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Harrison'sPrinciplesofInternalMedicine,18e>
Chapter314.Introductiontothe
ImmuneSystem
BartonF.HaynesKellyA.SoderbergAnthonyS.Fauci
IntroductiontotheImmuneSystem
Definitions
Adaptiveimmunesystem&mdahrecentlyevolvedsystemofimmuneresponsesmediatedbyTandBlymphocytes.Immuneresponsesby
thesecellsarebasedonspecificantigenrecognitionbyclonotypicreceptorsthatareproductsofgenesthatrearrangeduringdevelopment
andthroughoutthelifeoftheorganism.Additionalcellsoftheadaptiveimmunesystemincludevarioustypesofantigenpresentingcells.
AntibodyBcellproducedmoleculesencodedbygenesthatrearrangeduringBcelldevelopmentconsistingofimmunoglobulinheavy
andlightchainsthattogetherformthecentralcomponentoftheBcellreceptorforantigen.AntibodycanexistasBcellsurfaceantigen
recognitionmoleculesorassecretedmoleculesinplasmaandotherbodyfluids(Table31413).
Antigensforeignorselfmoleculesthatarerecognizedbytheadaptiveandinnateimmunesystemsresultinginimmunecelltriggering,T
cellactivation,and/orBcellantibodyproduction.
Antimicrobialpeptidessmallpeptides<100aminoacidsinlengththatareproducedbycellsoftheinnateimmunesystemandhaveanti
infectiousagentactivity(Table3142).
Apoptosistheprocessofprogrammedcelldeathwherebysignalingthroughvarious"deathreceptors"onthesurfaceofcells[e.g.,tumor
necrosisfactor(TNF)receptors,CD95]leadstoasignalingcascadethatinvolvesactivationofthecaspasefamilyofmoleculesandleads
toDNAcleavageandcelldeath.Apoptosis,whichdoesnotleadtoinductionofinordinateinflammation,istobecontrastedwithcell
necrosis,whichdoesleadtoinductionofinflammatoryresponses.
Autoimmunediseasesdiseasessuchassystemiclupuserythematosusandrheumatoidarthritisinwhichcellsoftheadaptiveimmune
systemsuchasautoreactiveTandBcellsbecomeoverreactiveandproduceselfreactiveTcellandantibodyresponses.
Autoinflammatorydiseaseshereditarydisorderssuchashereditaryperiodicfevers(HPFs)characterizedbyrecurrentepisodesofsevere
inflammationandfeverduetomutationsincontrolsoftheinnateinflammatoryresponse,i.e.,theinflammasome(seebelowandTable
3146).PatientswithHPFsalsohaverashesandserosalandjointinflammationandsomecanhaveneurologicsymptoms.
Autoinflammatorydiseasesaredifferentfromautoimmunediseasesinthatevidenceforactivationofadaptiveimmunecellssuchas
autoreactiveBcellsisnotpresent.
BcellreceptorforantigencomplexofsurfacemoleculesthatrearrangeduringpostnatalBcelldevelopment,madeupofsurface
immunoglobulin(Ig)andassociatedIgchainmoleculesthatrecognizenominalantigenviaIgheavyandlightchainvariableregions,
andsignaltheBcelltoterminallydifferentiatetomakeantigenspecificantibody(Fig.3148).
Blymphocytesbonemarrowderivedorbursalequivalentlymphocytesthatexpresssurfaceimmunoglobulin(theBcellreceptorfor
antigen)andsecretespecificantibodyafterinteractionwithantigen(Figs.3142and3146).
CDclassificationofhumanlymphocytedifferentiationantigensthedevelopmentofmonoclonalantibodytechnologyledtothediscovery
ofalargenumberofnewleukocytesurfacemolecules.In1982,theFirstInternationalWorkshoponLeukocyteDifferentiationAntigens
washeldtoestablishanomenclatureforcellsurfacemoleculesofhumanleukocytes.Fromthisandsubsequentleukocytedifferentiation
workshopshascometheclusterofdifferentiation(CD)classificationofleukocyteantigens(Table3141).
Chemokinessolublemoleculesthatdirectanddetermineimmunecellmovementandcirculationpathways.
Complementcascadingseriesofplasmaenzymesandeffectorproteinswhosefunctionistolysepathogensand/ortargetthemtobe
phagocytizedbyneutrophilsandmonocyte/macrophagelineagecellsofthereticuloendothelialsystem(Fig.3145).
Costimulatorymoleculesmoleculesofantigenpresentingcells(suchasB71andB72orCD40)thatleadtoTcellactivationwhen
boundbyligandsonactivatedTcells(suchasCD28orCD40ligand)(Fig.3147).
Cytokinessolubleproteinsthatinteractwithspecificcellularreceptorsthatareinvolvedintheregulationofthegrowthandactivationof
immunecellsandmediatenormalandpathologicinflammatoryandimmuneresponses(Tables3147,3149,and31410).
Dendriticcellsmyeloidand/orlymphoidlineageantigenpresentingcellsoftheadaptiveimmunesystem.Immaturedendriticcells,or
dendriticcellprecursors,arekeycomponentsoftheinnateimmunesystembyrespondingtoinfectionswithproductionofhighlevelsof
cytokines.Dendriticcellsarekeyinitiatorsbothofinnateimmuneresponsesviacytokineproductionandofadaptiveimmuneresponsesvia
presentationofantigentoTlymphocytes(Figs.3142and3143,Table3145).
Inflammasomelargecytoplasmiccomplexesofintracellularproteinsthatlinkthesensingofmicrobialproductsandcellularstresstothe
proteolyticactivationofinterleukin(IL)1andIL18inflammatorycytokines.Activationofmoleculesintheinflammasomeisakeystepin
theresponseoftheinnateimmunesystemforintracellularrecognitionofmicrobialandotherdangersignalsinbothhealthandpathologic
states(Table3146).
Innateimmunesystemancientimmunerecognitionsystemofhostcellsbearinggermlineencodedpatternrecognitionreceptors(PRRs)
thatrecognizepathogensandtriggeravarietyofmechanismsofpathogenelimination.Cellsoftheinnateimmunesystemincludenatural
killercelllymphocytes,monocytes/macrophages,dendriticcells,neutrophils,basophils,eosinophils,tissuemastcells,andepithelialcells
(Tables3142to3145and31412).
Largegranularlymphocyteslymphocytesoftheinnateimmunesystemwithazurophiliccytotoxicgranulesthathavenaturalkillercell
activitycapableofkillingforeignandhostcellswithfewornoselfmajorhistocompatibilitycomplex(MHC)classImolecules(Fig.3144).
Naturalkillercellslargegranularlymphocytesthatkilltargetcellsexpressingfewornohumanleukocyteantigen(HLA)classImolecules,
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suchasmalignantlytransformedcellsandvirallyinfectedcells.Naturalkillercellsexpressreceptorsthatinhibitkillercellfunctionwhen
selfmajorhistocompatibilitycomplexclassIispresent(Fig.3144).
Naturalkiller(NK)TcellsinnatelikelymphocytesthatuseaninvariantTcellreceptor(TCR)chaincombinedwithalimitedsetofTCR
chainsandcoexpressreceptorscommonlyfoundonNKcells.NKTcellsrecognizelipidantigensofbacterial,viral,fungal,andprotozoal
infectiousagents.
Pathogenassociatedmolecularpatterns(PAMPs)Invariantmolecularstructuresexpressedbylargegroupsofmicroorganismsthatare
recognizedbyhostcellularpatternrecognitionreceptorsinthemediationofinnateimmunity(Fig.3141).
Patternrecognitionreceptors(PRRs)germlineencodedreceptorsexpressedbycellsoftheinnateimmunesystemthatrecognize
pathogenassociatedmolecularpatterns(Table3143).
PolyreactivenaturalantibodiespreexistinglowaffinityantibodiesproducedbyinnateBcellsthatcrossreactwithmultipleantigensand
areavailableatthetimeofinfectiontobindtoandcoattheinvadingpathogenandharnessinnateresponsestoslowtheinfectionuntilan
adaptivehighaffinityprotectiveantibodyresponsecanbemade.
Tcellreceptor(TCR)forantigencomplexofsurfacemoleculesthatrearrangeduringpostnatalTcelldevelopmentmadeupofclonotypic
TCRandchainsthatareassociatedwiththeCD3complexcomposedofinvariant,,,,andchains.TCRandchains
recognizepeptidefragmentsofproteinantigenphysicallyboundinantigenpresentingcellmajorhistocompatibilitycomplexclassIorII
molecules,leadingtosignalingviatheCD3complextomediateeffectorfunctions(Fig.3147).
TcellsthymusderivedlymphocytesthatmediateadaptivecellularimmuneresponsesincludingThelper,Tregulatory,andcytotoxicT
lymphocyteeffectorcellfunctions(Figs.3142,3143,and3147).
ToleranceBandTcellnonresponsivenesstoantigensthatresultsfromencounterwithforeignorselfantigensbyBandTlymphocytes
intheabsenceofexpressionofantigenpresentingcellcostimulatorymolecules.Tolerancetoantigensmaybeinducedandmaintained
bymultiplemechanismseithercentrally(inthethymusforTcellsorbonemarrowforBcells)orperipherallyatsitesthroughoutthe
peripheralimmunesystem.
Introduction
Thehumanimmunesystemhasevolvedovermillionsofyearsfrombothinvertebrateandvertebrateorganismstodevelopsophisticated
defensemechanismstoprotectthehostfrommicrobesandtheirvirulencefactors.Thenormalimmunesystemhasthreekeyproperties:a
highlydiverserepertoireofantigenreceptorsthatenablesrecognitionofanearlyinfiniterangeofpathogensimmunememory,tomountrapid
recallimmuneresponsesandimmunologictolerance,toavoidimmunedamagetonormalselftissues.Frominvertebrates,humanshave
inheritedtheinnateimmunesystem,anancientdefensesystemthatusesgermlineencodedproteinstorecognizepathogens.Cellsofthe
innateimmunesystem,suchasmacrophages,dendriticcells,andnaturalkiller(NK)lymphocytes,recognizepathogenassociatedmolecular
patterns(PAMPs)thatarehighlyconservedamongmanymicrobesanduseadiversesetofpatternrecognitionreceptormolecules(PRRs).
Importantcomponentsoftherecognitionofmicrobesbytheinnateimmunesysteminclude(1)recognitionbygermlineencodedhost
molecules,(2)recognitionofkeymicrobevirulencefactorsbutnotrecognitionofselfmolecules,and(3)nonrecognitionofbenignforeign
moleculesormicrobes.Uponcontactwithpathogens,macrophagesandNKcellsmaykillpathogensdirectlyor,inconcertwithdendriticcells,
mayactivateaseriesofeventsthatbothslowtheinfectionandrecruitthemorerecentlyevolvedarmofthehumanimmunesystem,the
adaptiveimmunesystem.
AdaptiveimmunityisfoundonlyinvertebratesandisbasedonthegenerationofantigenreceptorsonTandBlymphocytesbygene
rearrangements,suchthatindividualTorBcellsexpressuniqueantigenreceptorsontheirsurfacecapableofspecificallyrecognizingdiverse
antigensofthemyriadinfectiousagentsintheenvironment.Coupledwithfinelytunedspecificrecognitionmechanismsthatmaintaintolerance
(nonreactivity)toselfantigens,TandBlymphocytesbringbothspecificityandimmunememorytovertebratehostdefenses.
Thischapterdescribesthecellularcomponents,keymolecules(Table3141),andmechanismsthatmakeuptheinnateandadaptiveimmune
systemsanddescribeshowadaptiveimmunityisrecruitedtothedefenseofthehostbyinnateimmuneresponses.Anappreciationofthe
cellularandmolecularbasesofinnateandadaptiveimmuneresponsesiscriticaltounderstandingthepathogenesisofinflammatory,
autoimmune,infectious,andimmunodeficiencydiseases.
Table3141.HumanLeukocyteSurfaceAntigenstheCDClassificationofLeukocyteDifferentiationAntigens
Surface
Antigen
(Other
Names)
CD1a
(T6,
HTA1)
CD1b
Family
Ig
Ig
Molecular
Mass,
kDa
Distribution
Ligand(s)
Function
49
CD,cortical
thymocytes,
Langerhanstypeof
dendriticcells
TCRTcells
CD1moleculespresentlipid
antigensofintracellularbacteria
suchasMycobacteriumlepraeand
M.tuberculosistoTCRTcells.
45
CD,cortical
thymocytes,
Langerhanstypeof
dendriticcells
TCRTcells
DC,cortical
thymocytes,subset
CD1c
Ig
43
ofBcells,
Langerhanstypeof
TCRTcells
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CD1d
CD2
(T12,
LFA2)
Langerhanstypeof
dendriticcells
Ig
Cortical
thymocytes,
intestinal
epithelium,
Langerhanstypeof
dendriticcells
TCRTcells
AlternativeTcellactivation,Tcell
anergy,Tcellcytokineproduction,
TorNKmediatedcytolysis,Tcell
apoptosis,celladhesion
Ig
50
T,NK
CD58,CD48,CD59,
CD15
CD3(T3,
Leu4)
Ig
:2528,
:2128,
:2025,
:2122,
:16
Associateswiththe
TCR
Tcellactivationandfunctionis
thesignaltransductioncomponent
oftheCD3complex
CD4(T4,
Leu3)
Ig
55
T,myeloid
MHCII,HIV,gp120,
IL16,SABP
Tcellselection,Tcellactivation,
signaltransductionwithp56lck,
primaryreceptorforHIV
CD7
(3A1,
Leu9)
Ig
40
T,NK
K12(CD7L)
TandNKcellsignaltransduction
andregulationofIFN,TNF
production
CD8(T8,
Leu2)
Ig
34
MHCI
Tcellselection,Tcellactivation,
signaltransductionwithp56lck
CD14
(LPS
receptor)
LRG
5355
M,G(weak),notby
myeloidprogenitors
Endotoxin
(lipopolysaccharide),
lipoteichoicacid,PI
TLR4mediateswithLPSandother
PAMPactivationofinnateimmunity
Notknown
AssociateswithCD21andCD81to
formacomplexinvolvedinsignal
transductioninBcelldevelopment,
activation,anddifferentiation
Notknown
Cellsignaling,maybeimportantfor
Bcellactivationandproliferation
CD19B4
Ig
95
B(exceptplasma
cells),FDC
CD20
(B1)
Unassigned
3337
B(exceptplasma
cells)
C3d,C3dg,iC3b,
CD23,EBV
AssociateswithCD19andCD81to
formacomplexinvolvedinsignal
transductioninBcelldevelopment,
activation,anddifferentiation
EpsteinBarrvirusreceptor
CD21
(B2,
CR2,
EBVR,
C3dR)
RCA
145
MatureB,FDC,
subsetof
thymocytes
CD22
(BL
CAM)
Ig
130140
MatureB
CDw75
Celladhesion,signalingthrough
associationwithp72sky,p53/56lyn,
PI3kinase,SHP1,fLC
CD23
(FcRII,
B6,Leu
20,
BLAST
2)
Ctype
lectin
45
B,M,FDC
IgE,CD21,CD11b,
CD11c
RegulatesIgEsynthesis,cytokine
releasebymonocytes
CD28
Ig
44
T,plasmacells
CD80,CD86
CostimulatoryforTcellactivation
involvedinthedecisionbetweenT
cellactivationandanergy
TNFR
4850
B,DC,EC,thymic
epithelium,MP,
cancers
CD154
Bcellactivation,proliferation,and
differentiationformationofGCs
isotypeswitchingrescuefrom
apoptosis
PTP
180,200,
210,220
Allleukocytes
Galectin1,CD2,
CD3,CD4
TandBactivation,thymocyte
development,signaltransduction,
CD40
CD45
(LCA,
T200,
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T200,
B220)
210,220
CD3,CD4
development,signaltransduction,
apoptosis
Galectin1,CD2,
CD3,CD4
IsoformsofCD45containingexon4
(A),restrictedtoasubsetofTcells
CD45RA
PTP
210,220
SubsetT,
medullary
thymocytes,
naive
CD45RB
PTP
200,210,
220
Allleukocytes
Galectin1,CD2,
CD3,CD4
(B)
Galectin1,CD2,
CD3,CD4
(C),restrictedtoasubsetofTcells
Galectin1,CD2,
CD3,CD4
IsoformsofCD45containingno
differentiallysplicedexons,
restrictedtoasubsetofTcells
CD28,CD152
CoregulatorofTcellactivation
signalingthroughCD28stimulates
andthroughCD152inhibitsTcell
activation
CD45RC
PTP
210,220
SubsetT,
medullary
thymocytes,
naive
CD45RO
PTP
180
SubsetT,cortical
thymocytes,
memory
60
ActivatedBandT,
MP,DC
CD28,CD152
CoregulatorofTcellactivation
signalingthroughCD28stimulates
andthroughCD152inhibitsTcell
activation
CD80
(B71,
BB1)
Ig
CD86
(B72,
B70)
Ig
80
SubsetB,DC,EC,
activatedT,thymic
epithelium
CD95
(APO1,
Fas)
TNFR
135
ActivatedTandB
Fasligand
Mediatesapoptosis
CD152
(CTLA4)
Ig
3033
ActivatedT
CD80,CD86
InhibitsTcellproliferation
CD154
(CD40L)
TNF
33
ActivatedCD4+T,
subsetCD8+T,
NK,M,basophil
CD40
CostimulatoryforTcellactivation,
Bcellproliferationanddifferentiation
Abbreviations:CTLA,cytotoxicTlymphocyteassociatedproteinDC,dendriticcellsEBV,
EpsteinBarrvirusEC,endothelialcellsECM,extracellularmatrixFcRIIIA,lowaffinityIgG
receptorisoformAFDC,folliculardendriticcellsG,granulocytesGC,germinalcenterGPI,
glycosylphosphatidylinositolHTA,humanthymocyteantigenIgG,immunoglobulinGLCA,
leukocytecommonantigenLPS,lipopolysaccharideMHCI,majorhistocompatibilitycomplex
classIMP,macrophagesMr,relativemolecularmassNK,naturalkillercellsP,plateletsPBT,
peripheralbloodTcellsPI,phosphatidylinositolPI3K,phosphatidylinositol3kinasePLC,
phospholipaseCPTP,proteintyrosinephosphataseTCR,TcellreceptorTNF,tumornecrosis
factorTNFR,tumornecrosisfactorreceptor.Foranexpandedlistofclusterofdifferentiation
(CD)humanantigens,seeHarrison'sOnlineathttp://www.accessmedicine.comandforafulllist
ofCDhumanantigensfromthemostrecentHumanWorkshoponLeukocyteDifferentiation
Antigens(VII),seehttp://mpr.nci.nih.gov/prow/.
Source:CompiledfromTKishimotoetal(eds):LeukocyteTypingVI,NewYork,Garland
Publishing1997RBrinesetal:ImmunologyToday18S:1,1997andSShaw(ed):Protein
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ReviewsontheWeb,http://mpr.nci.nih.gov/prow/.
TheInnateImmuneSystem
Allmulticellularorganisms,includinghumans,havedevelopedtheuseofalimitednumberofsurfaceandintracellulargermlineencoded
moleculesthatrecognizelargegroupsofpathogens.Becauseofthemyriadhumanpathogens,hostmoleculesofthehumaninnateimmune
systemsense"dangersignals"andeitherrecognizePAMPs,thecommonmolecularstructuressharedbymanypathogens,orrecognizehost
cellmoleculesproducedinresponsetoinfectionsuchasheatshockproteinsandfragmentsoftheextracellularmatrix.PAMPsmustbe
conservedstructuresvitaltopathogenvirulenceandsurvival,suchasbacterialendotoxin,sothatpathogenscannotmutatemoleculesof
PAMPstoevadehumaninnateimmuneresponses.PRRsarehostproteinsoftheinnateimmunesystemthatrecognizePAMPsashost
dangersignalmolecules(Tables3142and3143).Thus,recognitionofpathogenmoleculesbyhematopoieticandnonhematopoieticcell
typesleadstoactivation/productionofthecomplementcascade,cytokines,andantimicrobialpeptidesaseffectormolecules.Inaddition,
pathogenPAMPsashostdangersignalmoleculesactivatedendriticcellstomatureandtoexpressmoleculesonthedendriticcellsurfacethat
optimizeantigenpresentationtorespondtoforeignantigens.
Table3142.MajorComponentsoftheInnateImmuneSystem
Patternrecognition
receptors(PRR)
Ctypelectins,leucinerichproteins,scavengerreceptors,pentraxins,lipidtransferases,integrins,
inflammasomeproteins
Antimicrobialpeptides
Defensins,defensins,cathelin,protegrin,granulysin,histatin,secretoryleukoproteaseinhibitor,
andprobiotics
Cells
Macrophages,dendriticcells,NKcells,NKTcells,neutrophils,eosinophils,mastcells,basophils,
andepithelialcells
Complement
components
Classicandalternativecomplementpathway,andproteinsthatbindcomplementcomponents
Cytokines
Autocrine,paracrine,endocrinecytokinesthatmediatehostdefenseandinflammation,aswellas
recruit,direct,andregulateadaptiveimmuneresponses
Abbreviation:NKcells,naturalkillercells.
Table3143.MajorPatternRecognitionReceptors(PRR)oftheInnateImmuneSystem
PRR
Protein
Family
Sitesof
Expression
Examples
Ligands(PAMPs)
FunctionsofPRR
Tolllike
receptors
Multiplecelltypes
TLR210
Bacterialandviral
carbohydrates
Activateinnateimmunecellstorespondto
multiplepathogensandinitiateadaptive
immuneresponses
Ctype
Lectins
Plasmaproteins
Collectins
Humoral
Opsonizationofbacteriaandvirus,activation
ofcomplement
Terminalmannose
Macrophages,
dendriticcell
Macrophage
mannose
receptor
Naturalkiller(NK)
cells
NKG2A
Leucinerich
proteins
Macrophages,
dendriticcells,
epithelialcells
CD14
Lipopolysaccharide
(LPS)
BindsLPSandTollproteins
Scavenger
receptors
Macrophage
Macrophage
scavenger
receptors
Bacterialcellwalls
Phagocytosisofbacteria
Pentraxins
Plasmaprotein
Creactive
proteins
Phosphatidyl
choline
Opsonizationofbacteria,activationof
complement
Cellular
Carbohydrateon
HLAmolecules
Phagocytosisofpathogens
InhibitskillingofhostcellsexpressingHLA+
selfpeptides
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Plasmaprotein
Serum
amyloidP
Bacterialcellwalls
Opsonizationofbacteria,activationof
complement
Lipid
transferases
Plasmaprotein
LPSbinding
protein
LPS
BindsLPS,transfersLPStoCD14
Integrins
Macrophages,
dendriticcells,NK
cells
CD11b,c
CD18
LPS
Signalscells,activatesphagocytosis
NODlike
Receptors
Innatecells
NALP3
ViralDNABacterial
muramyldipeptide
Cytosolicproteinsinvolvedininnatesensing
Abbreviation:PAMPs,pathogenassociatedmolecularpatterns.
Source:AdaptedfromRMedzhitov,CAJaneway:CurrOpinImmunol9:4,1997.Copyright
1997,withpermissionfromElsevier.
PatternRecognition
MajorPRRfamiliesofproteinsincludeCtypelectins,leucinerichproteins,macrophagescavengerreceptorproteins,plasmapentraxins,lipid
transferases,andintegrins(Table3143).AmajorgroupofPRRcollagenousglycoproteinswithCtypelectindomainsaretermedcollectins
andincludetheserumproteinmannosebindinglectin(MBL).MBLandothercollectins,aswellastwootherproteinfamiliesthepentraxins
(suchasCreactiveproteinandserumamyloidP)andmacrophagescavengerreceptorsallhavethepropertyofopsonizing(coating)
bacteriaforphagocytosisbymacrophagesandcanalsoactivatethecomplementcascadetolysebacteria.Integrinsarecellsurfaceadhesion
moleculesthatsignalaftercellsbindbacteriallipopolysaccharide(LPS)andactivatephagocyticcellstoingestpathogens.
Therearemultipleconnectionsbetweentheinnateandadaptiveimmunesystemstheseinclude(1)aplasmaprotein,LPSbindingprotein,
whichbindsandtransfersLPStothemacrophageLPSreceptor,CD14(2)ahumanfamilyofproteinscalledTolllikereceptorproteins
(TLRs),someofwhichareassociatedwithCD14,bindLPS,andsignalepithelialcells,dendriticcells,andmacrophagestoproducecytokines
andupregulatecellsurfacemoleculesthatsignaltheinitiationofadaptiveimmuneresponses(Fig.3141,Tables3143and3144),and(3)
familiesofintracellularmicrobialsensorscalledNODlikereceptors(NLRs)andRIGlikehelicases(RLHs).ProteinsintheTollfamilycanbe
expressedonmacrophages,dendriticcells,andBcellsaswellasonavarietyofnonhematopoieticcelltypes,includingrespiratoryepithelial
cells.TenTLRshavebeenidentifiedinhumansand13TLRsinmice(Tables3144and3145).Uponligation,TLRsactivateaseriesof
intracellulareventsthatleadtothekillingofbacteriaandviralinfectedcellsaswellastotherecruitmentandultimateactivationofantigen
specificTandBlymphocytes(Fig.3141).Importantly,signalingbymassiveamountsofLPSthroughTLR4leadstothereleaseoflarge
amountsofcytokinesthatmediateLPSinducedshock.MutationsinTLR4proteinsinmiceprotectfromLPSshock,andTLRmutationsin
humansprotectfromLPSinducedinflammatorydiseasessuchasLPSinducedasthma(Fig.3141).
FIGURE3141
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OverviewofmajorTLRsignalingpathways.AllTLRssignalthroughMyD88,withtheexceptionofTLR3.TLR4andtheTLR2subfamily
(TLR1,TLR2,TLR6)alsoengageTIRAP.TLR3signalsthroughTRIF.TRIFisalsousedinconjunctionwithTRAMintheTLR4MyD88
independentpathway.Dashedarrrowsindicatetranslocationintothenucleus.LPS,lipopolysaccharidedsRNA,doublestrandRNAssRNA,
singlestrandRNAMAPK,mitogenactivatedproteinkinasesNFB,nuclearfactorBIFN,interferonIRF3,interferonregulatoryfactor3
TLR,Tolllikereceptor.(AdaptedfromDvanDuinetal.,withpermission.)
Table3144.TheRoleofPatternRecognitionReceptors(PRRs)inModulationofAdaptiveImmuneResponses
PRR
Family
PRRs
TLRs
TLR2
(heterodimer
withTLR1or6)
Ligand
DCor
Macrophage
Cytokine
Response
Adaptive
Immune
Response
Lipopeptides
LowIL12p70
TH1
Pam3cys(TLR2/1)
HighIL10
TH2
MALP(TLR2/6)
IL6
Tregulatory
IL12p70
TLR3
dsRNA
IFN
TH1
IL6
HighIL12p70
TLR4
E.coliLPS
IntermediateIL10
TH1
IL6
TLR5
Flagellin
ssRNA
TLR7/8
Imidazoquinolines
HighIL12p70
TH1
LowIL12p70
TH2
HighIL12p70
IFN
TH1
IL6
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HighIL12p70
LowIL10
TLR9
CpGDNA
IL6
TH1
IFN
TLR10
H.pylori,LewisAg
EnvofHIVcoreproteinofHCVcomponentsof
MycobacteriumtuberculosisHelicobacterpylori,
LewisAg
SuppressesIL
12p70
TH2
Ctype
lectins
DCSIGN
NOD
NOD2
Muramyldipeptideofpeptidoglycan
InducesIL10in
DCs
WeakTcell
response
(tolerogenic?)
Mannose
receptor
Mannose
receptor
Mannosylatedlipoarabinomannansfrombacillus
CalmetteGuerinandM.tuberculosis
SuppressesIL12
andTLRsignaling
inDCs
WeakTcell
response?
(tolerogenic?)
SuppressesTLR
signalinginDCs
Tregulatory
Abbreviations:dsRNA,doublestrandRNAssRNA,singlestrandRNALPS,
lipopolysaccharideTH2,helperTcellTH1,helperTcellCpG,sequencesinDNArecognized
byTLR9MALP,macrophageactivatinglipopeptideDCSIGN,DCspecificCtypelectinNOD,
NOTCHproteindomainTLR,TolllikereceptorHCV,hepatitisC.
Source:BPulendran:JImmunol174:2457,2005.Copyright2005TheAmericanAssociationof
Immunologists,Inc.,withpermission.
Table3145.CellsoftheInnateImmuneSystemandTheirMajorRolesinTriggeringAdaptiveImmunity
CellType
MajorRoleinInnateImmunity
MajorRoleinAdaptiveImmunity
Macrophages
Phagocytoseandkillbacteria
produceantimicrobialpeptides
bind(LPS)produceinflammatory
cytokines
ProduceIL1andTNFtoupregulatelymphocyteadhesion
moleculesandchemokinestoattractantigenspecificlymphocyte.
ProduceIL12torecruitTH1Thelpercellresponsesupregulateco
stimulatoryandMHCmoleculestofacilitateTandBlymphocyte
recognitionandactivation.Macrophagesanddendriticcells,after
LPSsignaling,upregulatecostimulatorymoleculesB71(CD80)
andB72(CD86)thatarerequiredforactivationofantigenspecific
antipathogenTcells.TherearealsoTolllikeproteinsonBcellsand
dendriticcellsthat,afterLPSligation,induceCD80andCD86on
thesecellsforTcellantigenpresentation.
Plasmacytoid
fdendritic
cells(DCs)of
lymphoid
lineage
Producelargeamountsof
interferon(IFN),whichhas
antitumorandantiviralactivity,and
arefoundinTcellzonesof
lymphoidorganstheycirculatein
blood
IFNisapotentactivatorofmacrophageandmatureDCsto
phagocytoseinvadingpathogensandpresentpathogenantigensto
TandBcells
Myeloid
dendriticcells
areoftwo
types
interstitial
and
Langerhans
InterstitialDCsarestrong
producersofIL12andIL10and
arelocatedinTcellzonesof
lymphoidorgans,circulateinblood,
andarepresentintheintersticesof
thelung,heart,andkidney
LangerhansDCsarestrong
producersofIL12arelocatedinT
cellzonesoflymphnodes,skin
epithelia,andthethymicmedulla
derived
InterstitialDCsarepotentactivatorsofmacrophageandmatureDCs
tophagocytoseinvadingpathogensandpresentpathogenantigens
toTandBcells
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andcirculateinblood
Naturalkiller
(NK)cells
Killforeignandhostcellsthathave
lowlevelsofMHC+selfpeptides.
ExpressNKreceptorsthatinhibit
NKfunctioninthepresenceofhigh
expressionofselfMHC.
ProduceTNFandIFN,whichrecruitTH1helperTcellresponses
NKTcells
LymphocyteswithbothTcelland
NKsurfacemarkersthatrecognize
lipidantigensofintracellular
bacteriasuchasMycobacterium
tuberculosisbyCD1moleculesand
killhostcellsinfectedwith
intracellularbacteria.
ProduceIL4torecruitTH2helperTcellresponses,IgG1andIgE
production
Neutrophils
Phagocytoseandkillbacteria,
produceantimicrobialpeptides
Producenitricoxidesynthaseandnitricoxide,whichinhibit
apoptosisinlymphocytesandcanprolongadaptiveimmune
responses
Eosinophils
Killinvadingparasites
ProduceIL5,whichrecruitsIgspecificantibodyresponses
Mastcells
and
basophils
ReleaseTNF,IL6,andIFNin
responsetoavarietyofbacterial
PAMPs
ProduceIL4,whichrecruitsTH2helperTcellresponsesandrecruit
IgG1andIgEspecificantibodyresponses
Epithelial
cells
Produceantimicrobialpeptides
tissuespecificepitheliaproduce
mediatoroflocalinnateimmunity
e.g.,lungepithelialcellsproduce
surfactantproteins(proteinswithin
thecollectinfamily)thatbindand
promoteclearanceoflunginvading
microbes
ProducesTGF,whichtriggersIgAspecificantibodyresponses
Abbreviations:LPS,lipopolysaccharidePAMP,pathogenassociatedmolecularpatternsTNF
,tumornecrosisfactoralphaIL4,IL5,IL6,IL10,andIL12,interleukin4,5,6,10,and12,
respectively.
Source:AdaptedfromRMedzhitov,CAJaneway:CurrOpinionImmunol9:4,1997.Copyright
1997,withpermissionfromElsevier.
TwootherfamiliesofintracellularPRRsaretheNLRs(NODlikereceptors)andtheRLHs(RIGlikehelicases).Thesefamilies,unliketheTLRs,
arecomposedprimarilyofsolubleintracellularproteinsthatscanthecytoplasmforintracellularpathogens(Tables3142and3143).
Theintracellularmicrobialsensors,NLRs,aftertriggering,formlargecytoplasmiccomplexestermedinflammasomes,whichareaggregatesof
moleculesincludingNODlikereceptorpyrin(NLRP)proteinsthataremembersoftheNLRfamily(Table3143).Inflammasomesactivate
inflammatorycaspasesandIL1inthepresenceofnonbacterialdangersignals(cellstress)andbacterialPAMPs.Mutationsin
inflammasomeproteinscanleadtochronicinflammationinagroupofperiodicfebrilediseasescalledautoinflammatorysyndromes(Table
3146).
Table3146.DiseasesAssociatedwithInflammasomeActivity
Inflammasome
Involvement
*Anakinra
NALP3
Overactive
Yes
NAPL3
Overactive
Yes
NALP3
Overactive
Yes
Disease
ClinicalFeatures
Gene
Mutated
Familialcoldautoinflammatory
syndrome(FCAS)
Fever,arthralgia,cold
inducedurticaria
MuckleWellssyndrome(MWS)
Fever,arthralgia,urticaria,
sensorineuraldeafness,
amyloidosis
Chronicinfantileneurologic
cutaneousandarticular
Fever,severearthralgia,
urticaria,neurologic
Etiologic
Agent
Response
9/50
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syndrome(CINCA,NOMID)
problems,severe
amyloidosis
FamilialMediterraneanfever
(FMF)
Fever,peritonitis,pleuritis,
amyloidosis
Pyrin
Overactive
Partial
Pyogenicarthritis,pyoderma
gangrenosum,andacne
syndrome(PAPA)
Pyogenicsterilearthritis
PSTPIP1
Overactive
Yes
HyperimmunoglobulinD
syndrome(HIDS)
Arthralgia,abdominalpain,
lymphadenopathy
Mevalonate
kinase
Tobe
demonstrated
Yes
Tumornecrosisfactorreceptor
1associatedsyndrome
(TRAPS)
Fever,abdominalpain,skin
lesions
TNFR1
Tobe
demonstrated
Yes
Systemiconsetjuvenile
idiopathicarthritis(SOJIA)
Chronicjointinflammation
Unknown
Tobe
demonstrated
Yes
AdultonsetStill'sdisease
(AOSD)
Arthralgia,fever
Unknown
Tobe
demonstrated
Yes
Behet'sdisease
Arthralgia,uveitis,ulcers
Unknown
Tobe
demonstrated
Yes
Schnitzler'ssyndrome
Urticaria,fever,arthralgia
Unknown
Tobe
demonstrated
Yes
Gout
Metabolicarthritis,pain
Uricacid
(MSU)
Activated
Yes
Pseudogout
Arthritis
CPPD
Activated
Yes
Contactdermatitis
Urticaria
Irritants
Activated
Unknown
Feversyndrome
Fever
NALP12
Unknown
Unknown
Hydatidiformmole
Hydatidmole
NALP7
Unknown
Unknown
Vitiligo
Skindepigmentation,
autoimmunity
NALP1
Unknown
Unknown
*AnakinraisarecombinantIL1receptorantagonistthatfunctionstoblockthebiologicactivityof
naturallyoccuringinterleukin1(IL1).
Source:FromFMartinonetal:AnnRevImmunol27:229,2009.Copyright2009.Reproduced
withpermissionfromAnnualReviewsInc.
EffectorCellsofInnateImmunity
CellsoftheinnateimmunesystemandtheirrolesinthefirstlineofhostdefensearelistedinTable3145.Equallyimportantastheirrolesin
themediationofinnateimmuneresponsesaretherolesthateachcelltypeplaysinrecruitingTandBlymphocytesoftheadaptiveimmune
systemtoengageinspecificantipathogenresponses.
MonocytesMacrophages
Monocytesarisefromprecursorcellswithinbonemarrow(Fig.3142)andcirculatewithahalfliferangingfrom1to3days.Monocytesleave
theperipheralcirculationbymarginatingincapillariesandmigratingintoavastextravascularpool.Tissuemacrophagesarisefrommonocytes
thathavemigratedoutofthecirculationandbyinsituproliferationofmacrophageprecursorsintissue.Commonlocationswheretissue
macrophages(andcertainoftheirspecializedforms)arefoundarelymphnode,spleen,bonemarrow,perivascularconnectivetissue,serous
cavitiessuchastheperitoneum,pleura,skinconnectivetissue,lung(alveolarmacrophages),liver(Kupffercells),bone(osteoclasts),central
nervoussystem(microgliacells),andsynovium(typeAliningcells).
FIGURE3142
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Schematicmodelofintercellularinteractionsofadaptiveimmunesystemcells.Inthisfigure,thearrowsdenotethatcellsdevelopfrom
precursorcellsorproducecytokinesorantibodieslinesendingwithbarsindicatesuppressiveintercellularinteractions.Stemcellsdifferentiate
intoeitherTcells,antigenpresentingdendriticcells,naturalkillercells,macrophages,granulocytes,orBcells.Foreignantigenisprocessed
bydendriticcells,andpeptidefragmentsofforeignantigenarepresentedtoCD4+and/orCD8+Tcells.CD8+Tcellactivationleadsto
inductionofcytotoxicTlymphocyte(CTL)orkillerTcellgeneration,aswellasinductionofcytokineproducingCD8+cytotoxicTcells.For
antibodyproductionagainstthesameantigen,activeantigenisboundtosIgwithintheBcellreceptorcomplexanddrivesBcellmaturation
intoplasmacellsthatsecreteIg.T H1orT H2CD4+Tcellsproducinginterleukin(IL)4,IL5,orinterferon(IFN)regulatetheIgclassswitching
anddeterminethetypeofantibodyproduced.T H17cellssecreteIL17,IL22,IL26,whichcontributetohostdefenseagainstextracellular
bacteriaandfungi,particularlyatmucosalsurfaces.CD4+,CD25+TregulatorycellsproduceIL10anddownregulateTandBcellresponses
oncethemicrobehasbeeneliminated.GMCSF,granulocytemacrophagecolonystimulatingfactorTNF,tumornecrosisfactor.
Ingeneral,monocytesmacrophagesareonthefirstlineofdefenseassociatedwithinnateimmunityandingestanddestroymicroorganisms
throughthereleaseoftoxicproductssuchashydrogenperoxide(H2O2)andnitricoxide(NO).Inflammatorymediatorsproducedby
macrophagesattractadditionaleffectorcellssuchasneutrophilstothesiteofinfection.Macrophagemediatorsincludeprostaglandins
leukotrienesplateletactivatingfactorcytokinessuchasinterleukin(IL)1,tumornecrosisfactor(TNF),IL6,andIL12andchemokines
(Tables3147,3148,3149,and31410).
Table3147.CytokinesandCytokineReceptors
Cytokine
IL1,
Receptor
TypeIIL1r,
TypeIIIL1r
CellSource
Monocytes/macrophages,
Bcells,fibroblasts,most
epithelialcellsincluding
thymicepithelium,
endothelialcells
CellTarget
Allcells
BiologicActivity
Upregulatesadhesion
moleculeexpression,
neutrophiland
macrophageemigration,
mimicsshock,fever,
upregulateshepatic
acutephaseprotein
11/50
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production,facilitates
hematopoiesis
IL2
IL2r,,
common
Tcells
Tcells,Bcells,NKcells,
monocytes
macrophages
PromotesTcell
activationand
proliferation,Bcell
growth,NKcell
proliferationand
activation,enhanced
monocyte/macrophage
cytolyticactivity
IL3
IL3r,common
Tcells,NKcells,mast
cells
Monocytes
macrophages,mast
cells,eosinophils,bone
marrowprogenitors
Stimulateshematopoietic
progenitors
StimulatesTH2helperT
celldifferentiationand
proliferation.Stimulates
BcellIgclassswitchto
IgG1andIgEanti
inflammatoryactiononT
cells,monocytes
IL4
IL4r,
common
Tcells,mastcells,
basophils
Tcells,Bcells,NKcells,
monocytes
macrophages,
neutrophils,eosinophils,
endothelialcells,
fibroblasts
IL5
IL5r,
common
Tcells,mastcells,
eosinophils
Eosinophils,basophils,
murineBcells
Regulateseosinophil
migrationandactivation
IL6
IL6r,gp130
Monocytes
macrophages,Bcells,
fibroblasts,most
epitheliumincluding
thymicepithelium,
endothelialcells
Tcells,Bcells,epithelial
cells,hepatocytes,
monocytes
macrophages
Inducesacutephase
proteinproduction,Tand
Bcelldifferentiationand
growth,myelomacell
growth,andosteoclast
growthandactivation
IL7
IL7r,
common
Bonemarrow,thymic
epithelialcells
Tcells,Bcells,bone
marrowcells
DifferentiatesB,T,and
NKcellprecursors,
activatesTandNKcells
Neutrophils,Tcells,
monocytes
macrophages,
endothelialcells,
basophils
Inducesneutrophil,
monocyte,andTcell
migration,induces
neutrophiladherenceto
endothelialcellsand
histaminereleasefrom
basophils,and
stimulatesangiogenesis.
Suppressesproliferation
ofhepaticprecursors
Bonemarrow
progenitors,Bcells,T
cells,mastcells
Inducesmastcell
proliferationand
function,synergizeswith
IL4inIgGandIgE
productionandTcell
growth,activation,and
differentiation
IL8
IL9
IL10
CXCR1,
CXCR2
IL9r,
common
IL10r
Monocytes
macrophages,Tcells,
neutrophils,fibroblasts,
endothelialcells,
epithelialcells
Tcells
Monocytes
macrophages,Tcells,B
cells,keratinocytes,mast
cells
Monocytes
macrophages,Tcells,B
cells,NKcells,mast
cells
Inhibitsmacrophage
proinflammatorycytokine
production,
downregulatescytokine
classIIantigenandB71
andB72expression,
inhibitsdifferentiationof
TH1helperTcells,
inhibitsNKcellfunction,
stimulatesmastcell
proliferationand
function,Bcell
activation,and
12/50
23/2/2558
differentiation
IL11
IL12(35kDand
40kDsubunits)
IL11,gp130
IL12r
Bonemarrowstromal
cells
Activatedmacrophages,
dendriticcells,
neutrophils
Megakaryocytes,Bcells,
hepatocytes
Inducesmegakaryocyte
colonyformationand
maturation,enhances
antibodyresponses,
stimulatesacutephase
proteinproduction
Tcells,NKcells
InducesTH1Thelper
cellformationand
lymphokineactivated
killercellformation.
IncreasesCD8+CTL
cytolyticactivityIL17,
IFN.
UpregulatesVCAM1
andCCchemokine
expressionon
endothelialcellsandB
cellactivationand
differentiation,and
inhibitsmacrophage
production
IL13
IL13/IL4
Tcells(TH2)
Monocytes
macrophages,Bcells,
endothelialcells,
keratinocytes
IL14
Unknown
Tcells
NormalandmalignantB
cells
InducesBcell
proliferation
IL15
IL15r,
common,IL2r
Monocytes
macrophages,epithelial
cells,fibroblasts
Tcells,NKcells
PromotesTcell
activationand
proliferation,
angiogenesis,andNK
cells
IL16
CD4
Mastcells,eosinophils,
CD8+Tcells,respiratory
epithelium
CD4+Tcells,
monocytesmacrophages,
eosinophils
Promotes
chemoattractionofCD4+
Tcells,monocytes,and
eosinophils.InhibitsHIV
replication.InhibitsTcell
activationthroughCD3/T
cellreceptor
IL17
IL17r
CD4+Tcells
Fibroblasts,endothelium,
epithelium
Enhancescytokine
secretion
IL18
IL18r(IL1R
relatedprotein)
Keratinocytes,
macrophages
Tcells,Bcells,NKcells
UpregulatesIFN
production,enhances
NKcellcytotoxicity
IL21
ILchain/IL
21R
CD4Tcells
NKcells
DownregulatesNKcell
activatingmolecules,
NKG2D/DAP10
IL23
IL12Rb1/IL23R
Macrophages,othercell
types
Tcells
OppositeeffectsofIL12
(IL17,IFN)
Allcells
Promotesantiviral
activity.StimulatesT
cell,macrophage,and
NKcellactivity.Direct
antitumoreffects.
UpregulatesMHCclassI
antigenexpression.
Usedtherapeuticallyin
viralandautoimmune
conditions
IFN
TypeI
interferon
receptor
Allcells
Antiviralactivity.
13/50
23/2/2558
IFN
TypeI
interferon
receptor
Allcells
Allcells
StimulatesTcell,
macrophage,andNK
cellactivity.Direct
antitumoreffects.
UpregulatesMHCclassI
antigenexpression.
Usedtherapeuticallyin
viralandautoimmune
conditions
Allcells
Regulatesmacrophage
andNKcellactivations.
Stimulates
immunoglobulin
secretionbyBcells.
InductionofclassII
histocompatibility
antigens.TH1Tcell
differentiation.
TNFrI,TNFrII
Monocytes
macrophages,mastcells,
basophils,eosinophils,
NKcells,Bcells,Tcells,
keratinocytes,fibroblasts,
thymicepithelialcells
Allcellsexcept
erythrocytes
Fever,anorexia,shock,
capillaryleaksyndrome,
enhancedleukocyte
cytotoxicity,enhanced
NKcellfunction,acute
phaseproteinsynthesis,
induction.
TNF
TNFrI,TNFrII
Tcells,Bcells
Allcellsexcept
erythrocytes
Cellcytotoxicity,lymph
nodeandspleen
development.
LT
LTR
Tcells
Allcellsexcept
erythrocytes
Cellcytotoxicity,normal
lymphnodedevelopment
GCSFrgp130
Monocytes
macrophages,fibroblasts,
endothelialcells,thymic
epithelialcells,stromal
cells
Myeloidcells,endothelial
cells
Regulatesmyelopoiesis.
Enhancessurvivaland
functionofneutrophils.
Clinicaluseinreversing
neutropeniaafter
cytotoxicchemotherapy.
GMCSFr,
common
Tcells,
fibroblasts,endothelial
cells,thymicepithelial
cells
Monocytes
macrophages,
neutrophils,eosinophils,
cells
Regulatesmyelopoiesis.
Enhancesmacrophage
bactericidaland
tumoricidalactivity.
Mediatorofdendriticcell
maturationandfunction.
UpregulatesNKcell
function.Clinicalusein
reversingneutropenia
aftercytotoxic
chemotherapy.
MCSFr(cfms
protooncogene
Fibroblasts,endothelial
cells,
Tcells,Bcells,epithelial
cellsincludingthymic
epithelium
Monocytes
macrophages
Regulatesmonocyte
macrophageproduction
andfunction.
TypeII
interferon
receptor
Tcells,NKcells
TNF
IFN
GCSF
GMCSF
MCSF
LIF
LIFrgp130
ActivatedTcells,bone
marrowstromalcells,
thymicepithelium
Megakaryocytes,
monocytes,hepatocytes,
possiblylymphocyte
subpopulations
Induceshepaticacute
phaseprotein
production.Stimulates
macrophage
differentiation.Promotes
growthofmyelomacells
andhematopoietic
progenitors.Stimulates
14/50
23/2/2558
thrombopoiesis.
OSM
SCF
TGF(3isoforms)
Lymphotactin/SCM
1
MCP1
MCP2
MCP3
MCP4
Activated
monocytesmacrophages
andTcells,bonemarrow
stromalcells,some
breastcarcinomacell
lines,myelomacells
Neurons,hepatocytes,
monocytes
macrophages,
adipocytes,alveolar
epithelialcells,
embryonicstemcells,
melanocytes,endothelial
cells,fibroblasts,
myelomacells
Induceshepaticacute
phaseprotein
production.Stimulates
macrophage
differentiation.Promotes
growthofmyelomacells
andhematopoietic
progenitors.Stimulates
thrombopoiesis.
Stimulatesgrowthof
Kaposi
ssarcomacells.
Bonemarrowstromal
cellsandfibroblasts
Embryonicstemcells,
myeloidandlymphoid
precursors,mastcells.
Stimulateshematopoietic
progenitorcellgrowth,
mastcellgrowth,
promotesembryonic
stemcellmigration.
Mostcelltypes
DownregulatesTcell,
macrophage,and
granulocyteresponses.
Stimulatessynthesisof
matrixproteins.
Stimulatesangiogenesis.
Tcells,NKcells
Chemoattractantfor
lymphocytes.Only
knownchemokineofC
class.
Monocytes
macrophages,NKcells,
memoryTcells,
basophils
Chemoattractantfor
monocytes,activated
memoryTcells,andNK
cells.Inducesgranule
releasefromCD8+T
cellsandNKcells.
Potenthistamine
releasingfactorfor
basophils.Suppresses
proliferationof
hematopoietic
precursors.Regulates
monocyteprotease
production.
Monocytes
macrophages,Tcells,
eosinophils,basophils,
NKcells
Chemoattractantfor
monocytes,memoryand
naveTcells,
eosinophils,?NKcells.
Activatesbasophilsand
eosinophils.Regulates
monocyteprotease
production.
CCR1,CCR2
Fibroblasts,activated
PBMCs
Monocytes
macrophages,Tcells,
eosinophils,basophils,
NKcells,dendriticcells
Chemoattractantfor
monocytes,memoryand
naveTcells,dendritic
cells,eosinophils,?NK
cells.Activatesbasophils
andeosinophils.
Regulatesmonocyte
proteaseproduction.
CCR2,CCR3
Lung,colon,small
intestinalepithelialcells,
activatedendothelialcells
Monocytes
macrophages,Tcells,
eosinophils,basophils
Chemoattractantfor
monocytes,Tcells,
eosinophils,and
basophils
OSMrLIFr
gp130
SCFr(ckit
protooncogene)
TypeI,II,III
TGFreceptor
Mostcelltypes
Unknown
NKcells,mastcells,
doublenegative
thymocytes,activated
CD8+Tcells
CCR2
CCR1,CCR2
Fibroblasts,
smoothmusclecells,
activatedPBMCs
Fibroblasts,activated
PBMCs
Potentchemoattractant
15/50
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foreosinophilsand
basophils.Induces
allergicairwaysdisease.
ActsinconcertwithIL5
toactivateeosinophils.
Antibodiestoeotaxin
inhibitairway
inflammation.
Eotaxin
CCR3
Pulmonaryepithelial
cells,heart
Eosinophils,basophils
TARC
CCR4
Thymus,dendriticcells,
activatedTcells
Tcells,NKcells
ChemoattractantforT
andNKcells.
CCR4
Monocytes
macrophages,dendritic
cells,thymus
ActivatedTcells
Chemoattractantfor
activatedTcells.Inhibits
infectionwithTcelltropic
HIV.
Monocytes
macrophages,Tcells,
dendriticcells,NKcells,
Chemoattractantfor
monocytes,Tcells,
dendriticcells,NKcells,
andweak
chemoattractantfor
eosinophilsand
basophils.ActivatesNK
cellfunction.Suppresses
proliferationof
hematopoietic
precursors.Necessary
formyocarditis
associatedwith
Coxsackievirus
infection.Inhibits
infectionwith
monocytotropicHIV.
Monocytesmacrophages,
Tcells,NKcells,
dendriticcells
Chemoattractantfor
monocytes,Tcells,and
NKcells.ActivatesNK
cellfunction.Inhibits
infectionwith
monocytotropicHIV.
MDC
MIP1
MIP1
CCR1,CCR5
CCR5
Monocytes
macrophages,Tcells
Monocytes
macrophages,Tcells
RANTES
CCR1,CCR2,
CCR5
Monocytes
macrophages,Tcells,
fibroblasts,eosinophils
Monocytes
macrophages,Tcells,
NKcells,dendriticcells,
Chemoattractantfor
CD4+,CD45Ro+Tcells,
CD8+Tcells,NKcells,
eosinophils,and
basophils.Induces
histaminereleasefrom
basophils.Inhibits
infectionswith
monocytotropicHIV.
LARC/MIP
3/Exodus1
CCR6
Dendriticcells,fetalliver
cells,activatedTcells
Tcells,Bcells
Chemoattractantfor
lymphocytes.
ActivatedTcellsandB
cells
ChemoattractantforB
andTcells.Receptor
upregulatedonEBV
infectedBcellsand
HSVinfectedTcells.
ELC/MIP3
CCR7
Thymus,lymphnode,
appendix
I309/TCA3
CCR8
ActivatedTcells
Monocytes
macrophages,Tcells
Chemoattractantfor
monocytes.Prevents
glucocorticoidinduced
apoptosisinsomeTcell
lines.
SLC/TCA
4/Exodus2
Unknown
Thymicepithelialcells,
lymphnode,appendix
andspleen
Tcells
ChemoattractantforT
lymphocytes.Inhibits
hematopoiesis.
16/50
23/2/2558
DCCK1/PARC
TECK
GRO/MGSA
GRO/MIP2
NAP2
IP10
MIG
SDF1
Fractalkine
PF4
Unknown
Dendriticcellsin
secondarylymphoid
tissues
NaveTcells
Mayhavearolein
inductionofimmune
responses.
Unknown
Dendriticcells,thymus,
liver,smallintestine
Tcells,
dendriticcells
Thymicdendriticcell
derivedcytokine,
possiblyinvolvedinT
celldevelopment
CXCR2
Activatedgranulocytes,
monocytemacrophages,
andepithelialcells.
Neutrophils,epithelial
cells,?endothelialcells
Neutrophil
chemoattractantand
activator.Mitogenicfor
somemelanomacell
lines.Suppresses
proliferationof
hematopoietic
precursors.Angiogenic
activity.
CXCR2
Activatedgranulocytes
andmonocyte
macrophages
Neutrophilsand?
endothelialcells.
Neutrophil
chemoattractantand
activator.Angiogenic
activity.
CXCR2
Platelets
Neutrophils,basophils
Derivedfromplatelet
basicprotein.Neutrophil
chemoattractantand
activator.
CXCR3
Monocytes
macrophages,Tcells,
cells,epithelialcells
ActivatedTcells,
tumorinfiltrating
lymphocytes,?
endothelialcells,?NK
cells
IFNinducibleprotein
thatisachemoattractant
forTcells.Suppresses
proliferationof
hematopoietic
precursors.
ActivatedTcells,
tumorinfiltrating
lymphocytes
IFNinducibleprotein
thatisachemoattractant
forTcells.Suppresses
proliferationof
hematopoietic
precursors.
Fibroblasts
Tcells,dendriticcells,?
basophils,?endothelial
cells
Lowpotency,high
efficacyTcell
chemoattractant.
RequiredforB
lymphocyte
development.Prevents
infectionofCD4+,
CXCR4+cellsbyTcell
tropicHIV.
Activatedendothelial
cells
NKcells,Tcells,
monocytes
macrophages
Cellsurface
chemokine/mucinhybrid
moleculethatfunctions
asachemoattractant,
leukocyteactivator,and
celladhesionmolecule.
Fibroblasts,endothelial
cells
Chemoattractantfor
fibroblasts.Suppresses
proliferationof
hematopoietic
precursors.Inhibits
endothelialcell
proliferationand
angiogenesis.
CXCR3
CXCR4
CX3CR1
Unknown
Monocytes
macrophages,Tcells,
fibroblasts
Platelets,
megakaryocytes
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Abbreviations:IL,interleukinNK,naturalkillerTH1andTH2,helperTcellsubsetsIg,
immunoglobulinCXCR,CXCtypechemokinereceptorB71,CD80,B72,CD86PBMC,
peripheralbloodmononuclearcellsVCAM,vascularcelladhesionmoleculeIFN,interferon
MHC,majorhistocompatibilitycomplexTNF,tumornecrosisfactorGCSF,granulocytecolony
stimulatingfactorGMCSF,granulocytemacrophageCSFMCSF,macrophageCSFLIF,
leukemiainhibitoryfactorOSM,oncostatinMSCF,stemcellfactorTGF,transforminggrowth
factorMCP,monocytechemotacticproteinCCR,CCtypechemokinereceptorTARC,thymus
andactivationregulatedchemokineMDC,macrophagederivedchemokineMIP,macrophage
inflammatoryproteinRANTES,regulatedonactivation,normallyTcellexpressedand
secretedLARC,liverandactivationregulatedchemokineEBV,EpsteinBarrvirusELC,EB11
ligandchemokine(MIP1b)HSV,herpessimplexvirusTCA,TcellactivationproteinDCCK,
dendriticcellchemokinePARC,pulmonaryandactivationregulatedchemokineSLC,
secondarylymphoidtissuechemokineTECK,thymusexpressedchemokineGRP,growth
relatedpeptideMGSA,melanomagrowthstimulatingactivityNAP,neutrophilactivatingprotein
IP10,IFNinducibleprotein10MIG,monokineinducedbyIFNSDF,stromalcellderived
factorPF,plateletfactor.
Source:DatafromJSSundyetal:AppendixB,inInflammation,BasicPrinciplesandClinical
Correlates,3rded,JGallinandRSnyderman(eds).Philadelphia,LippincottWilliamsand
Wilkins,1999.
Table3148.CC,CXC1,CX3,C1andXCFamiliesofChemokinesandChemokineReceptors
Chemokine
Receptor
ChemokineLigands
CellTypes
DiseaseConnection
CCR1
CCL3(MIP1),CCL5(RANTES),
CCL7(MCP3),CCL14(HCC1)
Tcells,monocytes,
Rheumatoidarthritis,multiplesclerosis
CCR2
CCL2(MCP1),CCL8(MCP2),
CCL7(MCP3),CCL13(MCP4),
CCL16(HCC4)
Monocytes,dendritic
cells(immature),
memoryTcells
Atherosclerosis,rheumatoidarthritis,
multiplesclerosis,resistanceto
intracellularpathogens,type2diabetes
mellitus
CCR3
CCL11(eotaxin),CCL13(eotaxin
2),CCL7(MCP3),CCL5
(RANTES),CCL8(MCP2),CCL13
(MCP4)
Eosinophils,basophils,
mastcells,TH2,
platelets
Allergicasthmaandrhinitis
CCR4
CCL17(TARC),CCL22(MDC)
Tcells(TH2)dendritic
cells(mature),
basophils,
macrophages,platelets
Parasiticinfection,graftrejection,Tcell
homingtoskin
CCR5
CCL3(MIP1),CCL4(MIP1),
CCL5(RANTES),CCL11(eotaxin),
CCL14(HCC1),CCL16(HCC4)
Tcells,monocytes
HIV1coreceptor(Tcelltropicstrains),
transplantrejection
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Tcells(Tregulatoryand
memory),Bcells,
dendriticcells
Mucosalhumoralimmunity,allergic
asthma,intestinalTcellhoming
CCR6
CCL20(MIP3,LARC)
CCR7
CCL19(ELC),CCL21(SLC)
Tcells,dendriticcells
(mature)
TransportofTcellsanddendriticcellsto
lymphnodes,antigenpresentation,and
cellularimmunity
CCR8
CCL1(1309)
Tcells(TH2),
monocytes,dendritic
cells
Dendriticcellmigrationtolymphnode,
type2cellularimmunity,granuloma
formation
CCR9
CCL25(TECK)
Tcells,IgA+plasma
cells
HomingofTcellsandIgA+plasmacells
totheintestine,inflammatorybowel
disease
CCR10
CCL27(CTACK),CCL28(MEC)
Tcells
Tcellhomingtointestineandskin
CXCR1
CXCL8(interleukin8),CXCL6
(GCP2)
Neutrophils,monocytes
Inflammatorylungdisease,COPD
CXCR2
CXCL8,CXCL1(GRO),CXCL2
(GRO),CXCL3(GRO),CXCL5
(ENA78),CXCL6
Neutrophils,monocytes,
microvascular
endothelialcells
Inflammatorylungdisease,COPD,
angiogenicfortumorgrowth
CXCR3A
CXCL9(MIG),CXCL10(IP10),
CXCL11(ITAC)
Type1helpercells,
mastcells,mesangial
cells
Inflammatoryskindisease,multiple
sclerosis,transplantrejection
CXCR3B
CXCL4(PF4),CXCL9(MIG),
CXCL10(IP10),CXCL11(ITAC)
Microvascular
endothelialcells,
neoplasticcells
Angiostaticfortumorgrowth
CXCR4
CXCL12(SDF1)
Widelyexpressed
HIV1coreceptor(Tcelltropic),tumor
metastases,hematopoiesis
CXCR5
CXCL13(BCA1)
Bcells,follicularhelper
Tcells
FormationofBcellfollicles
CXCR6
CXCL16(SRPSOX)
CD8+Tcells,natural
killercells,andmemory
CD4+Tcells
Inflammatoryliverdisease,
atherosclerosis(CXCL16)
CX3CR1
CX3CL1(fractalkine)
Macrophages,
endothelialcells,
smoothmusclecells
Atherosclerosis
XCR1
XCL1(lymphotactin),XCL2
Tcells,naturalkiller
cells
Rheumatoidarthritis,IgAnephropathy,
tumorresponse
Abbreviations:MIP,macrophageinflammatoryproteinMCP,monocytechemoattractant
proteinHCC,hemofiltratechemokineTH2,type2helperTcellsTARC,thymusandactivation
regulatedchemokineMDC,macrophagederivedchemokineLARC,liverandactivation
regulatedchemokineELC,EpsteinBarrI1ligandchemokineSLC,secondarylymphoidtissue
chemokineTECK,thymusexpressedchemokineCTACK,cutaneousTcellattracting
chemokineMEC,mammaryenrichedchemokineGCP,granulocytechemotacticprotein
COPD,chronicobstructivepulmonarydiseaseGRO,growthregulatedoncogeneENA,
epithelialcellderivedneutrophilactivatingpeptideMIG,monokineinducedbyinterferonIP
10,interferoninducible10ITAC,interferoninducibleTcellalphachemoattractantPF,platelet
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factorSDF,stromalcellderivedfactorBCA1,Bcellchemoattractant1SRPSOX,scavenger
receptorforphosphatidylserinecontainingoxidizedlipids.
Source:FromIFCharo,RMRanshohoff:NEnglJMed354:610,2006,withpermission.
CopyrightMassachusettsMedicalSociety.Allrightsreserved.
Table3149.MajorStructuralFamiliesofCytokines
Fourhelix
bundlefamily
interleukins
Interleukin2(IL2)Subfamily:
Interleukins:IL2,IL3,IL4,IL5,IL6,IL7,IL9,IL11,IL12,IL13,IL15,IL21,IL23
Notcalledinterleukins:Colonystimulatingfactor1(CSF1),granulocytemacrophagecolonystimulating
factor(CSF2),Flt3ligand,erythropoietin(EPO),thrombopoietin(THPO),leukocyteinhibitoryfactor
(LIF)
Notinterleukins:Growthhormone(GH1),prolactin(PRL),leptin(LEP),cardiotrophin(CTF1),ciliary
neurotrophicfactor(CNTF),cytokinereceptorlikefactor1(CLCorCLF)Interferon(IFN)subfamily:IFN
,IFN
IL10subfamily:IL10,IL19,IL20,IL22,IL24,andIL26
IL1family
IL1(IL1A),IL1(IL1B),IL18(IL18),andparalogues,IL17A,IL17B,IL17C,IL17D,IL17E,IL17F
Chemokines
IL8,MCP1,MCP2,MCP3,MCP4,eotaxin,TARC,LARC/MIP3,MDC,MIP1,MIP1,RANTES,
MIP3,I309,SLC,PARC,TECK,GRO,GRO,NAP2,IP19,MIG,SDF1,PF4
Abbreviations:GRO,growthrelatedpeptideIL,interleukinIP,INFinducibleproteinLARC,
liverandactivationregulatedchemokineMCP,monocytechemotacticproteinMDC,
macrophagederivedchemokineMIG,monokineinducedbyIFNMIP,macrophage
inflammatoryproteinNAP,neutrophilactivatingproteinPARC,pulmonaryandactivation
regulatedchemokinePF4,plateletfactorRANTES,regulatedonactivation,normallyTcell
expressedandsecretedSDF,stromalcellderivedfactorSLC,secondarylymphoidtissue.
Source:AdaptedfromJWSchrader:TrendsImmunol23:573,2002.Copyright2002,with
permissionfromElsevier.
Table31410.CytokineFamiliesGroupedbyStructuralSimilarity
Hematopoietins
IL2,IL3,IL4,IL5,IL6,IL7,IL9,IL11,IL12,IL15,IL16,IL17,IL21,IL23,EPO,LIF,GMCSF,G
CSF,OSM,CNTF,GH,andTPO
TNF,LT,LT,CD40L,CD30L,CD27L,41BBL,OX40,OPG,andFasL
IL1
IL1,IL1,IL1ra,IL18,bFGF,aFGF,andECGF
PDGF
PDGFA,PDGFB,andMCSF
TGF
TGFandBMPs(1,2,4etc.)
CXC
chemokines
IL8,Gro//,NAP2,ENA78,GCP2,PF4,CTAP3,MIG,andIP10
CC
chemokines
MCP1,MCP2,MCP3,MIP1,MIP1,RANTES
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Abbreviations:aFGF,acidicfibroblastgrowthfactor41BBL,401BBligandbFGF,basic
fibroblastgrowthfactorBMP,bonemarrowmorphogeneticproteinsCC,cysteinecysteineCD,
clusterofdifferentiationCNTF,ciliaryneurotrophicfactorCTAP,connectivetissueactivating
peptideCXC,cysteinexcysteineECGF,endothelialcellgrowthfactorEPO,erythropoietin
FasL,FasligandGCP2,granulocytechemotacticprotein2GCSF,granulocytecolony
stimulatingfactorGH,growthhormoneGMCSF,granulocytemacrophagecolonystimulating
factorGro,growthrelatedgeneproductsIFN,interferonIL,interleukinIP,interferon
inducibleproteinLIF,leukemiainhibitoryfactorLT,lymphotoxinMCP,monocyte
chemoattractantMCSF,macrophagecolonystimulatingfactorMIG,monokineinducedby
interferonMIP,macrophageinflammatoryproteinNAP2,neutrophilactivatingprotein2
OPG,osteoprotegerinOSM,oncostatinMPDGF,plateletderivedgrowthfactorPF,platelet
factorR,receptorRANTES,regulatedonactivation,normalTcellexpressedandsecreted
TGF,transforminggrowthfactorTNF,tumornecrosisfactorTPO,thyroperoxidase.
Althoughmonocytesmacrophageswereoriginallythoughttobethemajorantigenpresentingcells(APCs)oftheimmunesystem,itisnow
clearthatcelltypescalleddendriticcellsarethemostpotentandeffectiveAPCsinthebody(seebelow).Monocytesmacrophagesmediate
innateimmuneeffectorfunctionssuchasdestructionofantibodycoatedbacteria,tumorcells,orevennormalhematopoieticcellsincertain
typesofautoimmunecytopenias.Monocytesmacrophagesingestbacteriaorareinfectedbyviruses,andindoingso,theyfrequentlyundergo
programmedcelldeathorapoptosis.Macrophagesthatareinfectedbyintracellularinfectiousagentsarerecognizedbydendriticcellsas
infectedandapoptoticcellsandarephagocytosedbydendriticcells.Inthismanner,dendriticcells"crosspresent"infectiousagentantigensof
macrophagestoTcells.Activatedmacrophagescanalsomediateantigennonspecificlyticactivityandeliminatecelltypessuchastumorcells
intheabsenceofantibody.Thisactivityislargelymediatedbycytokines(i.e.,TNFandIL1).Monocytesmacrophagesexpresslineage
specificmolecules(e.g.,thecellsurfaceLPSreceptor,CD14)aswellassurfacereceptorsforanumberofmolecules,includingtheFcregion
ofIgG,activatedcomplementcomponents,andvariouscytokines(Table3147).
DendriticCells
Humandendriticcells(DCs)areheterogenousandcontainseveralsubsets,includingmyeloidDCsandplasmacytoidDCs.MyeloidDCscan
differentiateintoeithermacrophagesmonocytesortissuespecificDCs.IncontrasttomyeloidDCs,plasmacytoidDCsareinefficientantigen
presentingcellsbutarepotentproducersoftypeIinterferon(IFN)(e.g.,IFN)inresponsetoviralinfections.ThematurationofDCsis
regulatedthroughcelltocellcontactandsolublefactors,andDCsattractimmuneeffectorsthroughsecretionofchemokines.WhenDCscome
incontactwithbacterialproducts,viralproteins,orhostproteinsreleasedasdangersignalsfromdistressedhostcells(Figs.3142and3143),
infectiousagentmoleculesbindtovariousTLRsandactivateDCstoreleasecytokinesandchemokinesthatdrivecellsoftheinnateimmune
systemtobecomeactivatedtorespondtotheinvadingorganism,andrecruitTandBcellsoftheadaptiveimmunesystemtorespond.
PlasmacytoidDCsproduceantiviralIFNthatactivatesNKcellkillingofpathogeninfectedcellsIFNalsoactivatesTcellstomatureinto
antipathogencytotoxic(killer)Tcells.Followingcontactwithpathogens,bothplasmacytoidandmyeloidDCsproducechemokinesthatattract
helperandcytotoxicTcells,Bcells,polymorphonuclearcells,andnaveandmemoryTcellsaswellasregulatoryTcellstoultimatelydampen
theimmuneresponseoncethepathogeniscontrolled.TLRengagementonDCsupregulatesMHCclassII,B71(CD80),andB72(CD86),
whichenhanceDCspecificantigenpresentationandinducecytokineproduction(Table3147).Thus,DCsareimportantbridgesbetween
early(innate)andlater(adaptive)immunity.DCsalsomodulateanddeterminethetypesofimmuneresponsesinducedbypathogensviathe
TLRsexpressedonDCs(TLR79onplasmacytoidDCs,TLR4onmonocytoidDCs)andviatheTLRadapterproteinsthatareinducedto
associatewithTLRs(Fig.3141,Table3144).Inaddition,otherPRRs,suchasCtypelectins,NLRs,andmannosereceptors,uponligation
bypathogenproducts,activatecellsoftheadaptiveimmunesystemand,likeTLRstimulation,byavarietyoffactors,determinethetypeand
qualityoftheadaptiveimmuneresponsethatistriggered(Table3144).
FIGURE3143
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CD4+helperT1(T H1)cellsandT H2Tcellssecretedistinctbutoverlappingsetsofcytokines.T H1CD4+cellsarefrequentlyactivated

inimmuneandinflammatoryreactionsagainstintracellularbacteriaorviruses,whileT H2CD4+cellsarefrequentlyactivatedforcertaintypes
ofantibodyproductionagainstparasitesandextracellularencapsulatedbacteriatheyarealsoactivatedinallergicdiseases.GMCSF,
granulocytemacrophagecolonystimulatingfactorIFN,interferonIL,interleukinTNF,tumornecrosisfactor.(AdaptedfromRomagnaniwith
permission.)
LargeGranularLymphocytes/NaturalKillerCells
Largegranularlymphocytes(LGLs)orNKcellsaccountfor~515%ofperipheralbloodlymphocytes.NKcellsarenonadherent,
nonphagocyticcellswithlargeazurophiliccytoplasmicgranules.NKcellsexpresssurfacereceptorsfortheFcportionofIgG(CD16)andfor
NCAMI(CD56),andmanyNKcellsexpressTlineagemarkers,particularlyCD8,andproliferateinresponsetoIL2.NKcellsariseinboth
bonemarrowandthymicmicroenvironments.
Functionally,NKcellssharefeatureswithbothmonocytesmacrophagesandneutrophilsinthattheymediatebothantibodydependent
cellularcytotoxicity(ADCC)andNKcellactivity.ADCCisthebindingofanopsonized(antibodycoated)targetcelltoanFcreceptorbearing
effectorcellviatheFcregionofantibody,resultinginlysisofthetargetbytheeffectorcell.NKcellcytotoxicityisthenonimmune(i.e.,effector
cellneverhavinghadpreviouscontactwiththetarget),MHCunrestricted,nonantibodymediatedkillingoftargetcells,whichareusually
malignantcelltypes,transplantedforeigncells,orvirusinfectedcells.Thus,NKcellcytotoxicitymayplayanimportantroleinimmune
surveillanceanddestructionofmalignantandvirallyinfectedhostcells.NKcellhyporesponsivenessisalsoobservedinpatientswithChdiak
Higashisyndrome,anautosomalrecessivediseaseassociatedwithfusionofcytoplasmicgranulesanddefectivedegranulationofneutrophil
lysosomes.
NKcellshaveavarietyofsurfacereceptorsthathaveinhibitoryoractivatingfunctionsandbelongtotwostructuralfamilies.Thesefamilies
includetheimmunoglobulinsuperfamilyandthelectinliketypeIItransmembraneproteins.NKimmunoglobulinsuperfamilyreceptorsinclude
thekillercellimmunoglobulinlikeactivatingorinhibitoryreceptors(KIRs),manyofwhichhavebeenshowntohaveHLAclassIligands.The
KIRsaremadeupproteinswitheithertwo(KIR2D)orthree(KIR3D)extracellularimmunoglobulindomains(D).Moreover,theirnomenclature
designatestheirfunctionaseitherinhibitoryKIRswithalong(L)cytoplasmictailandimmunoreceptortyrosinebasedinhibitorymotif(ITIM)
(KIRDL)oractivatingKIRswithashort(S)cytoplasmictail(KIRDS).NKcellinactivationbyKIRsisacentralmechanismtopreventdamageto
normalhostcells.GeneticstudieshavedemonstratedtheassociationofKIRswithviralinfectionoutcomeandautoimmunedisease(Table
31411).
Table31411.AssociationofKIRswithDisease
Disease
KIRAssociation
Observation
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Psoriaticarthritis
KIR2DS1/KIR2DS2HLACwgroup
homozygosity
Susceptibility
Spondylarthritides
IncreasedKIR3DL2expression
Maycontributetodiseasepathology
InteractionHLAB27homodimerswith
KIR3DL1/KIR3DL2independentofpeptide
Maycontributetodiseasepathogenesis
Ankylosing
spondylitis
KIR3DL1/3DS1HLAB27genotypes
Susceptibility
Rheumatoid
vasculitis
KIR2DS2HLACw*03
Susceptibility
IncreasedKIR2L2/2DS2inpatientswithextra
articularmanifestations
Clinicalmanifestationsmayhavedifferentgenetic
backgroundswithrespecttoKIRgenotype
DecreasedKIR2DS1/3DS1inpatientswithout
boneerosions
Susceptibility
KIR2DS4HLACw4
Susceptibility
Scleroderma
KIR2DS2+/KIR2DL2
Susceptibility
Behet'sdisease
AlteredKIR3DL1expression
Associatedwithsevereeyedisease
Psoriasisvulgaris
2DS1HLACw*06
Susceptibility
2DS12DL5HaplotypeB
Susceptibility
IDDM
KIR2DS2HLAC1
Susceptibility
Type1diabetes
KIR2DS2HLAC1andnoHLAC2,noHLA
Bw4
Increaseddiseaseprogression
Preeclampsia
KIR2DL1withfewerKIR2DS(mother)HLA
C2(fetus)
AIDS
KIR3DS1HLABw4Ile80
Decreaseddiseaseprogression
KIR3DS1homozygousNoHLABw4Ile80
HCVinfection
KIR2DL3homozygousHLAC1homozygous
Decreaseddiseaseprogression
Cervicalneoplasia
(HPVinduced)
KIR3DS1HLAC1homozygousandnoHLA
Bw4
Malignant
melanoma
KIR2DL2and/orKIR2DL3HLAC1
Rheumatoid
arthritis
Abbreviations:HCV,hepatitisCvirusHLA,humanleukocyteantigenHPV,human
papillomavirusIDDM,insulindependentdiabetesmellitusKIR,killercellimmunoglobulinlike
receptor.
Source:AdaptedfromDiazPenaetal.
InadditiontotheKIRs,asecondsetofimmunoglobulinsuperfamilyreceptorsincludethenaturalcytotoxicityreceptors(NCRs),whichinclude
NKp46,NKp30,andNKp44.ThesereceptorshelptomediateNKcellactivationagainsttargetcells.TheligandstowhichNCRsbindontarget
cellsremainlargelyundefined.
NKcellsignalingis,therefore,ahighlycoordinatedseriesofinhibitingandactivatingsignalsthatpreventNKcellsfromrespondingto
uninfected,nonmalignantselfcellshowever,theyareactivatedtoattackmalignantandvirallyinfectedcells(Fig.3144).Recentevidence
suggeststhatNKcells,althoughnotpossessingrearrangingimmunerecognitiongenes,maybeabletomediaterecallforNKcellresponsesto
virusesandforimmuneresponsessuchascontacthypersensitivity.
FIGURE3144
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EncountersbetweenNKcells:potentialtargetsandpossibleoutcomes.TheamountofactivatingandinhibitoryreceptorsontheNK
cellsandtheamountofligandsonthetargetcell,aswellasthequalitativedifferencesinthesignalstransduced,determinetheextentofthe
NKresponse.A.WhentargetcellshavenoHLAclassInoractivatingligands,NKcellscannotkilltargetcells.B.Whentargetcellsbearself
HLA,NKcellscannotkilltargets.C.WhentargetcellsarepathogeninfectedandhavedownregulatedHLAandexpressactivatingligands,NK
cellskilltargetcells.D.WhenNKcellsencountertargetswithbothselfHLAandactivatingreceptors,thentheleveloftargetkillingis
determinedbythebalanceofinhibitoryandactivatingsignalstotheNKcell.HLA,humanleukocyteantigenNK,naturalkiller.(Adaptedfrom
LanierreproducedwithpermissionfromAnnualReviewsInc.Copyright2011byAnnualReviewsInc.)
SomeNKcellsexpressCD3andinvariantTcellreceptor(TCR)alphachainsandaretermedNKTcells.TCRsofNKTcellsrecognizelipid
moleculesofintracellularbacteriawhenpresentedinthecontextofCD1dmoleculesonAPCs.Uponactivation,NKTcellssecreteeffector
cytokinessuchasIL4andIFN.ThismodeofrecognitionofintracellularbacteriasuchasListeriamonocytogenesandMycobacterium
tuberculosisbyNKTcellsleadstoinductionofactivationofDCsandisthoughttobeanimportantinnatedefensemechanismagainstthese
organisms.
Neutrophils,Eosinophils,andBasophils
Granulocytesarepresentinnearlyallformsofinflammationandareamplifiersandeffectorsofinnateimmuneresponses(Figs.3142and
3143).Uncheckedaccumulationandactivationofgranulocytescanleadtohosttissuedamage,asseeninneutrophilandeosinophil
mediatedsystemicnecrotizingvasculitis.Granulocytesarederivedfromstemcellsinbonemarrow.Eachtypeofgranulocyte(neutrophil,
eosinophil,orbasophil)isderivedfromadifferentsubclassofprogenitorcellthatisstimulatedtoproliferatebycolonystimulatingfactors
(Table3147).Duringterminalmaturationofgranulocytes,classspecificnuclearmorphologyandcytoplasmicgranulesappearthatallowfor
histologicidentificationofgranulocytetype.
NeutrophilsexpressFcreceptorsforIgG(CD16)andreceptorsforactivatedcomplementcomponents(C3borCD35).Uponinteractionof
neutrophilswithopsonizedbacteriaorimmunecomplexes,azurophilicgranules(containingmyeloperoxidase,lysozyme,elastase,andother
enzymes)andspecificgranules(containinglactoferrin,lysozyme,collagenase,andotherenzymes)arereleased,andmicrobicidalsuperoxide
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radicals(O2)aregeneratedattheneutrophilsurface.Thegenerationofsuperoxideleadstoinflammationbydirectinjurytotissueandby
alterationofmacromoleculessuchascollagenandDNA.
EosinophilsexpressFcreceptorsforIgG(CD32)andarepotentcytotoxiceffectorcellsforvariousparasiticorganisms.InNippostrongylus
brasiliensishelminthinfection,eosinophilsareimportantcytotoxiceffectorcellsforremovaloftheseparasites.Keytoregulationofeosinophil
cytotoxicitytoN.brasiliensiswormsareantigenspecificThelpercellsthatproduceIL4,thusprovidinganexampleofregulationofinnate
immuneresponsesbyadaptiveimmunityantigenspecificTcells.Intracytoplasmiccontentsofeosinophils,suchasmajorbasicprotein,
eosinophilcationicprotein,andeosinophilderivedneurotoxin,arecapableofdirectlydamagingtissuesandmayberesponsibleinpartforthe
organsystemdysfunctioninthehypereosinophilicsyndromes(Chap.60).Sincetheeosinophilgranulecontainsantiinflammatorytypesof
enzymes(histaminase,arylsulfatase,phospholipaseD),eosinophilsmayhomeostaticallydownregulateorterminateongoinginflammatory
responses.
BasophilsandtissuemastcellsarepotentreservoirsofcytokinessuchasIL4andcanrespondtobacteriaandviruseswithantipathogen
cytokineproductionthroughmultipleTLRsexpressedontheirsurface.Mastcellsandbasophilscanalsomediateimmunitythroughthe
bindingofantipathogenantibodies.Thisisaparticularlyimportanthostdefensemechanismagainstparasiticdiseases.Basophilsexpress
highaffinitysurfacereceptorsforIgE(FcRI)and,uponcrosslinkingofbasophilboundIgEbyantigen,canreleasehistamine,eosinophil
chemotacticfactorofanaphylaxis,andneutralproteaseallmediatorsofallergicimmediate(anaphylaxis)hypersensitivityresponses(Table
31412).Inaddition,basophilsexpresssurfacereceptorsforactivatedcomplementcomponents(C3a,C5a),throughwhichmediatorrelease
canbedirectlyeffected.Thus,basophils,likemostcellsoftheimmunesystem,canbeactivatedintheserviceofhostdefenseagainst
pathogens,ortheycanbeactivatedformediationreleaseandcausepathogenicresponsesinallergicandinflammatorydiseases.Forfurther
discussionoftissuemastcells,seeChap.317.
Table31412.ExamplesofMediatorsReleasedfromHumanCellsandBasophils
Mediator
Actions
Histamine
Smoothmusclecontraction,increasedvascularpermeability
Slowreactingsubstanceofanaphylaxis
(SRSA)(leukotrieneC4,D4,E4)
Smoothmusclecontraction
Eosinophilchemotacticfactorofanaphylaxis
(ECFA)
Chemotacticattractionofeosinophils
Plateletactivatingfactor
Activatesplateletstosecreteserotoninandothermediators:smooth
musclecontractioninducesvascularpermeability
Neutrophilchemotacticfactor(NCF)
Chemotacticattractionofneutrophils
Leukotacticactivity(leukotrieneB4)
Chemotacticattractionofneutrophils
Heparin
Anticoagulant
Basophilkallikreinofanaphylaxis(BKA)
Cleaveskininogentoformbradykinin
TheComplementSystem
Thecomplementsystem,animportantsolublecomponentoftheinnateimmunesystem,isaseriesofplasmaenzymes,regulatoryproteins,
andproteinsthatareactivatedinacascadingfashion,resultingincelllysis.Therearefourpathwaysofthecomplementsystem:theclassic
activationpathwayactivatedbyantigen/antibodyimmunecomplexes,theMBL(aserumcollectinTable3143)activationpathwayactivatedby
microbeswithterminalmannosegroups,thealternativeactivationpathwayactivatedbymicrobesortumorcells,andtheterminalpathwaythat
iscommontothefirstthreepathwaysandleadstothemembraneattackcomplexthatlysescells(Fig.3145).Theseriesofenzymesofthe
complementsystemareserineproteases.
FIGURE3145
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Thefourpathwaysandtheeffectormechanismsofthecomplementsystem.Dashedarrowsindicatethefunctionsofpathway
components.(AfterMorleyandWalportwithpermission.CopyrightAcademicPress,London,2000.)
ActivationoftheclassiccomplementpathwayviaimmunecomplexbindingtoC1qlinkstheinnateandadaptiveimmunesystemsviaspecific
antibodyintheimmunecomplex.ThealternativecomplementactivationpathwayisantibodyindependentandisactivatedbybindingofC3
directlytopathogensand"alteredself"suchastumorcells.IntherenalglomerularinflammatorydiseaseIgAnephropathy,IgAactivatesthe
alternativecomplementpathwayandcausesglomerulardamageanddecreasedrenalfunction.Activationoftheclassiccomplementpathway
viaC1,C4,andC2andactivationofthealternativepathwayviafactorD,C3,andfactorBbothleadtocleavageandactivationofC3.C3
activationfragments,whenboundtotargetsurfacessuchasbacteriaandotherforeignantigens,arecriticalforopsonization(coatingby
antibodyandcomplement)inpreparationforphagocytosis.TheMBLpathwaysubstitutesMBLassociatedserineproteases(MASPs)1and2
forC1q,C1r,andC1stoactivateC4.TheMBLactivationpathwayisactivatedbymannoseonthesurfaceofbacteriaandviruses.
Thethreepathwaysofcomplementactivationallconvergeonthefinalcommonterminalpathway.C3cleavagebyeachpathwayresultsin
activationofC5,C6,C7,C8,andC9,resultinginthemembraneattackcomplexthatphysicallyinsertsintothemembranesoftargetcellsor
bacteriaandlysesthem.
Thus,complementactivationisacriticalcomponentofinnateimmunityforrespondingtomicrobialinfection.Thefunctionalconsequencesof
complementactivationbythethreeinitiatingpathwaysandtheterminalpathwayareshowninFig.3145.Ingeneralthecleavageproductsof
complementcomponentsfacilitatemicrobeordamagedcellclearance(C1q,C4,C3),promoteactivationandenhancementofinflammation
(anaphylatoxins,C3a,C5a),andpromotemicrobeoropsonizedcelllysis(membraneattackcomplex).
Cytokines
Cytokinesaresolubleproteinsproducedbyawidevarietyofhematopoieticandnonhematopoieticcelltypes(Tables3147,3148,3149,and
31410).Theyarecriticalforbothnormalinnateandadaptiveimmuneresponses,andtheirexpressionmaybeperturbedinmostimmune,
inflammatory,andinfectiousdiseasestates.
Cytokinesareinvolvedintheregulationofthegrowth,development,andactivationofimmunesystemcellsandinthemediationofthe
inflammatoryresponse.Ingeneral,cytokinesarecharacterizedbyconsiderableredundancydifferentcytokineshavesimilarfunctions.In
addition,manycytokinesarepleiotropicinthattheyarecapableofactingonmanydifferentcelltypes.Thispleiotropismresultsfromthe
expressiononmultiplecelltypesofreceptorsforthesamecytokine(seebelow),leadingtotheformationof"cytokinenetworks."Theactionof
cytokinesmaybe(1)autocrinewhenthetargetcellisthesamecellthatsecretesthecytokine,(2)paracrinewhenthetargetcellisnearby,
and(3)endocrinewhenthecytokineissecretedintothecirculationandactsdistaltothesource.
Cytokineshavebeennamedbasedonpresumedtargetsorbasedonpresumedfunctions.Thosecytokinesthatarethoughttoprimarilytarget
leukocyteshavebeennamedinterleukins(IL1,2,3,etc.).Manycytokinesthatwereoriginallydescribedashavingacertainfunctionhave
retainedthosenames(granulocytecolonystimulatingfactororGCSF,etc.).Cytokinesbelongingeneraltothreemajorstructuralfamilies:the
hematopoietinfamilytheTNF,IL1,plateletderivedgrowthfactor(PDGF),andtransforminggrowthfactor(TGF)familiesandtheCXCand
CCchemokinefamilies(Table31410).ChemokinesarecytokinesthatregulatecellmovementandtraffickingtheyactthroughGprotein
coupledreceptorsandhaveadistinctivethreedimensionalstructure.IL8istheonlychemokinethatearlyonwasnamedaninterleukin(Table
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3147).
Ingeneral,cytokinesexerttheireffectsbyinfluencinggeneactivationthatresultsincellularactivation,growth,differentiation,functionalcell
surfacemoleculeexpression,andcellulareffectorfunction.Inthisregard,cytokinescanhavedramaticeffectsontheregulationofimmune
responsesandthepathogenesisofavarietyofdiseases.Indeed,Tcellshavebeencategorizedonthebasisofthepatternofcytokinesthat
theysecrete,whichresultsineitherhumoralimmuneresponse(T H2)orcellmediatedimmuneresponse(T H1).AthirdtypeofThelpercellis
theT H17cellthatcontributestohostdefenseagainstextracellularbacteriaandfungi,particularlyatmucosalsites(Fig.3142).
Cytokinereceptorscanbegroupedintofivegeneralfamiliesbasedonsimilaritiesintheirextracellularaminoacidsequencesandconserved
structuraldomains.Theimmunoglobulin(Ig)superfamilyrepresentsalargenumberofcellsurfaceandsecretedproteins.TheIL1receptors
(type1,type2)areexamplesofcytokinereceptorswithextracellularIgdomains.
Thehallmarkofthehematopoieticgrowthfactor(type1)receptorfamilyisthattheextracellularregionsofeachreceptorcontaintwo
conservedmotifs.Onemotif,locatedattheNterminus,isrichincysteineresidues.TheothermotifislocatedattheCterminusproximaltothe
transmembraneregionandcomprisesfiveaminoacidresidues,tryptophanserineXtryptophanserine(WSXWS).Thisfamilycanbegrouped
onthebasisofthenumberofreceptorsubunitstheyhaveandontheutilizationofsharedsubunits.Anumberofcytokinereceptors,i.e.,IL6,
IL11,IL12,andleukemiainhibitoryfactor,arepairedwithgp130.Thereisalsoacommon150kDasubunitsharedbyIL3,IL5,and
granulocytemacrophagecolonystimulatingfactor(GMCSF)receptors.Thegammachain(c)oftheIL2receptoriscommontotheIL2,IL
4,IL7,IL9,andIL15receptors.Thus,thespecificcytokinereceptorisresponsibleforligandspecificbinding,whilethesubunitssuchas
gp130,the150kDasubunit,andcareimportantinsignaltransduction.ThecgeneisontheXchromosome,andmutationsinthec
proteinresultintheXlinkedformofseverecombinedimmunedeficiencysyndrome(XSCID)(Chap.316).
Themembersoftheinterferon(typeII)receptorfamilyincludethereceptorsforIFNand,whichshareasimilar210aminoacidbinding
domainwithconservedcysteinepairsatboththeaminoandcarboxytermini.ThemembersoftheTNF(typeIII)receptorfamilysharea
commonbindingdomaincomposedofrepeatedcysteinerichregions.Membersofthisfamilyincludethep55andp75receptorsforTNF
(TNFR1andTNFR2,respectively)CD40antigen,whichisanimportantBcellsurfacemarkerinvolvedinimmunoglobulinisotypeswitching
fas/Apo1,whosetriggeringinducesapoptosisCD27andCD30,whicharefoundonactivatedTcellsandBcellsandnervegrowthfactor
receptor.
ThecommonmotiffortheseventransmembranehelixfamilywasoriginallyfoundinreceptorslinkedtoGTPbindingproteins.Thisfamily
includesreceptorsforchemokines(Table3148),adrenergicreceptors,andretinalrhodopsin.Itisimportanttonotethattwomembersof
thechemokinereceptorfamily,CXCchemokinereceptortype4(CXCR4)andchemokinereceptortype5(CCR5),havebeenfoundtoserve
asthetwomajorcoreceptorsforbindingandentryofHIVintoCD4expressinghostcells(Chap.189).
Significantadvanceshavebeenmadeindefiningthesignalingpathwaysthroughwhichcytokinesexerttheireffectsintracellularly.TheJanus
familyofproteintyrosinekinases(JAK)isacriticalelementinvolvedinsignalingviathehematopoietinreceptors.FourJAKkinases,JAK1,
JAK2,JAK3,andTyk2,preferentiallybinddifferentcytokinereceptorsubunits.Cytokinebindingtoitsreceptorbringsthecytokinereceptor
subunitsintoappositionandallowsapairofJAKstotransphosphorylateandactivateoneanother.TheJAKsthenphosphorylatethereceptor
onthetyrosineresiduesandallowsignalingmoleculestobindtothereceptor,wherethesemoleculesbecomephosphorylated.Signaling
moleculesbindthereceptorbecausetheyhavedomains(SH2,orsrchomology2domains)thatcanbindphosphorylatedtyrosineresidues.
Thereareanumberoftheseimportantsignalingmoleculesthatbindthereceptor,suchastheadaptermoleculeSHC,whichcancouplethe
receptortotheactivationofthemitogenactivatedproteinkinasepathway.Inaddition,animportantclassofsubstrateoftheJAKsisthesignal
transducersandactivatorsoftranscription(STAT)familyoftranscriptionfactors.STATshaveSH2domainsthatenablethemtobindto
phosphorylatedreceptors,wheretheyarethenphosphorylatedbytheJAKs.ItappearsthatdifferentSTATshavespecificityfordifferent
receptorsubunits.TheSTATsthendissociatefromthereceptorandtranslocatetothenucleus,bindtoDNAmotifsthattheyrecognize,and
regulategeneexpression.TheSTATspreferentiallybindDNAmotifsthatareslightlydifferentfromoneanotherandtherebycontrol
transcriptionofspecificgenes.Theimportanceofthispathwayisparticularlyrelevanttolymphoiddevelopment.MutationsofJAK3itselfalso
resultinadisorderidenticaltoXSCIDhowever,sinceJAK3isfoundonchromosome19andnotontheXchromosome,JAK3deficiency
occursinboysandgirls(Chap.316).
TheAdaptiveImmuneSystem
Adaptiveimmunityischaracterizedbyantigenspecificresponsestoaforeignantigenorpathogen.Akeyfeatureofadaptiveimmunityisthat
followingtheinitialcontactwithantigen(immunologicpriming),subsequentantigenexposureleadstomorerapidandvigorousimmune
responses(immunologicmemory).Theadaptiveimmunesystemconsistsofduallimbsofcellularandhumoralimmunity.Theprincipal
effectorsofcellularimmunityareTlymphocytes,whiletheprincipaleffectorsofhumoralimmunityareBlymphocytes.BothBandT
lymphocytesderivefromacommonstemcell(Fig.3146).
FIGURE3146
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DevelopmentstagesofTandBcells.ElementsofthedevelopingTandBcellreceptorforantigenareshownschematically.The
classificationintothevariousstagesofBcelldevelopmentisprimarilydefinedbyrearrangementoftheimmunoglobulin(Ig),heavy(H),and
light(L)chaingenesandbytheabsenceorpresenceofspecificsurfacemarkers.[AdaptedfromCAJanewayetal(eds):Immunobiology.The
ImmuneSystemicHealthandDisease,4thed.NewYork,Garland,1999withpermission.]TheclassificationofstagesofTcelldevelopmentis
primarilydefinedbycellsurfacemarkerproteinexpression(sCD3,surfaceCD3expression,cCD3,cytoplasmicCD3expressionTCR,Tcell
receptor).
Theproportionanddistributionofimmunocompetentcellsinvarioustissuesreflectcelltraffic,homingpatterns,andfunctionalcapabilities.
BonemarrowisthemajorsiteofmaturationofBcells,monocytesmacrophages,dendriticcells,andgranulocytesandcontainspluripotent
stemcellsthat,undertheinfluenceofvariouscolonystimulatingfactors,arecapableofgivingrisetoallhematopoieticcelltypes.Tcell
precursorsalsoarisefromhematopoieticstemcellsandhometothethymusformaturation.MatureTlymphocytes,Blymphocytes,
monocytes,anddendriticcellsenterthecirculationandhometoperipherallymphoidorgans(lymphnodes,spleen)andmucosalsurface
associatedlymphoidtissue(gut,genitourinary,andrespiratorytracts)aswellastheskinandmucousmembranesandawaitactivationby
foreignantigen.
TCells
ThepoolofeffectorTcellsisestablishedinthethymusearlyinlifeandismaintainedthroughoutlifebothbynewTcellproductioninthe
thymusandbyantigendrivenexpansionofvirginperipheralTcellsinto"memory"Tcellsthatresideinperipherallymphoidorgans.The
thymusexports~2%ofthetotalnumberofthymocytesperdaythroughoutlife,withthetotalnumberofdailythymicemigrantsdecreasingby
~3%peryearduringthefirstfourdecadesoflife.
MatureTlymphocytesconstitute7080%ofnormalperipheralbloodlymphocytes(only2%ofthetotalbodylymphocytesarecontainedin
peripheralblood),90%ofthoracicductlymphocytes,3040%oflymphnodecells,and2030%ofspleenlymphoidcells.Inlymphnodes,T
cellsoccupydeepparacorticalareasaroundBcellgerminalcenters,andinthespleen,theyarelocatedinperiarteriolarareasofwhitepulp
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(Chap.59).Tcellsaretheprimaryeffectorsofcellmediatedimmunity,withsubsetsofTcellsmaturingintoCD8+cytotoxicTcellscapableof
lysisofvirusinfectedorforeigncells(shortlivedeffectorTcells).TwopopulationsoflonglivedmemoryTcellsaretriggeredbyinfections:
effectormemoryandcentralmemoryTcells.EffectormemoryTcellsresideinnonlymphoidorgansandrespondrapidlytorepeated
pathogenicinfectionswithcytokineproductionandcytotoxicfunctionstokillvirusinfectedcells.CentralmemoryTcellshometolymphoid
organswheretheyreplenishlongandshortlivedandeffectormemoryTcellsasneeded.
Ingeneral,CD4+TcellsarealsotheprimaryregulatorycellsofTandBlymphocyteandmonocytefunctionbytheproductionofcytokinesand
bydirectcellcontact(Fig.3142).Inaddition,Tcellsregulateerythroidcellmaturationinbonemarrowand,throughcellcontact(CD40
ligand),haveanimportantroleinactivationofBcellsandinductionofIgisotypeswitching.
HumanTcellsexpresscellsurfaceproteinsthatmarkstagesofintrathymicTcellmaturationoridentifyspecificfunctionalsubpopulationsof
matureTcells.ManyofthesemoleculesmediateorparticipateinimportantTcellfunctions(Table3141,Fig.3146).
TheearliestidentifiableTcellprecursorsinbonemarrowareCD34+proTcells(i.e.,cellsinwhichTCRgenesareneitherrearrangednor
expressed).Inthethymus,CD34+Tcellprecursorsbegincytoplasmic(c)synthesisofcomponentsoftheCD3complexofTCRassociated
molecules(Fig.3146).WithinTcellprecursors,TCRforantigengenerearrangementyieldstwoTcelllineages,expressingeitherTCR
chainsorTCRchains.TcellsexpressingtheTCRchainsconstitutethemajorityofperipheralTcellsinblood,lymphnode,andspleen
andterminallydifferentiateintoeitherCD4+orCD8+cells.CellsexpressingTCRchainscirculateasaminorpopulationinbloodtheir
functions,althoughnotfullyunderstood,havebeenpostulatedtobethoseofimmunesurveillanceatepithelialsurfacesandcellulardefenses
againstmycobacterialorganismsandotherintracellularbacteriathroughrecognitionofbacteriallipids.
Inthethymus,therecognitionofselfpeptidesonthymicepithelialcells,thymicmacrophages,anddendriticcellsplaysanimportantrolein
shapingtheTcellrepertoiretorecognizeforeignantigen(positiveselection)andineliminatinghighlyautoreactiveTcells(negativeselection).
AsimmaturecorticalthymocytesbegintoexpresssurfaceTCRforantigen,autoreactivethymocytesaredestroyed(negativeselection),
thymocyteswithTCRscapableofinteractingwithforeignantigenpeptidesinthecontextofselfMHCantigensareactivatedanddevelopto
maturity(positiveselection),andthymocyteswithTCRsthatareincapableofbindingtoselfMHCantigensdieofattrition(noselection).
MaturethymocytesthatarepositivelyselectedareeitherCD4+helperTcellsorMHCclassIIrestrictedcytotoxic(killer)Tcells,ortheyare
CD8+TcellsdestinedtobecomeMHCclassIrestrictedcytotoxicTcells.MHCclassIorclassIIrestrictedmeansthatTcellsrecognize
antigenpeptidefragmentsonlywhentheyarepresentedintheantigenrecognitionsiteofaclassIorclassIIMHCmolecule,respectively
(Chap.315).
Afterthymocytematurationandselection,CD4andCD8thymocytesleavethethymusandmigratetotheperipheralimmunesystem.The
thymuscontinuestobeacontributortotheperipheralimmunesystem,wellintoadultlife,bothnormallyandwhentheperipheralTcellpoolis
damaged,suchasoccursinAIDSandcancerchemotherapy.
MolecularBasisofTCellRecognitionofAntigen
TheTCRforantigenisacomplexofmoleculesconsistingofanantigenbindingheterodimerofeitherorchainsnoncovalentlylinkedwith
fiveCD3subunits(,,,,and)(Fig.3147).TheCD3chainsareeitherdisulfidelinkedhomodimers(CD32)ordisulfidelinked
heterodimerscomposedofonechainandonechain.TCRorTCRmoleculesmustbeassociatedwithCD3moleculestobeinserted
intotheTcellsurfacemembrane,TCRbeingpairedwithTCRandTCRbeingpairedwithTCR.MoleculesoftheCD3complex
mediatetransductionofTcellactivationsignalsviaTCRs,whileTCRandorandmoleculescombinetoformtheTCRantigen
bindingsite.
FIGURE3147
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SignalingthroughtheTcellreceptor.Activationsignalsaremediatedviaimmunoreceptortyrosinebasedactivation(ITAM)sequencesin
LATandCD3chains(bluebars)thatbindtoenzymesandtransduceactivationsignalstothenucleusviatheindicatedintracellularactivation
pathways.LigationoftheTcellreceptor(TCR)byMHCcomplexedwithantigenresultsinsequentialactivationofLCKandchainassociated
proteinkinaseof70kDa(ZAP70).ZAP70phosphorylatesseveraldownstreamtargets,includingLAT(linkerforactivationofTcells)and
SLP76[SCRhomology2(SH2)domaincontainingleukocyteproteinof76kDa].SLP76isrecruitedtomembraneboundLATthroughits
constitutiveinteractionwithGADS(GRB2relatedadaptorprotein).Together,SLP76andLATnucleateamultimolecularsignalingcomplex,
whichinducesahostofdownstreamresponses,includingcalciumflux,mitogenactivatedproteinkinase(MAPK)activation,integrinactivation,
andcytoskeletalreorganization.APCdenotesantigenpresentingcell.(AdaptedfromKoretzkyetalwithpermissionfromMacmillanPublishers
Ltd.Copyright2006.)
The,,,andTCRforantigenmoleculeshaveaminoacidsequencehomologyandstructuralsimilaritiestoimmunoglobulinheavyand
lightchainsandaremembersoftheimmunoglobulingenesuperfamilyofmolecules.ThegenesencodingTCRmoleculesareencodedas
clustersofgenesegmentsthatrearrangeduringthecourseofTcellmaturation.Thiscreatesanefficientandcompactmechanismforhousing
thediversityrequirementsofantigenreceptormolecules.TheTCRchainisonchromosome14andconsistsofaseriesofV(variable),J
(joining),andC(constant)regions.TheTCRchainisonchromosome7andconsistsofmultipleV,D(diversity),J,andCTCRloci.The
TCRchainisonchromosome7,andtheTCRchainisinthemiddleoftheTCRlocusonchromosome14.Thus,moleculesoftheTCR
forantigenhaveconstant(framework)andvariableregions,andthegenesegmentsencodingthe,,,andchainsofthesemoleculesare
recombinedandselectedinthethymus,culminatinginsynthesisofthecompletedmolecule.InbothTandBcellprecursors(seebelow),DNA
rearrangementsofantigenreceptorgenesinvolvethesameenzymes,recombinaseactivatinggene(RAG)1andRAG2,bothDNAdependent
proteinkinases.
TCRdiversityiscreatedbythedifferentV,D,andJsegmentsthatarepossibleforeachreceptorchainbythemanypermutationsofV,D,and
Jsegmentcombinations,by"Nregiondiversification"duetotheadditionofnucleotidesatthejunctionofrearrangedgenesegments,andby
thepairingofindividualchainstoformaTCRdimer.AsTcellsmatureinthethymus,therepertoireofantigenreactiveTcellsismodifiedby
selectionprocessesthateliminatemanyautoreactiveTcells,enhancetheproliferationofcellsthatfunctionappropriatelywithselfMHC
moleculesandantigen,andallowTcellswithnonproductiveTCRrearrangementstodie.
TCRcellsdonotrecognizenativeproteinorcarbohydrateantigens.Instead,Tcellsrecognizeonlyshort(~913aminoacids)peptide
fragmentsderivedfromproteinantigenstakenuporproducedinAPCs.Foreignantigensmaybetakenupbyendocytosisintoacidified
intracellularvesiclesorbyphagocytosisanddegradedintosmallpeptidesthatassociatewithMHCclassIImolecules(exogenousantigen
presentationpathway).Otherforeignantigensariseendogenouslyinthecytosol(suchasfromreplicatingviruses)andarebrokendowninto
smallpeptidesthatassociatewithMHCclassImolecules(endogenousantigenpresentingpathway).Thus,APCsproteolyticallydegrade
foreignproteinsanddisplaypeptidefragmentsembeddedintheMHCclassIorIIantigenrecognitionsiteontheMHCmoleculesurface,
whereforeignpeptidefragmentsareavailabletobindtoTCRorTCRchainsofreactiveTcells.CD4moleculesactasadhesivesand,
bydirectbindingtoMHCclassII(DR,DQ,orDP)molecules,stabilizetheinteractionofTCRwithpeptideantigen(Fig.3147).Similarly,CD8
moleculesalsoactasadhesivestostabilizetheTCRantigeninteractionbydirectCD8moleculebindingtoMHCclassI(A,B,orC)molecules.
Antigensthatariseinthecytosolandareprocessedviatheendogenousantigenpresentationpathwayarecleavedintosmallpeptidesbya
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complexofproteasescalledtheproteasome.Fromtheproteasome,antigenpeptidefragmentsaretransportedfromthecytosolintothelumen
oftheendoplasmicreticulumbyaheterodimericcomplextermedtransportersassociatedwithantigenprocessing,orTAPproteins.There,
MHCclassImoleculesintheendoplasmicreticulummembranephysicallyassociatewithprocessedcytosolicpeptides.Followingpeptide
associationwithclassImolecules,peptideclassIcomplexesareexportedtotheGolgiapparatus,andthentothecellsurface,forrecognition
byCD8+Tcells.
Antigenstakenupfromtheextracellularspaceviaendocytosisintointracellularacidifiedvesiclesaredegradedbyvesicleproteasesinto
peptidefragments.IntracellularvesiclescontainingMHCclassIImoleculesfusewithpeptidecontainingvesicles,thusallowingpeptide
fragmentstophysicallybindtoMHCclassIImolecules.PeptideMHCclassIIcomplexesarethentransportedtothecellsurfacefor
recognitionbyCD4+Tcells(Chap.315).
WhereasitisgenerallyagreedthattheTCRreceptorrecognizespeptideantigensinthecontextofMHCclassIorclassIImolecules,lipids
inthecellwallofintracellularbacteriasuchasM.tuberculosiscanalsobepresentedtoawidevarietyofTcells,includingsubsetsofTCRT
cells,andasubsetofCD8+TCRTcells.Importantly,bacteriallipidantigensarenotpresentedinthecontextofMHCclassIorII
molecules,butratherarepresentedinthecontextofMHCrelatedCD1molecules.SomeTcellsthatrecognizelipidantigensviaCD1
moleculeshaveveryrestrictedTCRusage,donotneedantigenprimingtorespondtobacteriallipids,andmayactuallybeaformofinnate
ratherthanacquiredimmunitytointracellularbacteria.
JustasforeignantigensaredegradedandtheirpeptidefragmentspresentedinthecontextofMHCclassIorclassIImoleculesonAPCs,
endogenousselfproteinsalsoaredegradedandselfpeptidefragmentsarepresentedtoTcellsinthecontextofMHCclassIorclassII
moleculesonAPCs.Inperipherallymphoidorgans,thereareTcellsthatarecapableofrecognizingselfproteinfragmentsbutnormallyare
anergicortolerant,i.e.,nonresponsivetoselfantigenicstimulation,duetolackofselfantigenupregulatingAPCcostimulatorymoleculessuch
asB71(CD80)andB72(CD86)(seebelow).
OnceengagementofmatureTcellTCRbyforeignpeptideoccursinthecontextofselfMHCclassIorclassIImolecules,bindingofnon
antigenspecificadhesionligandpairssuchasCD54CD11/CD18andCD58CD2stabilizesMHCpeptideTCRbinding,andtheexpressionof
theseadhesionmoleculesisupregulated(Fig.3147).OnceantigenligationoftheTCRoccurs,theTcellmembraneispartitionedintolipid
membranemicrodomains,orlipidrafts,thatcoalescethekeysignalingmoleculesTCR/CD3complex,CD28,CD2,LAT(linkerforactivationof
Tcells),intracellularactivated(dephosphorylated)srcfamilyproteintyrosinekinases(PTKs),andthekeyCD3associatedprotein70(ZAP
70)PTK(Fig.3147).Importantly,duringTcellactivation,theCD45molecule,withproteintyrosinephosphataseactivityispartitionedaway
fromtheTCRcomplextoallowactivatingphosphorylationeventstooccur.ThecoalescenceofsignalingmoleculesofactivatedTlymphocytes
inmicrodomainshassuggestedthatTcellAPCinteractionscanbeconsideredimmunologicsynapses,analogousinfunctiontoneuronal
synapses.
AfterTCRMHCbindingisstabilized,activationsignalsaretransmittedthroughthecelltothenucleusandleadtotheexpressionofgene
productsimportantinmediatingthewidediversityofTcellfunctionssuchasthesecretionofIL2.TheTCRdoesnothaveintrinsicsignaling
activitybutislinkedtoavarietyofsignalingpathwaysviaimmunoreceptortyrosinebasedactivationmotifs(ITAMs)expressedonthevarious
CD3chainsthatbindtoproteinsthatmediatesignaltransduction.Eachofthepathwaysresultsintheactivationofparticulartranscription
factorsthatcontroltheexpressionofcytokineandcytokinereceptorgenes.Thus,antigenMHCbindingtotheTCRinducestheactivationof
thesrcfamilyofPTKs,fynandlck(lckisassociatedwithCD4orCD8costimulatorymolecules)phosphorylationofCD3chainactivationof
therelatedtyrosinekinasesZAP70andsykanddownstreamactivationofthecalciumdependentcalcineurinpathway,theraspathway,and
theproteinkinaseCpathway.Eachofthesepathwaysleadstoactivationofspecificfamiliesoftranscriptionfactors(includingNFAT,fosand
jun,andrel/NFB)thatformheteromultimerscapableofinducingexpressionofIL2,IL2receptor,IL4,TNF,andotherTcellmediators.
InadditiontothesignalsdeliveredtotheTcellfromtheTCRcomplexandCD4andCD8,moleculesontheTcellsuchasCD28andinducible
costimulator(ICOS)andmoleculesondendriticcellssuchasB71(CD80)andB72(CD86)alsodeliverimportantcostimulatorysignalsthat
upregulateTcellcytokineproductionandareessentialforTcellactivation.IfsignalingthroughCD28orICOSdoesnotoccur,orifCD28is
blocked,theTcellbecomesanergicratherthanactivated(see"ImmuneToleranceandAutoimmunity"below).
TCellSuperantigens
ConventionalantigensbindtoMHCclassIorIImoleculesinthegrooveoftheheterodimerandbindtoTcellsviatheVregionsoftheTCR
andchains.Incontrast,superantigensbinddirectlytothelateralportionoftheTCRchainandMHCclassIIchainandstimulateTcells
basedsolelyontheVgenesegmentutilizedindependentoftheD,J,andVsequencespresent.Superantigensareproteinmolecules
capableofactivatingupto20%oftheperipheralTcellpool,whereasconventionalantigensactivate<1in10,000Tcells.Tcellsuperantigens
includestaphylococcalenterotoxinsandotherbacterialproducts.SuperantigenstimulationofhumanperipheralTcellsoccursintheclinical
settingofstaphylococcaltoxicshocksyndrome,leadingtomassiveoverproductionofTcellcytokinesthatleadstohypotensionandshock
(Chap.135).
BCells
MatureBcellsconstitute1015%ofhumanperipheralbloodlymphocytes,2030%oflymphnodecells,50%ofspleniclymphocytes,and
~10%ofbonemarrowlymphocytes.Bcellsexpressontheirsurfaceintramembraneimmunoglobulin(Ig)moleculesthatfunctionasBcell
receptors(BCRs)forantigeninacomplexofIgassociatedandsignalingmoleculeswithpropertiessimilartothosedescribedinTcells
(Fig.3148).UnlikeTcells,whichrecognizeonlyprocessedpeptidefragmentsofconventionalantigensembeddedinthenotchesofMHC
classIandclassIIantigensofAPCs,Bcellsarecapableofrecognizingandproliferatingtowholeunprocessednativeantigensviaantigen
bindingtoBcellsurfaceIg(sIg)receptors.BcellsalsoexpresssurfacereceptorsfortheFcregionofIgGmolecules(CD32)aswellas
receptorsforactivatedcomplementcomponents(C3dorCD21,C3borCD35).TheprimaryfunctionofBcellsistoproduceantibodies.Bcells
alsoserveasAPCsandarehighlyefficientatantigenprocessing.Theirantigenpresentingfunctionisenhancedbyavarietyofcytokines.
MatureBcellsarederivedfrombonemarrowprecursorcellsthatarisecontinuouslythroughoutlife(Fig.3146).
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FIGURE3148
Bcellreceptor(BCR)activationresultsinthesequentialactivationofproteintyrosinekinases,whichresultsintheformationofasignaling
complexandactivationofdownstreampathwaysasshown.WhereasSLP76isrecruitedtothemembranethroughGADSandLAT,the
mechanismofSLP65recruitmentisunclear.Studieshaveindicatedtwomechanisms:(a)directbindingbytheSH2domainofSLP65to
immunoglobulin(Ig)oftheBCRcomplexor(b)membranerecruitmentthroughaleucinezipperintheaminoterminusofSLP65andan
unknownbindingpartner.ADAP,adhesionanddegranulationpromotingadaptorproteinAP1,activatorprotein1BTK,Bruton'styrosine
kinaseDAG,diacylglycerolGRB2,growthfactorreceptorboundprotein2HPK1,hematopoieticprogenitorkinase1InsP3,inositol1,4,5
trisphosphateITK,interleukin2inducibleTcellkinaseNCK,noncatalyticregionoftyrosinekinaseNFB,nuclearfactorBPKC,protein
kinaseCPLC,phospholipaseCPtdIns(4,5)P2,phosphatidylinositol4,5bisphosphateRASGRP,RASguanylreleasingproteinSOS,sonof
sevenlesshomologueSYK,spleentyrosinekinase.(AdaptedfromKoretzkyetalwithpermissionfromMacmillanPublishersLtd.Copyright
2006.)
Blymphocytedevelopmentcanbeseparatedintoantigenindependentandantigendependentphases.AntigenindependentBcell
developmentoccursinprimarylymphoidorgansandincludesallstagesofBcellmaturationuptothesIg+matureBcell.AntigendependentB
cellmaturationisdrivenbytheinteractionofantigenwiththematureBcellsIg,leadingtomemoryBcellinduction,Igclassswitching,and
plasmacellformation.AntigendependentstagesofBcellmaturationoccurinsecondarylymphoidorgans,includinglymphnode,spleen,and
gutPeyer'spatches.IncontrasttotheTcellrepertoirethatisgeneratedintrathymicallybeforecontactwithforeignantigen,therepertoireofB
cellsexpressingdiverseantigenreactivesitesismodifiedbyfurtheralterationofIggenesafterstimulationbyantigenaprocesscalled
somatichypermutationwhichoccursinlymphnodegerminalcenters.
DuringBcelldevelopment,diversityoftheantigenbindingvariableregionofIgisgeneratedbyanorderedsetofIggenerearrangementsthat
aresimilartotherearrangementsundergonebyTCR,,,andgenes.Fortheheavychain,thereisfirstarearrangementofDsegments
toJsegments,followedbyasecondrearrangementbetweenaVgenesegmentandthenewlyformedDJsequencetheCsegmentis
alignedtotheVDJcomplextoyieldafunctionalIgheavychaingene(VDJC).Duringlaterstages,afunctionalorlightchaingeneis
generatedbyrearrangementofaVsegmenttoaJsegment,ultimatelyyieldinganintactIgmoleculecomposedofheavyandlightchains.
TheprocessofIggenerearrangementisregulatedandresultsinasingleantibodyspecificityproducedbyeachBcell,witheachIgmolecule
comprisingonetypeofheavychainandonetypeoflightchain.AlthougheachBcellcontainstwocopiesofIglightandheavychaingenes,
onlyonegeneofeachtypeisproductivelyrearrangedandexpressedineachBcell,aprocesstermedallelicexclusion.
Thereare~300Vgenesand5Jgenes,resultinginthepairingofVandJgenestocreate>1500differentlightchaincombinations.The
numberofdistinctlightchainsthatcanbegeneratedisincreasedbysomaticmutationswithintheVandJgenes,thuscreatinglarge
numbersofpossiblespecificitiesfromalimitedamountofgermlinegeneticinformation.Asnotedabove,inheavychainIggene
rearrangement,theVHdomainiscreatedbythejoiningofthreetypesofgermlinegenescalledVH,DH,andJH,thusallowingforeven
greaterdiversityinthevariableregionofheavychainsthanoflightchains.
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ThemostimmatureBcellprecursors(earlyproBcells)lackcytoplasmicIg(cIg)andsIg(Fig.3146).ThelargepreBcellismarkedbythe
acquisitionofthesurfacepreBCRcomposedofheavy(H)chainsandapreBlightchain,termedLC.LCisasurrogatelightchain
receptorencodedbythenonrearrangedVpreBandthe5lightchainlocus(thepreBCR).ProandpreBcellsaredriventoproliferateand
maturebysignalsfrombonemarrowstromainparticular,IL7.LightchainrearrangementoccursinthesmallpreBcellstagesuchthatthe
fullBCRisexpressedattheimmatureBcellstage.ImmatureBcellshaverearrangedIglightchaingenesandexpresssIgM.AsimmatureB
cellsdevelopintomatureBcells,sIgDisexpressedaswellassIgM.Atthispoint,Blineagedevelopmentinbonemarrowiscomplete,andB
cellsexitintotheperipheralcirculationandmigratetosecondarylymphoidorganstoencounterspecificantigens.
RandomrearrangementsofIggenesoccasionallygenerateselfreactiveantibodies,andmechanismsmustbeinplacetocorrectthese
mistakes.OnesuchmechanismisBCRediting,wherebyautoreactiveBCRsaremutatedtonotreactwithselfantigens.Ifreceptoreditingis
unsuccessfulineliminatingautoreactiveBcells,thenautoreactiveBcellsundergonegativeselectioninthebonemarrowthroughinductionof
apoptosisafterBCRengagementofselfantigen.
Afterleavingthebonemarrow,BcellspopulateperipheralBcellsites,suchaslymphnodeandspleen,andawaitcontactwithforeignantigens
thatreactwitheachBcell'sclonotypicreceptor.AntigendrivenBcellactivationoccursthroughtheBCR,andaprocessknownassomatic
hypermutationtakesplacewherebypointmutationsinrearrangedHandLgenesgiverisetomutantsIgmolecules,someofwhichbind
antigenbetterthantheoriginalsIgmolecules.Somatichypermutation,therefore,isaprocesswherebymemoryBcellsinperipherallymph
organshavethebestbinding,orthehighestaffinityantibodies.Thisoverallprocessofgeneratingthebestantibodiesiscalledaffinity
maturationofantibody.
LymphocytesthatsynthesizeIgG,IgA,andIgEarederivedfromsIgM+,sIgD+matureBcells.Igclassswitchingoccursinlymphnodeand
otherperipherallymphoidtissuegerminalcenters.CD40onBcellsandCD40ligandonTcellsconstituteacriticalcostimulatoryreceptor
ligandpairofimmunestimulatorymolecules.PairsofCD40+BcellsandCD40ligand+TcellsbindanddriveBcellIgclassswitchingviaT
cellproducedcytokinessuchasIL4andTGF.IL1,2,4,5,and6synergizetodrivematureBcellstoproliferateanddifferentiateintoIg
secretingcells.
HumoralMediatorsofAdaptiveImmunity:Immunoglobulins
ImmunoglobulinsaretheproductsofdifferentiatedBcellsandmediatethehumoralarmoftheimmuneresponse.Theprimaryfunctionsof
antibodiesaretobindspecificallytoantigenandbringabouttheinactivationorremovaloftheoffendingtoxin,microbe,parasite,orother
foreignsubstancefromthebody.ThestructuralbasisofIgmoleculefunctionandIggeneorganizationhasprovidedinsightintotheroleof
antibodiesinnormalprotectiveimmunity,pathologicimmunemediateddamagebyimmunecomplexes,andautoantibodyformationagainst
hostdeterminants.
Allimmunoglobulinshavethebasicstructureoftwoheavyandtwolightchains(Fig.3148).Immunoglobulinisotype(i.e.,G,M,A,D,E)is
determinedbythetypeofIgheavychainpresent.IgGandIgAisotypescanbedividedfurtherintosubclasses(G1,G2,G3,G4,andA1,A2)
basedonspecificantigenicdeterminantsonIgheavychains.ThecharacteristicsofhumanimmunoglobulinsareoutlinedinTable31413.The
fourchainsarecovalentlylinkedbydisulfidebonds.EachchainismadeupofaVregionandCregions(alsocalleddomains),themselves
madeupofunitsof~110aminoacids.Lightchainshaveonevariable(VL)andoneconstant(CL)unitheavychainshaveonevariableunit
(VH)andthreeorfourconstant(CH)units,dependingonisotype.Asthenamesuggests,theconstant,orC,regionsofIgmoleculesaremade
upofhomologoussequencesandsharethesameprimarystructureasallotherIgchainsofthesameisotypeandsubclass.Constantregions
areinvolvedinbiologicfunctionsofIgmolecules.TheCH2domainofIgGandtheCH4unitsofIgMareinvolvedwiththebindingoftheC1q
portionofC1duringcomplementactivation.TheCHregionatthecarboxyterminalendoftheIgGmolecule,theFcregion,bindstosurfaceFc
receptors(CD16,CD32,CD64)ofmacrophages,dendriticcells,NKcells,Bcells,neutrophils,andeosinophils.
Table31413.Physical,Chemical,andBiologicPropertiesofHumanImmunoglobulins
Property
IgG
IgA
IgM
IgD
IgE
Usualmolecular
form
Monomer
Monomer,
dimer
Pentamer,
hexamer
Monomer
Monomer
Otherchains
None
Jchain,SC
Jchain
None
None
Subclasses
G1,G2,G3,G4
A1,A2
None
None
None
Heavychain
allotypes
Gm(=30)
NoA1,A2m(2)
None
None
None
Molecularmass,
kDa
150
160,400
950,1150
175
190
Serumlevelin
averageadult,
mg/mL
9.512.5
1.52.6
0.71.7
0.04
0.0003
Percentageoftotal
serumIg
7585
715
510
0.3
0.019
23
2.5
Serumhalflife,
days
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days
Synthesisrate,
mg/kgperday
33
65
0.4
0.016
Antibodyvalence
2,4
10,12
Classical
complement
activation
+(G1,2?,3)
++
Alternate
complement
activation
+(G4)
BindingcellsviaFc
Macrophages,neutrophils,large
granularlymphocytes
Lymphocytes
Lymphocytes
None
Mastcells,
basophils,B
cells
Biologicproperties
Placentaltransfer,secondaryAbfor
mostantipathogenresponses
Secretory
immunoglobulin
PrimaryAb
responses
Markerfor
matureB
cells
Allergy,
antiparasite
responses
Source:AfterLCarayannopoulos,JDCapra,inWEPaul(ed):FundamentalImmunology,3rd
ed.NewYork,Raven,1993withpermission.
Variableregions(VLandVH)constitutetheantibodybinding(Fab)regionofthemolecule.WithintheVLandVHregionsarehypervariable
regions(extremesequencevariability)thatconstitutetheantigenbindingsiteuniquetoeachIgmolecule.Theidiotypeisdefinedasthe
specificregionoftheFabportionoftheIgmoleculetowhichantigenbinds.Antibodiesagainsttheidiotypeportionofanantibodymoleculeare
calledantiidiotypeantibodies.TheformationofsuchantibodiesinvivoduringanormalBcellantibodyresponsemaygenerateanegative(or
"off")signaltoBcellstoterminateantibodyproduction.
IgGconstitutes7585%oftotalserumimmunoglobulin.ThefourIgGsubclassesarenumberedinorderoftheirlevelinserum,IgG1being
foundingreatestamountsandIgG4theleast.IgGsubclasseshaveclinicalrelevanceintheirvaryingabilitytobindmacrophageand
neutrophilFcreceptorsandtoactivatecomplement(Table31413).Moreover,selectivedeficienciesofcertainIgGsubclassesgiveriseto
clinicalsyndromesinwhichthepatientisinordinatelysusceptibletobacterialinfections.IgGantibodiesarefrequentlythepredominant
antibodymadeafterrechallengeofthehostwithantigen(secondaryantibodyresponse).
IgMantibodiesnormallycirculateasa950kDapentamerwith160kDabivalentmonomersjoinedbyamoleculecalledtheJchain,a15kDa
nonimmunoglobulinmoleculethatalsoeffectspolymerizationofIgAmolecules.IgMisthefirstimmunoglobulintoappearintheimmune
response(primaryantibodyresponse)andistheinitialtypeofantibodymadebyneonates.MembraneIgMinthemonomericformalso
functionsasamajorantigenreceptoronthesurfaceofmatureBcells.IgMisanimportantcomponentofimmunecomplexesinautoimmune
diseases.Forexample,IgMantibodiesagainstIgGmolecules(rheumatoidfactors)arepresentinhightitersinrheumatoidarthritis,other
collagendiseases,andsomeinfectiousdiseases(subacutebacterialendocarditis).
IgAconstitutesonly715%oftotalserumimmunoglobulinbutisthepredominantclassofimmunoglobulininsecretions.IgAinsecretions
(tears,saliva,nasalsecretions,gastrointestinaltractfluid,andhumanmilk)isintheformofsecretoryIgA(sIgA),apolymerconsistingoftwo
IgAmonomers,ajoiningmolecule,againcalledtheJchain,andaglycoproteincalledthesecretoryprotein.OfthetwoIgAsubclasses,IgA1is
primarilyfoundinserum,whereasIgA2ismoreprevalentinsecretions.IgAfixescomplementviathealternativecomplementpathwayandhas
potentantiviralactivityinhumansbypreventionofvirusbindingtorespiratoryandgastrointestinalepithelialcells.
IgDisfoundinminutequantitiesinserumand,togetherwithIgM,isamajorreceptorforantigenontheBcellsurface.IgE,whichispresentin
seruminverylowconcentrations,isthemajorclassofimmunoglobulininvolvedinarmingmastcellsandbasophilsbybindingtothesecellsvia
theFcregion.AntigencrosslinkingofIgEmoleculesonbasophilandmastcellsurfacesresultsinreleaseofmediatorsoftheimmediate
hypersensitivity(allergic)response(Table31413).
CellularInteractionsinRegulationofNormalImmuneResponses
Thenetresultofactivationofthehumoral(Bcell)andcellular(Tcell)armsoftheadaptiveimmunesystembyforeignantigenisthe
eliminationofantigendirectlybyspecificeffectorTcellsorinconcertwithspecificantibody.Figure3142isasimplifiedschematicdiagramof
theTandBcellresponsesindicatingsomeofthesecellularinteractions.
Theexpressionofadaptiveimmunecellfunctionistheresultofacomplexseriesofimmunoregulatoryeventsthatoccurinphases.BothTand
Blymphocytesmediateimmunefunctions,andeachofthesecelltypes,whengivenappropriatesignals,passesthroughstages,from
activationandinductionthroughproliferation,differentiation,andultimatelyeffectorfunctions.Theeffectorfunctionexpressedmaybeatthe
endpointofaresponse,suchassecretionofantibodybyadifferentiatedplasmacell,oritmightservearegulatoryfunctionthatmodulates
otherfunctions,suchasisseenwithCD4+andCD8+TlymphocytesthatmodulatebothdifferentiationofBcellsandactivationofCD8+
cytotoxicTcells.
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CD4helperTcellscanbesubdividedonthebasisofcytokinesproduced(Fig.3142).ActivatedT H1typehelperTcellssecreteIL2,IFN,
IL3,TNF,GMCSF,andTNF,whileactivatedT H2typehelperTcellssecreteIL3,4,5,6,10,and13.T H1CD4+Tcells,through
elaborationofIFN,haveacentralroleinmediatingintracellularkillingbyavarietyofpathogens.T H1CD4+TcellsalsoprovideTcellhelp
forgenerationofcytotoxicTcellsandsometypesofopsonizingantibody,andtheygenerallyrespondtoantigensthatleadtodelayed
hypersensitivitytypesofimmuneresponsesformanyintracellularvirusesandbacteria(suchasHIVorM.tuberculosis).Incontrast,T H2cells
haveaprimaryroleinregulatoryhumoralimmunityandisotypeswitching.T H2cells,throughproductionofIL4andIL10,havearegulatory
roleinlimitingproinflammatoryresponsesmediatedbyT H1cells(Fig.3142).Inaddition,T H2CD4+TcellsprovidehelptoBcellsforspecific
Igproductionandrespondtoantigensthatrequirehighantibodylevelsforforeignantigenelimination(extracellularencapsulatedbacteria
suchasStreptococcuspneumoniaeandcertainparasiteinfections).Morerecently,anewsubsetoftheT Hfamilyhasbeendescribedtermed
T h17characterizedbythesecellstosecretecytokinessuchasIL17,22,and26.T h17cellshavebeenshowntoplayaroleinautoimmune
inflammatorydisordersinadditiontodefenseagainstextracellularbacteriaandfungi,particularlyatmucosalsurfaces(Fig.3143).In
summary,thetypeofTcellresponsegeneratedinanimmuneresponseisdeterminedbythemicrobePAMPspresentedtotheDCs,theTLRs
ontheDCsthatbecomeactivated,thetypesofDCsthatareactivated,andthecytokinesthatareproduced.Commonly,myeloidDCsproduce
IL12andactivateT H1TcellresponsesthatresultinIFNandcytotoxicTcellinduction,andplasmacytoidDCsproduceIFNandleadto
T H2responsesthatresultinIL4productionandenhancedantibodyresponses.
AsshowninFigs.3142and3143,uponactivationbyDCs,TcellsubsetsthatproduceIL2,IL3,IFN,and/orIL4,5,6,10,and13are
generatedandexertpositiveandnegativeinfluencesoneffectorTandBcells.ForBcells,trophiceffectsaremediatedbyavarietyof
cytokines,particularlyTcellderivedIL3,4,5,and6,thatactatsequentialstagesofBcellmaturation,resultinginBcellproliferation,
differentiation,andultimatelyantibodysecretion.ForcytotoxicTcells,trophicfactorsincludeinducerTcellsecretionofIL2,IFN,andIL12.
AnimportanttypeofimmunomodulatoryTcellthatcontrolsimmuneresponsesisCD4+andCD8+Tregulatorycells.Thesecellsconstitutively
expressthechainoftheIL2receptor(CD25),producelargeamountsofIL10,andcansuppressbothTandBcellresponses.Tregulatory
cellsareinducedbyimmaturedendriticcellsandplaykeyrolesinmaintainingtolerancetoselfantigensintheperiphery.LossofTregulatory
cellsisthecauseoforganspecificautoimmunediseaseinmicesuchasautoimmunethyroiditis,adrenalitis,andoophoritis(see"Immune
ToleranceandAutoimmunity"below).Tregulatorycellsalsoplaykeyrolesincontrollingthemagnitudeanddurationofimmuneresponsesto
microbes.Normally,aftertheinitialimmuneresponsetoamicrobehaseliminatedtheinvader,Tregulatorycellsareactivatedtosuppressthe
antimicroberesponseandpreventhostinjury.SomemicrobeshaveadaptedtoinduceTregulatorycellactivationatthesiteofinfectionto
promoteparasiteinfectionandsurvival.InLeishmaniainfection,theparasitelocallyinducesTregulatorycellaccumulationatskininfection
sitesthatdampensantiLeishmaniaTcellresponsesandpreventseliminationoftheparasite.Itisthoughtthatmanychronicinfectionssuch
asbyM.tuberculosisareassociatedwithabnormalTregulatorycellactivationthatpreventseliminationofthemicrobe.
AlthoughBcellsrecognizenativeantigenviaBcellsurfaceIgreceptors,BcellsrequireTcellhelptoproducehighaffinityantibodyofmultiple
isotypesthatarethemosteffectiveineliminatingforeignantigen.ThisTcelldependencelikelyfunctionsintheregulationofBcellresponses
andinprotectionagainstexcessiveautoantibodyproduction.TcellBcellinteractionsthatleadtohighaffinityantibodyproductionrequire(1)
processingofnativeantigenbyBcellsandexpressionofpeptidefragmentsontheBcellsurfaceforpresentationtoT Hcells,(2)theligationof
BcellsbyboththeTCRcomplexandtheCD40ligand,(3)inductionoftheprocesstermedantibodyisotypeswitchinginantigenspecificBcell
clones,and(4)inductionoftheprocessofaffinitymaturationofantibodyinthegerminalcentersofBcellfolliclesoflymphnodeandspleen.
NaveBcellsexpresscellsurfaceIgDandIgM,andinitialcontactofnaveBcellswithantigenisviabindingofnativeantigentoBcellsurface
IgM.Tcellcytokines,releasedfollowingT H2cellcontactwithBcellsorbya"bystander"effect,inducechangesinIggeneconformationthat
promoterecombinationofIggenes.Theseeventsthenresultinthe"switching"ofexpressionofheavychainexonsinatriggeredBcell,
leadingtothesecretionofIgG,IgA,or,insomecases,IgEantibodywiththesameVregionantigenspecificityastheoriginalIgMantibody,for
responsetoawidevarietyofextracellularbacteria,protozoa,andhelminths.CD40ligandexpressionbyactivatedTcellsiscriticalfor
inductionofBcellantibodyisotypeswitchingandforBcellresponsivenesstocytokines.PatientswithmutationsinTcellCD40ligandhaveB
cellsthatareunabletoundergoisotypeswitching,resultinginlackofmemoryBcellgenerationandtheimmunodeficiencysyndromeofX
linkedhyperIgMsyndrome(Chap.316).
ImmuneToleranceandAutoimmunity
Immunetoleranceisdefinedastheabsenceofactivationofpathogenicautoreactivity.Autoimmunediseasesaresyndromescausedbythe
activationofTorBcellsorboth,withnoevidenceofothercausessuchasinfectionsormalignancies(Chap.318).Oncethoughttobe
mutuallyexclusive,immunetoleranceandautoimmunityarenowbothrecognizedtobepresentnormallyinhealthwhenabnormal,they
representextremesfromthenormalstate.Forexample,itisnowknownthatlowlevelsofautoreactivityofTandBcellswithselfantigensin
theperipheryarecriticaltotheirsurvival.Similarly,lowlevelsofautoreactivityandthymocyterecognitionofselfantigensinthethymusarethe
mechanismswhereby(1)normalTcellsarepositivelyselectedtosurviveandleavethethymustorespondtoforeignmicrobesinthe
peripheryand(2)TcellshighlyreactivetoselfantigensarenegativelyselectedanddietopreventoverlyselfreactiveTcellsfromgettinginto
theperiphery(centraltolerance).However,notallselfantigensareexpressedinthethymustodeletehighlyselfreactiveTcells,andthere
aremechanismsforperipheraltoleranceinductionofTcellsaswell.Unlikethepresentationofmicrobialantigensbymaturedendriticcells,the
presentationofselfantigensbyimmaturedendriticcellsneitheractivatesnormaturesthedendriticcellstoexpresshighlevelsofco
stimulatorymoleculessuchasB71(CD80)orB72(CD86).WhenperipheralTcellsarestimulatedbydendriticcellsexpressingselfantigens
inthecontextofHLAmolecules,sufficientstimulationofTcellsoccurstokeepthemalive,butotherwisetheyremainanergic,or
nonresponsive,untiltheycontactadendriticcellwithhighlevelsofcostimulatorymoleculesexpressingmicrobialantigens.Inthelattersetting,
normalTcellsthenbecomeactivatedtorespondtothemicrobe.IfBcellshavehighselfreactivityBCRs,theynormallyundergoeither
deletioninthebonemarroworreceptoreditingtoexpressalessautoreactivereceptor.Althoughmanyautoimmunediseasesare
characterizedbyabnormalorpathogenicautoantibodyproduction(Table31414),mostautoimmunediseasesarecausedbyacombination
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ofexcessTandBcellreactivity.
Table31414.RecombinantorPurifiedAutoantigensRecognizedbyAutoantibodiesAssociatedwithHumanAutoimmuneDisorders
Autoantigen
Autoimmune
Diseases
Autoantigen
AutoimmuneDiseases
CellorOrganSpecificAutoimmunity
Acetylcholinereceptor
Myastheniagravis
Insulinreceptor
TypeBinsulinresistance,acanthosis,
systemiclupuserythematosus(SLE)
Actin
Chronicactive
hepatitis,primary
biliarycirrhosis
Intrinsicfactor
type1
Perniciousanemia
Adeninenucleotidetranslator
(ANT)
Dilated
cardiomyopathy,
myocarditis
Leukocyte
function
associated
antigen(LFA1)
TreatmentresistantLymearthritis
Adrenoreceptor
Dilated
cardiomyopathy
AromaticLaminoacid
decarboxylase
Autoimmune
polyendocrine
syndrometype1(APS
1)
Myelin
associated
glycoprotein
(MAG)
Polyneuropathy
Asialoglycoproteinreceptor
Autoimmunehepatitis
Myelinbasic
protein
Multiplesclerosis,demyelinatingdiseases
Bactericidal/permeability
increasingprotein(Bpi)
Cysticfibrosis
vasculitides
Myelin
oligodendrocyte
glycoprotein
(MOG)
Multiplesclerosis
Calciumsensingreceptor
Acquired
hypoparathyroidism
Myosin
Rheumaticfever
Cholesterolsidechain
cleavageenzyme(CYPlla)
Autoimmune
polyglandular
syndrome1
p80Collin
Atopicdermatitis
CollagentypeIV3chain
Goodpasture
syndrome
Pyruvate
dehydrogenase
complexE2
(PDCE2)
Primarybiliarycirrhosis
CytochromeP4502D6
(CYP2D6)
Autoimmunehepatitis
Desmin
Crohn'sdisease,
coronaryartery
disease
Sodiumiodide
symporter(NIS)
Graves'disease,autoimmune
hypothyroidism
Desmoglein1
Pemphigusfoliaceus
Desmoglein3
Pemphigusvulgaris
SOX10
Vitiligo
Factin
Autoimmunehepatitis
Thyroidandeye
muscleshared
protein
Thyroidassociatedophthalmopathy
GMgangliosides
GuillainBarr
syndrome
Glutamatedecarboxylase
(GAD65)
Type1diabetes,stiff
personsyndrome
Thyroglobulin
Autoimmunethyroiditis
Glutamatereceptor(GLUR)
Rasmussen
encephalitis
Thyroid
peroxidase
AutoimmuneHashimotothyroiditis
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H/KATPase
Autoimmunegastritis
Thyrotropin
receptor
Graves'disease
17Hydroxylase(CYP17)
Autoimmune
polyglandular
syndrome1
Tissue
transglutaminase
Celiacdisease
21Hydroxylase(CYP21)
Addisondisease
Transcription
coactivatorp75
Atopicdermatitis
IA2(ICA512)
Type1diabetes
Tryptophan
hydroxylase
Autoimmunepolyglandularsyndrome1
Insulin
Type1diabetes,
insulinhypoglycemic
syndrome(Hirata
disease)
Tyrosinase
Tyrosine
hydroxylase
Vitiligo,metastaticmelanomaAutoimmune
polyglandularsyndrome1
ACTH
ACTHdeficiency
HistoneH2A
H2BDNA
SLE
AminoacyltRANhistidyl
synthetase
Myositis,
dermatomyositis
IgEreceptor
Chronicidiopathicurticaria
AminoacyltRNAsynthetase
(several)
Polymyositis,
dermatomyositis
Keratin
RA
Cardiolipin
SLE,antiphospholipid
syndrome
KuDNAprotein
kinase
SLE
CarbonicanhydraseII
SLE,Sjgren's
syndrome,systemic
sclerosis
Collagen(multipletypes)
Rheumatoidarthritis
(RA),SLE,progressive
systemicsclerosis
Myeloperoxidase
Necrotizingandcrescentic
glomerulonephritis(NCGN),systemic
vasculitis
Centromereassociated
proteins
Systemicsclerosis
Proteinase3
(PR3)
Granulomatosiswithpolyangiitis
(Wegener
s),ChurgStrausssyndrome
DNAdependentnucleoside
stimulatedATPase
Dermatomyositis
RNApolymerase
I
III(RNP)
Systemicsclerosis,SLE
Fibrillarin
Scleroderma
Signal
recognition
protein(SRP54)
Polymyositis
Fibronectin
SLE,RA,morphea
Topoisomerase
1(Scl70)
Scleroderma,Raynaudsyndrome
Glucose6phosphate
isomerase
RA
Tublin
Chronicliverdisease,visceralleishmaniasis
2GlycoproteinI(B2GPI)
Primary
antiphospholipid
syndrome
Golgin(95,97,160,180)
Sjgren
ssyndrome,
SLE,RA
Vimentin
Systemicautoimmunedisease
Heatshockprotein
Variousimmune
relateddisorders
SystemicAutoimmunity
Kunucleoprotein
Hemidesmosomalprotein
180
La
phosphoprotein
(La55B)
Connectivetissuesyndrome
Sjgren'ssyndrome
Bullouspemphigoid,
herpesgestationis,
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cicatricialpemphigoid
PlasmaProteinand
CytokineAutoimmunity
C1inhibitor
AutoimmuneC1
deficiency
Glycoprotein
IIb/IIIgandIb/IX
Autoimmunethrombocytopeniapurpura
C1q
SLE,membrane
proliferative
glomerulonephritis
(MPGN)
IgA
ImmunodeficiencyassociatedwithSLE,
perniciousanemia,thyroiditis,Sjgren
s
syndromeandchronicactivehepatitis
Cytokines(IL1,IL1,IL6,
IL10,LIF)
RA,systemicsclerosis,
normalsubjects
FactorII,factorV,factorVII,
factorVIII,factorIX,factorX,
factorXI,thrombinvWF
Prolongedcoagulation
time
OxidizedLDL
(OxLDL)
Atherosclerosis
Amphiphysin
Neuropathy,smallcell
lungcancer
p62(IGFII
mRNAbinding
protein)
Hepatocellularcarcinoma(China)
CyclinB1
Hepatocellular
carcinoma
Recoverin
Cancerassociatedretinopathy
DNAtopoisomeraseII
Livercancer
Riprotein
Paraneoplasticopsoclonusmyoclonus
ataxia
Desmoplakin
Paraneoplastic
pemphigus
Gephyrin
Paraneoplasticstiff
personsyndrome
IVspectrin
Lowermotorneuronsyndrome
Huproteins
Paraneoplastic
encephalomyelitis
Synaptotagmin
LambertEatonmyasthenicsyndrome
Neuronalnicotinic
acetylcholinereceptor
Subacuteautonomic
neuropathy,cancer
Voltagegated
calcium
channels
LambertEatonmyasthenicsyndrome
p53
Cancer,SLE
Yoprotein
Paraneoplasticcerebellardegeneration
CancerandParaneoplastic
Autoimmunity
Source:FromALernmarketal:JClinInvest108:1091,2001withpermission.
Multiplefactorscontributetothegenesisofclinicalautoimmunediseasesyndromes,includinggeneticsusceptibility(Table31414),
environmentalimmunestimulantssuchasdrugs[e.g.,procainamideandphenytoin(Dilantin)withdruginducedsystemiclupus
erythematosus],infectiousagenttriggers(suchasEpsteinBarrvirusandautoantibodyproductionagainstredbloodcellsandplatelets),and
lossofTregulatorycells(leadingtothyroiditis,adrenalitis,andoophoritis).
ImmunityatMucosalSurfaces
Mucosacoveringtherespiratory,digestive,andurogenitaltractstheeyeconjunctivatheinnerearandtheductsofallexocrineglands
containcellsoftheinnateandadaptivemucosalimmunesystemthatprotectthesesurfacesagainstpathogens.Inthehealthyadult,mucosa
associatedlymphoidtissue(MALT)contains80%ofallimmunecellswithinthebodyandconstitutesthelargestmammalianlymphoidorgan
system.
MALThasthreemainfunctions:(1)toprotectthemucousmembranesfrominvasivepathogens(2)topreventuptakeofforeignantigensfrom
food,commensalorganisms,andairbornepathogensandparticulatematterand(3)topreventpathologicimmuneresponsesfromforeign
antigensiftheydocrossthemucosalbarriersofthebody(Fig.3149).
FIGURE3149
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IncreasedepithelialpermeabilitymaybeimportantinthedevelopmentofchronicgutTcellmediatedinflammation.CD4Tcellsactivated
bygutantigensinPeyer'spatchesmigratetotheLP.Inhealthyindividuals,thesecellsdiebyapoptosis.Increasedepithelialpermeabilitymay
allowsufficientantigentoentertheLPtotriggerTcellactivation,breakingtolerancemediatedbyimmunosuppressivecytokinesandperhaps
Tregulatorycells.Proinflammatorycytokinesthenfurtherincreaseepithelialpermeability,settingupaviciouscycleofchronicinflammation.
(FromMacDonaldandMonteleonewithpermission.)
MALTisacompartmentalizedsystemofimmunecellsthatfunctionsindependentlyfromsystemicimmuneorgans.Whereasthesystemic
immuneorgansareessentiallysterileundernormalconditionsandrespondvigorouslytopathogens,MALTimmunecellsarecontinuously
bathedinforeignproteinsandcommensalbacteria,andtheymustselectthosepathogenicantigensthatmustbeeliminated.MALTcontains
anatomicallydefinedfociofimmunecellsintheintestine,tonsil,appendix,andperibronchialareasthatareinductivesitesformucosalimmune
responses.Fromthesesites,immuneTandBcellsmigratetoeffectorsitesinmucosalparenchymaandexocrineglandswheremucosal
immunecellseliminatepathogeninfectedcells.Inadditiontomucosalimmuneresponses,allmucosalsiteshavestrongmechanicaland
chemicalbarriersandcleansingfunctionstorepelpathogens.
KeycomponentsofMALTincludespecializedepithelialcellscalled"membrane"or"M"cellsthattakeupantigensanddeliverthemtodendritic
cellsorotherAPCs.EffectorcellsinMALTincludeBcellsproducingantipathogenneutralizingantibodiesofsecretoryIgAaswellasIgG
isotype,Tcellsproducingsimilarcytokinesasinsystemicimmunesystemresponse,andThelperandcytotoxicTcellsthatrespondto
pathogeninfectedcells.
SecretoryIgAisproducedinamountsof>50mg/kgofbodyweightper24handfunctionstoinhibitbacterialadhesion,inhibitmacromolecule
absorptioninthegut,neutralizeviruses,andenhanceantigeneliminationintissuethroughbindingtoIgAandreceptormediatedtransportof
immunecomplexesthroughepithelialcells.
Recentstudieshavedemonstratedtheimportanceofcommensalgutandothermucosalbacteriatothehealthofthehumanimmunesystem.
NormalcommensalflorainducesantiinflammatoryeventsinthegutandprotectsepithelialcellsfrompathogensthroughTLRsandotherPRR
signaling.Whenthegutisdepletedofnormalcommensalflora,theimmunesystembecomesabnormal,withlossofT H1Tcellfunction.
RestorationofthenormalgutfloracanreestablishthebalanceinThelpercellratioscharacteristicofthenormalimmunesystem.Whenthe
gutbarrierisintact,eitherantigensdonottransversethegutepitheliumor,whenpathogensarepresent,aselflimited,protectiveMALT
immuneresponseeliminatesthepathogen(Fig.3149).However,whenthegutbarrierbreaksdown,immuneresponsestocommensalflora
antigenscancauseinflammatoryboweldiseasessuchasCrohn'sdiseaseand,perhaps,ulcerativecolitis(Fig.3149)(Chap.295).
UncontrolledMALTimmuneresponsestofoodantigens,suchasgluten,cancauseceliacdisease(Chap.295).
TheCellularandMolecularControlofProgrammedCellDeath
Theprocessofapoptosis(programmedcelldeath)playsacrucialroleinregulatingnormalimmuneresponsestoantigen.Ingeneral,awide
varietyofstimulitriggeroneofseveralapoptoticpathwaystoeliminatemicrobeinfectedcells,eliminatecellswithdamagedDNA,oreliminate
activatedimmunecellsthatarenolongerneeded(Fig.31410).Thelargestknownfamilyof"deathreceptors"isthetumornecrosisfactor
receptor(TNFR)family[TNFR1,TNFR2,Fas(CD95),deathreceptor3(DR3),deathreceptor4[DR4,TNFrelatedapoptosisincluding
ligandreceptor1(TRAILR1)],anddeathreceptor5(DR5,TRAILR2)]theirligandsareallintheTNFfamily.Bindingofligandstothese
deathreceptorsleadstoasignalingcascadethatinvolvesactivationofthecaspasefamilyofmoleculesthatleadstoDNAcleavageandcell
death.Twootherpathwaysofprogrammedcelldeathinvolvenuclearp53intheeliminationofcellswithabnormalDNAandmitochondrial
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cytochromectoinducecelldeathindamagedcells(Fig.31410).Anumberofhumandiseaseshavenowbeendescribedthatresultfrom,or
areassociatedwith,mutatedapoptosisgenes(Table31415).TheseincludemutationsintheFasandFasligandgenesinautoimmuneand
lymphoproliferationsyndromes,andmultipleassociationsofmutationsingenesintheapoptoticpathwaywithmalignantsyndromes.
FIGURE31410
PathwaysofCellularApoptosis.Therearetwomajorpathwaysofapoptosis:thedeathreceptorpathway,whichismediatedbyactivationof
deathreceptors,andtheBCL2regulatedmitochondrialpathway,whichismediatedbynoxiousstimulithatultimatelyleadtomitochondrial
injury.LigationofdeathreceptorsrecruitstheadaptorproteinFASassociateddeathdomain(FADD).FADDinturnrecruitscaspase8,which
ultimatelyactivatescaspase3,thekey"executioner"caspase.CellularFLICEinhibitoryprotein(cFLIP)caneitherinhibitorpotentiatebinding
ofFADDandcaspase8,dependingonitsconcentration.Intheintrinsicpathway,proapoptoticBH3proteinsareactivatedbynoxiousstimuli,
whichinteractwithandinhibitantiapoptoticBCL2orBCLXL.Thus,BAXandBAKarefreetoinducemitochondrialpermeabilizationwith
releaseofcytochromec,whichultimatelyresultsintheactivationofcaspase9throughtheapoptosome.Caspase9thenactivatescaspase3.
SMAC/DIABLOisalsoreleasedaftermitochondrialpermeabilizationandactstoblocktheactionofinhibitorsofapoptosisprotein(IAPs),which
inhibitcaspaseactivation.Thereispotentialcrosstalkbetweenthetwopathways,whichismediatedbythetruncatedformofBID(tBID)thatis
producedbycaspase8mediatedBIDcleavagetBIDactstoinhibittheBCL2BCLXLpathwayandtoactivateBAXandBAK.Thereisdebate
(indicatedbythequestionmark)astowhetherproapoptoticBH3molecules(e.g.,BIMandPUMA)actdirectlyonBAXandBAKtoinduce
mitochondrialpermeabilityorwhethertheyactonlyonBCL2BCLXL.APAF1,apoptoticproteaseactivatingfactor1BH3,BCLhomologue
TNF,tumornecrosisfactorTRAIL,TNFrelatedapoptosisinducingligand.(FromHotchkissetalwithpermission.)
Table31415.ImmuneSystemMoleculeDefectsinAnimalsorHumansthatCauseAutoimmuneorMalignantSyndromes
Protein
Defect
DiseaseorSyndrome
Observationin
AnimalModelsor
Humans
CytokinesandSignalingProteins
Tumornecrosisfactor
(TNF)
Overexpression
Inflammatoryboweldisease(IBD),arthritis,
vasculitis
Mice
TNF
Underexpression
Systemiclupuserythematosus(SLE)
Mice
Interleukin1receptor
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Interleukin1receptor
antagonist
Underexpression
Arthritis
Mice
IL2
Overexpression
IBD
Mice
IL7
Overexpression
IBD
Mice
IL10
Overexpression
IBD
Mice
IL2receptor
Overexpression
IBD
Mice
IL10receptor
Overexpression
IBD
Mice
IL3
Overexpression
Demyelinatingsyndrome
Mice
Interferon
Overexpression
inskin
SLE
Mice
STAT3
Underexpression
IBD
Mice
STAT4
Overexpression
IBD
Mice
Transforminggrowth
factor(TGF)
Underexpression
SystemicwastingsyndromeandIBD
Mice
TGFreceptorinT
cells
Underexpression
SLE
Mice
Programmeddeath
(PD1)
Underexpression
SLElikesyndrome
Mice
CytotoxicT
lymphocyte,antigen4
(CTLA4)
Underexpression
Systemiclymphoproliferativedisease
Mice
IL10
Underexpression
IBD(mouse)Type1diabetes,thyroiddisease,
primary(human)
Miceandhumans
Inflammatoryboweldisease
Ratsandhumans
MajorHistocompatibilityLocusMolecules*
HLAB27
Alleleexpression
or
overexpression
Complement
deficiencyofC1,2,3
or4
Underexpression
LIGHT(TNF
superfamily14)
Overexpression
Systemiclymphoproliferative(mouse)and
autoimmunity
Mice
HLAclassII
DQB10301,
DQB10302
Alleleexpression
Juvenileonsetdiabetes
Humans
HLAclassII
DQB10401,
DQB10402
Alleleexpression
Rheumatoidarthritis
Humans
HLAclassIB27
Alleleexpression
Ankylosingspondylitis,IBD
Ratsandhumans
TNFreceptor1(TNF
R1)
Underexpression
Familialperiodicfeversyndrome
Humans
Fas(CD95Apo1)
Underexpression
Autoimmunelymphoproliferativesyndrometype1
(ALPS1)malignantlymphomabladdercancer
Humans
Fasligand
Underexpression
SLE(onlyonecaseidentified)
Humans
Perforin
Underexpression
Familialhemophagocyticlymphohistiocytosis(FHL)
Humans
Humans
ApoptosisProteins
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Perforin
Underexpression
Familialhemophagocyticlymphohistiocytosis(FHL)
Humans
Caspase10
Underexpression
AutoimmunelymphoproliferativesyndrometypeII
(ALPSII)
Humans
bcl10
Underexpression
NonHodgkin'slymphoma
Humans
P53
Underexpression
Variousmalignantneoplasms
Humans
Bax
Underexpression
Coloncancerhematopoieticmalignancies
Humans
bcl2
Underexpression
NonHodgkin'slymphoma
Humans
cIAP2
Underexpression
LowgradeMALTlymphoma
Humans
NAIP1
Underexpression
Spinalmuscularatrophy
Humans
*Manyautoimmunediseasesareassociatedwithamyriadofmajorcompatibilitycomplex
geneallele(HLA)types.Theyarepresentedhereasexamples.
Abbreviation:MALT,mucosaassociatedlymphoidtissue.
Source:AdaptedfromMullauerandfromDavidsonandDiamondwithpermission.
MechanismsofImmuneMediatedDamagetoMicrobesorHostTissues
Severalresponsesbythehostinnateandadaptiveimmunesystemstoforeignmicrobesculminateinrapidandefficienteliminationof
microbes.Inthesescenarios,theclassicweaponsoftheadaptiveimmunesystem(Tcells,Bcells)interfacewithcells(macrophages,dendritic
cells,NKcells,neutrophils,eosinophils,basophils)andsolubleproducts(microbialpeptides,pentraxins,complementandcoagulation
systems)oftheinnateimmunesystem(Chaps.60and317).
Therearefivegeneralphasesofhostdefenses:(1)migrationofleukocytestositesofantigenlocalization(2)antigennonspecificrecognition
ofpathogensbymacrophagesandothercellsandsystemsoftheinnateimmunesystem(3)specificrecognitionofforeignantigensmediated
byTandBlymphocytes(4)amplificationoftheinflammatoryresponsewithrecruitmentofspecificandnonspecificeffectorcellsby
complementcomponents,cytokines,kinins,arachidonicacidmetabolites,andmastcellbasophilproductsand(5)macrophage,neutrophil,
andlymphocyteparticipationindestructionofantigenwithultimateremovalofantigenparticlesbyphagocytosis(bymacrophagesor
neutrophils)orbydirectcytotoxicmechanisms(involvingmacrophages,neutrophils,DCs,andlymphocytes).Undernormalcircumstances,
orderlyprogressionofhostdefensesthroughthesephasesresultsinawellcontrolledimmuneandinflammatoryresponsethatprotectsthe
hostfromtheoffendingantigen.However,dysfunctionofanyofthehostdefensesystemscandamagehosttissueandproduceclinical
disease.Furthermore,forcertainpathogensorantigens,thenormalimmuneresponseitselfmightcontributesubstantiallytothetissue
damage.Forexample,theimmuneandinflammatoryresponseinthebraintocertainpathogenssuchasM.tuberculosismayberesponsible
formuchofthemorbidityrateofthisdiseaseinthatorgansystem(Chap.165).Inaddition,themorbidityrateassociatedwithcertain
pneumoniassuchasthatcausedbyPneumocystisjirovecimaybeassociatedmorewithinflammatoryinfiltratesthanwiththetissue
destructiveeffectsofthemicroorganismitself(Chap.207).
TheMolecularBasisofLymphocyteEndothelialCellInteractions
Thecontroloflymphocytecirculatorypatternsbetweenthebloodstreamandperipherallymphoidorgansoperatesattheleveloflymphocyte
endothelialcellinteractionstocontrolthespecificityoflymphocytesubsetentryintoorgans.Similarly,lymphocyteendothelialcellinteractions
regulatetheentryoflymphocytesintoinflamedtissue.Adhesionmoleculeexpressiononlymphocytesandendothelialcellsregulatesthe
retentionandsubsequentegressoflymphocyteswithintissuesitesofantigenicstimulation,delayingcellexitfromtissueandpreventing
reentryintothecirculatinglymphocytepool(Fig.31411).Alltypesoflymphocytemigrationbeginwithlymphocyteattachmenttospecialized
regionsofvessels,termedhighendothelialvenules(HEVs).Animportantconceptisthatadhesionmoleculesdonotgenerallybindtheirligand
untilaconformationalchange(ligandactivation)occursintheadhesionmoleculethatallowsligandbinding.Inductionofaconformation
dependentdeterminantonanadhesionmoleculecanbeaccomplishedbycytokinesorvialigationofotheradhesionmoleculesonthecell.
FIGURE31411
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Keymigrationstepsofimmunecellsatsitesofinflammation.Inflammationduetotissuedamageorinfectioninducesthereleaseof
cytokines(notshown)andinflammatorychemoattractants(redarrowheads)fromdistressedstromalcellsand"professional"sentinels,suchas
mastcellsandmacrophages(notshown).Theinflammatorysignalsinduceupregulationofendothelialselectinsandimmunoglobulin
"superfamily"members,particularlyICAM1and/orVCAM1.Chemoattractants,particularlychemokines,areproducedbyortranslocated
acrossvenularendothelialcells(redarrow)andaredisplayedinthelumentorollingleukocytes.Thoseleukocytesthatexpressthe
appropriatesetoftraffickingmoleculesundergoamultistepadhesioncascade(steps13)andthenpolarizeandmovebydiapedesisacross
thevenularwall(steps4and5).Diapedesisinvolvestransientdisassemblyofendothelialjunctionsandpenetrationthroughtheunderlying
basementmembrane(step6).Onceintheextravascular(interstitial)space,themigratingcellusesdifferentintegrinstogain"footholds"on
collagenfibersandotherECMmolecules,suchaslamininandfibronectin,andoninflammationinducedICAM1onthesurfaceof
parenchymalcells(step7).Themigratingcellreceivesguidancecuesfromdistinctsetsofchemoattractants,particularlychemokines,which
maybeimmobilizedonglycosaminoglycans(GAG)that"decorate"manyECMmoleculesandstromalcells.Inflammatorysignalsalsoinduce
tissueDCstoundergomaturation.OnceDCsprocessmaterialfromdamagedtissuesandinvadingpathogens,theyupregulateCCR7,which
allowsthemtoenterdraininglymphvesselsthatexpresstheCCR7ligandCCL21(andCCL19).Inlymphnodes(LN),theseantigenloaded
matureDCsactivatenaveTcellsandexpandpoolsofeffectorlymphocytes,whichenterthebloodandmigratebacktothesiteof
inflammation.TcellsintissuealsousethisCCR7dependentroutetomigratefromperipheralsitestodraininglymphnodesthroughafferent
lymphatics.(AdaptedfromADLusteretal:NatImmunol6:1182,2005withpermissionfromMacmillanPublishersLtd.Copyright2005.)
Thefirststageoflymphocyteendothelialcellinteractions,attachmentandrolling,occurswhenlymphocytesleavethestreamofflowingblood
cellsinapostcapillaryvenuleandrollalongvenuleendothelialcells(Fig.31411).Lymphocyterollingismediatedbythelselectinmolecule
(LECAM1,LAM1,CD62L)andslowscelltransittimethroughvenules,allowingtimeforactivationofadherentcells.
Thesecondstageoflymphocyteendothelialcellinteractions,firmadhesionwithactivationdependentstablearrest,requiresstimulationof
lymphocytesbychemoattractantsorbyendothelialcellderivedcytokines.Cytokinesthoughttoparticipateinadherentcellactivationinclude
membersoftheIL8family,plateletactivationfactor,leukotrieneB4,andC5a.Inaddition,HEVsexpresschemokines,SLC(CCL21)andELC
(CCL19),whichparticipateinthisprocess.Followingactivationbychemoattractants,lymphocytesshedlselectinfromthecellsurfaceand
upregulatecellCD11b/18(MAC1)orCD11a/18(LFA1)molecules,resultinginfirmattachmentoflymphocytestoHEVs.
LymphocytehomingtoperipherallymphnodesinvolvesadhesionoflselectintoglycoproteinHEVligandscollectivelyreferredtoasperipheral
nodeaddressin(PNAd),whereashomingoflymphocytestointestinePeyer'spatchesprimarilyinvolvesadhesionofthe4,7integrinto
mucosaladdressincelladhesionmolecule1(MAdCAM1)onthePeyer'spatchHEVs.However,formigrationtomucosalPeyer'spatch
lymphoidaggregates,navelymphocytesprimarilyuselselectin,whereasmemorylymphocytesuse4,7integrin.4,1Integrin
(CD49d/CD29,VLA4)VCAM1interactionsareimportantintheinitialinteractionofmemorylymphocyteswithHEVsofmultipleorgansinsites
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ofinflammation(Table31416).
Table31416.TraffickingMoleculesInvolvedinInflammatoryDiseaseProcesses
ProposedLeukocyteReceptorsforEndothelialTrafficSignals
Disease
KeyEffector
Cell
LSelectin,Ligand
GPCR
Integrina
AcuteInflammation
Myocardial
infarction
Neutrophil
PSGL1
CXCR1,CXCR2,PAFR,BLT1
LFA1,Mac1
Stroke
Neutrophil
LSelectin,PSGL1
LFA1,Mac1
Ischemia
reperfusion
Neutrophil
PSGL1
LFA1,Mac1
Monocyte
PSGL1
CCR1,CCR2,BLT1,CXCR2,
CX3CR1
VLA4
TH1
PSGL1
CXCR3,CCR5
VLA4
TH1
PSGL1(?)
CXCR3,CXCR6
VLA4,LFA1
Monocyte
PSGL1(?)
CCR2,CCR1
VLA4,LFA1
Monocyte
PSGL1
CCR1,CCR2
VLA1,VLA2,VLA4,
LFA1
TH1
PSGL1
CXCR3,CXCR6
VLA1,VLA2,VLA4,
LFA1
Neutrophil
LSelectin,PSGL1
CXCR2,BLT1
LFA1b
Psoriasis
Skinhoming
TH1
CLA
CCR4,CCR10,CXCR3
VLA4c,LFA1
Crohndisease
Guthoming
TH1
PSGL1
CCR9,CXCR3
4,7,LFA1
TypeIdiabetes
TH1
PSGL1(?)
CCR4,CCR5
VLA4,LFA1
CD8
LSelectin(?),PSGL
1(?)
CXCR3
VLA4,LFA1
CD8
PSGL1
CXCR3,CX3CR1,BLT1
VLA4,LFA1
Bcell
LSelectin,PSGL1
CXCR5,CXCR4
VLA4,LFA1
Hepatitis
CD8
PSGL1
CXCR3,CCR5,CXCR6
VLA4
Lupus
TH1
None
CXCR6
VLA4d
Plasmacytoid
DC
LSelectin,CLA
CCR7,CXCR3,ChemR23
LFA1,Mac1
Bcell
CLA(?)
CXCR5,CXCR4
LFA1
TH2
PSGL1
CCR4,CCR8,BLT1
LFA1
Eosinophil
PSGL1
CCR3,PAFR,BLT1
VLA4,LFA1
Mastcells
PSGL1
CCR2,CCR3,BLT1
VLA4,LFA1
TH1Inflammation
Atherosclerosis
Multiplesclerosis
Rheumatoid
arthritis
Allograftrejection
TH2Inflammation
Asthma
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Atopicdermatitis
Skinhoming
TH2
CLA
CCR4,CCR10
VLA4,LFA1
aVarious integrinshavebeenlinkedindifferentwaysinbasallaminaandinterstitialmigration
1
ofdistinctcelltypesandinflammatorysettings.
bInsomesettings,Mac1hasbeenlinkedtotransmigration.
cCD44canactinconcertwithVLA4inparticularmodelsofleukocytearrest.
dT 2cellsrequireVAP1totraffictoinflamedliver.
H
Source:FromADLusteretal:NatImmunol6:1182,2005withpermissionfromMacmillan
PublishersLtd.Copyright2005.
ThethirdstageofleukocyteemigrationinHEVsisstickingandarrest.Stickingofthelymphocytetoendothelialcellsandarrestatthesiteof
stickingaremediatedpredominantlybyligationof1,2integrinLFA1totheintegrinligandICAM1onHEVs.Whilethefirstthreestagesof
lymphocyteattachmenttoHEVstakeonlyafewseconds,thefourthstageoflymphocyteemigration,transendothelialmigration,takes10
min.Althoughthemolecularmechanismsthatcontrollymphocytetransendothelialmigrationarenotfullycharacterized,theHEVCD44
moleculeandmoleculesoftheHEVglycocalyx(extracellularmatrix)arethoughttoplayimportantregulatoryrolesinthisprocess(Fig.314
11).Finally,expressionofmatrixmetalloproteasescapableofdigestingthesubendothelialbasementmembrane,richinnonfibrillarcollagen,
appearstoberequiredforthepenetrationoflymphoidcellsintotheextravascularsites.
AbnormalinductionofHEVformationanduseofthemoleculesdiscussedabovehavebeenimplicatedintheinductionandmaintenanceof
inflammationinanumberofchronicinflammatorydiseases.InanimalmodelsofType1diabetesmellitus,MAdCAM1andGlyCAM1have
beenshowntobehighlyexpressedonHEVsininflamedpancreaticislets,andtreatmentoftheseanimalswithinhibitorsoflselectinand4
integrinfunctionblockedthedevelopmentofType1diabetesmellitus(Chap.344).Asimilarroleforabnormalinductionoftheadhesion
moleculesoflymphocyteemigrationhasbeensuggestedinrheumatoidarthritis(Chap.321),Hashimoto'sthyroiditis(Chap.341),Graves'
disease(Chap.341),multiplesclerosis(Chap.380),Crohn'sdisease(Chap.295),andulcerativecolitis(Chap.295).
ImmuneComplexFormation
Clearanceofantigenbyimmunecomplexformationbetweenantigen,complement,andantibodyisahighlyeffectivemechanismofhost
defense.However,dependingonthelevelofimmunecomplexesformedandtheirphysicochemicalproperties,immunecomplexesmayor
maynotresultinhostandforeigncelldamage.Afterantigenexposure,certaintypesofsolubleantigenantibodycomplexesfreelycirculate
and,ifnotclearedbythereticuloendothelialsystem,canbedepositedinbloodvesselwallsandinothertissuessuchasrenalglomeruliand
causevasculitisorglomerulonephritissyndromes(Chaps.283and326).Deficienciesofearlycomplementcomponentsareassociatedwith
inefficientclearanceofimmunecomplexesandimmunecomplexmediatedtissuedamageinautoimmunesyndromes,whiledeficienciesofthe
latercomplementcomponentsareassociatedwithsusceptibilitytorecurrentneisseriainfections(Table31417).
Table31417.ComplementDeficienciesandAssociatedDiseases
Component
AssociatedDiseases
ClassicPathway
Clq,Clr,Cls,C4
Immunecomplexsyndromes,*pyogenicinfections
C2
Immunecomplexsyndromes,*fewwithpyogenicinfections
C1Inhibitor
Rareimmunecomplexdisease,fewwithpyogenicinfections
C3andAlternativePathwayC3
C3
Immunecomplexsyndromes,*pyogenicinfections
Pyogenicinfections
Properdin
Neisseriainfections
Pyogenicinfections
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Hemolyticuremicsyndrome
MembraneAttackComplex
C5,C6,C7,C8
RecurrentNeisseriainfections,immunecomplexdisease
C9
RareNeisseriainfections
*Immunecomplexsyndromesincludesystemiclupuserythematosus(SLE)andSLElike
syndromes,glomerulonephritis,andvasculitissyndromes.
Source:AfterJASchifferli,DKPeters:Lancet88:957,1983.Copyright1983,withpermission
fromElsevier.
ImmediateTypeHypersensitivity
HelperTcellsthatdriveantiallergenIgEresponsesareusuallyT H2typeinducerTcellsthatsecreteIL4,IL5,IL6,andIL10.Mastcellsand
basophilshavehighaffinityreceptorsfortheFcportionofIgE(FcRI),andcellboundantiallergenIgEeffectively"arms"basophilsandmast
cells.Mediatorreleaseistriggeredbyantigen(allergen)interactionwithFcreceptorboundIgE,themediatorsreleasedareresponsiblefor
thepathophysiologicchangesofallergicdiseases(Table31412).Mediatorsreleasedfrommastcellsandbasophilscanbedividedintothree
broadfunctionaltypes:(1)thosethatincreasevascularpermeabilityandcontractsmoothmuscle(histamine,plateletactivatingfactor,SRSA,
BKA),(2)thosethatarechemotacticfororactivateotherinflammatorycells(ECFA,NCF,leukotrieneB4),and(3)thosethatmodulatethe
releaseofothermediators(BKA,plateletactivatingfactor)(Chap.317).
CytotoxicReactionsofAntibody
Inthistypeofimmunologicinjury,complementfixing(C1binding)antibodiesagainstnormalorforeigncellsortissues(IgM,IgG1,IgG2,IgG3)
bindcomplementviatheclassicpathwayandinitiateasequenceofeventssimilartothatinitiatedbyimmunecomplexdeposition,resultingin
celllysisortissueinjury.Examplesofantibodymediatedcytotoxicreactionsincluderedcelllysisintransfusionreactions,Goodpasture's
syndromewithantiglomerularbasementmembraneantibodyformation,andpemphigusvulgariswithantiepidermalantibodiesinducing
blisteringskindisease.
ClassicDelayedTypeHypersensitivityReactions
Inflammatoryreactionsinitiatedbymononuclearleukocytesandnotbyantibodyalonehavebeentermeddelayedtypehypersensitivity
reactions.Thetermdelayedhasbeenusedtocontrastasecondarycellularresponsethatappears4872hafterantigenexposurewithan
immediatehypersensitivityresponsegenerallyseenwithin12hofantigenchallengeandinitiatedbybasophilmediatorreleaseorpreformed
antibody.Forexample,inanindividualpreviouslyinfectedwithM.tuberculosisorganisms,intradermalplacementoftuberculinpurifiedprotein
derivativeasaskintestchallengeresultsinaninduratedareaofskinat4872h,indicatingpreviousexposuretotuberculosis.
ThecellulareventsthatresultinclassicdelayedtypehypersensitivityresponsesarecenteredaroundTcells(predominantly,thoughnot
exclusively,IFN,IL2,andTNFsecretingT H1typehelperTcells)andmacrophages.RecentlyNKcellshavebeensuggestedtoplaya
majorroleintheformofdelayedhypersensitivitythatoccursfollowingskincontactwithimmunogens.First,localimmuneandinflammatory
responsesatthesiteofforeignantigenupregulateendothelialcelladhesionmoleculeexpression,promotingtheaccumulationoflymphocytes
atthetissuesite.InthegeneralschemesoutlinedinFigs.3142and3143,antigenisprocessedbydendriticcellsandpresentedtosmall
numbersofCD4+TcellsexpressingaTCRspecificfortheantigen.IL12producedbyAPCsinducesTcellstoproduceIFN(T H1response).
MacrophagesfrequentlyundergoepithelioidcelltransformationandfusetoformmultinucleatedgiantcellsinresponsetoIFN.Thistypeof
mononuclearcellinfiltrateistermedgranulomatousinflammation.Examplesofdiseasesinwhichdelayedtypehypersensitivityplaysamajor
rolearefungalinfections(histoplasmosisChap.199),mycobacterialinfections(tuberculosis,leprosyChaps.165and166),chlamydial
infections(lymphogranulomavenereumChap.176),helminthinfections(schistosomiasisChap.219),reactionstotoxins(berylliosisChap.
256),andhypersensitivityreactionstoorganicdusts(hypersensitivitypneumonitisChap.255).Inaddition,delayedtypehypersensitivity
responsesplayimportantrolesintissuedamageinautoimmunediseasessuchasrheumatoidarthritis,temporalarteritis,andgranulomatosis
withpolyangiitis(Wegener's)(Chaps.321and326).
ClinicalEvaluationofImmuneFunction
Clinicalassessmentofimmunityrequiresinvestigationofthefourmajorcomponentsoftheimmunesystemthatparticipateinhostdefense
andinthepathogenesisofautoimmunediseases:(1)humoralimmunity(Bcells)(2)cellmediatedimmunity(Tcells,monocytes)(3)
phagocyticcellsofthereticuloendothelialsystem(macrophages),aswellaspolymorphonuclearleukocytesand(4)complement.Clinical
problemsthatrequireanevaluationofimmunityincludechronicinfections,recurrentinfections,unusualinfectingagents,andcertain
autoimmunesyndromes.Thetypeofclinicalsyndromeunderevaluationcanprovideinformationregardingpossibleimmunedefects(Chap.
316).Defectsincellularimmunitygenerallyresultinviral,mycobacterial,andfungalinfections.Anextremeexampleofdeficiencyincellular
immunityisAIDS(Chap.189).Antibodydeficienciesresultinrecurrentbacterialinfections,frequentlywithorganismssuchasS.pneumoniae
andHaemophilusinfluenzae(Chap.316).Disordersofphagocytefunctionarefrequentlymanifestedbyrecurrentskininfections,oftendueto
Staphylococcusaureus(Chap.60).Finally,deficienciesofearlyandlatecomplementcomponentsareassociatedwithautoimmune
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phenomenaandrecurrentNeisseriainfections(Table31417).Forfurtherdiscussionofusefulinitialscreeningtestsofimmune
function,seeChap.316.
Immunotherapy
Manytherapiesforautoimmuneandinflammatorydiseasesinvolvetheuseofnonspecificimmunemodulatingorimmunosuppressiveagents
suchasglucocorticoidsorcytotoxicdrugs.Thegoalofdevelopmentofnewtreatmentsforimmunemediateddiseasesistodesignwaysto
specificallyinterruptpathologicimmuneresponses,leavingnonpathologicimmuneresponsesintact.Novelwaystointerruptpathologic
immuneresponsesthatareunderinvestigationincludetheuseofantiinflammatorycytokinesorspecificcytokineinhibitorsasanti
inflammatoryagents,theuseofmonoclonalantibodiesagainstTorBlymphocytesastherapeuticagents,theinductionofanergyby
administrationofsolubleCTLA4protein,theuseofintravenousIgforcertaininfectionsandimmunecomplexmediateddiseases,theuseof
specificcytokinestoreconstitutecomponentsoftheimmunesystem,andbonemarrowtransplantationtoreplacethepathogenicimmune
systemwithamorenormalimmunesystem(Chaps.60,316,and189).Inparticular,theuseofamonoclonalantibodytoBcells(rituximab,
antiCD20MAb)isapprovedintheUnitedStatesforthetreatmentofnonHodgkin'slymphoma(Chap.110)and,incombinationwith
methotrexate,fortreatmentofadultpatientswithsevererheumatoidarthritisresistanttoTNFinhibitors(Chap.321).
CytokinesandCytokineInhibitors
Recently,ahumanizedmouseantiTNFmonoclonalantibody(MAb)hasbeenshowntobeeffectiveinbothrheumatoidarthritisand
ulcerativecolitis.UseofantiTNFantibodytherapyhasresultedinclinicalimprovementinpatientswiththesediseasesandhasopenedthe
wayfortargetingTNFtotreatothersevereformsofautoimmuneand/orinflammatorydisease.BlockageofTNFhasbeeneffectivein
rheumatoidarthritis,psoriasis,Crohn'sdisease,andankylosingspondylitis.AntiTNFMAb(infliximab)hasbeenapprovedbytheFDAfor
treatmentofpatientswithrheumatoidarthritis.
OthercytokineinhibitorsarerecombinantsolubleTNFreceptor(R)fusedtohumanIgandAnakinra(solubleIL1receptorantagonist,orIL
1ra).Thetreatmentofautoinflammatorysyndromes(Table3146)withrecombinantIL1receptorantagonistcanpreventsymptomsinthese
syndromes,sincetheoverproductionofIL1isahallmarkofthesediseases.SolubleTNFR(etanercept)andIL1raacttoinhibitthe
activityofpathogeniccytokinesinrheumatoidarthritis,i.e.,TNFandIL1,respectively.Similarly,antiIL6,IFN,andIL11acttoinhibit
pathogenicproinflammatorycytokines.AntiIL6inhibitsIL6activity,whileIFNandIL11decreaseIL1andTNFproduction.
OfparticularnotehasbeenthesuccessfuluseofIFNinthetreatmentofthephagocyticcelldefectinchronicgranulomatousdisease(Chap.
60).
MonoclonalAntibodiestoTandBCells
TheOKT3MAbagainsthumanTcellshasbeenusedforseveralyearsasaTcellspecificimmunosuppressiveagentthatcansubstitutefor
horseantithymocyteglobulin(ATG)inthetreatmentofsolidorgantransplantrejection.OKT3producesfewerallergicreactionsthanATGbut
doesinducehumanantimouseIgantibodythuslimitingitsuse.AntiCD4MAbtherapyhasbeenusedintrialstotreatpatientswith
rheumatoidarthritis.Whileinducingprofoundimmunosuppression,antiCD4MAbtreatmentalsoinducessusceptibilitytosevereinfections.
TreatmentofpatientswithaMAbagainsttheTcellmoleculeCD40ligand(CD154)isunderinvestigationtoinducetolerancetoorgan
transplants,withpromisingresultsreportedinanimalstudies.MonoclonalantibodiestotheCD25(IL2)receptor(Basiliximab)arebeingused
fortreatmentofgraftversushostdiseaseinbonemarrowtransplantation,andantiCD20MAb(rituximab)isusedtotreat
hematologicneoplasms,autoimmunediseases,andkidneytransplantrejection.TheantiIgEmonoclonalantibody(omalizumab)isusedfor
blockingantigenspecificIgEthatcauseshayfeverandallergicrhinitis(Chap.317)however,sideeffectsofantiIgEincludeincreasedriskof
anaphylaxis.StudieshaveshownthatT h17cells,inadditiontoT h1,aremediatorsofinflammationinCrohn'sdisease,andantiIL12/IL
23p40antibodytherapyhasbeenstudiedasatreatment.
Itisimportanttorealizethepotentialrisksfortheseimmunosuppressivemonoclonalantibodies.NatalizumabisahumanizedIgGantibody
againstan4integrinthatinhibitsleukocytemigrationintotissues,andhasbeenapprovedfortreatmentofmultiplesclerosisintheUnited
States.BothitandantiCD20(rituximab)havebeenassociatedwiththeonsetofprogressivemultifocalleukoencephalopathy(PML)a
seriousandusuallyfatalCNSinfectioncausedbyJCpolyomavirus.Efalizumab,ahumanizedIgGmonoclonalantibodypreviouslyapproved
fortreatmentofplaquepsoriasis,hasnowbeentakenoffthemarketduetoreactivationofJCvirusleadingtofatalPML.Thus,useofany
currentlyapprovedimmunosuppressantimmunotherapiesshouldbeundertakenwithcautionandwithcarefulmonitoringofpatientsaccording
toFDAguidelines.
ToleranceInduction
SpecificimmunotherapyhasmovedintoanewerawiththeintroductionofsolubleCTLA4proteinintoclinicaltrials.Useofthismoleculeto
blockTcellactivationviaTCR/CD28ligationduringorganorbonemarrowtransplantationhasshowedpromisingresultsinanimalsandin
earlyhumanclinicaltrials.Specifically,treatmentofbonemarrowwithCTLA4proteinreducesrejectionofthegraftinHLAmismatchedbone
marrowtransplantation.Inaddition,promisingresultswithsolubleCTLA4havebeenreportedinthedownmodulationofautoimmuneTcell
responsesinthetreatmentofpsoriasisanditisbeingstudiedfortreatmentofsystemiclupuserythematosus(Chap.319).
IntravenousImmunoglobulin(Ivig)
IVIghasbeenusedsuccessfullytoblockreticuloendothelialcellfunctionandimmunecomplexclearanceinvariousimmunecytopeniassuch
asimmunethrombocytopenia(Chap.115).Inaddition,IVIgisusefulforpreventionoftissuedamageincertaininflammatorysyndromessuch
asKawasakidisease(Chap.326)andasIgreplacementtherapyforcertaintypesofimmunoglobulindeficiencies(Chap.316).Inaddition,
controlledclinicaltrialssupporttheuseofIVIginselectedpatientswithgraftversushostdisease,multiplesclerosis,myastheniagravis,
GuillainBarrsyndrome,andchronicdemyelinatingpolyneuropathy.
StemCellTransplantation
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Hematopoieticstemcelltransplantation(SCT)isnowbeingcomprehensivelystudiedtotreatseveralautoimmunediseases,includingsystemic
lupuserythematosus,multiplesclerosis,andscleroderma.Thegoalofimmunereconstitutioninautoimmunediseasesyndromesistoreplace
adysfunctionalimmunesystemwithanormallyreactiveimmunecellrepertoire.Preliminaryresultsinpatientswithsclerodermaandlupus
haveshowedencouragingresults.ControlledclinicaltrialsinthesethreediseasesarenowbeinglaunchedintheUnitedStatesandEuropeto
comparethetoxicityandefficacyofconventionalimmunosuppressiontherapywiththatofmyeloablativeautologousSCT.
Thus,anumberofrecentinsightsintoimmunesystemfunctionhavespawnedanewfieldofinterventionalimmunotherapyandhave
enhancedtheprospectfordevelopmentofspecificandnontoxictherapiesforimmuneandinflammatorydiseases.
FurtherReadings
AndreakosETHetal:Roleofcytokines,inRheumatoidArthritis,EWSt.Clairetal(eds).Philadelphia,LippincottWilliams&Wilkins,2004,pp
134149
BergerJRetal:Monoclonalantibodiesandprogressivemultifocalleukoencephalopathy.MAbs1:583,2009[PubMed:20073129]
BlanderJMetal:Tolldependentselectionofmicrobialantigensforpresentationbydendriticcells.Nature440:808,2006[PubMed:
16489357]
CarsonKRetal:Monoclonalantibodyassociatedprogressivemultifocalleucoencephalopathyinpatientstreatedwithrituximab,natalizumab,
andefalizumab:AreviewfromtheResearchonAdverseDrugEventsandReports(RADAR)Project.LancetOncol10:816,2009[PubMed:
19647202]
DavidsonA,DiamondB:Autoimmunediseases.NEnglJMed345:340,2001[PubMed:11484692]
DiazPenaRetal:KIRgenesandtheirroleinspondyloarthropathies.AdvExpMedBiol649:286,2009[PubMed:19731638]
FalschlehnerCetal:FollowingTRAIL'spathintheimmunesystem.Immunology127:145,2009[PubMed:19476510]
FranchiLetal:Theinflammasome:Acaspase1activationplatformthatregulatesimmuneresponses.NatImmunol10:241,2009[PubMed:
19221555]
HotchkissRSetal:Celldeath.NEnglJMed361:1570,2009[PubMed:19828534]
IwasakiA,MedzhitovR:Regulationofadaptiveimmunitybytheinnateimmunesystem.Science327:291,2010[PubMed:20075244]
KelleyWNetal(eds):TextbookofRheumatology,4thed.Philadelphia,Saunders,1993,chaps.6,7,10,13,15,16
KoretzkyGAetal:SLP76andSLP65:Complexregulationofsignalinginlymphocytesandbeyond.NatRevImmunol6:67,2006[PubMed:
16493428]
KormanBDetal:Progressivemultifocalleukoencephalopathy,efalizumab,andimmunosuppression:Acautionarytalefordermatologists.Arch
Dermatol145:937,2009[PubMed:19687432]
KronenbergMetal:InnatelikerecognitionofmicrobesbyinvariantnaturalkillerTcells.CurrOpinImmunol21:391,2009[PubMed:
19646850]
LanierL:NKcellrecognition.AnnuRevImmunol23:225,2005[PubMed:15771571]
LernmarkA:Autoimmunediseases:Aremarkersreadyforprediction?JClinInvest108:1091,2001[PubMed:11602614]
LoutenJetal:DevelopmentandfunctionofTh17cellsinhealthanddisease.JAllergyClinImmunol123:1004,2009[PubMed:19410689]
MacdonaldTTetal:Immunity,inflammation,andallergyinthegut.Science307:1920,2005[PubMed:15790845]
MartinonFetal:Theinflammasomes:Guardiansofthebody.AnnuRevImmunol27:229,2009[PubMed:19302040]
MiddendorpSetal:NKTcellsinmucosalimmunity.MucosalImmunol2(5):393,2009[PubMed:19587641]
MorleyBJ,WalportMJ:TheComplementFactsBooks.London,AcademicPress,2000,Chap.2
MullauerLetal:Mutationsinapoptosisgenes:Apathogeneticfactorforhumandisease.MutatRes488:211,2001[PubMed:11397650]
PaustSetal:Adaptiveimmuneresponsesmediatedbynaturalkillercells.ImmunolRev235:286,2010[PubMed:20536570]
RajagopalanSetal:UnderstandinghowcombinationsofHLAandKIRgenesinfluencedisease.JExpMed201:1025,2005[PubMed:
15809348]
RamaswamyMetal:Harnessingprogrammedcelldeathasatherapeuticstrategyinrheumaticdiseases.NatRevRheumatol2011[epub
aheadofprint]
RinaudoCetal:VaccinologyintheGenomeEra.JClinInvest119:2515,2009[PubMed:19729849]
RiveraJetal:Molecularregulationofmastcellactivation.JAllergyClinImmunol6:1214,2006
RomagnaniS:CD4effectorcells,inInflammation:BasicPrinciplesandClinicalCorrelates,3rded,JGallin,RSnyderman(eds).Philadelphia,
LippincottWilliams&Wilkins,1999,pp177
SchroderKetal:TheNLRP3inflammasome:asensorformetabolicdanger?Science327:296,2010[PubMed:20075245]
SteinmanRM,BanchereauJ:Takingdendriticcellsintomedicine.Nature449:419,2007[PubMed:17898760]
TingJpyetal:HowthenoninflammasomeNLRsfunctionintheinnateimmunesystem.Science327:286,2010[PubMed:20075243]
UenoHetal:Targetinghumandendriticcellsubsetsforimprovedvaccines.SeminImmunol23:21,2011[PubMed:21277223]
vanDuinDetal:TriggeringTLRsignalinginvaccination.TrendsImmunol27:49,2006
WeaverCetal:InterplaybetweentheTh17andTregcelllineages:acoevolutionaryperspective.NatRevImmunol9:883,2009[PubMed:
19935807]
WhelanBetal:mAbsinnonlupusautoimmunerheumaticdisease.CurrOpinHemat16:280,2009[PubMed:19444098]
WilliamsAPetal:Hanginginthebalance.MolInterv5:226,2005[PubMed:16123537]
CopyrightMcGrawHillGlobalEducationHoldings,LLC.
Allrightsreserved.
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YourIPaddressis202.28.35.247
OverviewofmajorTLRsignalingpathways.AllTLRssignalthroughMyD88,withtheexceptionofTLR3.TLR4andtheTLR2subfamily
(TLR1,TLR2,TLR6)alsoengageTIRAP.TLR3signalsthroughTRIF.TRIFisalsousedinconjunctionwithTRAMintheTLR4MyD88
independentpathway.Dashedarrrowsindicatetranslocationintothenucleus.LPS,lipopolysaccharidedsRNA,doublestrandRNAssRNA,
singlestrandRNAMAPK,mitogenactivatedproteinkinasesNFB,nuclearfactorBIFN,interferonIRF3,interferonregulatoryfactor3
TLR,Tolllikereceptor.(AdaptedfromDvanDuinetal.,withpermission.)
Schematicmodelofintercellularinteractionsofadaptiveimmunesystemcells.Inthisfigure,thearrowsdenotethatcellsdevelopfrom
precursorcellsorproducecytokinesorantibodieslinesendingwithbarsindicatesuppressiveintercellularinteractions.Stemcellsdifferentiate
intoeitherTcells,antigenpresentingdendriticcells,naturalkillercells,macrophages,granulocytes,orBcells.Foreignantigenisprocessed
bydendriticcells,andpeptidefragmentsofforeignantigenarepresentedtoCD4+and/orCD8+Tcells.CD8+Tcellactivationleadsto
inductionofcytotoxicTlymphocyte(CTL)orkillerTcellgeneration,aswellasinductionofcytokineproducingCD8+cytotoxicTcells.For
antibodyproductionagainstthesameantigen,activeantigenisboundtosIgwithintheBcellreceptorcomplexanddrivesBcellmaturation
intoplasmacellsthatsecreteIg.T H1orT H2CD4+Tcellsproducinginterleukin(IL)4,IL5,orinterferon(IFN)regulatetheIgclassswitching
anddeterminethetypeofantibodyproduced.T H17cellssecreteIL17,IL22,IL26,whichcontributetohostdefenseagainstextracellular
bacteriaandfungi,particularlyatmucosalsurfaces.CD4+,CD25+TregulatorycellsproduceIL10anddownregulateTandBcellresponses
oncethemicrobehasbeeneliminated.GMCSF,granulocytemacrophagecolonystimulatingfactorTNF,tumornecrosisfactor.
CD4+helperT1(T H1)cellsandT H2Tcellssecretedistinctbutoverlappingsetsofcytokines.T H1CD4+cellsarefrequentlyactivated
inimmuneandinflammatoryreactionsagainstintracellularbacteriaorviruses,whileT H2CD4+cellsarefrequentlyactivatedforcertaintypes
ofantibodyproductionagainstparasitesandextracellularencapsulatedbacteriatheyarealsoactivatedinallergicdiseases.GMCSF,
granulocytemacrophagecolonystimulatingfactorIFN,interferonIL,interleukinTNF,tumornecrosisfactor.(AdaptedfromRomagnaniwith
permission.)
EncountersbetweenNKcells:potentialtargetsandpossibleoutcomes.TheamountofactivatingandinhibitoryreceptorsontheNK
cellsandtheamountofligandsonthetargetcell,aswellasthequalitativedifferencesinthesignalstransduced,determinetheextentofthe
NKresponse.A.WhentargetcellshavenoHLAclassInoractivatingligands,NKcellscannotkilltargetcells.B.Whentargetcellsbearself
HLA,NKcellscannotkilltargets.C.WhentargetcellsarepathogeninfectedandhavedownregulatedHLAandexpressactivatingligands,NK
cellskilltargetcells.D.WhenNKcellsencountertargetswithbothselfHLAandactivatingreceptors,thentheleveloftargetkillingis
determinedbythebalanceofinhibitoryandactivatingsignalstotheNKcell.HLA,humanleukocyteantigenNK,naturalkiller.(Adaptedfrom
LanierreproducedwithpermissionfromAnnualReviewsInc.Copyright2011byAnnualReviewsInc.)
Thefourpathwaysandtheeffectormechanismsofthecomplementsystem.Dashedarrowsindicatethefunctionsofpathway
components.(AfterMorleyandWalportwithpermission.CopyrightAcademicPress,London,2000.)
DevelopmentstagesofTandBcells.ElementsofthedevelopingTandBcellreceptorforantigenareshownschematically.The
classificationintothevariousstagesofBcelldevelopmentisprimarilydefinedbyrearrangementoftheimmunoglobulin(Ig),heavy(H),and
light(L)chaingenesandbytheabsenceorpresenceofspecificsurfacemarkers.[AdaptedfromCAJanewayetal(eds):Immunobiology.The
ImmuneSystemicHealthandDisease,4thed.NewYork,Garland,1999withpermission.]TheclassificationofstagesofTcelldevelopmentis
primarilydefinedbycellsurfacemarkerproteinexpression(sCD3,surfaceCD3expression,cCD3,cytoplasmicCD3expressionTCR,Tcell
receptor).
SignalingthroughtheTcellreceptor.Activationsignalsaremediatedviaimmunoreceptortyrosinebasedactivation(ITAM)sequencesin
LATandCD3chains(bluebars)thatbindtoenzymesandtransduceactivationsignalstothenucleusviatheindicatedintracellularactivation
pathways.LigationoftheTcellreceptor(TCR)byMHCcomplexedwithantigenresultsinsequentialactivationofLCKandchainassociated
proteinkinaseof70kDa(ZAP70).ZAP70phosphorylatesseveraldownstreamtargets,includingLAT(linkerforactivationofTcells)and
SLP76[SCRhomology2(SH2)domaincontainingleukocyteproteinof76kDa].SLP76isrecruitedtomembraneboundLATthroughits
constitutiveinteractionwithGADS(GRB2relatedadaptorprotein).Together,SLP76andLATnucleateamultimolecularsignalingcomplex,
whichinducesahostofdownstreamresponses,includingcalciumflux,mitogenactivatedproteinkinase(MAPK)activation,integrinactivation,
andcytoskeletalreorganization.APCdenotesantigenpresentingcell.(AdaptedfromKoretzkyetalwithpermissionfromMacmillanPublishers
Ltd.Copyright2006.)
Bcellreceptor(BCR)activationresultsinthesequentialactivationofproteintyrosinekinases,whichresultsintheformationofasignaling
complexandactivationofdownstreampathwaysasshown.WhereasSLP76isrecruitedtothemembranethroughGADSandLAT,the
mechanismofSLP65recruitmentisunclear.Studieshaveindicatedtwomechanisms:(a)directbindingbytheSH2domainofSLP65to
immunoglobulin(Ig)oftheBCRcomplexor(b)membranerecruitmentthroughaleucinezipperintheaminoterminusofSLP65andan
unknownbindingpartner.ADAP,adhesionanddegranulationpromotingadaptorproteinAP1,activatorprotein1BTK,Bruton'styrosine
kinaseDAG,diacylglycerolGRB2,growthfactorreceptorboundprotein2HPK1,hematopoieticprogenitorkinase1InsP3,inositol1,4,5
trisphosphateITK,interleukin2inducibleTcellkinaseNCK,noncatalyticregionoftyrosinekinaseNFB,nuclearfactorBPKC,protein
kinaseCPLC,phospholipaseCPtdIns(4,5)P2,phosphatidylinositol4,5bisphosphateRASGRP,RASguanylreleasingproteinSOS,sonof
sevenlesshomologueSYK,spleentyrosinekinase.(AdaptedfromKoretzkyetalwithpermissionfromMacmillanPublishersLtd.Copyright
2006.)
IncreasedepithelialpermeabilitymaybeimportantinthedevelopmentofchronicgutTcellmediatedinflammation.CD4Tcellsactivated
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bygutantigensinPeyer'spatchesmigratetotheLP.Inhealthyindividuals,thesecellsdiebyapoptosis.Increasedepithelialpermeabilitymay
allowsufficientantigentoentertheLPtotriggerTcellactivation,breakingtolerancemediatedbyimmunosuppressivecytokinesandperhaps
Tregulatorycells.Proinflammatorycytokinesthenfurtherincreaseepithelialpermeability,settingupaviciouscycleofchronicinflammation.
(FromMacDonaldandMonteleonewithpermission.)
PathwaysofCellularApoptosis.Therearetwomajorpathwaysofapoptosis:thedeathreceptorpathway,whichismediatedbyactivationof
deathreceptors,andtheBCL2regulatedmitochondrialpathway,whichismediatedbynoxiousstimulithatultimatelyleadtomitochondrial
injury.LigationofdeathreceptorsrecruitstheadaptorproteinFASassociateddeathdomain(FADD).FADDinturnrecruitscaspase8,which
ultimatelyactivatescaspase3,thekey"executioner"caspase.CellularFLICEinhibitoryprotein(cFLIP)caneitherinhibitorpotentiatebinding
ofFADDandcaspase8,dependingonitsconcentration.Intheintrinsicpathway,proapoptoticBH3proteinsareactivatedbynoxiousstimuli,
whichinteractwithandinhibitantiapoptoticBCL2orBCLXL.Thus,BAXandBAKarefreetoinducemitochondrialpermeabilizationwith
releaseofcytochromec,whichultimatelyresultsintheactivationofcaspase9throughtheapoptosome.Caspase9thenactivatescaspase3.
SMAC/DIABLOisalsoreleasedaftermitochondrialpermeabilizationandactstoblocktheactionofinhibitorsofapoptosisprotein(IAPs),which
inhibitcaspaseactivation.Thereispotentialcrosstalkbetweenthetwopathways,whichismediatedbythetruncatedformofBID(tBID)thatis
producedbycaspase8mediatedBIDcleavagetBIDactstoinhibittheBCL2BCLXLpathwayandtoactivateBAXandBAK.Thereisdebate
(indicatedbythequestionmark)astowhetherproapoptoticBH3molecules(e.g.,BIMandPUMA)actdirectlyonBAXandBAKtoinduce
mitochondrialpermeabilityorwhethertheyactonlyonBCL2BCLXL.APAF1,apoptoticproteaseactivatingfactor1BH3,BCLhomologue
TNF,tumornecrosisfactorTRAIL,TNFrelatedapoptosisinducingligand.(FromHotchkissetalwithpermission.)
Keymigrationstepsofimmunecellsatsitesofinflammation.Inflammationduetotissuedamageorinfectioninducesthereleaseof
cytokines(notshown)andinflammatorychemoattractants(redarrowheads)fromdistressedstromalcellsand"professional"sentinels,suchas
mastcellsandmacrophages(notshown).Theinflammatorysignalsinduceupregulationofendothelialselectinsandimmunoglobulin
"superfamily"members,particularlyICAM1and/orVCAM1.Chemoattractants,particularlychemokines,areproducedbyortranslocated
acrossvenularendothelialcells(redarrow)andaredisplayedinthelumentorollingleukocytes.Thoseleukocytesthatexpressthe
appropriatesetoftraffickingmoleculesundergoamultistepadhesioncascade(steps13)andthenpolarizeandmovebydiapedesisacross
thevenularwall(steps4and5).Diapedesisinvolvestransientdisassemblyofendothelialjunctionsandpenetrationthroughtheunderlying
basementmembrane(step6).Onceintheextravascular(interstitial)space,themigratingcellusesdifferentintegrinstogain"footholds"on
collagenfibersandotherECMmolecules,suchaslamininandfibronectin,andoninflammationinducedICAM1onthesurfaceof
parenchymalcells(step7).Themigratingcellreceivesguidancecuesfromdistinctsetsofchemoattractants,particularlychemokines,which
maybeimmobilizedonglycosaminoglycans(GAG)that"decorate"manyECMmoleculesandstromalcells.Inflammatorysignalsalsoinduce
tissueDCstoundergomaturation.OnceDCsprocessmaterialfromdamagedtissuesandinvadingpathogens,theyupregulateCCR7,which
allowsthemtoenterdraininglymphvesselsthatexpresstheCCR7ligandCCL21(andCCL19).Inlymphnodes(LN),theseantigenloaded
matureDCsactivatenaveTcellsandexpandpoolsofeffectorlymphocytes,whichenterthebloodandmigratebacktothesiteof
inflammation.TcellsintissuealsousethisCCR7dependentroutetomigratefromperipheralsitestodraininglymphnodesthroughafferent
lymphatics.(AdaptedfromADLusteretal:NatImmunol6:1182,2005withpermissionfromMacmillanPublishersLtd.Copyright2005.)
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CD4+helperT1(T H1)cellsandT H2Tcellssecretedistinctbutoverlappingsetsofcytokines.T H1CD4+cellsarefrequentlyactivated

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