsosome, containing digestive em _ymes, approaches 2 phagosome. (B) The sosome “membrane fuses with the phagosome membra (6) The lysosome and phagosome become a sinale Vesicle, known as a phagolso- ‘membrane-bound Jame. The phagolysosome contains the ingested bacterial cell plus digest fs digestive enzymes, (D) The bac tena cell is digested within the phagelysosome. 1, nucleus we Mechanisns © 4 Pnagosomo Lysosome 5“9, Phatomicrogaph of rat Leuk vit oy eontain phagocytized Giardia tropho- ef Wi yes coed WG eine he Pesextch laboratory (Provided by 8, ee eat) (HIME), « condition in which the bacteria tn re phagocytes. naplama spp. cause human ee or human granulocytic ehrlichiosis [HE], as ss called), 4 condition in which the Bacteria Plemne aes scnaeen ese fe ee penia—ah ally ow number lating leskocytes. Neutropenia an abnormally tow umber of circulating neutrophil, Sore, Pow number of ci H fkoetes— cond cairn 4 leukopenia 3 op the te abe einen ae ON mearmowsly, they ae nh CHNTELYS » Nonspecific How Defense Mechinimm 263 STUDY Ai Bessare of Similer Sounding Words na patent has an abnormally low number of Circulating leakoeytes, the condition is known #6 | Teukopenia. When a patient has an abnormally high | number of circulating leukocytes, the condition is | known as leukocytosis (which is usually the result | of an infection). Leukemia is a type of cancer in | | which theresa proliferation of abnormal leukocytes | in the Hood, Acai here ae ees diferent ‘types oF leukemia, classified by the dominant type of (Leakooye — ) really synonyms. Technically, neutropenia is an ab- ‘normally low number of circulating neutrophils; neu- tropenia = neutrophilic leukopenia.) Leukopenia may result from bone marrow injury asa result of ionizing ‘adiation or drugs, nutritional deficiencies, or congeni- tal stem cell defects. Disorders and Conditions Affecting Leukocyte Monility and Chemotaxis The inability of leukocytes to migrate in_ response to chemotactic agents may be related toa defect in the production of acon, a strictural protein associated with ‘mouiiry: Some drugs (€g. corticosteroids) can also inhibi the chemotactic activity of leukocytes. Decreased neutrophil chemotaxis also occurs inthe inherited child- hood disease known as Chediak-Higishi_ syndrome (CHS). In addition, the PMN of individuals with CHS ‘contain abnormal lysosomes thac do not readily fuse with phagosomes, resulting in decreased bactericidal activity. CCHS is characterized by symptoms such as albinism, cen- tral nervous system abnormalities, and recurrent Bacte- rial infections Scanning electron micrographs (A,8) illustrating the phagocytosis of Giardia trophozoites (6) by rat leukocytes (L). The phagocytosis occured under experimental conditions in a veseurch aboratary. (Provided by 5. iandsen and . En ekki.)264 SECTION VIt « Pathogenesis and Host Defense Mechanisms FACTOR Nutritional status Increased iron levels, Stress ‘Age Cancer and cancer chemotherapy AIDS Drugs Various genetic defects COMMENTS ___ Malnutrition is accompanied by decreased resistance to infections sncentrations of iron make it easier for bacteria to satisfy their iron > rents; high concentrations of iron reduce the chemotactic and creased iron levels may result from a High cor requirem phagocytic activities of phagocytes: variety of conditions or habits — People living under stressful conditions are more susceptible to infections thay people living under less stressful conditions a Newborn infants lack a fully developed immune system: the efficiency ofthe immune system and other host defenses declines after age 50 Cancer chemotherapeutic agents kill heathy cells and malignant ones Destruction of the AIDS patient's helper T cells (Ty cells) decreases the patient’s ability to produce antibodies to certain pathogens (discussed in Chapter 16) — Steroids and alcohol, for example 5Paricere= = Atos pee iy _—gteroids and alcohol, gst and T-cell dec 5. . —— - Ss Disorders and Conditions Affecting Intracellular $s Killing by Phagocytes Pat A The phagocytes of some individuals are capable of in 4 sting bacteria, but are incapable of killing certain meses This is usually the result of deficiencies in myeloperoxidase or an inability to generate superoxide anion, hydrogen peroxide, or hypochlorite. Chronic granulomatous disease (CGD) is an often fatal genetic disorder that is characterized by repeated bacterial in- fections. The PMNs of individuals with CGD can in- gest bacteria but cannot kill certain species. In one form of CGD, the person’s PMNs are unable to produce hy- drogen peroxide. In another hereditary disorder, the in- dividual’s PMNs completely lack myeloperoxidase. Their PMNs do possess other microbicidal mecha- nisms, however, so these individuals usually do not ex- perience recurrent infections.