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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
FormerlycalledBrutonagammaglobulinemia,Xlinkedagammaglobulinemia(XLA)isthoughttobepathophysiologicallyandclinicallymorehomogeneous
thanSCID.Itisprincipallyadiseaseofchildhood,presentingclinicallywithinthefirst2yearsoflifewithmultipleandrecurrentsinopulmonaryinfectionscaused
primarilybypyogenicbacteriaand,toamuchlesserextent,viruses.Becauseencapsulatedbacteriarequireantibodybindingforefficientopsonization,these
humoralimmunedeficientpatientssufferfromsinusitis,pneumonia,pharyngitis,bronchitis,andotitismediasecondarytoinfectionwithStreptococcus
pneumoniae,otherstreptococci,andHaemophilusinfluenzae.Althoughinfectionsfromfungalandopportunisticpathogensarerare,patientsdisplayaunique
susceptibilitytoararebutdeadlyenteroviralmeningoencephalitis.
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
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.
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
InpatientswithhyperIgMimmunodeficiency,serumlevelsofIgGandIgAareveryloworabsent,butserumIgM(andsometimesIgD)levelsarenormalor
elevated.Inheritanceofthisdisordermaybeautosomal,althoughitismostoftenXlinked.Clinically,thissyndromeismanifestedbyrecurrentpyogenic
infectionsandanarrayofautoimmunephenomenasuchasCoombspositivehemolyticanemiaandimmunethrombocytopenia.
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
ChronicgranulomatousdiseaseistypicallyXlinkedandcharacterizedbyimpairedgranulocytefunction.Thisdisorderofphagocyticcellfunctionpresentswith
recurrentskininfections,abscesses,andgranulomasatsitesofchronicinflammation.Abscessescaninvolveskinorvisceraandmaybeaccompaniedby
lymphadenitis.CatalasepositiveorganismspredominateSaureusisthusthemostcommonpathogen,althoughinfectionswithNocardiaspecies,gram
negativeSerratiamarcescens,andBurkholderiacepaciacanalsooccur.AspergillusspeciesandCandidarepresentcommonfungalpathogensinchronic
granulomatousdisease.SterilenoncaseatinggranulomasresultingfromchronicinflammatorystimulicanleadtoGIorgenitourinarytractobstruction.Chronic
granulomatousdiseasetypicallypresentsinchildhood,althoughcasesinadulthoodareoccasionallyreported.
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
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.
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.
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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