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PathophysiologyofDisease:AnIntroductiontoClinicalMedicine,7e>

3:DisordersoftheImmuneSystem
JeffreyL.Kishiyama,MD

Introduction
Thefunctionoftheimmunesystemistoprotectthehostfrominvasionofforeignorganismsbydistinguishingselffromnonself.Suchasystemisnecessary
forsurvival.Awellfunctioningimmunesystemnotonlyprotectsthehostfromexternalfactorssuchasmicroorganismsortoxinsbutalsopreventsandrepels
attacksbyendogenousfactorssuchastumorsorautoimmunephenomena.Anormalimmuneresponsereliesonthecarefulcoordinationofacomplexnetwork
ofbiologicalfactors,specializedcells,tissue,andorgansnecessaryfortherecognitionofpathogensandsubsequenteliminationofforeignantigens.
Dysfunctionordeficiencyofcomponentsoftheimmunesystemleadstoavarietyofclinicaldiseasesofvaryingexpressionandseverity,rangingfromatopic
diseasetorheumatoidarthritis,severecombinedimmunodeficiency,andcancer.Thischapterintroducestheintricatephysiologyoftheimmunesystemand
abnormalitiesthatleadtodiseasesofhypersensitivityandimmunodeficiency.

NormalStructure&FunctionoftheImmuneSystem
Anatomy
CellsoftheImmuneSystem

Theimmunesystemconsistsofbothantigenspecificandnonspecificcomponentsthathavedistinctyetoverlappingfunctions.Theantibodymediatedandcell
mediatedimmunesystemsprovidespecificityandmemoryofpreviouslyencounteredantigens.Thenonspecificorinnatedefensesincludeepithelialbarriers,
mucociliaryclearance,phagocyticcells,andcomplementproteins.Despitetheirlackofspecificity,thesecomponentsareessentialbecausetheyarelargely
responsiblefornaturalimmunitytoavastarrayofenvironmentalthreatsandmicroorganisms.Knowledgeofthecomponentsandphysiologyofnormalimmunity
isessentialforunderstandingthepathophysiologyofdiseasesoftheimmunesystem.
Themajorcellularcomponentsoftheimmunesystemconsistofmonocytesandmacrophages,lymphocytes,andthefamilyofgranulocyticcells,including
neutrophils,eosinophils,andbasophils.Derivedfromhematopoieticstemcells,thesefullydifferentiatedeffectorcellshavemembranereceptorsforvarious
chemoattractantsandmediators,facilitatingtheactivationordestructionoftargetcells.
Mononuclearphagocytesplayacentralroleintheimmuneresponse.Tissuemacrophagesarederivedfrombloodmonocytesandparticipateinantigen
processing,tissuerepair,andsecretionofmediatorsvitaltoinitiationofspecificimmuneresponses.Thesecells,abundantnearmucosalsurfacesthat
internalizemicroorganismsanddebris,traveltosecondarylymphoidorganswheretheyprocessandpresentthatantigeninaformrecognizabletoT
lymphocytes.Inaddition,theyfunctionaseffectorcellsforcertaintypesoftumorimmunity.Circulatingmonocytesarerecruitedtositesofinflammationwhere
theymatureintomacrophages.BothmonocytesandmacrophagescontainreceptorsforC3b(activatedboundcomplement)andtheFcportionofboth
immunoglobulinG(IgG)andIgE,whichfacilitatetheactivationofthesecellsthroughantigenspecificandnonspecificimmunepathways.Activationofthese
cellsoccursbothafterbindingtoimmunecomplexesthroughexposuretovariouscytokinesandafterphagocytosisofantigenorparticulatessuchassilicaand
asbestos.Proteolyticenzymesandproinflammatorymediatorsincludingcytokines,arachidonicacidmetabolites,andoxidativemetabolitesareutilizedinthe
monocytesandmacrophages.Macrophagesconstitutivelyexpresstolllikereceptor4(TLR4),whichcanbindbacterialendotoxin,triggeringcytokinerelease
andbridginginnateandadaptiveimmuneresponses.Itishypothesizedthatmacrophagederivedinterleukin12(IL12)andtumornecrosisfactor(TNF)
influenceT H1andT H2differentiation,therebyaffectingtheexpressionofatopyandallergicdisease.Manyepithelialdendriticcells(eg,Langerhanscells,
oligodendrocytes,Kupffercells)mayshareacommonhematopoieticprecursorandfunctiontoprocessandtransportantigenfromskin,respiratory,and
gastrointestinal(GI)surfacestoregionallymphoidtissues.

ADA

Adenosinedeaminase

ADCC

Antibodydependentcellmediatedcytotoxicity

AIDS

Acquiredimmunodeficiencysyndrome

APC

Antigenpresentingcell

ART

Antiretroviraltherapy

BCR

Bcellreceptor

BTK

Brutontyrosinekinase

C1,C2,etc

Complementfactor1,complementfactor2,etc

cAMP

Cyclicadenosinemonophosphate

CCR5

CCsubfamilychemokinereceptor5

CD

Clustersofdifferentiation

CD4

HelperTcellsubset

CD8

CytotoxicTcellsubset

CGD

Chronicgranulomatousdisease

CMV

Cytomegalovirus

CNS

Centralnervoussystem

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CTL

Cytotoxiclymphocyte

CVID

Commonvariableimmunodeficiency

CXCR5

CXCsubfamilychemoreceptor5

F(ab)

Antigenbindingfragment

Fc

Crystallizablefragment

FcRI

HighaffinityIgEreceptor

FcR

Fcgammareceptor

FOXP3

ForkheadboxP3

GALT

Gutassociatedlymphoidtissue

GMCSF

Granulocytemacrophagecolonystimulatingfactor

H1,H2,H3

Histaminereceptortype1,2,3

HBV

HepatitisBvirus

HCV

HepatitisCvirus

HIV

Humanimmunodeficiencyvirus

HPV

Humanpapillomavirus

HSV

Herpessimplexvirus

HZV

Herpeszostervirus

ICAM1

Intercellularadhesionmolecule1

IFN

Interferon

Ig

Immunoglobulin

IVIG

Intravenousimmunoglobulin

IL1,IL2,etc

Interleukin1,interleukin2,etc.

JAK

Januskinase

JC

JakobCreutzfeldt

LAKcell

Lymphokineactivatedkillercell

LPS

Lipopolysaccharide

LT

Leukotriene

MAC

Mycobacteriumaviumcomplex

MBP

Majorbasicprotein

MHC

Majorhistocompatibilitycomplex

MSMD

Mendeliansusceptibilitytomycobacterialdisease

NADPH

Nicotinamideadeninedinucleotidephosphate

NHL

NonHodgkinlymphoma

NK

Naturalkillercells

PAF

Plateletactivatingfactor

PCP

Pneumocystispneumonia

PGD

ProstaglandinD

PNP

Purinenucleosidephosphorylase

PTK

Proteintyrosinekinase

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RAG

Recombinationactivatinggene

RANTES

ChemokineregulatedonactivationnormalTexpressedandsecreted

RAST

Radioallergosorbenttest

SCID

Severecombinedimmunodeficiencydisease

STAT

Signaltransducerandactivatoroftranscription

TACI

Transmembraneactivatorandcalciummodulatorandcyclophilinligandinteractor

TAME

NptosylLargininemethylesteresterase

TCR

Tcellreceptor

TH1

HelperT1subset

TH2

HelperT2subset

TH17

HelperTsubsetsecretingIL17

Treg

HelperTsubsetwithregulatoryfunction

TGF

Transforminggrowthfactorbeta

TLR

Tolllikereceptor

TNF

Tumornecrosisfactor

TSH

Thyroidstimulatinghormone

TX

Thromboxane

VCAM1

Vascularcelladhesionmolecule1

VIP

Vasoactiveintestinalpeptide

XLA

Xlinkedagammaglobulinemia

XSCID

Xlinkedseverecombinedimmunodeficiencydisease

ZAP70

ProteintyrosinekinaseZAP70

Lymphocytesareresponsiblefortheinitialspecificrecognitionofantigen.TheyarefunctionallyandphenotypicallydividedintoBandTlymphocytes.
Structurally,BandTlymphocytescannotbedistinguishedvisuallyfromeachotherunderthemicroscopetheycanbeenumeratedbyflowcytometric
phenotypingorbyimmunohistochemicalmethods.Approximately7080%ofcirculatingbloodlymphocytesareTcells(CD3)and1015%areBcells(CD19)
theremainderarereferredtoasnaturalkiller(NK)cells(CD56,CD161,alsoknownasNKcellsornullcells).
Thethymusderivedcells(TlymphocytesorTcells)areinvolvedincellularimmuneresponses.BlymphocytesorBcellsareinvolvedinhumoralorantibody
responses.PrecursorsofTcellsmigratetothethymus,wheretheydevelopsomeofthefunctionalandcellsurfacecharacteristicsofmatureTcells.Through
positiveandnegativeselection,clonesofautoreactiveTcellsareeliminated,andmatureTcellsmigratetotheperipherallymphoidtissues.There,theyenter
thepooloflonglivedlymphocytesthatrecirculatefromthebloodtothelymph.
Tlymphocytesareheterogeneouswithrespecttotheircellsurfacemarkersandfunctionalcharacteristics.NumeroussubpopulationsofTcellsarenow
recognized.HelperinducerTcells(CD4)helptoamplifyBcellproductionofimmunoglobulinandamplifyTcell(CD8)mediatedcytotoxicity.ActivatedCD4T
cellsregulateimmuneresponsesthroughcelltocellcontactandbyelaborationofsolublefactorsorcytokines.
SubsetsofCD4Tcellscanbeidentifiedonthebasisoftheirpatternofcytokineproduction.T H1cellsdevelopinthepresenceofIL12,secretedfromactivated
macrophages,especiallyinthepresenceofinfectionwithintracellularmicrobes.T H1cellselaborateinterferon(IFN)andTNFbutnotIL4andIL5.They
participateincellularimmuneresponsestointracellularpathogensandtypeIVdelayedhypersensitivityreactions.T H2cellsdevelopinthepresenceofIL4and
secreteIL4,IL5,andIL13,whichfacilitatehumoralresponses.BecauseIL4andIL13promoteIgEproductionandIL5isaneosinophilproliferationand
differentiationfactor,T H2cellshavebeenimplicatedinresponsetoallergensandhelminthes.
CytotoxicorkillerTcells(CTLs)aregeneratedaftermatureTcellsinteractwithcertainforeignantigens.Theyareresponsiblefordefenseagainst
intracellularpathogens(eg,viruses),tumorimmunity,andorgangraftrejection.MostkillerTcellsexpresstheCD8phenotype,althoughincertain
circumstances,CD4Tcellscanbecytotoxic.CTLsmaykilltheirtargetthroughosmoticlysis,bysecretionofTNF,orbyinductionofapoptosis,thatis,
programmedcelldeath.
AnumberofadditionalThelpersubsetshavebeendiscoveredthatcontributetoimmuneregulation.Mucosaldendriticcellscontrolthegenerationof
regulatoryTcells,whichmodulateinflammatoryresponsesthroughthesecretionofregulatorycytokines.T H17cellsubsetsappeartoboostearlyphagocytic
cellresponsesbyrecruitingneutrophilstositesofacuteinflammationviaelaborationofIL17andmayplayaroleinautoimmunediseases.T regcellsexpress
highaffinityreceptorsforIL2(CD25)andFOXP3,atranscriptionfactorthatmaysuppressautoimmunedisease.T regcellsareinhibitory,suppressingactivated
Teffectorcellsbytheirsecretionoftransforminggrowthfactor(TGF),modulatingresponsestoantigen,therebyregulatinghomeostasisandtolerance
versusinflammation,allergy,andautoimmunity.MutationsofFOXP3havebeenassociatedwithinflammatoryautoimmunedisease,immunedysregulation,
polyendocrinopathy,andXlinkedsyndrome(IPEX).
Blymphocytematurationproceedsinantigenindependentandantigendependentstages.Antigenindependentdevelopmentoccursinthemarrowwhere
preBcellsmatureintoimmunoglobulinbearingnaiveBcells(cellsthathavenotbeenexposedtoantigenpreviously).Inperipherallymphoidtissues,antigen
dependentactivationproducescirculatinglonglivedmemoryBcellsandplasmacellsfoundpredominantlyinprimaryfolliclesandgerminalcentersofthelymph

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nodesandspleen.AllmatureBcellsbearsurfaceimmunoglobulinthatistheirantigenspecificreceptor.ThemajorroleofBcellsisdifferentiationtoantibody
secretingplasmacells.However,Bcellsmayalsoreleasecytokinesandfunctionasantigenpresentingcells(APCs).
Nullcellsprobablyincludeanumberofdifferentcelltypes,includingagroupcalledNKcells.Thesecellsappeardistinctfromotherlymphocytesinthattheyare
slightlylarger,withakidneyshapednucleolus,haveagranularappearance(largegranularlymphocytes),expressdistinctcellsurfacemarkers(CD56,CD161),
butlackantigenspecificTcellreceptors(CD3,orTCRs).Recruitedtositesofinflammation,NKcellspossessmembranereceptorsfortheIgGmolecules
(FcR),facilitatingantibodydependentcellmediatedcytotoxicity(ADCC).Bindingofanantibodycoatedcellorforeignsubstancetriggersreleaseofperforin,a
poreformingproteinthatcausescytolysis.OtherNKcellfunctionsincludeantibodyindependentcellularkilling,inductionofapoptosisinFasexpressingcells,
andimmunomodulationofresponsestoviruses,malignancy,andtransplantedtissuethroughapotentreleaseofIFN,TNF,andotherkeycytokines.
Polymorphonuclearleukocytes(neutrophils)aregranulocytesthatphagocytoseanddestroyforeignantigensandmicrobialorganisms.Theyareattracted
tothesiteofantigenbychemotacticfactors,includingplasmaactivatedcomplement5(C5a),leukotrieneB4(LTB4),granulocytecolonystimulatingfactor(G
CSF),granulocytemacrophagecolonystimulatingfactor(GMCSF),IL8,andplateletactivatingfactor(PAF).ThepresenceofreceptorsforcomplementC3b
andinvariant/constantregionsofIgGmolecules(Fc)onthesurfaceofneutrophilsalsofacilitatestheclearanceofopsonizedmicrobesthroughthe
reticuloendothelialsystem.Smallerantigensarephagocytosedanddestroyedbylysosomalenzymes.Locallyreleasedlysosomalenzymesdestroyparticlestoo
largetobephagocytosed.Neutrophilscontainorgenerateanumberofantimicrobialfactors,includingoxidativemetabolites,superoxide,andhydrogen
peroxide,aswellasmyeloperoxidase,whichcatalyzestheproductionofhypochlorite,andproteolyticenzymes,includingcollagenase,elastase,andcathepsin
B.
Eosinophilsareoftenfoundininflammatorysitesoratsitesofimmunereactivityandplayacrucialroleinthehostsdefenseagainstparasites.Despitemany
sharedfunctionalsimilaritiestoneutrophils,eosinophilsareconsiderablylessefficientthanneutrophilsatphagocytosis.Eosinophilsplaybothaproactiveanda
modulatoryroleininflammation.TheyareattractedtothesiteoftheantigenantibodyreactionsbyPAF,C5a,chemokines,histamine,andLTB4.Theyare
importantinthedefenseagainstparasites.Whenstimulated,theyreleasenumerousinflammatoryfactors,includingmajorbasicprotein(MBP),eosinophil
derivedneurotoxin,eosinophilcationicprotein(ECP),eosinophilperoxidase,lysosomalhydrolases,andLTC4.MBPdestroysparasites,impairsciliarybeating,
andcausesexfoliationofrespiratoryepithelialcellsitmaytriggerhistaminereleasefrommastcellsandbasophils.Eosinophilderivedproductsmayplayarole
inthedevelopmentofairwayhyperreactivity.
Basophilsplayanimportantroleinbothimmediateandlatephaseallergicresponses.Thesecellsreleasemanyofthepotentmediatorsofallergic
inflammatorydiseases,includinghistamine,leukotrienes(LTs),prostaglandins(PGs),andPAF,allofwhichhavesignificanteffectsonthevasculatureandon
theinflammatoryresponse.Basophilsarepresentinthecirculation,possesshighaffinityreceptorsforIgE(FcRI),andmediateimmediatehypersensitivity
(allergic)responses.
Mastcellsarebasophilicstainingcellsfoundchieflyinconnectiveandsubcutaneoustissue.Theyhaveprominentgranulesthatarethesourceofmany
mediatorsofimmediatehypersensitivityandhave30,000200,000cellsurfacemembranereceptorsfortheFcfragmentofIgE.Whenanallergenmolecule
crosslinkstwoadjacentmastcellsurfaceassociatedIgEantibodies,calciumdependentcellularactivationleadstothereleaseofbothpreformedandnewly
generatedmediators.Mastcellsalsohavesurfacereceptorsforanaphylatoxins(activatedcomplementfragments,C3a,C4a,andC5a),cytokines,and
neuropeptides,suchassubstanceP.ActivationbythesenonIgEmediatedmechanismsmaycontributetohostimmunityandprovidetiesbetweentheimmune
andneuroendocrinesystems.Mastcelldeficientmicedisplayaparticularvulnerabilitytosepsisandrapiddeathafterperitonitis,possiblyduetoinsufficientTNF
productionduringbacterialinfection.Mastcellsalsoappearinareasofwoundhealingandinfibroticlungdisease.Experimentally,mastcellderivedmediators
promoteangiogenesisandfibrogenesis,suggestingtheirpresenceinthesesitesispathologicallyrelevant.
OrgansoftheImmuneSystem

Severaltissuesandorgansplayrolesinhostdefensesandarefunctionallyclassifiedastheimmunesystem.Inmammals,theprimarylymphoidorgansarethe
thymusandthebonemarrow.
Allcellsoftheimmunesystemareoriginallyderivedfrombonemarrow.Pluripotentstemcellsdifferentiateintolymphocyte,granulocyte,monocyte,erythrocyte,
andmegakaryocytepopulations.Inhumans,Blymphocytes,whicharetheantibodyproducingcells,undergoearlyantigenindependentmaturationinto
immunocompetentcellsinthebonemarrow.Deficiencyordysfunctionofthepluripotentstemcellorthevariouscelllinesdevelopingfromitcanresultin
immunedeficiencydisordersofvaryingexpressionandseverity.
Thethymus,derivedfromthethirdandfourthembryonicpharyngealpouches,functionstoproduceTlymphocytesandisthesiteofinitialTlymphocyte
differentiation.Itsreticularstructureallowsasignificantnumberoflymphocytestomigratethroughittobecomefullyimmunocompetentthymusderivedcells.
DevelopingTcellsinthethymiccortexarefirstpositivelyselectedfortheirabilitytorecognizeselfpeptides(ie,majorhistocompatibilitycomplex,MHC).In
subsequentnegativeselection,Tcellsthatavidlyrecognizeselfpeptidesaredestroyed,thusremovingdeleteriousselfreactiveclones.Insomemurinemodels,
autoimmunediseasessuchassystemiclupuserythematosusmaydevelopinmicewithdefectiveapoptotic(programmedcelldeath)pathwaysinTcells
recognizingselfantigen.ThethymusalsoregulatesimmunefunctionbysecretionofmultiplehormonesthatpromoteTlymphocytedifferentiationandare
essentialforTlymphocytemediatedimmunity.
Inmammals,thelymphnodes,spleen,andgutassociatedlymphoidtissuearesecondarylymphoidorgansconnectedbybloodandlymphaticvessels.
Lymphnodesarestrategicallydispersedthroughoutthevasculatureandaretheprincipalorgansoftheimmunesystemthatlocalizeantigen,promotecellcell
interactionandlymphocyteactivation,andpreventthespreadofinfection.Lymphnodeshaveaframeworkofreticularcellsandfibersthatarearrangedintoa
cortexandmedulla.Blymphocytes,theprecursorsofantibodyproducingcells,orplasmacells,arefoundinthecortex(thefolliclesandgerminalcenters)as
wellasinthemedulla.Tlymphocytesarefoundchieflyinthemedullaryandparacorticalareasofthelymphnode(Figure31).Thespleenfiltersandprocesses
antigensfromthebloodandisfunctionallyandstructurallydividedintoBlymphocyteandTlymphocyteareas,similartothoseofthelymphnodes.
FIGURE31

Anatomyofanormallymphnode.(Redrawn,withpermission,fromChandrasomaPetal,eds.ConcisePathology,3rded.OriginallypublishedbyAppleton&
Lange.Copyright1998byTheMcGrawHillCompanies,Inc.)

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Gutassociatedlymphoidtissueincludesthetonsils,Peyerpatchesofthesmallintestine,andtheappendix.Likethelymphnodesandspleen,thesetissues
exhibitseparationintoBlymphocytedependentandTlymphocytedependentareas.MucosalimmuneresponsestendtogenerateantigenspecificIgA,and
withsomeorallyadministeredantigens,Tcellanergyortolerancemayoccurratherthanimmunestimulation.
InflammatoryMediators

Mediatorsarereleasedorgeneratedduringimmuneresponsestocoordinateandregulateimmunecellactivitiestogeneratephysiologicalorcytotoxic
responses.Theytargetmanydiversecelltypes,canhaveantiviral,proinflammatory,orantiinflammatoryactivities,actlocallyorsystemically,andcanbe
redundantintheiractions(Table31).Mediatorsmayexistinapreformedstateinthegranulesofmastcellsandbasophilsorarenewlysynthesizedatthetime
ofactivationoftheseandsomeothernucleatedcells.Increasedawarenessoftheimmunologicandphysiologiceffectsofmediatorshasledtoabetter
understandingofimmunopathologyandprovidespotentialtargetsforfuturepharmacotherapies.
Table31Cytokinesandtheirfunctions.

Cytokine

MajorCellularSource

PrincipalEffect

IFN

Macrophages,dendriticcells

Inhibitviralreplication

IFN

Virallyinfectedcells

IFN

Tcells,NKcells

UpregulationofadhesionandMHCmolecules,increasedmacrophageandantigen
presentingcell(APC)activity

IL1

Macrophage

Endogenouspyrogen,endothelialcellactivation,inducesacutephasereactants

IL2

Tcells

Tcellgrowthfactorandregulatoryfactor,BcellandNKcellactivation

IL3

Tcells

Hematopoieticgrowthfactor

IL4

Tcells,mastcells

InducesIgEsynthesis,TH2responses

IL5

Tcells

Eosinophilactivationandgrowthfactor,Bcellactivationfactor

IL6

Macrophages,Tcells,endothelial
cells

InducesIgsynthesisandacutephasereactants

IL7

Bonemarrow

BcellandTcellgrowthanddifferentiationfactor

IL8

Macrophage,neutrophils,
endothelial,andepithelialcells

Leukocytechemotacticfactor

IL10

Tcells,macrophages

Inhibitsantigenpresentation,cytokineresponses

IL12

Macrophage

InducesTH1responses

IL13

Tcells,mastcells

InducesIgEresponses

IL17

TH17

ActivationofCD4Tcells

GMCSF

Macrophages,Tcells

Hematopoieticgrowthfactorforneutrophils,eosinophils,andmacrophages

TGF

Platelets

Immunemodulatorforleukocytes,tissuegrowthfactorforwoundhealing

TNF

Macrophage,Tcell

Endogenouspyrogenactivatesneutrophils,endothelialcells,andacutephase
reactantspromotesangiogenesisandcoagulation

Preformedmediatorsincludehistamine,eosinophilandneutrophilchemoattractants,proteoglycans(heparin,chondroitinsulfate),andvariousproteolytic
enzymes.Histamineisabioactiveamine,packagedindenseintracellulargranules,thatwhenreleasedbindstomembraneboundH1,H2,andH3receptors,
resultinginsignificantphysiologiceffects.BindingtoH1receptorscausessmoothmusclecontraction,vasodilatation,increasedvascularpermeability,and
stimulationofnasalmucousglands.StimulationofH2receptorscausesenhancedgastricacidsecretion,mucussecretion,andleukocytechemotaxis.Histamine

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isimportantinthepathogenesisofallergicrhinitis,allergicasthma,andanaphylaxis.
Newlygeneratedmediatorsincludekinins,PAF,andarachidonicacidmetabolites,includingLTsandPGs.Inmanyimmunecells,arachidonicacid,liberated
frommembranephospholipidbilayers,ismetabolizedeitherbythelipoxygenasepathwaytoformLTsorbythecyclooxygenasepathwaytoformPGsand
thromboxanesA2andB2(TXA2andTXB2).LTB4isapotentchemoattractantforneutrophils.LTC4,LTD4,andLTE4constituteslowreactingsubstanceof
anaphylaxis,whichhasbronchialsmoothmusclespasmogenicpotency1001000timesthatofhistamine,andwhichalsocausesvasculardilationandvascular
permeability.
AlmostallnucleatedcellsgeneratePGs.ThemostimportantmembersarePGD2,PGE2,PGF 2,andPGI2(prostacyclin).Humanmastcellsproducelarge
amountsofPGD2,whichcausesvasodilatation,vascularpermeability,andairwayconstriction.Activatedpolymorphonuclearneutrophilsandmacrophages
generatePGF 2,abronchoconstrictor,andPGE2,abronchodilator.PGI2causesplateletdisaggregation.TXA2causesplateletaggregation,bronchial
constriction,andvasoconstriction.
Macrophages,neutrophils,eosinophils,andmastcellsgeneratePAF,whichcausesplateletaggregation,vasodilatation,increasedvascularpermeability,and
bronchialsmoothmusclecontraction.PAFisthemostpotenteosinophilchemoattractantdescribedandalsoplaysaroleinanaphylaxis.Thekininsare
vasoactivepeptidesformedinplasmawhenkallikrein,releasedbybasophilsandmastcells,digestsplasmakininogen.Kinins,includingbradykinin,contributeto
humanangioedemaandanaphylaxisbycausingslow,sustainedcontractionofbronchialandvascularsmoothmuscle,vascularpermeability,secretionof
mucus,andstimulationofpainfibers.
ComplementCascades

TheunionofantigenwithIgGorIgMantibodyinitiatesactivationoftheclassiccomplementpathway.Complementfixingsitesontheseimmunecomplexes
areexposed,allowingbindingofthefirstcomponentofthecomplementsequence,C1q.Othercomponentsofthecomplementsequencearesubsequently
bound,activated,andcleaved,eventuallyleadingtocelllysis.Importantbyproductsoftheclassicpathwayincludeactivatedcleavageproducts,the
anaphylatoxinsC3a,C5a,andlesspotentC4a.C5aisapotentleukocytechemotacticfactorandcausesmediatorreleasefrommastcellsandbasophils.C4b
andC3bmediatebindingofimmunecomplexestophagocyticcells,facilitatingopsonization.
Activationofthecomplementsequencebythealternativepathwayisinitiatedbyanumberofagents,includinglipopolysaccharides(LPSs),trypsinlike
molecules,aggregatedIgAandIgG,andcobravenom.Activationofthealternativepathwaydoesnotrequirethepresenceofantigenantibodycomplexesor
usetheearlycomponentsofthecomplementsequence,C1,C4,andC2.Ultimately,asaresultofactivationoftheclassicoralternativepathway,activationof
theterminalcomplementsequenceoccurs,resultingincelllysisand/ortissueinflammation.Solubleinhibitorsregulatethecomplementpathwaytoprevent
uncheckedactivationandprolongedinflammation.Deficiencyofonefactor,C1esteraseinhibitor,leadstorecurrent,potentiallylifethreateningattacksoffacial,
laryngeal,andGIswellinginhereditaryangioedema.
Cytokines

Manyimmunefunctionsareregulatedormediatedbycytokines,whicharesolublefactorssecretedbyactivatedimmunecells.Cytokinescanbefunctionally
organizedintogroupsaccordingtotheirmajoractivities:(1)thosethatpromoteinflammationandmediatenaturalimmunity,suchasIL1,IL6,IL8,TNF,and
IFN(2)thosethatsupportallergicinflammation,suchasIL4,IL5,andIL13(3)thosethatcontrollymphocyteregulatoryactivity,suchasIL10,IL12,and
IFNand(4)thosethatactashematopoieticgrowthfactors,IL3,IL7,andGMCSF(Table31).Agroupofchemotacticfactors(chemokines)regulate
homingandmigrationofimmunecellstositesofinflammation.Humanimmunodeficiencyvirus(HIV)mayexploitcertainchemokinereceptorstoinfecthost
cells,andnaturalmutationsinthesesamechemokinecoreceptorsmayconferasusceptibilityorresistancetoinfection.
Checkpoint
1. Whatarethespecificandnonspecificcomponentsofthecellularandnoncellularlimbsoftheimmunesystem?
2. Whatistheroleofmacrophagesintheimmunesystem,andwhataresomeoftheproductstheysecrete?
3. Whatarethecategoriesoflymphocytes,andhowaretheydistinguished?
4. Whatistheroleoflymphocytesintheimmunesystem,andwhataresomeoftheproductstheysecrete?
5. Whatistheroleofeosinophilsintheimmunesystem,andwhataresomeoftheproductstheysecrete?
6. Whatistheroleofbasophilsintheimmunesystem,andwhataresomeoftheproductstheysecrete?
7. Whatistheroleofepithelialcellsintheimmunesystem,andwhataresomeoftheproductstheysecrete?
8. Whataretheprimaryandsecondarylymphoidorgans,andwhatrolesdotheyplayintheproperfunctioningoftheimmunesystem?
Physiology
Innate&AdaptiveImmunity

Livingorganismsexhibittwolevelsofresponseagainstexternalinvasion:aninnatesystemofnaturalimmunityandanadaptivesystemthatisacquired.
Innateimmunityispresentfrombirth,doesnotrequirepreviousantigenicexposure,andisnonspecificinitsactivity.Theskinandepithelialsurfacesserveas
thefirstlineofdefenseoftheinnateimmunesystem,whereasenzymes,thealternativecomplementsystempathway,acutephaseproteins,phagocytic,NK
cells,andcytokinesprovideadditionallayersofprotection.MicrobialcellwallsornucleicacidscontainnonmammalianpatternsormotifsthatcanbindtoTLRs
oninnateimmunecellsincludingmacrophagesanddendriticcells.TheirstructureishighlyconservedandeachTLRbindstospecificmicrobialproducts,such
asLPS(orbacterialendotoxin),viralRNA,microbialDNAandyeastwallmannonproteins.BindingofTLRandligandtriggerstranscriptionofproinflammatory
factorsandcytokinesynthesispriortoadaptiveresponses.Throughaseriesofproteolyticactivations,theserumandmembranecomponentsofthe
complementcascadeamplifyandregulatemicrobialkillingandinflammation.Despitethelackofspecificity,innateimmunityislargelyresponsiblefor
protectionagainstavastarrayofenvironmentalmicroorganismsandforeignsubstances.
Higherorganismshaveevolvedanadaptiveimmunesystem,whichistriggeredbyencounterswithforeignagentsthathaveevadedorpenetratedtheinnate
immunedefenses.Theadaptiveimmunesystemischaracterizedbothbyspecificityforindividualforeignagentsandbyimmunologicmemory,whichmakes
possibleanintensifiedresponsetosubsequentencounterswiththesameorcloselyrelatedagents.Primaryadaptiveimmuneresponsesrequireclonal
expansion,leadingtoadelayedresponsetonewexposures.Secondaryimmuneresponsesaremorerapid,larger,andmoreefficient.Stimulationofthe
adaptiveimmunesystemtriggersacomplexsequenceofeventsthatinitiatetheactivationoflymphocytes,theproductionofantigenspecificantibodies
(humoralimmunity)andeffectorcells(cellularorcellmediatedimmunity),andultimately,theeliminationoftheincitingsubstance.Althoughadaptiveimmunityis
antigenspecific,therepertoireofresponsesistremendouslydiverse,withanestimated109antigenicspecificities.
Antigens(Immunogens)

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Foreignsubstancesthatcaninduceanimmuneresponsearecalledantigensorimmunogens.Immunogenicityimpliesthatthesubstancehastheabilitytoreact
withantigenbindingsitesonantibodymoleculesorTCRs.Complexforeignagentspossessdistinctandmultipleantigenicdeterminantsorepitopes,
dependentonthepeptidesequenceandconformationalfoldingofimmunogenicproteins.Mostimmunogensareproteins,althoughpurecarbohydratesmaybe
immunogenicaswell.Itisestimatedthatthehumanimmunesystemcanrespondto107109differentantigens,anamazinglydiverserepertoire.
ImmuneResponse

Theprimaryroleoftheimmunesystemistodiscriminateselffromnonselfandtoeliminatetheforeignsubstance.Thephysiologyofthenormalimmune
responsetoantigenissummarizedinFigure32.Acomplexnetworkofspecializedcells,organs,andbiologicfactorsisnecessaryfortherecognitionand
subsequenteliminationofforeignantigens.Thesecomplexcellularinteractionsrequirespecializedmicroenvironmentsinwhichcellscancollaborateefficiently.
BothTandBcellsneedtomigratethroughoutthebodytoincreasethelikelihoodthattheywillencounteranantigentowhichtheyhavespecificity.Soluble
antigensaretransportedtoregionallymphtissuesthroughafferentlymphaticvessels,whileotherantigensarecarriedbyphagocyticdendriticcells.Regional,
peripherallymphoidorgansandthespleenaresitesforconcentratedimmuneresponsestoantigenbyrecirculatinglymphocytesandAPCs.Antigens
encounteredviainhaledoringestedroutesactivatecellsinthemucosaassociatedlymphoidtissues.Themajorpathwaysofantigeneliminationincludethe
directkillingoftargetcellsbycytotoxicTlymphocytes(CTLscellularresponse)andtheeliminationofantigenthroughantibodymediatedeventsarisingfrom
TandBlymphocyteinteractions(humoralresponse).Theseriesofeventsthatinitiatetheimmuneresponseincludesantigenprocessingandpresentation,
lymphocyterecognitionandactivation,cellularorhumoralimmuneresponses,andantigenicdestructionorelimination.
FIGURE32

Thenormalimmuneresponse.CytotoxicTcellresponseisshownontheleftsideofthefigureandthehelperTcellresponseontherightside.Asdepictedon
theleft,mostCD8TcellsrecognizeprocessedantigenpresentedbyMHCclassImoleculesanddestroyinfectedcells,therebypreventingviralreplication.
ActivatedTcellssecreteinterferonthat,alongwithinterferonandinterferonsecretedbyinfectedcells,producescellularresistancetoviralinfection.On
therightandatthebottom,CD4helpercells(T H1andT H2cells)recognizeprocessedantigenpresentedbyMHCclassIImolecules.T H1cellssecrete
interferonandinterleukin2,whichactivatemacrophagesandcytotoxicTcellstokillintracellularorganismsT H2cellssecreteinterleukin4,5,and6,which
helpBcellssecreteprotectiveantibodies.Bcellsrecognizeantigendirectlyorintheformofimmunecomplexesonfolliculardendriticcellsingerminalcenters.

AntigenProcessing&Presentation

MostforeignimmunogensarenotrecognizedbytheimmunesystemintheirnativeformandrequirecaptureandprocessingbyprofessionalAPCs,which
constitutivelyexpressclassIIMHCmoleculesandaccessorycostimulatorymoleculesontheirsurfaces.Suchspecializedcellsincludemacrophages,dendritic
cellsinlymphoidtissue,Langerhanscellsintheskin,Kupffercellsintheliver,microglialcellsinthenervoussystem,andBlymphocytes.Dendriticcellsinthe
spleenandlymphnodesmaybetheprimaryAPCsduringaprimaryimmuneresponse.Followinganencounterwithimmunogens,theAPCsinternalizethe
foreignsubstancebyphagocytosisorpinocytosis,modifytheparentstructure,anddisplayantigenicfragmentsofthenativeproteinonitssurfacesin
associationwithMHCclassIImolecules(seelaterdiscussion).TcellindependentantigenssuchaspolysaccharidescanactivateBcellswithoutassistance
fromTcellsbybindingtoBcellreceptors(BCRs,orsurfaceboundantibody),leadingtorapidIgMresponses,withoutgenerationofmemorycellsorlonglived
plasmacells.Mostantigens,however,requireinternalizationandprocessingbyBcellsorotherAPCswithsubsequentrecognitionbyCD4Tcells.
TLymphocyteRecognition&Activation

TherecognitionofprocessedantigenbyspecializedTlymphocytesknownashelperT(CD4)lymphocytesandthesubsequentactivationofthesecells
constitutethecriticaleventsintheimmuneresponse.ThehelperTlymphocytesorchestratethemanycellsandbiologicsignals(cytokines)thatarenecessary
tocarryouttheimmuneresponse.ActivatedCD4Tlymphocytesaremainlycytokinesecretinghelpercells,whereasCD8Tlymphocytesaremainlycytotoxic
killercells.
HelperTlymphocytesrecognizeprocessedantigendisplayedbyAPCsonlyinassociationwithpolymorphiccellsurfaceproteinscalledthemajor
histocompatibilitycomplex(MHC).MHCgenesarehighlypolymorphicanddetermineimmuneresponsiveness.Theyareknownashumanleukocyteantigen

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(HLA).ThegenesencodingMHCdistinguishselffromnonself,therebydeterminingimmuneresponsivenesstoforeignagents,enablinggraftrejection,and
conferringsusceptibilitytocertainautoimmunedisorders.AllsomaticcellsexpressMHCclassI,whereasonlythespecializedAPCscanexpressMHCclassII.
ExogenousforeignantigensareexpressedinassociationwithMHCclassIIstructures,expressedonlybyspecializedAPCs.
DuringcellcellcontactbetweenThelpercellsandAPCs,theprocessofdualrecognitionisreferredtoasMHCrestriction.TheantigenMHCclassIIcomplex
formstheepitopethatisrecognizedbyantigenspecificTCRsonthesurfaceoftheCD4molecules.TheTCRiscomposedofsixgeneproducts,TCRand
subunits,CD3(,,andtwosubunits),and2chains.Besidesbindingtomodifiedantigen,activationofTcellsdependsonthecostimulationofaccessory
molecules.AccessorymoleculesonTcellsbindtoligandsfoundonAPCs,epithelialcells,vascularendothelium,andextracellularmatrix,controllingthe
subsequentTcellfunctionorhoming(Table32).Intheabsenceofsuchsignals,theTcellmaybetolerizedormayundergoapoptosisinsteadofbeing
activated.Biologicproductsthatblocksomeofthesecostimulatorypathwaysarecurrentlybeinginvestigatedaspotentialtherapeuticagentstopreventorgan
rejectionintransplantationandinthemanagementofsomeautoimmunediseases.
Table32TcellandAPCsurfacemoleculesandtheirinteractions.

TCellSurfaceReceptor

APCCounterReceptor

FunctionandEffect

Tcellreceptor(CD3)

Processedantigen+MHCcomplex

Antigenpresentation

CD4

MHCclassII

PresentationofantigentohelperTcellbyAPC

CD8

MHCclassI

PresentationofantigentocytotoxicTcell

CD40ligand(CD154)

CD40

TcellinducedBcellactivation

CD28

B7

Tcellproliferationanddifferentiation

CTLA4

B7

Tcellanergy

LFA1

ICAM1

Adhesion

BeforeanactivatedTcellcandifferentiate,proliferate,producecytokines,orparticipateincellkilling,theactivationsignalmustbetransducedintothe
cytoplasmornucleusofthecell.TheprincipalsignalingmoleculesintheTCRcomplexappeartobetheCD3andthehomodimerorheterodimer.The
presenceofimmunoreceptortyrosineactivationmotifsassociatedwitheachTCRcomplexfacilitatesamplificationofsignaling.ThebindingofZAP70(zeta
associatedprotein70),aSykfamilyproteintyrosinekinase(PTK),toCD3andsubunitsaftertheyarephosphorylatediscriticalfordownstreamsignaling.
AnotherimportantenzymeintheactivationofTcellsisCD45,aproteintyrosinephosphatase.Thecriticalnatureoftheseenzymesinlymphocytedevelopment
isunderscoredbythediscoveryofZAP70andCD45deficiencysyndromes,disordersthatresultinvariousformsofseverecombinedimmunodeficiency
disease(SCID,seePrimaryImmunodeficiencyDiseases).
ActivationofTcellsdoesnotoccurinisolationbutisalsodependentonthecytokinemilieu.Intrueautocrinefashion,theAPCsinvolvedinantigenpresentation
releaseIL1,whichinducesthereleaseofbothIL2andIFNfromCD4cells.IL2feedsbacktostimulatetheexpressionofadditionalIL2receptorsonthe
surfaceoftheCD4cellsandstimulatestheproductionofvariouscellgrowthanddifferentiationfactors(cytokines)bytheactivatedCD4cells.InductionofIL2
expressionisparticularlycriticalforTcells.Cyclosporineandtacrolimus(FK506),twoimmunosuppressiveagentsusedforpreventionoforgantransplant
rejection,functionbydownregulatingIL2productionbyTcells.
CD8EffectorCells(CellularImmuneResponse)

CTLseliminatetargetcells(virallyinfectedcells,tumor,orforeigntissues),thusconstitutingthecellularimmuneresponse.CTLsdifferfromhelperT
lymphocytesintheirexpressionofthesurfaceantigenCD8andbytherecognitionofantigencomplexedtocellsurfaceproteinsofMHCclassI.Allsomaticcells
canexpressMHCclassImolecules.Pathogenicmicroorganisms,whoseproteinsgainaccesstothecellcytoplasm(eg,malarialparasites)orbydenovogene
expressionintheinfectedcellcytoplasm(eg,viruses)stimulateCD8classIMHCrestrictedTcellresponses.KillingoftargetcellsbyCTLsrequiresdirectcell
tocellcontact.Twomajormechanismsforkillingtargetcellshavebeendescribed:(1)CTLsecretionofaporeformingprotein(perforin)thatinsertsinthe
plasmamembraneoftargetcellsalongwithserineproteasescalledgranzymes,leadingtoosmoticlysisand(2)expressionoftheFasligandonthesurfaceof
CTLsthatbindtoFasonthetargetcellmembraneinducingprogrammedcelldeath(apoptosis).Inadditiontokillinginfectedcellsdirectly,CD8Tcellscan
elaborateanumberofcytokines,includingTNFandlymphotoxin.MemoryCTLsmaybelonglivedtoproviderecallresponsesandimmunityagainstlatentor
persistentviralinfections.
ActivationofBLymphocytes(HumoralImmuneResponse)

TheprimaryfunctionofmatureBlymphocytesistosynthesizeantibodies.LikeTcellactivation,BlymphocyteactivationistriggeredafterantigenbindstoBCRs
(ie,surfaceboundimmunoglobulin)andisregulatedthroughconcomitantcoreceptorbinding.Insecondarylymphoidtissues,releaseofcytokinesIL2,IL4,IL
5,andIL6byactivatedhelperTlymphocytespromotestheproliferationandterminaldifferentiationofBcellsintohighrateantibodyproducingcellscalled
plasmacells,whichsecreteantigenspecificimmunoglobulin.IfcomplementfragmentsbindBcellsurfacecomplementreceptorsatthesametimeantigen
engagesBCRs,cellularresponsesareheightened.TcellsalsomodulatehumoralimmunitythroughtheiractivationdependentmembraneexpressionofCD40
ligandprotein.ThroughdirectTandBcellcontact,CD40ligandbindstotheCD40receptoronthesurfaceofBcells,inducingapoptosis(programmedcell
death)oractivationofimmunoglobulinsynthesis,dependingonthesituation.TheimportanceofCD40ligandCD40bindinginnormalhumoralimmunityis
highlightedbythecongenitalimmunodeficiency,XlinkedhyperIgMsyndrome.AdefectinthesynthesisofCD40ligandonactivatedTcellsresultsinimpaired
isotypeswitchingandhyperIgM,withsubsequentdeficientproductionofIgG,IgA,andimpairedhumoralimmunity.
Althoughtheirprimaryfunctionissynthesisofimmunoglobulin,Blymphocytesmayalsobindandinternalizeforeignantigendirectly,processthatantigen,and
presentittoCD4Tlymphocytes.ApoolofactivatedBlymphocytesmaydifferentiateintomemorycells,whichrespondmorerapidlyandefficientlyto
subsequentencounterswithidenticalorcloselyrelatedantigenicstructures.
AntibodyStructure&Function

Antibodies(immunoglobulins)areproteinsthatpossessspecificity,enablingthemtocombinewithoneparticularantigenicstructure.Antigenbindingsitesfor
immunoglobulinwillrecognizethreedimensionalstructures,whereasTCRwillbindshortpeptidesegmentswithouttertiarystructure.Humoral(antibody
mediated)immuneresponsesresultintheproductionofadiverserepertoire(estimated1091011)ofantibodyspecificities,providingtheabilitytorecognizeand
bindwithabroadrangeofantigens.ThisdiversityisafunctionofsomaticrecombinationofgenesegmentswithinBlymphocytesearlyinontogenetic
development.Somaticmutationsoccurringafterantigenicstimulationleadtoaffinitymaturation,ie,theaverageaffinityofantibodybindingincreasesthroughout
theimmuneresponse.Somaticrecombination,inbothTcellsandBcells,isdependentonrecombinationactivatinggenes(RAG1andRAG2),thedeficiencyof

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whichleadstoalackofTandBlymphocytes,anautosomalrecessiveformofSCID.
Allimmunoglobulinmoleculesshareafourchainpolypeptidestructureconsistingoftwoheavyandtwolightchains(Figure33).Eachchainincludesanamino
terminalportion,containingthevariable(V)region,andacarboxylterminalportion,containingfourorfiveconstant(C)regions.Vregionsarehighlyvariable
structuresthatformtheantigenbindingsite,whereastheCdomainssupporteffectorfunctionsofthemolecules.Thefiveclasses(isotypes)of
immunoglobulinsareIgG,IgA,IgM,IgD,andIgEandaredefinedonthebasisofdifferencesintheCregionoftheheavychains.Theisotypeexpressedbya
particularBlymphocyteisdependentonthestateofcellulardifferentiationandisotypeswitching,aprocesscharacterizedbysplicingofheavychainmRNA
priortotranslation.Differentisotypescontributetodifferenteffectorfunctionsonthebasisoftheabilityofthemoleculetobindtospecificreceptorsandtheir
efficiencyinfixingserumcomplement.IgGisthepredominantimmunoglobulininserumwiththelongesthalflife.FoursubclassesIgG1,IgG2,IgG3,andIgG4
differintheirrelativequantitiesandtargets(proteinvs.carbohydrateantigens).IgAisthepredominantimmunoglobulinonmucousmembranesurfaces.It
existspredominantlyasamonomerinserumandasadimerortrimerwhensecretedonmucousmembranesurfaces.IgAantibodiesprotectthehostfrom
foreignantigensonmucousmembranesurfaces,buttheydonotfixcomplementbytheclassicpathway.IgMisapentamerthatisfoundalmostexclusivelyin
theintravascularcompartment.IgMisexpressedearlyinimmuneresponses,providingrapidadaptiveimmunityanddetectionofantigenspecificIgMcanbe
useddiagnosticallyduringcertaininfections.IgDisamonomericimmunoglobulin.Itsbiologicalfunctionisunknown.IgEistheheaviestimmunoglobulin
monomer,withanormalconcentrationinserumvaryingfrom20to100IU,buttheconcentrationmaybe5timesnormalorevenhigherinanatopicindividual.
TheFcportionofIgEbindstoreceptorsonthesurfacesofmastcellsandbasophils.IgEantibodiesplayanimportantroleinimmediatehypersensitivity
reactions.
FIGURE33

StructureofahumanIgGantibodymolecule.Depictedarethefourchainstructureandthevariableandconstantdomains.(V,variableregionC,constant
region.Thesitesofpepsinandpapaincleavageareshown.)(Redrawn,withpermission,fromStitesDPetal,eds.Basic&ClinicalImmunology,9thed.
OriginallypublishedbyAppleton&Lange.Copyright1997byTheMcGrawHillCompanies,Inc.)

HumoralMechanismsofAntigenElimination

Antibodiesinducetheeliminationofforeignantigenthroughanumberofdifferentmechanisms.Bindingofantibodytobacterialtoxinsorforeignvenomsmay
causeneutralizationorpromoteeliminationoftheseantigenantibodyimmunecomplexesthroughthereticuloendothelialsystem.Antibodiesmaycoatbacterial
surfaces,enhancingphagocytosisbymacrophagesinaprocessknownasopsonization.Someclassesofantibodiesmaycomplexwithantigenandactivatethe
complementcascade(complementfixation),culminatinginlysisofthetargetcell.Finally,themajorclassofantibody,IgG,canbindtoNKcellsthat
subsequentlycomplexwithtargetcellsandreleasecytotoxins(seepriordiscussionofantibodydependentcellularcytotoxicity).IgGpassestransplacentally,
providingpassiveimmunizationofneonates.
Afterthesuccessfuleliminationofantigen,theimmunesystemusesseveralmechanismstoreturntobasalhomeostasis.IgGcanswitchoffitsownresponseto
antigenthroughthebindingofimmunecomplexesthattransmitinhibitorysignalsintothenucleiofBcells.
MechanismsofInflammation

Eliminationofforeignantigenbycellularorhumoralprocessesisintegrallylinkedtotheinflammatoryresponse,inwhichcytokinesandantibodiestriggerthe
recruitmentofadditionalcellsandthereleaseofendogenousvasoactiveandproinflammatoryenzymaticsubstances(inflammatorymediators).
Inflammationmayhavebothpositiveanddeleteriouseffects.Tightcontrolofinflammatorymechanismspromotesefficienteliminationofforeignsubstances,
killingofmicrobes,infectedcells,andtumors.Uncontrolledlymphocyteactivationandunregulatedantibodyproduction,however,canleadtotissuedamageand
organdysfunction.Pathogenicimmunedysfunctionisresponsibleforhypersensitivityreactions,immunodeficiency,andmanyoftheclinicaleffectsof
autoimmunity.Imbalancesintheinflammatorysystemmayresultfromgeneticdefects,infection,neoplasms,andexposuretoenvironmentaltriggers,although
precisemechanismsthatpromoteabnormalregulationandpersistenceofinflammatoryprocessesarecomplexandpoorlyunderstood.
HypersensitivityImmuneResponses

GellandCoombsclassifiedthemechanismsofimmuneresponsestoantigenintofourdistincttypesofreactionstoallowforclearerunderstandingofthe

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immunopathogenesisofdisease.
TYPEI

ClinicalallergyrepresentsIgEmediatedhypersensitivityresponsearisingfromdeleteriousinflammationinresponsetothepresenceofnormallyharmless
environmentalantigens.AnaphylacticorimmediatehypersensitivityreactionsoccurafterbindingofantigentoIgEantibodiesattachedtothesurfaceofthemast
cellorbasophilandresultinthereleaseofpreformedandnewlygeneratedinflammatorymediatorsthatproducetheclinicalmanifestations.ExamplesoftypeI
mediatedreactionsincludeanaphylacticshock,allergicrhinitis,allergicasthma,andallergicdrugreactions.
TYPEII

CytotoxicreactionsinvolvethebindingofeitherIgGorIgMantibodytoantigenscovalentlyboundtocellmembranestructures.Antigenantibodybinding
activatesthecomplementcascadeandresultsindestructionofthecelltowhichtheantigenisbound.Examplesoftissueinjurybythismechanisminclude
immunehemolyticanemiaandRhhemolyticdiseaseinthenewborn.AnotherexampleofthetypeIImediateddiseaseprocesswithoutcelldeathis
autoimmunehyperthyroidism,adisorderinwhichantithyroidantibodiesstimulatethyroidtissue.
TYPEIII

Antigenbindingtoantibodieswithfixationofcomplementformsimmunecomplexmediatedreactions.Complementboundimmunecomplexesfacilitate
opsonizationbyphagocytesandADCC.Complexesareusuallyclearedfromthecirculationinthereticuloendothelialsystem.However,depositionofthese
complexesintissuesorinvascularendotheliumcanproduceimmunecomplexmediatedtissueinjurythroughcomplementactivation,anaphylatoxin
generation,chemotaxisofpolymorphonuclearleukocytes,mediatorreleaseandtissueinjury.CutaneousArthusreaction,systemicserumsickness,some
aspectsofclinicalautoimmunity,andcertainfeaturesofinfectiveendocarditisareclinicalexamplesoftypeIIImediateddiseases.
TYPEIV

Cellmediatedimmunityisresponsibleforhostdefensesagainstintracellularpathogenicorganisms,althoughabnormalregulationofthissystemmayresultin
delayedtypehypersensitivity.TypeIVhypersensitivityreactionsaremediatednotbyantibodybutbyantigenspecificTlymphocytes.Classicexamplesare
tuberculinskintestreactionsandcontactdermatitis.
SynthesisofIgEinAllergicReactivity

AllergichypersensitivityresultsfromtheinappropriateandsustainedproductionofIgEinresponsetoallergen.T H2cytokinesIL4andIL13arecriticalto
isotypeswitchingthroughinductionofgermlinetranscriptionofIgEheavychaingenes.IL13hasabout30%structuralhomologywithIL4andsharesmuchof
theactivitiesofIL4onmononuclearcellsandBlymphocytes.Thereisastronggeneticpredispositiontowardthedevelopmentofatopicdisease.Evidencehas
beenfoundforthelinkageof5q31.1andtheIL4gene,suggestingthatIL4oranearbygeneinthischromosomelocaleregulatesoverallIgEproduction.
Incontrast,T H1generatedIFNinhibitsIL4dependentIgEsynthesisinhumans.Thus,animbalancefavoringIL4overIFNmayinduceIgEformation.In
onestudy,reducedcordbloodIFNatbirthwasassociatedwithclinicalatopyatage12months.
Inallergicinflammatoryprocesses,T H2lymphocytesrepresentasourceofIL4aswellassecondarysignalsnecessarytodrivetheproductionofIgEbyB
lymphocytes.AnotherT H2cytokine,IL5,promotesmaturation,activation,chemotaxis,andprolongationofsurvivalineosinophils.Insituhybridizationanalyses
ofTcellmRNAinairwaymucosalbiopsiesfromallergicrhinitisandasthmapatientsshowadistinctT H2pattern.ThedemonstrationofallergenspecificTcell
linesthatproliferateandsecretelargeamountsofIL4onexposuretorelevantantigeninvitrofurthersupportstheexistenceofspecificT H2likeclones.The
originalsourceoftheIL4responsibleforT H2differentiationisunclear,althoughsomeobservationssuggestthatthereexistsaT H2biasduringfetal
developmentinbothatopicandnonatopicindividuals.Thehygienehypothesispositsthatenvironmentalexposures,possiblytobacterialproductssuchas
endotoxinorbacterialDNA,encourageashifttowardT H1andsubsequentreducedriskofclinicalatopicdisease.Mononuclearphagocytesarethemajorsource
ofIL12,suggestingamechanismwherebyantigensmorelikelytobeprocessedbymacrophages,includingbacterialantigensandintracellularpathogens,
produceT H1responses.Epidemiologicstudiesofchildrensuggestthoseexposedtodaycareatearlyagesandthosewithnumeroussiblingsareatreducedrisk
foratopyandasthma.
SincethediscoveryofIgEmorethan3decadesago,scientistshaveconsideredvarioustherapeuticstrategiestoselectivelyinhibitIgEantibodyproductionand
action.ResearchhasfocusedonunderstandingthemechanismscontrollingIgEproduction,includingthemoleculareventsofBcellswitchingtoIgEsynthesis,
IL4andIL13signaling,TandBcellsurfacereceptorinteractions,andmechanismsdrivingT H2differentiation.Solublecytokinereceptorsandgenetically
engineeredmonoclonalantibodiesarecurrentlyunderdevelopmentforthepurposeofcytokineneutralizationinallergicdiseases.Manyofthesespecifically
targetIL4,IL5,IL13,orCD23(alowaffinityIgEreceptor).OtherexperimentalstrategiesincludetreatmentwithagentssuchasDNAoligonucleotidesthatare
biasedtowardT H1immuneresponses.Conventionalandmodifiedimmunotherapymayworkbyeliminating(anergize)ratherthanstimulatingT H2responses
toenvironmentalallergen,potentiallythroughgenerationofT reg.Besidesconventionalimmunotherapy(allergyshots),theonlyotherU.S.FoodandDrug
Administration(FDA)approvedimmunomodulatorystrategyfortreatmentofallergicdiseaseisomalizumaborantiIgE.Omalizumabisahumanized
monoclonalantibodydirectedagainsttheregionofIgEheavychaininvolvedintheinteractionwithIgEreceptors.Clinicaltrialsinasthmapatientshaveshown
thatthisantibodycanreducesymptomsandmedicationrequirementsinpatientswithallergicasthma,thoughanaphylaxishasoccurredbothafterfirstdoseand
after>1yearofuse.
Checkpoint
9. Whatarethecomponentsofanddistinctionsbetweentheinnateandadaptiveformsofimmunity?
10. Indicatetheprimaryroleoftheimmunesystemandthemajorclassesofeventsbywhichthisisaccomplished.
11. WhatisthephenomenonofMHCrestriction?
12. WhatsignalsarenecessaryforactivationofhelperTlymphocytes?
13. WhattwosignalsarenecessaryforactivationofcytotoxicTlymphocytes?
14. Whatarethecommonstructuralfeaturesofantibodies?
15. Namefourdifferentmechanismsbywhichantibodiescaninducetheeliminationofforeignantigens.
16. WhatarethefourtypesofimmunereactionsintheGellandCoombsclassificationscheme,andwhataresomeexamplesofdisordersinwhicheachis
involved?
17. WhatisthecriticalfactorinswitchingIgsynthesistotheIgEisotype?Whataresomesecondaryfactorsthatcontributeto,orinhibit,IgEsynthesis?

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PathophysiologyofSelectedImmuneDisorders
AllergicRhinitis
ClinicalPresentation

Allergicairwaydiseasessuchasallergicrhinitisandasthmaarecharacterizedbylocaltissuedamageandorgandysfunctionintheupperandlowerrespiratory
tractarisingfromanabnormalhypersensitivityimmuneresponsetonormallyharmlessandubiquitousenvironmentalallergens.Allergensthatcauseairway
diseasearepredominantlyseasonaltree,grass,andweedpollensorperennialinhalants(eg,housedustmiteantigen,cockroach,mold,animaldander,and
someoccupationalproteinantigens).Allergicdiseaseisacommoncauseofpediatricandadultacuteandchronicairwayproblems.Bothallergicrhinitisand
asthmaaccountforsignificantmorbidity,andatopicdisordershaveincreasedinprevalenceoverthepastfewdecades.InaDanishsurvey,theprevalenceof
skintestpositiveallergicrhinitisinpersons1541yearsofageincreasedfrom12.9%in1990to22.5%in1998.Allergicrhinitisisdiscussedhereasamodelfor
thepathophysiologyofIgEmediatedallergicairwaydisease.
Etiology

AllergicrhinitisimpliestheexistenceoftypeI(IgEmediated)immediatehypersensitivitytoenvironmentalallergensthatimpacttheupperrespiratorymucosa
directly.Particleslargerthan5marefilteredalmostcompletelybythenasalmucosa.Becausemostpollengrainsareatleastthislarge,fewintactparticles
wouldbeexpectedtopenetratethelowerairwaywhenthenoseisfunctioningnormally.Theallergicoratopicstateischaracterizedbyaninheritedtendencyto
generateIgEantibodiestospecificenvironmentalallergensandthephysiologicresponsesthatensuefrominflammatorymediatorsreleasedaftertheinteraction
ofallergenwithmastcellboundIgE.Theclinicalpresentationofallergicrhinitisincludesnasal,ocular,andpalatalpruritus,paroxysmalsneezing,rhinorrhea,
andnasalcongestion.Apersonalorfamilyhistoryofotherallergicdiseasessuchasasthmaoratopicdermatitissupportsadiagnosisofallergy.Evidenceof
nasaleosinophiliaorbasophiliabynasalsmearorscrapingmaysupportthediagnosisalso.Confirmationofallergicrhinitisrequiresthedemonstrationof
specificIgEantibodiestocommonallergensbyinvitrotestssuchastheradioallergosorbenttestorinvivo(skin)testinginpatientswithahistoryofsymptoms
withrelevantexposures.
Pathology&Pathogenesis

Inflammatorychangesintheairwaysarerecognizedascriticalfeaturesofbothallergicrhinitisandchronicasthma.CrosslinkingofsurfaceboundIgEby
antigenactivatestissuemastcellsandbasophils,inducingtheimmediatereleaseofpreformedmediatorsandthesynthesisofnewlygeneratedmediators.Mast
cellsandbasophilsalsohavetheabilitytosynthesizeandreleaseproinflammatorycytokines,growthandregulatoryfactorsthatinteractincomplexnetworks.
Theinteractionofmediatorswithvarioustargetorgansandcellsoftheairwaycaninduceabiphasicallergicresponse:anearlyphasemediatedchieflyby
releaseofhistamineandotherstoredmediators(tryptase,chymase,heparin,chondroitinsulfate,andTNF),whereaslatephaseeventsareinducedafter
generationofarachidonicacidmetabolites(LTsandPGs),PAF,anddenovocytokinesynthesis.
Theearlyphaseresponseoccurswithinminutesafterexposuretoanantigen.Afterintranasalchallengeorambientexposuretorelevantallergen,theallergic
patientbeginssneezinganddevelopsanincreaseinnasalsecretions.Afterapproximately5minutes,thepatientdevelopsmucosalswellingleadingtoreduced
airflow.Thesechangesaresecondarytotheeffectsofvasoactiveandsmoothmuscleconstrictivemediators,includinghistamine,NptosylLarginine
methylesteresterase(TAME),LTs,PGD2,andkininsandkininogensfrommastcellsandbasophils.Histologically,theearlyresponseischaracterizedby
vascularpermeability,vasodilatation,tissueedema,andamildcellularinfiltrateofmostlygranulocytes.
Thelatephaseallergicresponsemayfollowtheearlyphaseresponse(dualresponse)ormayoccurasanisolatedevent.Latephasereactionsbegin24
hoursafterinitialexposuretoantigen,reachmaximalactivityat612hours,andusuallyresolvewithin1224hours.Iftheexposureisfrequentorongoing,
however,theinflammatoryresponsebecomeschronic.Thelatephaseresponseischaracterizedbyerythema,induration,heat,burning,anditchingand
microscopicallybyasignificantcellularinfluxofmainlyeosinophilsandmononuclearcells.Changesconsistentwithairwayremodelingandtissuehyperreactivity
mayalsooccur.
MediatorsoftheearlyphaseresponseexceptforPGD2reappearduringthelatephaseresponseintheabsenceofantigenreexposure.AbsenceofPGD2,
anexclusiveproductofmastcellrelease,inthepresenceofcontinuedhistaminereleasesuggeststhatbasophilsandnotmastcellsareanimportantsourceof
mediatorsinthelatephaseresponse.Thereisanearlyaccumulationofneutrophilsandeosinophils,withlateraccumulationofactivatedTcells,synthesizing
T H2cytokines.Inflammatorycellsinfiltratingtissuesinthelateresponsemayfurtherelaboratecytokinesandhistaminereleasingfactorsthatmayperpetuate
thelatephaseresponse,leadingtosustainedhyperresponsiveness,mucushypersecretion,IgEproduction,eosinophilia,anddisruptionofthetargettissue(eg,
bronchi,skin,ornasalmucosa).
Thereisstrongcircumstantialevidencethateosinophilsarekeyproinflammatorycellsinallergicairwaydisease.Eosinophilsarefrequentlyfoundinsecretions
fromthenasalmucosaofpatientswithallergicrhinitisandinthesputumofasthmatics.ProductsofactivatedeosinophilssuchasMBPandeosinophiliccationic
protein,whicharedestructivetoairwayepithelialtissueandpredisposetopersistentairwayreactivity,havealsobeenlocalizedtotheairwaysofpatientswith
allergicdisease.
Therecruitmentofeosinophilsandotherinflammatorycellstotheairwayislargelyaproductofactivatedchemokinesandadhesionmolecules.Thereare
twosubfamiliesofchemokines,whichdifferinthecellstheyprimarilyattractandinthechromosomelocationoftheirgenes.TheCCchemokines,including
RANTES,MCP1,MCP3,andeotaxin,arelocatedonchromosomesegment7q11q21andselectivelyrecruiteosinophils.Leukocytesattachtovascular
endothelialcellsthroughreceptorligandinteractionofcellsurfaceadhesionmoleculesoftheintegrin,selectin,andimmunoglobulinsupergenefamily.The
interactionoftheseadhesionmoleculesandtheircounterreceptorsmediatesasequenceofeventsthatincludesmarginationofleukocytesalongthewallsof
themicrovasculature,adhesionofleukocytestotheepithelium,transmigrationofleukocytesthroughvesselwalls,andmigrationalongachemotacticgradientto
reachtissuecompartments.Bothchemokineproductionandadhesionmoleculeexpressionareupregulatedbysolubleinflammatorymediators.Forinstance,
endothelialcelladhesionmoleculereceptors,ICAM1,VCAM1,andEselectin,areupregulatedbyIL1,TNF,andLPS.
ClinicalManifestations

Theclinicalmanifestationsofallergicairwaydisease(Table33)arisefromtheinteractionofmastcellandbasophilmediatorswithtargetorgansoftheupper
andlowerairway.Thesymptomsofallergicrhinitisappearimmediatelyafterexposuretoarelevantallergen(earlyphaseresponse),althoughmanypatients
experiencechronicandrecurrentsymptomsonthebasisofthelatephaseinflammatoryresponse.Complicationsofsevereoruntreatedallergicrhinitisinclude
sinusitis,auditorytubedysfunction,hyposmia,sleepdisturbances,asthmaexacerbations,andchronicmouthbreathing.
Table33Clinicalmanifestationsofallergicrhinitis.

Symptomsandsigns
Sneezingparoxysms
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Nasal,ocular,palatalitching
Clearrhinorrhea
Nasalcongestion
Pale,bluishnasalmucosa
Transversenasalcrease
Infraorbitalcyanosis(allergicshiners)
Serousotitismedia
Laboratoryfindings
Nasaleosinophilia
EvidenceofallergenspecificIgEbyskinorRASTtesting
SNEEZING,PRURITUS,MUCUSHYPERSECRETION

Patientswithallergicrhinitisdevelopchronicorepisodicparoxysmalsneezingnasal,ocular,orpalatalpruritusandwateryrhinorrheatriggeredbyexposureto
aspecificallergen.Patientsmaydemonstratesignsofchronicpruritusoftheupperairway,includingahorizontalnasalcreasefromfrequentnoserubbing
(allergicsalute)andpalatalclickingfromrubbingtheitchingpalatewiththetongue.Manytissuemastcellsarelocatednearterminalsensorynerveendings.
PruritusandsneezingarecausedbyhistaminemediatedstimulationoftheseCfibers.Mucushypersecretionresultsprimarilyfromexcitationof
parasympatheticcholinergicpathways.Earlyphasesymptomsarebesttreatedwithavoidanceofrelevantallergensandoralortopicalantihistamines,which
competitivelyantagonizeH1receptorsitesintargettissues.Antiinflammatorytreatmentcanreducecellularinflammationduringthelatephase,providingmore
effectivesymptomreliefthanantihistaminesalone.Allergenimmunotherapy(hyposensitization)hasshowneffectivenessinreducingsymptomsandairway
inflammationbyinhibitingbothearlyandlatephaseallergicresponses.Diversemechanismsofimmunotherapyhavebeenobserved,includingreductionof
seasonalincreasesinIL4andallergenspecificIgE,inductionofallergenspecificIgG1andIgG4(blockingantibodies),modulationofTcellcytokinesynthesis
byenhancingT H1andinhibitingT H2responses,upregulationofT reganddownregulationofeosinophilicandbasophilicinflammatoryresponsestoallergen.One
trialfoundthatimmunotherapyadministeredtopatientswithgrasspollenallergyfor34yearsinducedprolongedclinicalremissionaccompaniedbya
persistentalterationinimmunologicreactivitythatincludedsustainedreductionsinthelateskinresponseandassociatedTcellinfiltrationandIL4mRNA
expression.
NASALSTUFFINESS

Symptomsofnasalobstructionmaybecomechronicasaresultofpersistentlatephaseallergicmechanisms.Nasalmucousmembranesmayappearpaleblue
andboggy.Childrenfrequentlyshowsignsofobligatemouthbreathing,includinglongfacies,narrowmaxillae,flattenedmalareminences,markedoverbite,and
higharchedpalates(socalledadenoidfacies).Thesesymptomsarenotmediatedbyhistamineandare,therefore,poorlyresponsivetoantihistaminetherapy.
Oralsympathomimeticsthatinducevasoconstrictionbystimulationofadrenergicreceptorsareoftenusedinconjunctionwithantihistaminestotreatnasal
congestion.Topicaldecongestantsmaybeusedtorelieveacutecongestionbuthavelimitedvalueinpatientswithchronicallergicrhinitisbecausefrequentuse
resultsinreboundvasodilation(rhinitismedicamentosa).
AIRWAYHYPERRESPONSIVENESS

Thephenomenonofheightenednasalsensitivitytoreducedlevelsofallergenafterinitialexposurestotheallergenisknownaspriming.Clinically,primingmay
beobservedinpatientswhodevelopincreasedsymptomslateinthepollenseasoncomparedwithearlyintheseason.Latephaseinflammationinducesastate
ofnasalairwayhyperresponsivenesstobothirritantsandallergensinpatientswithchronicallergicrhinitisandasthma.Airwayhyperreactivitycancause
heightenedsensitivitytobothenvironmentalirritantssuchastobaccosmokeandnoxiousodorsaswellastoallergenssuchaspollens.Thereareno
standardizedclinicaltoolstoaccuratelyassesslatephasehyperresponsivenessinallergicrhinitisasthereareforasthma(methacholineorhistamine
bronchoprovocationchallenge).Geneticmarkersforbronchialairwayhyperresponsiveness,however,havebeenidentified.Italsoappearsthatlatephase
cellularinfiltrationandeosinophilbyproductsmayinflictairwayepithelialdamage,whichinturncanpredisposetoupperandlowerairwayshyperreactivity.
Accumulatingevidencesupportsarelationshipbetweenallergicrhinitisandasthma.Manypatientswithrhinitisalonedemonstratenonspecificbronchial
hyperresponsiveness,andprospectivestudiessuggestthatnasalallergymaybeapredisposingriskfactorfordevelopingasthma.Treatmentofpatientswith
allergicrhinitismayresultinimprovementofasthmasymptoms,airwaycaliber,andbronchialhyperresponsivenesstomethacholineandexercise.Finally,
mechanisticstudiesofairwayphysiologyhavedemonstratedthatnasaldiseasemayinfluencepulmonaryfunctionviabothdirectandindirectmechanisms.
Suchmechanismsmayincludetheexistenceofanasalbronchialreflex(withnasalstimulationcausingbronchialconstriction),postnasaldripofinflammatory
cellsandmediatorsfromthenoseintothelowerairways,absorptionofinflammatorycellsandmediatorsintothesystemiccirculationandultimatelytothelung,
andnasalblockageandsubsequentmouthbreathing,whichmayfacilitatetheentryofasthmagenictriggerstothelowerairway.
INVIVOORINVITROMEASUREMENTOFALLERGENSPECIFICIGE

Thisistheprimarytoolfortheconfirmationofsuspectedallergicdisease.Invivoskintestingwithallergenssuspectedofcausinghypersensitivityconstitutesan
indirectbioassayforthepresenceofallergenspecificIgEontissuemastcellsorbasophils.Percutaneousorintradermaladministrationofdiluteconcentrations
ofspecificantigenselicitsanimmediatewhealandflareresponseinasensitizedindividual.Thisresponsemarksalocalanaphylaxisresultingfromthe
controlledreleaseofmediatorsfromactivatedmastcells.Positiveskintestresultstoairborneallergens,combinedwithahistoryandexaminationsuggestiveof
allergy,stronglyimplicatetheallergenasacauseofthepatientssymptoms.Negativeskintestresultswithanunconvincingallergyhistoryarguestrongly
againstanallergicorigin.Majoradvantagestoskintestingincludesimplicity,rapidityofperformance,andlowcost.
InvitrotestsprovidequantitativeassaysofallergenspecificIgEintheserum.Intheseassays,patientserumisreactedinitiallywithantigenboundtoasolid
phasematerialandthenlabeledwitharadioactiveorenzymelinkedantiIgEantibody.Theseimmunoallergosorbenttestsshowa7080%correlationwithskin
testingtopollens,dustmites,anddandersandareusefulinpatientsreceivingchronicantihistaminetherapywhoareunabletoundergoskintestingandin
patientswithextensivedermatitis.
COMPLICATIONSOFALLERGICRHINITIS

Serousotitismediaandsinusitisaremajorcomorbiditiesinpatientswithallergicrhinitis.Bothconditionsoccursecondarilytotheobstructednasalpassagesand
sinusostiainpatientswithchronicallergicornonallergicrhinitis.Complicationsofchronicrhinitisshouldbeconsideredinpatientswithprotractedrhinitis

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unresponsivetotherapy,refractoryasthma,orpersistentbronchitis.Serousotitisresultsfromauditorytubeobstructionbymucosaledemaandhypersecretion.
Childrenwithserousotitismediacanpresentwithconductivehearingloss,delayedspeech,andrecurrentotitismediaassociatedwithchronicnasalobstruction.
Sinusitismaybeacute,subacute,orchronicdependingonthedurationofsymptoms.Obstructionofosteomeataldrainageinpatientswithchronicrhinitis
predisposestobacterialinfectioninthesinuscavities.Patientsmanifestsymptomsofpersistentnasaldischarge,cough,sinusdiscomfort,andnasalobstruction.
Examinationmayrevealchronicotitismedia,infraorbitaledema,inflamednasalmucosa,andpurulentnasaldischarge.Radiographicdiagnosisbyxrayfilmor
computedtomographic(CT)scanrevealssinusopacification,membranethickening,orthepresenceofanairfluidlevel.Effectivetreatmentofinfectious
complicationsofchronicrhinitisrequiresantibiotics,systemicantihistamineanddecongestants,andperhapsintranasalorsystemiccorticosteroids.
Checkpoint
18. Whatarethemajorclinicalmanifestationsofallergicrhinitis?
19. Whatarethemajoretiologicfactorsinallergicrhinitis?
20. Whatarethepathogeneticmechanismsinallergicrhinitis?

PrimaryImmunodeficiencyDiseases
Therearemanypotentialsiteswheredevelopmentalaberrationsintheimmunesystemcanleadtoabnormalitiesinimmunocompetence(Figure34Tables3
4and35).Whenthesedefectsaregeneticinorigin,theyarereferredtoasprimaryimmunodeficiencydisorders.Thisisincontrasttocompromisedimmunity
secondarytopharmacologictherapy,HIV,malnutrition,orsystemicillnessessuchassystemiclupuserythematosusordiabetesmellitus.
FIGURE34

Simplifiedschemaofdefectsincellsurfacereceptordependentactivationleadingtodifferentprimaryimmunodeficiencydisorders.InTable34arelistedthe
syndromesandimmunologicdeficitsseenwithavarietyofthesehumoral,cellular,neutrophil,orcombinedimmunodeficiencydisorders.

Table34Primaryimmunodeficiencydisorders.

Combinedimmunodeficiency
XSCID

DeficiencyofcommonchainofIL2receptor

Defectivecytokinesignaling

ZAP70deficiency

DefectiveTCRsignaling

CD8Tcelllymphopenia,CD4Tcell
dysfunction

SCIDADAdeficiency

Enzymedefect

Tcell(),Bcell(),NKcell()

P56lckdeficiency

DefectiveTcellreceptorassociatedtyrosinekinase

Tcell(+),Bcell(+),NKcell(+)

JAK3deficiency

Defectivecytokinesignaling

Tcell(),Bcell(+),NKcell(+)

RAG1deficiency

Recombinationdefect

Tcell(),Bcell(),NKcell(+)

PNPdeficiency

Enzymedefect

Tcell()

MHCclassIdeficiency

Defectintransporterassociatedwithantigenpresentation(TAP)

Barelymphocytesyndrome,noMHC
classIexpression

MHCclassIIdeficiency

DefectivetranscriptionofMHCclassIIgenes

Barelymphocytesyndrome,noMHC
classIIexpression

Xlinked
agammaglobulinemia

DefectinBTK

ArrestedmaturationofBcelllineage

Commonvariable
immunodeficiency

AbnormalproliferationanddifferentiationofBcellsorabnormal
regulatorycellfunction1

Heterogeneousdisorderwith
agammaglobulinemia

RAG2deficiency

Humoralimmunodeficiency

Abnormalimmunoglobulinisotype
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HyperIgMsyndrome

DefectiveCD40ligandbinding

switching

Mosthavechromosome22q11deletion

CompleteorpartialTcelldeficiency

Chronicgranulomatous
disease

DefectiveNADPHoxidase

Abnormaloxidativemetabolism

Leukocyteadhesion
deficiency

DefectinCD18subunitof2integrinmolecule

Cellularimmunodeficiency
DiGeorgesyndrome
Phagocyticcelldisorders

1Variabledefects,althoughthemostcommonisinterminaldifferentiationofBlymphocytes.

Table35Relationshipofvariouspathogenstoinfectioninprimaryimmunodeficiencydisorders.

Fungi

Parasites

Pyogenic
Bacteria

Mycobacteria

Pneumocystis
jiroveci

Other
Fungi

Viruses

Giardia
lamblia

Toxoplasma
gondii

Cryptosporidium,
Isospora

SCID

Thymichypoplasia

Xlinked
agammaglobulinemia

Commonvariable
immunodeficiency

Complement
deficiency

Phagocyticdefects

Key:+=association=noassociation.
Clinicalinvestigationsofvariouscongenitaldefectshavehelpedcharacterizemanyaspectsofnormalimmunephysiology.Theverynatureofadefectinhost
immuneresponsesplacesthesusceptibleindividualathighriskforavarietyofinfectious,malignant,andautoimmunediseasesanddisorders.Thenatureof
thespecificfunctionaldefectwillsignificantlyinfluencethetypeofinfectionthataffectsthehost.Table35listssomeofthetypicalorganismscausinginfection
inpatientswithvariousimmunodeficiencydisorders.AnyimmunopathogenicmechanismthatimpairsTlymphocytefunction,orcellmediatedimmunity,
predisposesthehosttothedevelopmentofseriouschronicandpotentiallylifethreateningopportunisticinfectionswithviruses,mycobacteria,fungi,and
protozoainvolvinganyorallorgansystems.Similarly,immunopathogenicdysfunctionofBlymphocytesresultinginantibodydeficiencywillpredisposethe
hosttopyogenicsinopulmonaryandmucosalinfections.Asthemolecularbasesofmanyprimaryimmunodeficiencydisordersarebeingdiscovered,ithas
becomeapparentthatdifferentmoleculardefectscanresultincommonclinicalphenotypes.
TheTlymphocyteplaysacentralroleininducingandcoordinatingimmuneresponses,anddysfunctioncanbeassociatedwithanincreasedincidenceof
autoimmunephenomena.Theseincludediseasesclinicallysimilartorheumatoidarthritis,systemiclupuserythematosus,andimmunehematologiccytopenias.
Patientswithimpairedimmuneresponsesarealsoatgreaterriskforcertainmalignanciesthanthegeneralpopulation.Theoccurrenceofcancermaybe
relatedtoanunderlyingimpairmentoftumorsurveillance,dysregulationofcellularproliferationanddifferentiation,chromosomaltranslocationsduringdefective
antigenreceptorgenerearrangement,orthepresenceofinfectiousagentspredisposingtoorcausingcellulartransformation.NonHodgkinlymphomaorBcell
lymphoproliferativedisease,skincarcinomas,andgastriccarcinomasarethemostfrequentlyoccurringtumorsinpatientswithimmunodeficiency.
Traditionally,theprimaryimmunodeficienciesareclassifiedaccordingtowhichcomponentoftheimmuneresponseisprincipallycompromised:thehumoral
response,cellmediatedimmunity,complement,orphagocyticcellfunction(Table34).Distinctdevelopmentalstagescharacterizethematurationand
differentiationofthecellularcomponentsoftheimmunesystem.Theunderlyingpathophysiologicabnormalitiesleadingtoprimaryimmunodeficiencyare
diverseandincludethefollowing:(1)earlydevelopmentaldefectsincellularmaturation,(2)specificenzymedefects,(3)abnormalitiesincellularproliferation
andfunctionaldifferentiation,(4)abnormalitiesincellularregulation,and(5)abnormalresponsestocytokines.
CombinedImmunodeficiency
SevereCombinedImmunodeficiencyDisease
CLINICALPRESENTATION

Clinically,manyprimaryimmunodeficiencydisorderspresentearlyintheneonatalperiod.InpatientswithSCID,thereisanabsenceofnormalthymictissue,
andthelymphnodes,spleen,andotherperipherallymphoidtissuesaredevoidoflymphocytes.Inthesepatients,thecompleteornearcompletefailureof
developmentofboththecellularandthehumoralcomponentoftheimmunesystemresultsinsevereinfections.Thespectrumofinfectionsisbroadbecause
thesepatientsmayalsosufferfromoverwhelminginfectionbyopportunisticpathogens,disseminatedviruses,andintracellularorganisms.Failuretothrivemay
betheinitialpresentingsymptom,butmucocutaneouscandidiasis,chronicdiarrhea,andpneumonitisarecommon.Vaccinationwithliveviralvaccinesor
bacillusCalmetteGurin(BCG)mayleadtodisseminateddisease.Withoutimmunereconstitutionbybonemarrowtransplantation,SCIDisinevitablyfatalwithin
12years.
PATHOLOGYANDPATHOGENESIS

SCIDisaheterogeneousgroupofdisorderscharacterizedbyafailureinthecellularmaturationoflymphoidstemcells,resultinginreducednumbersand
functionofbothBandTlymphocytesandhypogammaglobulinemia.ThemolecularbasisformanytypesofSCIDhavebeendiscovered(Table34).The
geneticandcellulardefectscanoccuratmanydifferentlevels,startingwithsurfacemembranereceptorsbutalsoincludingdeficienciesinsignaltransductionor

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metabolicbiochemicalpathways.Althoughthedifferentmoleculardefectsmaycauseclinicallyindistinguishablephenotypes,identificationofspecificmutations
allowsforimprovedgeneticcounseling,prenataldiagnosis,andcarrierdetection.Moreover,specificgenetransferoffershopeasafuturetherapy.
DefectiveCytokineSignaling
XlinkedSCID(XSCID)isthemostprevalentform,resultingfromageneticmutationinthecommonchainofthetrimeric()IL2receptor.Thisdefective
chainissharedbythereceptorsforIL4,IL7,IL9,andIL15,leadingtodysfunctionofallofthesecytokinereceptors.DefectivesignalingthroughtheIL7
receptorappearstoblocknormalmaturationofTlymphocytes.CirculatingBcellnumbersmaybepreserved,butdefectiveIL2responsesinhibitproliferationof
T,B,andNKcells,explainingthecombinedimmunedefectsseeninXSCIDpatients.AdefectinthechainoftheIL7receptorcanalsoleadtoanautosomal
recessiveformofSCIDthroughmechanismssimilartoXSCIDbutwithintactNKcells.
DefectiveTCellReceptor
ThegeneticdefectsforseveralotherformsoftheautosomalrecessiveSCIDhavealsobeenidentified.AdeficiencyofZAP70,aproteintyrosinekinase
importantinsignaltransductionthroughtheTCR,leadstoatotalabsenceofCD8Tlymphocytes.ZAP70playsanessentialroleinthymicselectionduringT
celldevelopment.Consequently,thesepatientspossessfunctionallydefectiveCD4TlymphocytesandnocirculatingCD8TlymphocytesbutnormalB
lymphocyteandNKcellactivity.MutationsofCD3,CD3,andCD3subunitsmayleadtopartiallyarresteddevelopmentofTCRexpressionandsevereTcell
deficiency.
Deficienciesofbothp56lckandJak3(Januskinase3)canalsoleadtoSCIDthroughdefectivesignaltransduction.P56lckisaTCRassociatedtyrosinekinase
thatisessentialforTcelldifferentiation,activation,andproliferation.Jak3isacytokinereceptorassociatedsignalingmolecule.
DefectiveReceptorGeneRecombination
Patientshavebeenidentifiedwithdefectiverecombinationactivatinggene(RAG1andRAG2)products.RAG1andRAG2initiaterecombinationofantigen
bindingproteins,immunoglobulins,andTCRs.ThefailuretoformantigenreceptorsleadstoaquantitativeandfunctionaldeficiencyofTandBlymphocytes.NK
cellsarenotantigenspecificandforthatreasonareunaffected.ArtemisandDNAligase4proteinsareinvolvedindoublestrandedDNAbreakageandrepair,
duringVDJrecombinationofTcellreceptorsandBCRs.MutationsofArtemismayalsoleadtoincreasedsensitivitytoionizingradiation.BecauseNKcellsare
invariant,theirnumbersaretypicallypreserved,evenasTandBcellnumbersareseverelydeficient.
DefectiveNucleotideSalvagePathway
Approximately20%ofSCIDcasesarecausedbyadeficiencyofadenosinedeaminase(ADA),whichisanenzymeinthepurinesalvagepathway,
responsibleforthemetabolismofadenosine.AbsenceoftheADAenzymeresultsinanaccumulationoftoxicadenosinemetaboliteswithinthecells.These
metabolitesinhibitnormallymphocyteproliferationandleadtoextremecytopeniaofbothBandTlymphocytes.Thecombinedimmunologicdeficiencyand
clinicalpresentationofthisdisorder,knownasSCIDADA,isidenticaltothatoftheotherformsofSCID.Skeletalabnormalitiesandneurologicabnormalities
maybeassociatedwiththisdisease.Insimilarfashion,purinenucleosidephosphorylasedeficiencyleadstoanaccumulationoftoxicdeoxyguanosine
metabolites.Tcelldevelopmentisimpaired,possiblythroughinducedapoptosisofdoublepositivethymocytesinthecorticomedullaryjunctionofthethymus.B
celldysfunctionismorevariable.
CellMediatedImmunodeficiency
CongenitalThymicAplasia(DiGeorgeSyndrome)
CLINICALPRESENTATIONANDPATHOGENESIS

TheclinicalmanifestationsofDiGeorgesyndromereflectthedefectiveembryonicdevelopmentoforgansderivedfromthethirdandfourthpharyngealarches,
includingthethymus,parathyroids,andcardiacoutflowtract.Occasionally,thefirstandsixthpharyngealpouchesmayalsobeinvolved.Cytogenetic
abnormalities,mostcommonlychromosome22q11deletions,areassociatedwithDiGeorgesyndrome,especiallyinpatientsmanifestingcardiacdefects.
DiGeorgesyndromeisclassifiedascompleteorpartialdependingonthepresenceorabsenceofimmunologicabnormalities.Inthissyndrome,thespectrumof
immunologicdeficiencyiswide,rangingfromimmunecompetencytoconditionsinwhichtherearelifethreateninginfectionswithorganismstypicallyoflow
virulence.PatientsaffectedbythecompletesyndromehaveaprofoundTlymphocytopeniaresultingfromthymicaplasiawithimpairedTlymphocyte
maturation,severelydepressedcellmediatedimmunity,anddecreasedsuppressorTlymphocyteactivity.Blymphocytesandimmunoglobulinproductionare
unaffectedinmostpatients,althoughinrareinstancespatientsmaypresentwithmildhypogammaglobulinemiaandabsentorpoorantibodyresponsesto
neoantigens.Inthissubsetofpatients,inadequatehelperTfunctionasaresultofdysfunctionalTandBcellinteractionandinadequatecytokineproduction
leadstoimpairedhumoralimmunity.
DiGeorgesyndromeistrulyadevelopmentalanomalyandcanbeassociatedwithstructuralabnormalitiesinthecardiovascularsystemsuchastruncus
arteriosusorrightsidedaorticarch.Parathyroidabnormalitiesmayleadtohypocalcemia,presentingwithneonataltetanyorseizures.Inaddition,itiscommon
forpatientstoexhibitfacialabnormalitiessuchasmicrognathia,hypertelorism,lowsetearswithnotchedpinnae,andashortphiltrum.
HumoralImmunodeficiency
XLinkedAgammaglobulinemia
CLINICALPRESENTATION

FormerlycalledBrutonagammaglobulinemia,Xlinkedagammaglobulinemia(XLA)isthoughttobepathophysiologicallyandclinicallymorehomogeneous
thanSCID.Itisprincipallyadiseaseofchildhood,presentingclinicallywithinthefirst2yearsoflifewithmultipleandrecurrentsinopulmonaryinfectionscaused
primarilybypyogenicbacteriaand,toamuchlesserextent,viruses.Becauseencapsulatedbacteriarequireantibodybindingforefficientopsonization,these
humoralimmunedeficientpatientssufferfromsinusitis,pneumonia,pharyngitis,bronchitis,andotitismediasecondarytoinfectionwithStreptococcus
pneumoniae,otherstreptococci,andHaemophilusinfluenzae.Althoughinfectionsfromfungalandopportunisticpathogensarerare,patientsdisplayaunique
susceptibilitytoararebutdeadlyenteroviralmeningoencephalitis.
PATHOLOGYANDPATHOGENESIS

PatientswithXLAhavepanhypogammaglobulinemia,withdecreasedlevelsofIgG,IgM,andIgA.Theyexhibitpoortoabsentresponsestoantigenchallenge
eventhoughvirtuallyalldemonstratenormalfunctionalTlymphocyteresponsestoinvitroaswellasinvivotests(eg,delayedhypersensitivityskinreactions).
ThebasicdefectinthisdisorderappearstobearrestedcellularmaturationatthepreBlymphocytestage.Indeed,normalnumbersofpreBlymphocytescan
befoundinthebonemarrow,althoughinthecirculationBlymphocytesarevirtuallyabsent.LymphoidtissueslackfullydifferentiatedBlymphocytes(antibody
secretingplasmacells),andlymphnodeslackdevelopedgerminalcenters.ThegenethatisdefectiveinXLAhasbeenisolated.Thedefectivegeneproduct,
BTK(Brutontyrosinekinase),isaBcellspecificsignalingproteinbelongingtothecytoplasmictyrosinekinasefamilyofintracellularproteins.Genedeletions
andpointmutationsinthecatalyticdomainoftheBTKgeneblocknormalBTKfunction,necessaryforBcellmaturation.

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CommonVariableImmunodeficiencyDisease
CLINICALPRESENTATION

Commonvariableimmunodeficiencydiseaseisoftenreferredtoasacquiredoradultonsethypogammaglobulinemia.Itisthemostcommonseriousprimary
immunedeficiencydisorderinadults.InNorthAmerica,forexample,itaffectsanestimated1:75,000to1:50,000individuals.Theclinicalspectrumisbroad,and
patientsusuallypresentwithinthefirst2decadesoflife.Affectedindividualscommonlydeveloprecurrentsinopulmonaryinfections,includingsinusitis,otitis,
bronchitis,andpneumonia.CommonpathogensareencapsulatedbacteriasuchasSpneumoniae,Hinfluenzae,andMoraxellacatarrhalis.Bronchiectasiscan
betheresultofrecurrentseriousrespiratoryinfections,leadingtoinfectionwithmorevirulentpathogens,includingStaphylococcusaureusandPseudomonas
aeruginosa,whichinturncanchangethelongtermprognosis.Anumberofimportantnoninfectiousdisordersarecommonlyassociatedwithcommonvariable
immunodeficiency,includingGImalabsorption,autoimmunedisorders,andneoplasms.Themostfrequentlyoccurringmalignanciesarelymphoreticular,but
gastriccarcinomaandskincanceralsooccur.Autoimmunedisordersoccurin2030%ofpatientsandmayprecedetherecurrentinfections.Autoimmune
cytopeniasoccurmostfrequently,butrheumaticdiseasescanalsobeseen.Serologictestingforinfectiousorautoimmunediseaseisunreliablein
hypogammaglobulinemia.Monthlyinfusionsofintravenousimmunoglobulincanreconstitutehumoralimmunity,decreaseinfections,andimprovequalityoflife.
PATHOLOGYANDPATHOGENESIS

Commonvariableimmunodeficiencyisheterogeneousdisorderinwhichtheprimaryimmunologicabnormalityisamarkedreductioninantibodyproduction.The
vastmajorityofpatientsdemonstrateaninvitrodefectinterminaldifferentiationofBlymphocytes.Peripheralbloodlymphocytephenotypingdemonstrates
normalorreducednumbersofcirculatingBlymphocytes,butantibodysecretingplasmacellsareconspicuouslysparseinlymphoidtissues.Insharpcontrastto
XLA,nosinglegenedefectcanbeheldaccountableforthemultitudeofdefectsknowntocausecommonvariableimmunodeficiency.Inmanypatients,the
defectisintrinsictotheBlymphocytepopulation.Approximately15%ofpatientswithcommonvariableimmunodeficiencydiseasedemonstratedefectiveBcell
surfaceexpressionofTACI(transmembraneactivatorandcalciummodulatorandcyclophilinligandinteractor),amemberoftheTNFreceptorfamily.Lackinga
functionalTACI,theaffectedBcellswillnotrespondtoBcellactivatingfactors,resultingindeficientimmunoglobulinproduction.Anotherdefectthatmaylead
tocommonvariableimmunodeficiencydiseaseinvolvesdeficientexpressionofBcellsurfacemarkerCD19.WhencomplexedwithCD21andCD81,CD19
facilitatescellularactivationthroughBCRs.Bcelldevelopmentisnotaffected,buthumoralfunctionisdeficient.AvarietyofTcellabnormalitiesmayalsoleadto
immunedefectswithsubsequentimpairmentofBcelldifferentiation.AmutationofinducibleTcellcostimulatorgene(ICOS),expressedbyactivatedTcellsand
responsibleforBcellactivation/antibodyproduction,maybethemoleculardefectinsomecasesofcommonvariableimmunodeficiencydisease.Morethan
50%ofpatientsalsohavesomedegreeofTlymphocytedysfunctionasdeterminedbyabsentordiminishedcutaneousresponsestorecallantigens.Immune
dysregulationmaycontributetothemorbidityandthemyriadautoimmunemanifestationsassociatedwithcommonvariableimmunodeficiency.
HyperIgMImmunodeficiency
CLINICALPRESENTATION

InpatientswithhyperIgMimmunodeficiency,serumlevelsofIgGandIgAareveryloworabsent,butserumIgM(andsometimesIgD)levelsarenormalor
elevated.Inheritanceofthisdisordermaybeautosomal,althoughitismostoftenXlinked.Clinically,thissyndromeismanifestedbyrecurrentpyogenic
infectionsandanarrayofautoimmunephenomenasuchasCoombspositivehemolyticanemiaandimmunethrombocytopenia.
PATHOLOGYANDPATHOGENESIS

TheprincipalabnormalityisthedefectiveexpressionofCD40ligand(CD40L),aTlymphocyteactivationsurfacemarker(alsoknownasCD154orgp39).Inthe
courseofnormalimmuneresponses,CD40LinteractswithCD40onBcellsurfacesduringcellularactivation,initiatingproliferationandimmunoglobulinisotype
switching.InhyperIgMsyndrome,defectiveCD40coreceptorstimulationduringTandBcellinteractionsleadstoimpairmentofBcellisotypeswitchingand
subsequentproductionofIgMbutnoproductionofIgGorIgA.CD40LCD40interactionalsopromotesdendriticcellmaturationandIL12andIFNsecretion,
soCD40Ldeficiencycanbeassociatedwithimpairedcellmediatedimmunityandincreasedriskofopportunisticinfection.
SelectiveIgADeficiency

Thisisthemostcommonprimaryimmunodeficiencyinadults,withaprevalenceof1:700to1:500individuals.Mostaffectedindividualshavefewornoclinical
manifestations,butthereisanincreasedincidenceofupperrespiratorytractinfections,allergy,asthma,andautoimmunedisorders.Whereasserumlevelsof
theotherimmunoglobulinisotypesaretypicallynormal,serumIgAlevelsintheseindividualsaremarkedlydepressed,oftenlessthan5mg/dL.
Asincommonvariableimmunodeficiency,theprimaryfunctionaldefectisaninabilityofBcellstoterminallydifferentiatetoIgAsecretingplasmacells.An
associateddeficiencyofIgGsubclasses(mainlyIgG2andIgG4)andlowmolecularweightmonomericIgMisnotuncommonandcanbeclinicallysignificant.
BecauseoftheroleofsecretoryIgAinmucosalimmunity,patientswiththisimmunodeficiencyfrequentlydevelopsignificantinfectionsinvolvingthemucous
membranesofthegut,conjunctiva,andrespiratorytract.Thereisnospecifictherapy,butpromptantibiotictreatmentisnecessaryinpatientswithrecurrent
infections.AsubsetofpatientsmayrecognizeIgAasaforeignantigen.Thesepatientsareatriskfortransfusionreactionstounwashedredbloodcellsorother
bloodproductscontainingtraceamountsofIgA.
DisordersofPhagocyticCells&InnateImmunity
Defectivephagocyticcellfunctionpresentswithinfectionsatsitesofinterfacebetweenthebodyandtheoutsideworld.Recurrentskininfections,abscesses,
gingivitis,lymphadenitis,andpoorwoundhealingareseeninpatientswithmacrophageorneutrophildisorders.Moredifficulttoassay,clinicalimmunodeficiency
canoccurthroughdefectsinphagocyticcellmigration,adhesion,opsonization,orkilling.
ChronicGranulomatousDisease
CLINICALPRESENTATION

ChronicgranulomatousdiseaseistypicallyXlinkedandcharacterizedbyimpairedgranulocytefunction.Thisdisorderofphagocyticcellfunctionpresentswith
recurrentskininfections,abscesses,andgranulomasatsitesofchronicinflammation.Abscessescaninvolveskinorvisceraandmaybeaccompaniedby
lymphadenitis.CatalasepositiveorganismspredominateSaureusisthusthemostcommonpathogen,althoughinfectionswithNocardiaspecies,gram
negativeSerratiamarcescens,andBurkholderiacepaciacanalsooccur.AspergillusspeciesandCandidarepresentcommonfungalpathogensinchronic
granulomatousdisease.SterilenoncaseatinggranulomasresultingfromchronicinflammatorystimulicanleadtoGIorgenitourinarytractobstruction.Chronic
granulomatousdiseasetypicallypresentsinchildhood,althoughcasesinadulthoodareoccasionallyreported.
PATHOLOGYANDPATHOGENESIS

Defectsinthegenecodingfornicotinamideadeninedinucleotidephosphate(NADPH)oxidaseinhibitoxidativemetabolismandseverelycompromiseneutrophil
killingactivity.NADPHoxidaseisassembledfromtwomembraneandtwocytosoliccomponentsafterphagocyticcellactivation,leadingtocatalyticconversionof
molecularoxygenintosuperoxide.Oxidativeburstandintracellularkillingrelyonproductionofsuperoxide,whichislaterconvertedtohydrogenperoxideand
sodiumhypochlorite(bleach).Inpatientswithchronicgranulomatousdisease,otherneutrophilfunctionssuchaschemotaxis,phagocytosis,anddegranulation

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remainintactbutmicrobialkillingisdeficient.Catalasenegativebacteriaareeffectivelykilledbecausemicrobesproducesmallamountsofperoxide,
concentratedinphagosomes,leadingtomicrobialdeath.Catalasepositiveorganismsscavengetheserelativelysmallamountsofperoxideandarenotkilled
withoutneutrophiloxidativemetabolism.Xlinkedinheritanceismostfrequentlyseen,butautosomalrecessiveformsandspontaneousmutationscanalsolead
toclinicaldisease.
LeukocyteAdhesionDeficiency,Type1

Integrinsandselectinsarespecializedmoleculesthatplayaroleinleukocytehomingtositesofinflammation.Theseadhesionmoleculesfacilitatecellcelland
cellextracellularmatrixinteractions,allowingcirculatingleukocytestostickandrollalongendothelialcellsurfacespriortodiapedesisintoextravasculartissues.
Anautosomalrecessivetrain,leukocyteadhesiondeficiencytype1,anddefectiveexpressionof2integrin(CD11/CD18)adhesionmoleculesresultinimpaired
traffickingofleukocytes,leadingtorecurrentinfections,lackofpusformation,andpoorwoundhealing.Leukocytosisoccursbecausecellscannotexitthe
circulation,andrecurrentinfectionsofskin,airways,bowels,perirectalarea,andgingivalandperiodontalareasarecommon.
MendelianSusceptibilitytoMycobacterialDisease

Inresponsetomycobacterialinfection,macrophagessecreteIL12,stimulatingcellmediatedimmunityandincreasedT H1secretionofIFN.Atleastadozen
Mendelian,ie,singlegeneproduct,mutationsleadtoimpairmentofthesynthesisoforresponsetoIL12orIFN,thatunderlieMendeliansusceptibilityto
mycobacterialdisease.AssociateddefectshavebeendescribedingenesencodingforIFN,IFNreceptors1and2,JAK1and2(Januskinase,acytokine
receptorsignalingprotein),STAT1and4(signaltransducerandactivatoroftranscription,atranscriptionfactoractivatedbyJAK),IL12anditsreceptors,and
IL12RB1andIL12RB2.Increasedsusceptibilitytolessvirulent,nontuberculousspeciesofmycobacteriaMycobacteriumintracellulareaviumcomplex(MAC),
Mycobacteriumkansasii,Mycobacteriumfortuitum,andBCGarecharacteristicofaffectedindividuals.Infectionwithnontyphoidalsalmonellaemayalsobe
associatedwithMendeliansusceptibilitytomycobacterialdisease.
HyperIgEImmunodeficiency
CLINICALPRESENTATION

ThisdisorderisoftenreferredtoasJobsyndromebecauseaffectedindividualssufferfromrecurrentboilslikethetormentedbiblicalfigure.Theinitial
descriptionofthisimmunodeficiencydisorderwasintwofairskinnedgirlswithrecurrentstaphylococcalcoldskinabscessesassociatedwithfurunculosis,
cellulitis,recurrentotitis,sinusitis,pneumatoceles,andacoarsefacialappearance.ThepredominantorganismisolatedfromsitesofinfectionisSaureus,
althoughotherorganismssuchasHinfluenzae,pneumococci,gramnegativeorganisms,Aspergillussp.andCalbicansareoftenidentifiedalso.
Characteristically,patientshaveachronicpruriticeczematoiddermatitis,defectivesheddingofprimaryteeth,growthretardation,coarsefacies,scoliosis,
osteopenia,vascularabnormalities,andhyperkeratoticfingernails.ExtremelyhighIgElevels(>3000IU/mL)havealsobeenobservedinpatientsserum.
PATHOLOGYANDPATHOGENESIS

ThehighIgElevelsarethoughttobeaconsequenceofdysregulatedimmunologicresponsivenesstocytokines,yetitisunclearwhetherthehyperIgE
contributestotheobservedsusceptibilitytoinfectionorissimplyanimmunologicepiphenomenon.Autosomaldominantformshavebeenassociatedwith
mutationsinSTAT3,atranscriptionalfactorinvolvedintheactivationofcytokineandgrowthfactorreceptors.Responsestonumerouscytokinesdoappear
impaired,alongwithdecreasedT H17function.Aspectrumofimmuneabnormalitiesisalsoobserved.Humoralimmunodeficiencyissuggestedbypoorantibody
responsestoneoantigens,deficiencyofIgAantibodyagainstSaureus,andlowlevelsofantibodiestocarbohydrateantigens.Tlymphocytefunctional
abnormalitiesaresuggestedbydecreasedabsolutenumbersofsuppressorTlymphocytes,poorinvitroproliferativeresponses,anddefectsincytokine
production.Severalreportshavealsodocumentedhighlyvariableabnormalitiesinneutrophilchemotaxis.
TollLikeReceptor3Deficiency

PatientswithTLR3deficiencyhaveshownspecificsusceptibilitytoherpessimplex1(HSV1)encephalitis.Typically,bindingofpathogenassociatedmolecular
patternstoTLRwillactivatetranscriptionfactors,suchasnuclearfactorkappabeta(NF),IFNregulatoryfactors,andactivatorprotein1,leadingtoimmune
responsiveness.Defectsinthispathwayimpairviralimmunity.InTLR3deficiency,defectiveIFN,IFN,andIFNsynthesisleadstouninhibitedHSV1
replicationinneuronsandoligodendriticcells.AsimilarphenotypeisseeninautosomalrecessiveUNC93bdeficiency.UNC93bisrequiredforTLR3function,
asittranslocatesTLR3toitsendosomalsiteofaction.
Checkpoint
21. Whatarethemajorclinicalmanifestationsofeachofthefivecategoriesofprimaryimmunedeficiency?
22. Whatarethemajorpathogeneticmechanismsineachcategoryofprimaryimmunedeficiency?
AIDS

AIDSisthemostcommonimmunodeficiencydisorderworldwide,andHIVinfectionisoneofthegreatestepidemicsinhumanhistory.AIDSistheconsequence
ofachronicretroviralinfectionthatproducessevere,lifethreateningCD4helperTlymphocytedysfunction,opportunisticinfections,andmalignancy.AIDSis
definedbyserologicevidenceofHIVinfectionwiththepresenceofavarietyofindicatordiseasesassociatedwithclinicalimmunodeficiency.Table36lists
criteriafordefininganddiagnosingAIDS.HIVistransmittedbyexposuretoinfectedbodyfluidsorsexualorperinatalcontact.Verticaltransmissionfrommother
toinfantmayoccurinutero,duringchildbirth,andalsothroughbreastfeeding.TransmissibilityoftheHIVvirusisrelatedtosubtypevirulence,viralload,and
immunologichostfactors.
Table361993revisedclassificationsystemforHIVinfectionandexpandedAIDSsurveillancecasedefinitionforadolescentsandadults.

I.Clinicalandlymphocytecategories:
ClinicalCategories
CD4TCell
Categories

(A)Asymptomatic,Acute(Primary)HIV
orPGL1

(B)Symptomatic,Not(A)or(C)
Conditions

(C)AIDSIndicator
Conditions

(1)500/L

A1

B1

C1

(2)200499/mL

A2

B2

C2

(3)<200/mL

A3

B3

C3

II.Conditionsincludedinthe1993AIDSsurveillancecasedefinition:
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Candidiasisoftheesophagus,bronchi,trachea,orlungs
Cervicalcancer,invasive
Coccidioidomycosis,disseminatedorextrapulmonary
Cryptococcosis,extrapulmonary
Cryptosporidiosis,chronicintestinal(>1monthduration)
Cytomegalovirusdisease(otherthanliver,spleen,ornodes)cytomegalovirusretinitis(withlossofvision)
Encephalopathy,HIVrelated
Herpessimplex:chroniculcers(>1monthduration)orbronchitis,pneumonitis,oresophagitis
Histoplasmosis,disseminatedorextrapulmonary
Isosporiasis,chronicintestinal(>1monthduration)
Kaposisarcoma
Lymphoma,Burkitt(orequivalentterm)immunoblasticlymphoma(orequivalentterm)primarybrainlymphoma
MycobacteriumaviumcomplexorMycobacteriumkansasii,disseminatedorextrapulmonary
Mycobacteriumtuberculosis,anysite(pulmonaryorextrapulmonary)
Mycobacterium,otherspeciesorunidentifiedspecies,disseminatedorextrapulmonary
Pneumocystisjiroveciipneumonia
Pneumonia,recurrent
Progressivemultifocalleukoencephalopathy
Salmonellasepticemia,recurrent
Toxoplasmosisofbrain
WastingsyndromeresultingfromHIV
III.Clinicalcategories:
A.CategoryAconsistsofoneormoreoftheconditionslistedbelowinanadolescent(>13years)oradultwithdocumentedHIVinfection.
ConditionslistedincategoriesBandCmustnothaveoccurred.
AsymptomaticHIVinfection
Persistentgeneralizedlymphadenopathy
Acute(primary)HIVinfectionwithaccompanyingillnessorhistoryofacuteHIVinfection
B.CategoryBconsistsofsymptomaticconditionsinanHIVinfectedadolescentoradultthatarenotincludedamongconditionslistedin
clinicalcategoryCandthatmeetatleastoneofthefollowingcriteria:(a)theconditionsareattributedtoHIVinfectionorareindicativeofa
defectincellmediatedimmunityor(b)theconditionsareconsideredbyphysicianstohaveaclinicalcourseortorequiremanagementthat
iscomplicatedbyHIVinfection.
ExamplesofconditionsinclinicalcategoryBincludebutarenotlimitedto:
Bacillaryangiomatosis
Oropharyngealcandidiasis(thrush)
Vulvovaginalcandidiasis,persistent,frequent,orpoorlyresponsivetotherapy
Cervicaldysplasia(moderateorsevere)orcervicalcarcinomainsitu
Constitutionalsymptoms,suchasfever(38.5C)ordiarrhealasting>1month
Hairyleukoplakia
Herpeszoster(shingles),involvingatleasttwodistinctdermatomesormorethanoneepisode
Idiopathicthrombocytopenicpurpura
Listeriosis
Pelvicinflammatorydisease,particularlyifcomplicatedbytuboovarianabscess
Peripheralneuropathy
Forclassificationpurposes,categoryBconditionstakeprecedenceoverthoseincategoryA.Forexample,someonepreviouslytreated
fororalorpersistentvaginalcandidiasis(andwhohasnotdevelopedacategoryCdisease)butwhoisnowasymptomaticshouldbe
classifiedinclinicalcategoryB.

C.CategoryCincludestheclinicalconditionslistedintheAIDSsurveillancecasedefinition(sectionIIabove).Forclassificationpurposes,
onceacategoryCconditionhasoccurred,thepersonwillremainincategoryC.
IncludingtheexpandedAIDSsurveillancecasedefinition.PersonswithAIDSindicatorconditions(categoryC)aswellasthosewithAIDSindicatorCD4T

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lymphocytecounts<200/L(categoriesA3orB3)havebeenreportableasAIDScasesintheUnitedStatesandTerritoriessinceJanuary1,1993.Datafrom
MMWRMorbMortalWklyRep.199241[RR17].SectionsIIandIIIofthistablearemodifiedandreproduced,withpermission,fromLawlorGLJretal,eds.
ManualofAllergyandImmmunology.Little,Brown,1994.
1PGL,persistentgeneralizedlymphadenopathy.ClinicalcategoryAincludesacute(primary)HIVinfection.

AcuteHIVinfectionmaypresentasaselflimited,febrileviralsyndromecharacterizedbyfatigue,pharyngitis,myalgias,maculopapularrash,lymphadenopathy,
andsignificantviremia,withoutdetectableantiHIVantibodies.Lesscommonly,primaryHIVinfectionmayalsobeassociatedwithorogenitaloresophageal
ulcers,meningoencephalitis,oropportunisticinfection.Afteraninitialviremicphase,patientsseroconvertandaperiodofclinicallatencyisusuallyseen.Lymph
tissuesbecomecentersformassiveviralreplicationduringasilent,orasymptomatic,stageofHIVinfectiondespiteanabsenceofdetectablevirusinthe
peripheralblood.Overtime,thereisaprogressivedeclineinCD4Tlymphocytes,areversalofthenormalCD4:CD8Tlymphocyteratio,andnumerousother
immunologicderangements.TheclinicalmanifestationsaredirectlyrelatedtoHIVtissuetropismanddefectiveimmunefunction.Developmentofneurologic
complications,opportunisticinfections,ormalignancysignalmarkedimmunedeficiency.Thetimecourseforprogressionishighlyvariable,butthemediantime
beforeappearanceofclinicaldiseaseisabout10yearsinuntreatedindividuals.Approximately10%ofthoseinfectedmanifestrapidprogressiontoAIDSwithin
5yearsafterinfection.Aminorityofindividualsarelongtermnonprogressors.Geneticfactors,hostcytotoxicimmuneresponses,viralload,andvirulence
appeartohaveanimpactonsusceptibilitytoinfectionandtherateofdiseaseprogression.Althoughnotcurative,modernantiretroviraltherapiescan
significantlyreduceviralreplication,restoreimmunefunction,leadtoclinicalrecovery,andmarkedlyextendlifeexpectancy.
PATHOLOGYANDPATHOGENESIS

HIVisagroupofrelatedretroviruses,whoseRNAencodesforninegenes(seeTable37).Chemokines(chemoattractantcytokines)regulateleukocyte
traffickingtositesofinflammationandhavebeendiscoveredtoplayasignificantroleinthepathogenesisofHIVdisease.Duringtheinitialstagesofinfection
andviralproliferation,virionentryandcellularinfectionrequiresbindingtotwocoreceptorsontargetTlymphocytesandmonocyte/macrophages.AllHIVstrains
expresstheenvelopeproteingp120thatbindstoCD4surfacereceptormolecules,butdifferentviralstrainsdisplaytissuetropismorspecificityonthebasisof
thecoreceptortheyrecognize.ChangesinviralphenotypeduringthecourseofHIVinfectionmayleadtochangesintropismandcytopathologyatdifferent
stagesofdisease.Viralstrainsisolatedinearlystagesofinfectionandassociatedwithmucosalandintravenoustransmission(eg,R5trophicviruses)bind
macrophagesexpressingchemokinereceptorCCR5.X4trophicstrainsofHIVaremorecommonlyseeninlaterstagesofdisease.X4trophicvirusesbindto
chemokinereceptorCXCR4,morebroadlyexpressedonTcells,andareassociatedwithsyncytiumformation.Sincechemokinereceptorsplayaroleinviralcell
entry,specificinheritedpolymorphismsofchemokinereceptorsinfluencesusceptibilitytoinfectionanddiseaseprogression.PresenceofcertainHLAalleleshas
alsobeenassociatedwithdifferencesinsusceptibilityandclinicalcourse.
Table37HIVgenesandgeneproducts.

Ltr

Longterminalrepeat

Controlsgenetranscription

Gag

Polyprotein,processedintoseveralgeneproducts

Capsid,matrix,andnucleocapsidproteins

Pol

Polymerase

Encodesviralenzymes,includingreversetranscriptase

Vif

Viralinfectivityfactor(p23)

Overcomesviralinhibitor

Vpr

ViralproteinR

Participatesinnuclearimportationofviralprointegrationcomplex

Rev

Regulatorofviralgeneexpression

Env

Envelopeproteingp160

Cleavedintogp120,gp41,whichmediateviralbindingandfusion

Tat

Transcriptionalactivator

Increasesviralgeneexpression

Nef

Negativeeffector(p24)

RegulatesHIVreplication

MathematicalmodelsestimatethatduringHIVinfectionbillionsofvirionsareproducedandclearedeachday.ThereversetranscriptionstepofHIVreplicationis
errorprone.Mutationsoccurfrequently,andevenwithinanindividualpatient,HIVheterogeneitydevelopsrapidly.Patientsmaybeinfectedwithmorethanone
strainconcomitantly,andthroughmechanismsofrecombination,genesfromseparatestrainsmayintermingle,contributingtogeneticdiversity.The
developmentofantigenicallyandphenotypicallydistinctstrainscontributestoprogressionofdisease,clinicaldrugresistance,andlackofefficacyofearly
vaccines.
CellularactivationiscriticalforviralinfectivityandreactivationofintegratedproviralDNA.Afterviralentryandcapsiddisassembly,HIVreversetranscriptase
convertsuncoatedviralRNAintodoublestrandedviralDNA.Utilizingseveralhostproteins,thedoublestrandedviralDNAcomplexpenetratesthehostcell
nucleusandintegratesintothehostchromosome.Onceintegrated,theviralprovirusmayremainlatentorbecometranscriptionallyactive,dependingonthe
activationstateofthehostcell.CellularactivationtriggersNF,acytoplasmictranscriptionfactorthatmigratestothenucleusinitiatingviralgeneexpression.
HIVproteinNefenhancesviralreplicationandreduceshostantiviralimmuneresponses.Newinfectiousvirionsareassembled.ViralproteinsandRNAare
packagedattheinfectedcellsexteriormembranethroughaprocesscalledbudding.
Althoughonly2%ofmononuclearcellsarefoundperipherally,lymphnodesfromHIVinfectedindividualscancontainlargeamountsofvirussequestered
amonginfectedfolliculardendriticcellsinthegerminalcenters.Forpatientsinfectedthroughvaginalorrectalmucosa,gutassociatedlymphoidtissueisamajor
siteofviralreplicationandpersistence.GutassociatedlymphoidtissueharborsthemajorityofthehostsTcells,andwhenHIVinfectedepidermalLangerhans
cellsmigratetodraininglymphnodes,largenumbersoflymphocytesencountersurfaceboundvirus.Thepersistenceofvirusinthesesecondarylymphoid
structurestriggerscellularactivationandmassive,irrevocabledepletionofCD4Tlymphocytereservoirs,aswellasdiseaselatency.ThemarkeddeclineinCD4
Tlymphocytecountsisduetoseveralmechanisms:(1)directHIVmediatedinfectionanddestructionofCD4Tlymphocytesduringviralreplication(2)
depletionbyfusionandformationofmultinucleatedgiantcells(syncytiumformation)(3)toxicityofviralproteinstoCD4Tlymphocytesandhematopoietic
precursors(4)lossofTlymphocytecostimulatoryfactorssuchasCD28and(5)inductionofapoptosis(programmedcelldeath)ofuninfectedTcells.CD8CTL
activityisinitiallybriskandeffectiveatcontrollingviremiabutlaterinducesthegenerationofviralescapemutations.Ultimately,viralproliferationoutstripshost
responses,andHIVinducedimmunosuppressionleadstodiseaseprogression.Neutralizingantibodiesaregeneratedverylate,butmutationsinHIVenvelope
proteinsoutfoxprotectivehumoralresponses.Overtime,theinfectionischaracterizedbysystemic,generalizedcytokinedysregulationandimmuneactivation.
HyperactivityoftheimmunesystemincreasesnaveTcellinfection.Ultimately,theseeventsprovedeleterioustomaintenanceoflymphaticorgans,bone
marrowintegrity,andeffectiveimmuneresponses.
Inadditiontothecellmediatedimmunedefects,Blymphocytefunctionisalteredsuchthatmanyinfectedindividualshavemarkedhypergammaglobulinemia

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butimpairedspecificantibodyresponses.Bothanamnesticresponsesandthosetoneoantigenscanbeimpaired.
Thedevelopmentofassaystomeasureviralburden(plasmaHIVRNAquantification)hasledtoabetterunderstandingofHIVdynamicsandhasprovidedatool
forassessingresponsetotherapy.Itisnowwellrecognizedthatviralreplicationcontinuesthroughoutthedisease,andimmunedeteriorationoccursdespite
clinicallatency.TheriskofprogressiontoAIDSappearscorrelatedwithanindividualsviralloadafterseroconversion.Datafromseverallargeclinicalcohorts
haveshownthatthereisadirectcorrelationbetweentheCD4TlymphocytecountandtheriskofAIDSdefiningopportunisticinfectionsandmalignancy.The
viralloadandthedegreeofCD4TlymphocytedepletionserveasimportantclinicalindicatorsofimmunestatusinHIVinfectedindividuals.CD4countmaybe
betterfordiseasestaging,butviralloadmaybeabetterproxyfordiseaseprogressionormonitoringresponsetotherapy.Prophylaxisforopportunistic
infectionssuchaspneumocystispneumonia(PCP)isstartedwhenCD4Tlymphocytecountsreachthe200250cells/Lrange.Similarly,patientswithHIV
infectionwithfewerthan50CD4Tlymphocytes/Lareatsignificantlyincreasedriskforcytomegalovirus(CMV)retinitisandMaviumcomplex(MAC)infection.
Unfortunately,somecomplicationsofHIVinfection,includingtuberculosisinfection,nonHodgkinlymphoma,andcardiovascular,hepatic,andneurocognitive
diseases,mayoccurevenwithrobustCD4counts.
Monocytes,macrophages,anddendriticcellsalsoexpressHIVreceptors(CD4)andcanbeinfectedwithHIV.Thisfacilitatestransferofvirustolymphoid
tissuesandimmunoprivilegedsites,suchastheCNS.HIVinfectedmonocyteswillalsoreleaselargequantitiesoftheacutephasereactantcytokines,including
IL1,IL6,andTNF,contributingtoconstitutionalsymptomatology.TNF,inparticular,hasbeenimplicatedintheseverewastingsyndromeseeninpatientswith
advanceddisease.ConcomitantinfectionsmayserveascofactorsforHIVinfection,facilitatemucosalentry,andincreaseexpressionofHIVthroughenhanced
cytokineproduction,coreceptorsurfaceexpression,orincreasedcellularactivationmechanisms.EpidemiologicstudiesofHSV2infectedpatientsdemonstrate
a2to7foldincreasedriskofacquisitionofHIVcomparedwithsimilarcohorts.
CLINICALMANIFESTATIONS

TheclinicalmanifestationsofAIDSarethedirectconsequenceoftheprogressiveandsevereimmunologicdeficiencyinducedbyHIV.Patientsaresusceptible
toawiderangeofatypicaloropportunisticinfectionswithbacterial,viral,protozoal,andfungalpathogens.Commonnonspecificsymptomsincludefever,night
sweats,andweightloss.Weightlossandcachexiacanbeduetonausea,vomiting,anorexia,ordiarrhea.Theyoftenportendapoorprognosis.
TheincidenceofinfectionincreasesastheCD4Tlymphocytenumberdeclines.Fungalpathogensmayaffectimmunocompetenthostsbutarefrequently
opportunisticinHIVinfectedpatients.InfectionswithCryptococcusneoformansmeningoencephalitis,disseminatedHistoplasmacapsulatum,anddisseminated
Coccidioidesimmitisaretypicallyseeninlatestagesofdisease,whenCD4countsarebelow200cells/mm3.Cneoformansmeningoencephalitisismanifested
byfevers,malaise,headache,photophobia,andnausea.Presentationwithalteredmentalstatusorelevatedintracranialpressureisassociatedwithahigher
riskofdeathorneurologicsequelae.Occasionally,acerebralcryptococcomapresentsasamasslesion.
Foundendemicallyinregionalsoilcontaminatedwithbirdandbatdroppings,Hcapsulatuminfectionischaracterizedbyprominentconstitutionalsymptoms,
frequentpulmonarysymptoms,andsubacutemeningoencephalitis.Disseminateddiseasemayrepresentreactivationoflatentdiseasewhencellularimmunity
fails.
Previouslythoughttobeaprotozoan,nowclassifiedasafungus,Pneumocystisjiroveciiisthemostcommonopportunisticinfection,affecting75%ofpatients.
Patientspresentclinicallywithfevers,cough,shortnessofbreath,andhypoxemia,ranginginseverityfrommildtolifethreatening.PCPmayrepresentnew
acquisitionoractivationofoldinfections.AdiagnosisofPCPcanbemadebysubstantiationoftheclinicalandradiographicfindingswithWrightGiemsaorsilver
methenaminestainingofinducedsputumsamples.Anegativesputumstaindoesnotruleoutdiseaseinpatientsinwhomthereisastrongclinicalsuspicionof
disease,andfurtherdiagnosticmaneuverssuchasbronchoalveolarlavageorfiberoptictransbronchialbiopsymayberequiredtoestablishthediagnosis.
ComplicationsofPCPincludepneumothoraces,progressiveparenchymaldiseasewithsevererespiratoryinsufficiency,and,mostcommonly,adversereactions
tothemedicationsusedfortreatmentandprophylaxis.
Asaconsequenceofchronicimmunedysfunction,HIVinfectedindividualsarealsoathighriskforotherpulmonaryinfections,includingbacterialinfections
withSpneumoniae,Hinfluenzae,andPaeruginosamycobacterialinfectionswithMycobacteriumtuberculosisorMACandfungalinfectionswithC
neoformans,Hcapsulatum,Aspergillussp,orCimmitis.Clinicalsuspicionfollowedbyearlydiagnosisoftheseinfectionsshouldleadtoaggressivetreatment.
TheriskofMtuberculosisreactivationisestimatedtobe510%peryearinHIVinfectedpatientscomparedwithalifetimeriskof10%inthosewithoutHIV.The
developmentofactivetuberculosisissignificantlyacceleratedinHIVinfectionasaresultofcompromisedcellularimmunity.Furthermore,diagnosismaybe
delayedbecauseofanergicskinresponses.Respiratorysymptomsofcough,dyspnea,orpleuriticchestpainmaybeassociatedwiththeinsidiousonsetof
fever,malaise,weightloss,andanorexia.Extrapulmonarymanifestationsoccurinupto70%ofHIVinfectedpatientswithtuberculosis,withmiliarytuberculosis
andmeningitisrepresentingmoreseriouscomplications.Theemergenceofmultidrugresistancemaycompoundtheproblem.Maviumisalessvirulent
pathogenthanMtuberculosis,anddisseminatedinfectionsusuallyoccuronlywithsevereclinicalimmunodeficiency.Maviumsurvivesintracellularlywithin
macrophagesduetodefectivecytokine(IFN,IL2,IL12,TNF)synthesis,leadingtoimpairedkillingofphagocytosedorganisms.SymptomsofMACare
nonspecificandtypicallyconsistoffever,weightloss,anemia,andGIdistresswithdiarrhea.
Thepresenceonphysicalexaminationoforalcandidiasis(thrush)andhairyleukoplakiaishighlycorrelatedwithHIVinfectionandportendsrapid
progressiontoAIDS.Oralcandidiasisdevelopswhenreducedlocalandsystemicimmunefunction,sometimescombinedwithmetabolicimbalances,contributes
toopportunisticoutgrowthofCandida,whichisnormallyacommoncommensalorganism.HIVinfectedindividualswithoralcandidiasisareatmuchgreaterrisk
foresophagealcandidiasis,whichmaypresentassubsternalpainanddysphagia.Thisinfectionanditscharacteristicclinicalpresentationaresocommonthat
mostpractitionerstreatwithempiricoralantifungaltherapy.Shouldthepatientnotrespondrapidly,otherexplanationsfortheesophagealsymptomsshouldbe
explored,includingherpessimplexandCMVinfections.EpsteinBarrvirus(EBV)isthecauseofhairyleukoplakia,anotheroralcomplicationofHIV,manifested
bywhitethickeningofmucosalfolds,prominentinthebuccalmucosa,thesoftpalate,andthefloorofthemouth.
DiarrheahasbeenahallmarkfeatureofAIDSandleadstosignificantwasting,morbidity,andmortality.Persistentdiarrhea,especiallywhenaccompaniedby
highfeversandabdominalpain,maysignalinfectiousenterocolitis.ThedegreeofCD4lymphopeniaissignificantlycorrelatedwiththeriskofopportunisticGI
tractinfections.Thelistofpotentialpathogensinsuchcasesislongandincludesbacteria,MAC,protozoans(cryptosporidium,microsporidia,Isosporabelli,
Entamoebahistolytica,Giardialamblia),andevenHIVitself.Becauseoftheirreducedgastricacidconcentrations,patientsalsohaveanincreasedsusceptibility
tononopportunisticinfectiousgastroenteritiswithCampylobacter,Salmonella,andShigella.Coinfectionwithviralhepatitis(HBV,HCV,CMV)canleadto
acceleratedcirrhosisandendstageliverdisease,butfortunately,institutionofhighlyactiveantiretroviraltherapy(HAART)canleadtoareductioninclinical
disease.
SkinlesionscommonlyassociatedwithHIVinfectionaretypicallyclassifiedasinfectious(viral,bacterial,fungal),neoplastic,ornonspecific.Herpessimplex
virus(HSV)andherpeszostervirus(HZV)maycausechronicpersistentorprogressivelesionsinpatientswithcompromisedcellularimmunity.HSVcommonly
causesoralandperianallesionsbutcanbeanAIDSdefiningillnesswheninvolvingthelungoresophagus.TheriskofdisseminatedHSVorHZVinfectionand
thepresenceofmolluscumcontagiosumappeartobecorrelatedwiththeextentofimmunoincompetence.SeborrheicdermatitiscausedbyPityrosporumovale
andfungalskininfections(Calbicans,dermatophytespecies)arealsocommonlyseeninHIVinfectedpatients.StaphylococcusincludingmethicillinresistantS
aureuscancausethefolliculitis,furunculosis,andbullousimpetigocommonlyobservedinHIVinfectedpatients,whichmayrequireaggressivetreatmentto

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preventdisseminationandsepsis.Bacillaryangiomatosisisapotentiallyfataldermatologicdisorderoftumorlikeproliferatingvascularendothelialcelllesions,
theresultofinfectionbyBartonellaquintanaorBartonellahenselae.ThelesionsmayresemblethoseofKaposisarcomabutrespondtotreatmentwith
erythromycinortetracycline.
CNSmanifestationsinHIVinfectedpatientsincludeinfectionsandmalignancies.Toxoplasmosisfrequentlypresentswithspaceoccupyinglesions,causing
headache,alteredmentalstatus,seizures,orfocalneurologicdeficits.Cryptococcalmeningitiscommonlymanifestsasheadacheandfever.Upto90%of
patientswithcryptococcalmeningitisexhibitapositiveserumtestforCneoformansantigen.
PatientswithHIVassociatedneurocognitivedisordertypicallyhavedifficultywithcognitivetasks,poorshorttermmemory,slowedmotorfunction,personality
oraffectivechanges,andwaxingandwaningdementia.Inthesevereform,AIDSdementiamaybecharacterizedbyseverepsychomotorretardation,akinesis,
andlanguageimpairment,associatedwithwidespreadcorticalatrophyandventricularenlargement.Upto50%ofpatientswithAIDSsufferfromthisdisorder,
perhapscausedbyglialormacrophageinfectionbyHIVresultingindestructiveinflammatorychangeswithintheCNS.R5virusesaretrophicforcellsof
monocyticlineageintheCNS.Thedifferentialdiagnosiscanbebroad,includingmetabolicdisturbancesandtoxicencephalopathyresultingfromdrugs.Other
causesofalteredmentalstatusincludeneurosyphilis,CMVorherpessimplexencephalitis,mycobacterialorcryptococcalmeningitis,lymphoma,and
progressivemultifocalleukoencephalopathy,aprogressivedemyelinatingdiseasecausedbyaJCpapovavirus.
PeripheralnervoussystemmanifestationsofHIVinfectionincludesensory,motor,andinflammatorypolyneuropathies.Almost33%ofpatientswithadvanced
HIVdiseasedevelopperipheraltingling,numbness,andpainintheirextremities.Thesesymptomsarelikelytobeduetolossofnerveaxonsfromdirect
neuronalHIVinfection.Alcoholism,thyroiddisease,syphilis,vitaminB12deficiency,drugtoxicity(ddI,ddC),CMVassociatedascendingpolyradiculopathy,and
transversemyelitisalsocauseperipheralneuropathies.Lesscommonly,HIVinfectedpatientscandevelopaninflammatorydemyelinatingpolyneuropathy
similartoGuillainBarrsyndromehowever,unlikethesensoryneuropathies,thisinflammatorydemyelinatingpolyneuropathytypicallypresentsbeforethe
onsetofclinicallyapparentimmunodeficiency.Theoriginofthisconditionisnotknown,althoughanautoimmunereactionissuspected.Retinitisresultingfrom
CMVinfectionisthemostcommoncauseofrapidlyprogressivevisuallossinHIVinfection.ThediagnosiscanbedifficulttomakebecauseToxoplasmagondii
infection,microinfarction,andretinalnecrosiscanallcausevisualloss.
HIVrelatedmalignanciescommonlyseeninAIDSincludeKaposisarcoma,nonHodgkinlymphoma,primaryCNSlymphoma,invasivecervicalcarcinoma,and
analsquamouscellcarcinoma.Impairmentofimmunesurveillanceanddefenseandincreasedexposuretooncogenicvirusesappeartocontributetothe
developmentofneoplasms.
KaposisarcomaisthemostcommonHIVassociatedcancer.InSanFrancisco,1520%ofHIVinfectedhomosexualmendevelopthistumorduringthe
progressionoftheirdisease.Kaposisarcomaisuncommoninwomenandchildrenforreasonsthatarenotclear.UnlikeclassicKaposisarcoma,whichaffects
elderlymenintheMediterranean,thediseaseinHIVinfectedpatientsmaypresentwitheitherlocalizedcutaneouslesions,lymphaticordisseminatedvisceral
involvement.Itisoftenaprogressivedisease,andpulmonaryinvolvementcanbefatal.Histologically,thelesionsofKaposisarcomaconsistofamixedcell
populationthatincludesvascularendothelialcellsandspindlecellswithinacollagennetwork.Humanherpesvirus8(HHV8)inimmunocompromisedpatients
appearstopromoteangiogenesisthroughgrowthfactorandproinflammatorygeneproductproduction.HIVitselfappearstoinducecytokinesandgrowth
factorsthatstimulatetumorcellproliferationratherthancausingmalignantcellulartransformation.Clinically,cutaneousKaposisarcomatypicallypresentsasa
purplishnodularskinlesionorpainlessorallesion.Sitesofvisceralinvolvementincludethelung,lymphnodes,liver,andGItract.IntheGItract,Kaposi
sarcomacanproducechronicbloodlossoracutehemorrhage.Inthelung,itoftenpresentsascoarsenodularinfiltratesbilaterally,frequentlyassociatedwith
pleuraleffusions.
NonHodgkinlymphomaisparticularlyaggressiveinHIVinfectedpatientsandusuallyindicativeofsignificantimmunecompromise.Themajorityofthese
tumorsarehighgradeBcelllymphomaswithapredilectionfordissemination.ChronicBcellstimulation,immunedysfunction,andlossofimmunoregulationof
EBVinfectedcellsareallriskfactorsfortransformationofclonallyselectedcellsanddevelopmentofnonHodgkinlymphoma.LargecellandBurkitttype
lymphomaareoftenassociatedwithEBVbutonlyaccountforabouthalfofcases.Manycasesarediagnosedatadvancedstagesofdisease,andtheCNSis
frequentlyinvolvedeitherasaprimarysiteorasanextranodalsiteofwidespreaddisease.
AnaldysplasiaandsquamouscellcarcinomaarealsomorecommonlyfoundinHIVinfectedhomosexualmen.Thesetumorsappeartobeassociatedwith
concomitantanalorrectalinfectionwithhumanpapillomavirus(HPV).InHIVinfectedwomen,theincidenceofHPVrelatedcervicaldysplasiaisashighas
40%,anddysplasiacanprogressrapidlytoinvasivecervicalcarcinoma.
Adherencetomultidrugregimensremainsachallenge,butclearlyantiretroviraltherapyimprovesimmunefunction.Forreasonsthatarenotclear,HIVinfected
patientshaveanunusuallyhighrateofadversereactionstoawidevarietyofantibioticsandfrequentlydevelopseveredebilitatingcutaneousreactions.Drug
hypersensitivityandtoxicitycanbesevere,potentiallylifethreatening,andlimitingwithcertainagents.Immunereconstitutionsyndromeisadescribed
reactionoccurringdaystoweeksafterinitiationofHAART.Clinicalrelapseorworseningofmycobacterial,pneumocystis,hepatitis,orneurologicalinfections
occursasaresultofaresurgenceofimmuneactivity,causingparadoxicalworseningofinflammation,possiblyasresidualantigensorsubclinicalpathogensare
attacked.
OthercomplicationsofHIVinfectionincludearthritides,myopathy,GIsyndromes,dysfunctionoftheadrenalandthyroidglands,hematologiccytopenias,and
nephropathy.Aspatientsarelivinglongerduetopotentantiretroviraltherapy(ART),cardiovascularcomplicationsaremoreprominent.ARThasbeen
associatedwithdyslipidemiaandmetabolicabnormalitiesincludinginsulinresistance.HIVinfectionmaybeatherogenicaswell,througheffectsonlipidsand
proinflammatorymechanisms.
Sincethediseasewasfirstdescribedin1981,medicalknowledgeoftheunderlyingpathogenesisofAIDShasincreasedatarateunprecedentedinmedical
history.ThisknowledgehasledtotherapiddevelopmentoftherapiesdirectedatcontrollingHIVinfectionaswellasthemultitudeofcomplicatingopportunistic
infectionsandcancers.
Checkpoint
23. WhatarethemajorclinicalmanifestationsofAIDS?
24. WhatarethemajorstepsindevelopmentofAIDSafterinfectionwithHIV?

CaseStudies
YeongKwok,MD
Case6
AllergicRhinitis
A40yearoldwomancomestotheclinicwithahistoryofworseningnasalcongestionandrecurrentsinusinfections.Shehadbeenhealthyuntilabout1year
agowhenshefirstnoticedpersistentrhinorrhea,sneezing,andstuffiness.Shenotedthatwhenshewentona2weekvacationtoMexico,herrhinorrhea

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disappeared,onlytoreturnwhenshecamehomeagain.Shehaslivedinthesamehouseforthepast5yearsalongwithherhusbandandonechild.Theyhave
hadadogfor4yearsandacatfor1year.Onphysicalexamination,shehasboggy,swollennasalturbinatesandacobblestoneappearanceofherposterior
pharynx.
Questions

A.Whatarethepathophysiologicmechanismsinallergicrhinitis?
CrosslinkingofsurfaceboundIgEbyantigenactivatestissuemastcellsandbasophils,inducingtheimmediatereleaseofpreformedmediatorsandthe
synthesisofnewlygeneratedmediators.Mastcellsandbasophilsalsohavetheabilitytosynthesizeandreleaseproinflammatorycytokines,whicharegrowth
andregulatoryfactorsthatinteractincomplexnetworks.Theinteractionofmediatorswithvarioustargetorgansandcellsoftheairwaycaninduceabiphasic
allergicresponse:anearlyphasemediatedchieflybyreleaseofhistamineandotherstoredmediators(tryptase,chymase,heparin,chondroitinsulfate,and
tumornecrosisfactor[TNF]),whereaslatephaseeventsareinducedaftergenerationofarachidonicacidmetabolites(leukotrienesandprostaglandins),
plateletactivatingfactor,anddenovocytokinesynthesis.
Histologically,theearlyresponseischaracterizedbyvascularpermeability,vasodilatation,tissueedema,andamildcellularinfiltrateofmostlygranulocytes.The
latephaseresponseischaracterizedbyerythema,induration,heat,burning,anditchingandmicroscopicallybyasignificantcellularinfluxofmainlyeosinophils
andmononuclearcells.Changesconsistentwithairwayremodelingandtissuehyperreactivitymayalsooccur.
B.Whatsymptomsandsignsofallergicrhinitis?
Patientswithallergicrhinitisdevelopchronicorepisodicparoxysmalsneezingnasal,ocular,orpalatalpruritusandwateryrhinorrheatriggeredbyexposureto
aspecificallergen.Patientsmaydemonstratesignsofchronicpruritusoftheupperairway,includingahorizontalnasalcreasefromfrequentnoserubbing
(allergicsalute)andpalatalclickingfromrubbingtheitchingpalatewiththetongue.Symptomsofnasalobstructionmaybecomechronicasaresultof
persistentlatephaseallergicmechanisms.Nasalmucousmembranesmayappearpaleblueandboggy.Childrenfrequentlyshowsignsofobligatemouth
breathing,includinglongfacies,narrowmaxillae,flattenedmalareminences,markedoverbite,andhigharchedpalates(socalledadenoidfacies).
C.Whatarepossiblecomplicationsofallergicrhinitis?
Serousotitismediaandsinusitisaremajorcomorbiditiesinpatientswithallergicrhinitis.Bothconditionsoccursecondarilytotheobstructednasalpassagesand
sinusostiainpatientswithchronicallergicornonallergicrhinitis.Complicationsofchronicrhinitisshouldbeconsideredinpatientswithprotractedrhinitis
unresponsivetotherapy,refractoryasthma,orpersistentbronchitis.Serousotitisresultsfromauditorytubeobstructionbymucosaledemaandhypersecretion.
Childrenwithserousotitismediacanpresentwithconductivehearingloss,delayedspeech,andrecurrentotitismediaassociatedwithchronicnasalobstruction.
Sinusitismaybeacute,subacute,orchronicdependingonthedurationofsymptoms.Obstructionofosteomeataldrainageinpatientswithchronicrhinitis
predisposestobacterialinfectioninthesinuscavities.Patientsmanifestsymptomsofpersistentnasaldischarge,cough,sinusdiscomfort,andnasalobstruction.
Examinationmayrevealchronicotitismedia,infraorbitaledema,inflamednasalmucosa,andpurulentnasaldischarge.Radiographicdiagnosisbyxrayfilmor
computedtomographic(CT)scanrevealssinusopacification,membranethickening,orthepresenceofanairfluidlevel.
Case7
SevereCombinedImmunodeficiencyDisease
A2montholdchildisadmittedtotheICUwithfever,hypotension,tachycardia,andlethargy.Themedicalhistoryisnotableforasimilarhospitalizationat2
weeksofage.Physicalexaminationisnotableforatemperatureof39C,oralthrush,andralesintherightlungfields.Chestxrayfilmrevealsmultilobar
pneumonia.Giventhehistoryofrecurrentsevereinfection,thepediatriciansuspectsanimmunodeficiencydisorder.
Questions

A.Whatisthemostlikelyimmunodeficiencyinthischild?Why?
Themostlikelycauseofthischildsrecurrentinfectionsisseverecombinedimmunodeficiencydisease(SCID).Thesepatientshavecompleteornearcomplete
failureofdevelopmentofbothcellularandhumoralcomponentsoftheimmunesystem.Placentaltransferofmaternalimmunoglobulinisinsufficienttoprotect
thesechildrenfrominfection,andforthatreasontheypresentataveryearlyagewithsevereinfections.
B.Whataretheunderlyinggeneticandcellulardefectsassociatedwiththisdisease?
SCIDisaheterogeneousgroupofgeneticandcellulardisorderscharacterizedbyafailureinthecellularmaturationoflymphoidstemcells,resultinginreduced
numbersandfunctionofbothBandTlymphocytesandhypogammaglobulinemia.Thegeneticandcellulardefectscanoccuratmanydifferentlevels,starting
withsurfacemembranereceptors,butalsoincludingdeficienciesinsignaltransductionormetabolicbiochemicalpathways.Althoughthedifferentmolecular
defectsmaycauseclinicallyindistinguishablephenotypes,identificationofspecificmutationsallowsforimprovedgeneticcounseling,prenataldiagnosis,and
carrierdetection.
ThemostcommongeneticdefectisanXlinkedformofSCID(XSCID)inwhichthematurationdefectismainlyintheTlymphocytelineageandisduetoapoint
mutationinthechainoftheIL2receptor.ThisdefectivechainissharedbythereceptorsforIL4,IL7,IL9,andIL15,leadingtodysfunctionofallofthese
cytokinereceptors.DefectivesignalingthroughtheIL7receptorappearstoblocknormalmaturationofTlymphocytes.CirculatingBcellnumbersmaybe
preserved,butdefectiveIL2responsesinhibitproliferationofT,B,andNKcells,explainingthecombinedimmunedefectsseeninXSCIDpatients.
Severalautosomallyinheriteddefectshavealsobeenidentified.AdefectinthechainoftheIL7receptorcanleadtoanautosomalrecessiveformofSCID
throughmechanismssimilartoXSCIDbutwithintactNKcells.
About20%ofSCIDcasesarecausedbyadeficiencyofadenosinedeaminase(ADA),whichisanenzymeinthepurinesalvagepathway,responsibleforthe
metabolismofadenosine.AbsenceoftheADAenzymeresultsinanaccumulationoftoxicadenosinemetaboliteswithinthecells.Thesemetabolitesinhibit
normallymphocyteproliferationandleadtoextremecytopeniaofbothBandTlymphocytes.Thecombinedimmunologicdeficiencyandclinicalpresentationof
thisdisorder,knownasSCIDADA,areidenticaltothoseoftheotherformsofSCID.Skeletalabnormalitiesandneurologicabnormalitiesmaybeassociatedwith
thisdisease.
AnalternateautosomallyrecessiveformofSCIDisadeficiencyofZAP70,atyrosinekinaseimportantinnormalTlymphocytefunction.Deficiencyofthis
tyrosinekinaseresultsintotalabsenceofCD8TlymphocytesandfunctionallydefectiveCD4Tlymphocytes,butnormalBlymphocyteandNKactivity.
MutationsofCD3,CD3,andCD3subunitsmayleadtopartiallyarresteddevelopmentofTCRexpressionandsevereTcelldeficiency.
Deficienciesofbothp56kkandJak3(Januskinase3)canalsoleadtoSCIDthroughdefectivesignaltransductionp56kkisaTcellreceptorassociatedtyrosine
kinasethatisessentialforTcelldifferentiation,activation,andproliferation.Jak3isacytokinereceptorassociatedsignalingmolecule.Finally,patientshave
beenidentifiedwithdefectiverecombinationactivatinggene(RAG1andRAG2)products.RAG1andRAG2initiaterecombinationofantigenbindingproteins,
immunoglobulinsandTcellreceptors.Thedefectleadstobothquantitativeandqualitative(functional)deficienciesofTandBlymphocytes.

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C.Whatistheoverallprognosisforpatientswiththisdisorder?
Withouttreatment,mostpatientswithSCIDdiewithinthefirst12years.
Case8
XLinkedAgammaglobulinemia
An18montholdboyisbroughttotheemergencydepartmentbyhisparentswithahighfever,shortnessofbreath,andcough.Theboywaswelluntilhewas6
monthsold.Sincethen,hehashadfourboutsofotitismedia,andbecauseoftheirseverityandrecurrence,hewasplacedforseveralmonthsonprophylactic
antibiotics.Hewasrecentlytakenofftheantibioticstoseehowhewoulddo.Thedaybeforepresentation,hedevelopedacoughthathasquicklyprogressed
intoanillnesswithhighfeversandlethargy.Bothofhisparentsarehealthy,andhehasahealthyoldersister.Hisfathersfamilyhistoryisunremarkable,buthis
maternalunclediedofpneumoniaininfancy.Examinationisremarkableforanormallydevelopedtoddlerwhoislethargicandtachypneic.Histemperatureis
39C,andhehasdecreasedbreathsoundsatbothlungbases.Chestxrayfilmshowsconsolidationoftherightandleftlowerlobes,aswellasbilateralpleural
effusions.Heisadmittedtothehospital,andtheboysbloodculturesgrowoutStreptococcuspneumoniaethenextday.Immunologictestingshowsverylow
levelsofIgG,IgM,andIgAantibodiesintheserum,andflowcytometryshowstheabsenceofcirculatingBlymphocytes.
Questions

A.Whatisthelikelydiagnosisinthispatientandwhy?
ThischildhasXlinkedagammaglobinemia,formerlycalledBrutonagammaglobinemia.Thehistoryofmultipleinfectionsoccurringaftertheageof6months,
thefamilyhistoryofamaternalunclewithlethalinfection,theseverecurrentinfectionwithStreptococcuspneumoniae,andtheabsenceofcirculatingB
lymphocytesarecharacteristicofthisdisorder.
B.Whatistheprimarypathophysiologicdefectinthecondition,andhowdoesitleadtothisclinicalpresentation?
ThemaindefectisamutationintheBTK(Brutontyrosinekinase)gene,whichislocatedontheXchromosome.ThisgenesproductisaBcellspecific
signalingproteinnecessaryfornormalBcellmaturation.Themutationaffectsthecatalyticdomainoftheprotein,haltingBcellmaturation.This,inturn,leadsto
absenceorgreatlyreducedlevelsoftheimmunoglobulinsIgA,IgG,andIgM.Theirabsenceorreductionisaparticularproblemwithfightinginfectionsfrom
encapsulatedbacteriabecausethesebacteriarequireantibodybindingforefficientopsonization.Therefore,patientsareparticularlysusceptibletoinfections
withbacteriasuchasHaemophilusinfluenzaeandSpneumoniae.Becausetheycannotmountanantibodyresponse,theyalsodevelopverylittleimmunityto
theseinfectionsandarethussusceptibletorepeatedinfectionswiththesameorganism.
C.Whyaretheaffectedchildrengenerallyfineuntiltheyreach46monthsofage?
Theaffectedchildisrelativelyprotectedbycirculatingmaternalantibodiesuntil46monthsofage.Thechildsimmunesystemisotherwiseunaffected,butas
thelevelsofmaternalantibodiesdecrease,thechildbecomesincreasinglysusceptibletoinfection,particularlyfromencapsulatedbacteria.
Case9
CommonVariableImmunodeficiency
An18yearoldmanpresentswithcomplaintsoffever,facialpain,andnasalcongestionconsistentwithadiagnosisofacutesinusitis.Hismedicalhistoryis
notableformultiplesinusinfections,twoepisodesofpneumonia,andchronicdiarrhea,allsuggestiveofprimaryimmunodeficiencysyndrome.Workup
establishesadiagnosisofcommonvariableimmunodeficiency.
Questions

A.Whatarethecommoninfectiousmanifestationsofcommonvariableimmunodeficiency?
Individualswithcommonvariableimmunodeficiency(CVI)commonlydeveloprecurrentsinopulmonaryinfectionssuchassinusitis,otitismedia,bronchitis,and
pneumonia.CommonpathogensareencapsulatedbacteriasuchasSpneumoniae,Hinfluenzae,andMoraxellacatarrhalis.Bronchiectasismaydevelopasa
resultoftheserecurrentinfections.TheymayalsodevelopGImalabsorptionfrombacterialovergrowthorchronicGiardiainfectioninthesmallbowel.
B.Whataretheunderlyingimmunologicabnormalitiesresponsiblefortheseinfectiousmanifestations?
CVIisaheterogeneousdisorderinwhichtheprimaryimmunologicabnormalityisamarkedreductioninantibodyproduction,withnormalorreducednumbersof
circulatingBcells.ThisismostcommonlycausedbyadefectintheterminaldifferentiationofBlymphocytesinresponsetoTlymphocytedependentandT
lymphocyteindependentstimuli.However,defectsinBlymphocytedevelopmenthavebeenshowntooccuratanystageofthematurationpathway.
Inmanypatients,thedefectisintrinsictotheBlymphocytepopulation.Approximately15%ofpatientswithCVIdemonstratedefectiveBcellsurfaceexpression
ofTACI(transmembraneactivatorandcalciummodulatorandcyclophilinligandinteractor),amemberoftheTNFreceptorfamily.LackingafunctionalTACI,the
affectedBcellswillnotrespondtoBcellactivatingfactors,resultingindeficientimmunoglobulinproduction.Anotherdefect,whichmayleadtoCVI,involves
deficientexpressionoftheBcellsurfacemarker,CD19.WhencomplexedwithCD21andCD81,CD19facilitatescellularactivationthroughBcellreceptors.B
celldevelopmentisnotaffectedbuthumoralfunctionisdeficient.AvarietyofTcellabnormalitiesmayalsoleadtoimmunedefectswithsubsequentimpairment
ofBcelldifferentiation.AmutationofinducibleTcellcostimulatorgene(ICOS),expressedbyactivatedTcellsandresponsibleforBcellactivationandantibody
production,maybethemoleculardefectinsomecasesofCVI.TlymphocytedysfunctioncanbemanifestedasincreasedsuppressorTlymphocyteactivity,
decreasedcytokineproduction,defectivesynthesisofBlymphocytegrowthfactors,defectivecytokinegeneexpressioninTcells,decreasedTcellmitogenesis,
anddeficientlymphokineactivatedkillercellfunction.
C.Whatotherdiseasesisthispatientatincreasedriskfor?
IndividualswithCVIareatincreasedriskofautoimmunedisordersandmalignancies.TheautoimmunedisordersmostcommonlyseeninassociationwithCVI
includeimmunethrombocytopenicpurpura,hemolyticanemia,andsymmetricseronegativearthritis.ThemalignanciesassociatedwithCVIincludelymphomas,
gastriccarcinoma,andskincancers.
D.Whattreatmentisindicated?
TreatmentismainlysymptomaticalongwithreplacementofimmuneglobulinwithmonthlyinfusionsofIVIG.
Case10
AcquiredImmunodeficiencySyndrome(AIDS)
A31yearoldmaleinjectiondruguserpresentstotheemergencydepartmentwithachiefcomplaintofshortnessofbreath.Hedescribesa1monthhistoryof
intermittentfeversandnightsweatsassociatedwithanonproductivecough.Hehasbecomeprogressivelymoreshortofbreath,initiallyonlywithexertion,but
nowhefeelsdyspneicatrest.Heappearstobeinmoderaterespiratorydistress.Hisvitalsignsareabnormal,withfeverto39C,heartrateof112bpm,

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respiratoryrateof20/minute,andoxygensaturationof88%onroomair.Physicalexaminationisotherwiseunremarkablebutnotablefortheabsenceof
abnormallungsounds.Chestxrayfilmrevealsadiffuseinterstitialinfiltratecharacteristicofpneumocystispneumonia,anopportunisticinfection.
Questions

A.Whatistheunderlyingdiseasemostlikelyresponsibleforthismanssusceptibilitytopneumocystispneumonia?
PneumocystispneumoniaiscommonlyseeninAIDS.AnHIV1antibodytestshouldbeobtainedwheneverthediagnosisofPneumocystisjiroveciiissuspected.
B.Whatisthepathogenesisoftheimmunosuppressioncausedbythisunderlyingdisease?
AIDSistheconsequenceofinfectionwithHIV1,aretrovirusthatinfectsmultiplecelllines,includinglymphocytes,monocytes,macrophages,anddendriticcells.
WithHIVinfection,thereisanabsolutereductionofCD4Tlymphocytes,anaccompanyingdeficitinCD4Tlymphocytefunction,andanassociatedincreasein
CD8cytotoxicTlymphocytes(CTLs).Inadditiontothecellmediatedimmunedefects,Blymphocytefunctionisalteredsuchthatmanyinfectedindividualshave
markedhypergammaglobulinemiabutimpairedspecificantibodyresponses.Theresultantimmunosuppressionpredisposespatientstotheconstellationof
opportunisticinfectionsthatcharacterizesAIDS.
ThelossofCD4cellsseeninHIVinfectionistheresultofmultiplemechanisms,including(1)autoimmunedestruction,(2)directviralinfectionanddestruction,
(3)fusionandformationintomultinucleatedgiantcells,(4)toxicityofviralproteinstoCD4Tlymphocytesandhematopoieticprecursors,and(5)apoptosis
(programmedcelldeath).
C.Whatisthenaturalhistoryofthisdisease?Whataresomeofthecommonclinicalmanifestationsseenduringitsprogression?
TheclinicalmanifestationsofHIVinfectionandAIDSarethedirectconsequenceofprogressiveandsevereimmunosuppressionandcanbecorrelatedwiththe
degreeofCD4Tlymphocytedestruction.HIVinfectionmaypresentasanacute,selflimitedfebrilesyndrome.Thisisoftenfollowedbyalong,clinicallysilent
period,sometimesassociatedwithgeneralizedlymphadenopathy.Thetimecourseofdiseaseprogressionmayvarythemajorityofindividualsremain
asymptomaticfor510years.Approximately70%ofHIVinfectedindividualswilldevelopAIDSafteradecadeofinfection.Approximately10%ofthoseinfected
manifestrapidprogressiontoAIDSwithin5yearsafterinfection.Aminorityofindividualsarelongtermnonprogressors.Geneticfactors,hostcytotoxic
immuneresponses,andviralloadandvirulenceallappeartohaveanimpactonsusceptibilitytoinfectionandtherateofdiseaseprogression.Multidrug
antiretroviraltherapyhasdramaticallychangedthisnaturalhistoryandmarkedlyprolongedsurvival.
AstheCD4countdeclines,theincidenceofinfectionincreases.AtCD4countsbetween200/Land500/L,patientsareatanincreasedriskforbacterial
infections,includingpneumoniaandsinusitis.AsCD4countscontinuetodropgenerallybelow250/Ltheyareathighriskforopportunisticinfectionssuchas
pneumocysticpneumonia,candidiasis,toxoplasmosis,cryptococcalmeningitis,cytomegalovirus(CMV)retinitis,andMycobacteriumaviumcomplexinfection.
HIVinfectedindividualsarealsoatincreasedriskforcertainmalignancies,includingKaposisarcoma,nonHodgkinlymphoma,primaryCNSlymphoma,invasive
cervicalcarcinoma,andanalsquamouscellcarcinoma.OthermanifestationsofAIDSincludeAIDSdementiacomplex,peripheralneuropathy,monoarticular
andpolyarticulararthritides,unexplainedfevers,andweightloss.Sincepatientsarelivinglongerduetopotentantiretroviraltherapies(ART),cardiovascular
complicationsaremoreprominent.ARThasbeenassociatedwithdyslipidemiaandmetabolicabnormalitiesincludinginsulinresistance.HIVinfectionmaybe
atherogenicaswell,througheffectsonlipidsandproinflammatorymechanisms.

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