大二上医学免疫学课件chenwei

WeiChen,PhDInstituteofImmunology,ZJU

IMMUNOLOGYImmunoregulationchapterⅩVIConceptofimmuneregulation

Immuneresponsesaretightlyregulatedbycomplexinteractionofcells&mediators,andbymechanismstopreventanti-selfreactivity.Failureofregulatorycontrolcanoccur:-Enhancementofimmuneresponsescangenerateautoimmunereactions(lossofself-tolerance)-Decreaseofimmuneresponsesmayleadtoanimmunodeficiencystate-ShiftinimmuneresponsecanleadtoallergyTheregulationofAbproductionbytheconcentrationofAb家兔经抗原免疫后产生特异性抗体，用血清交换人为降低抗体浓度后，可引起抗体产生量的反馈性升高,并在到达一定强度后逐渐下降。说明机体可感知自身抗体浓度的变化，并自行启动调节机制

ImmunoregulationImmuneResponseandRegulation:IncludingPositive&Negativeregulation.Positiveregulationensuresfastresponse.Whilenegativeregulationaftertheclearanceofinfectionisveryessentialforrestoretheimmunehomeostasis.Immunoregulation

andintervention:Upontheunderstandingofimmunoregulationmechanisms,wecandeliberatelyenhanceortakeawayoneofthecontroltoenhanceorblockanimmuneresponse. ImmunoregulationandDisease:Sinceimmuneregulationisachievedatmanydifferentlevelsbydifferentmechanisms,anydefectinthissystemwillcauseanimmunedisorder.microbeSARSpatienthealthysubjectsevereinflammationreactioninlungImmunoregulationininnateimmuneresponseRoleofsuppressingreceptorsRoleofregulatoryTcellsRoleoftheidiotypicnetworkRoleofapoptosisRoleofneuroendocrinesystemImmunoregulationamongpopulationContentImmunoregulationininnateimmuneresponseFeedbackregulationofinflammatoryfactorsecretion

TheroleofSOCSincytokinesecretionRegulationofcomplementactivationToll-likereceptorsandrecognitionofpathogensK.Takeda&S.Akira,Cell.Microbiol.5:143-53,2003diacyl-triacyl-lipopeptide酰基脂肽；flagellin:鞭毛蛋白;LPS:脂多糖(Lipopolysaccharides)

Toll-likereceptorsignalingpathwaysMyD88pathwayandTRIFpathway;TranscriptionfactorsCytokine

expressionNegativeregulationininnateimmuneresponseInhibitorysignal：PKB及凋亡信号调节激酶1（ASK1）。IRAK-M：IL-1受体相关激酶M；SOCS-1:I型细胞因子信号转导抑制因子刺激信号NF-B,MAPKIRAK-M,SOCS-1PI-3K早期后期抑制信号抑制信号*效应期特点：维持适当的反应强度耐受期特点：无反应性

炎症反应时间

细胞应答强度FeedbackregulationofinflammatoryfactorRegulationofTLR4signalingTIR:Toll/IL-1receptor;ASK1:凋亡信号调节激酶1;

IRAK:IL-1受体相关激酶;MAPK:丝裂原激活蛋白激酶;MyD88:髓样分化因子88;NF-B:核因子B;PI3K:磷酸肌醇3激酶;PIP2：2磷酸磷脂酰肌醇;PIP3:3磷酸磷脂酰肌醇；PKB:蛋白激酶B;Rac:小G蛋白;SIGIRR:单一IgIL-1R相关分子;TIRAP:TIR(Toll/IL-1

受体)相关蛋白;TRAF6:TNF受体相关因子6。炎症细胞因子基因转录TLR4CD14ST2SIGIRRMD2MyD88TIRAPTRAF6SOCS1IRAK1IRAK4NF-BMAPKPKBPI3KMyD88sIRAK-M受体衔接蛋白信号分子激酶转录因子抑制因子基因转录激活抑制Rac1PIP2PIP3ASK1TIRTIRRegulationofTLR4signalingInflammatorycytokines

InnateTLRsignaling:SIGIRR:singleimmunoglobulinIL-1R-relatedmoleculeMyD88s:myeloiddifferentiationprimary-responseprotein88shortIRAK-M:interleukin-1-receptorassociatedkinaseMSOCS1:suppressorofcytokinesignaling1.C蛋白质泛素化降解JakStatCISSOCS1SOCS3JakAJakStatStat胞核DNA细胞因子受体细胞因子SOCS家族部分成员DN端区SH2结构域SOCS框胞核B

基因X,Y,ZSOCS基因生物学效应YpStat

其它信号途径基因转录Stat细胞因子细胞因子受体磷酸化胞核JakYCISSOCS1SOCS2SOCS3pYSOCSproteininhibitscytokinesignalingpathwaybyanegativefeedbackloopUbiqutinationandProteosomeThefactorsregulatedbySOCS

cytokine

CSF

GFandhormonesPAMPCIS

IL-2,3EPOGH,催乳素SOCS-1IL-2,-4,-6,-7,-12,-15EPO,TPO,TDLPGH,催乳素,胰岛素,LPS,CpGIFN-/,-,LIF,TNF-leptinSOCS-2IL-6GH,IGF-1SOCS-3IL-2,-4,-6,-9,-11,EPOGH,催乳素,胰岛素,IFN-/,-,LIFleptinSOCS-5IL-4,-6

CIS:细胞因子诱导的SH2结构域携带蛋白；EPO:红细胞生成素；GH:生长激素；IGF-1：胰岛素样生长因子；LIF:白血病抑制因子；TPO:血小板生成素；TSLP:胸腺基质淋巴细胞生成素。RegulationofcomplementactivationC1INH:inhibittheactivationofC1InhibitionofconvertaseformationC4bp,FactorI,MCP,DAF:inhibitC4b2bFactorH,I,CR1,DAF:inhibitC3bBbFormationofMACMIRL（膜裂解抑制物），C8bp:inhibittheformationofMAC

调节因子分布靶分子作用机制

1CI抑制物(C1INH)血浆蛋白C1r,CIs与靶目标结合使其与C1q解离C4结合蛋白(C4BP)

血浆蛋白

C4b取代C2b与C4b结合协助I因子裂介C4bI因子血浆蛋白C4b,C3b丝氨酸蛋白酶，裂介C3b和C4bH因子血浆蛋白C3b取代Bb与C3b结合促进I因子对C4b降解1型补体受体(CR1)Bl,FDC

C4b,C3b协助I因子,使靶分子降解膜辅蛋白(MCP)Wc,Ep,En

C3b,C4b促进I因子对C3b和C4b的降解衰变加速因子(DAF)Bl,Ep,EnC4b2b取代C2b与C4b结合，取代Bb与C3b结合膜裂介抑制物(MIRL)广泛攻膜复合物与C9结合,干扰复合物形成

Bl:血细胞；Wc:白细胞；Ep:上皮细胞；En:内皮细胞；FDC：滤泡树突状细胞

ComplementregulatorypriteinsC3

C3bC3dC3cC3fC3转化酶

I因子I因子+辅助因子C3dgC3aiC3b

C3gC3转化酶C3转化酶C4bAg-AbcomplexcytolysisMACC5b6789C2bC1activation

C4a

C4b

C2b

C2aC4b2b3bhDAFC4b

C5aC5C5bC5transferaseC3transferaseNoactivityofcomplementDecayacceleratingfactor(衰变加速因子)pDAFDAFDAFC1C4C2ImmunoregulationininnateimmuneresponseRoleofsuppressingreceptorsRoleofregulatoryTcellsRoleoftheidiotypicnetworkRoleofapoptosisRoleofneuroendocrinesystemImmunoregulationamongpopulationContentRoleofsuppressingreceptorsRoleofactivatingsignalingcomponentsandmolecularRoleofsuppressingsignalingcomponentsandmolecularRegulationbysuppressingreceptorsImmunecellsareactivatedbyLigandbindingtotheiractivatingreceptorsActivationofImmunecellsismediatedbyProteinPhosphorylation:Phosphorylationismediatedbyproteinkinases(PTK);Dephosporylationiscatalyzedbyproteinphosphotases(PPT).蛋白质ATP-OH+ADP+蛋白质O

‖-O-P-O-|O-蛋白质O

‖-O-P-O-|O-蛋白质-OH++

O

‖HO-O-P-O-

|

O-H2O蛋白激酶蛋白磷酸酶

蛋白磷酸化

蛋白脱磷酸化蛋白激酶和蛋白磷酸酶PhosphorylationanddephosporylationbyPTKandPTP1).Activatingreceptor:ITAM(immunoreceptortyrosine-basedactivationmotif)Motifs：YxxL/V

Recruit:kinases,adaptorproteinsInduceactivationsignal2).Inhibitoryreceptor:ITIM(immunoreceptortyrosine-basedinhibitorymotif)Motifs：I/VxYxxLRecruitProteinphosphatasesTransduceinhibitorysingnalTwotypeofreceptorsRegulationbysuppressingreceptorsActivatingreceptorandinhibitoryreceptor

基因转录

激活

抑制Zap-70,SykSHP-1,SHP-2ITAMITIMSrcPTKPTKPTP磷酸化激活性受体抑制性受体磷酸化脱磷酸化CelltypeActivationTriggeractivationmotifKinaserecruitedBcellBCRITAM(IgIg)LynTcellTCRITAM(CD3)LckNKcellNKG2DITAM（DAP12）Syk..ActivatingreceptorsmediatecellularactivationRegulationbyInhibitoryreceptorsBcell,mastcell:

FcRIIB，PIRBCross-linkingimmunecomplexoranti-idiotypeantibodywithBCRTcell:CTLA-4,PD-1CTLA-4andPD-1transmitsignalsthatinhibitlymphocyteactivation,providingapathwayofclassicalfeedbackinhibition.NK,CTL:KIR，Ly49(typeI),CD94/NKG2A(typeII)

家族配体受体

ITAM/ITIM

Ig-SF

B7-1

CD28

ITAMB7-2

CTLA-4ITIM

B7-H1PD-1

ITIM

B7-DC?B7-H2

ICOSB7-H3

?HVEMBTLAITIM

TNF

CD40L

CD40

OX40L

OX40

4-1BBL

4-1BB

TTAPCAPCCo-stimulatorymoleculeofTcellactivationInhibitoryreceptorsInhibitoryreceptorsforTcell.CTLA-4Y201YVKMY208InhibitoryreceptorsDynamicregulationsofTcellactivationbyCD28andCTLA4:CD28andCTLA-4hasthesameligandB7.RestingTcellonlyexpressCD28,whichisanactivatingcoreceptorprovides2ndsignalingtoensureTcellactivation.ActivatedTcellsstarttoexpressCTLA-4ontheirsurface,becauseCTLA-4has100folderhigheraffinitytoB7,CTLA-4activationedominantwhichinhibittheTCRsignaling.BeforeAfteractivationactivation24

hB7CD28AgTCRB7CTLA-4激活信号I

T

I

MI

TAM抑制信号T细胞CTLA-4inhibitTcellactivation

用特异性单抗Fab段封闭抑制性受体CTLA-4增强机体抗肿瘤免疫力InhibitoryreceptorsOncetheITIMofFcRIIBisphosphorylated,SH2-containingSHIParerecruited,whichinfluencesPI3KandERKpathways.PIRB（pairedimmunoglobulin-likereceptorB）ITIMsrecruitesSHP1，whichdephosphorylatesvariousprotein-tyrosinekinases,includingSYKandBruton'styrosinekinase(BTK).InhibitoryreceptorsonBcellTheinhibitoryreceptorFcRII-B干扰

B细胞激活的信号转导BCR(mIgM)抗BCR抗体Ag-Ab复合物FcRII-BFcRII-BITIMITIMBCR(mIgM)抗BCR抗体

(Ab2)FcRII-BITIMB细胞激活信号转导受阻TheinhibitoryreceptorFcRII-BTheinhibitoryreceptorsonNKcellsTheactivatingreceptorsandinhibitoryreceptorsofNKcellsKIR:杀伤细胞免疫球蛋白样受体；

ILT:杀伤细胞免疫球蛋白样转录体受体；NCR:自然细胞毒受体；

UL18:人巨细胞病毒糖蛋白（一种HLAI类分子同源物）；ULBP:人巨细胞病毒糖蛋白结合蛋白HumanKillerCellIg-likeReceptors(KIR)Igsuperfamily7-12functionalgenesonhumanchromosome19q13Extensiveallelicpolymorphism(norearrangement)InhibitoryKIRrecognizepolymorphicHLA-A,-B,and–CActivatingreceptorshavenointrinsicsignalingcapacity..associatewithDAP12ITAM-adapterprotein

ExpressedbysubsetsofNKcellsandmemoryTcells(usuallyCD8+Tcells)InhibitoryreceptorsonNKcellsHumanKIRReceptors

C-typelectin-likesuperfamilyPolygenic&polymorphicExtensiveallelicpolymorphism(norearrangement)InhibitoryLy49recognizepolymorphicH-2DandH-2KActivatingreceptorshavenointrinsicsignalingcapacity..associatewithDAP12ITAM-adapterproteinExpressedbysubsetsofNKcellsandmemoryTcells(usuallyCD8+Tcells)MouseLy49ReceptorsInhibitoryreceptorsonNKcellsallo-celltumorcellnormalcellvirus-Infectedcell

NK

NK

NK

NK++++–kill

kill

killnokillNK’scytotoxicactivitydependsonactivationofthesignalinginitiatedbytheligationofinhibitoryreceptorwithitsligandactivationreceptorinhibitoryreceptorImmunesurveillancefor

‘MissingSelf’byNKcellsExistenceofinhibitoryreceptorsforMHCclassIsparenormalcellsfromNKcellattackwhichensuresNKcellspreferentiallykillcellsthathavelostMHCclassI.

1.Viral-infectedcellsortumorcellstendstoreducetheirsurfaceexpressionofMHCItoavoidCD8cellattacks.2.NKcellsthusProvidesprotectionagainstcellsescapingTcellrecognition.3.NKcellswillalsokillforeigncellswithmismatchedMHCclassImolecule.

Karreetal.Nature319:675,1986InhibitoryreceptorsonNKcellsT

细胞B

细胞肥大细胞NK

细胞TCR-CD3BCR-Ig/IgFcRIKIR-S+DAP12CD94/NKG2C+DAP12NKG2D+DAP10NCR+/FcR1CD16+/FcR1CTLA-4,PDL-1,BTLAFcRII-B,CD22FcRII-BKIR-LCD94/NKG2AILT2

免疫细胞激活性受体（ITAM+）抑制性受体（ITIM+）

T

细胞V9V2TCRCD94/NKG2AActivatingreceptorandinhibitoryreceptorofimmunecellsImmunoregulationininnateimmuneresponseRoleofsuppressingreceptorsRoleofregulatoryTcellsRoleoftheidiotypicnetworkRoleofapoptosisRoleofneuroendocrinesystemImmunoregulationamongpopulationContentRegulationbyTregsRegulationbyTregsTypesofTregs:NaturallyarisingThymusgiverisetotheCD4+CD25+Foxp3+regulatoryTcellsSuppressincell-celldependentmanner50

Surfacemarkers:

CD25(IL-2Rα),CTLA-4,GITR,foxp3+

CD44high,CD45RB,CD5high,ICAM-1high,LFA-1high,partlyCD62L.TheexpressionpatternofsomeaccessorymoleculesonCD4+CD25+Tregisinpartsimilarto‘primed’,‘activated’,‘effector’,or‘memory’Tcells.

RegulationbyTregsTypesofTregs:inducedTregsIntheperipherysomeTsinducedtoTregRequiresAg,IL-10,orTGF-βIL-10:CD4+CD25+Foxp3-,theseareTr1TGF-β:CD4+CD25+Foxp3+Ag:CD4+CD25-Foxp3-Suppressbysecretionof:Tr1byIL-10InducedTreg(Th3)byTGF-βRegulationbyTregsTypesofTregs:CD8+Tregs(CTL2cells)releaseaspectrumofcytokinessimilartoTh2cells:IFN-γ,IL-6,IL-10DifferentiationaffectedbyCD4+cytokineprofile,Ag,andIL-10CD8+Foxp3+Suppressinacell-contactdependentmannerdownregulationofco-stimulatorymoleculesonAPC→tolerancePrimedbyCD4+during1°,suppressduring2°TwotypesofTregs自然调节T细胞（nTreg）直接来自胸腺，也可经TGF-诱导产生，通过细胞-细胞间接触行使抑制功能。适应性调节T细胞（aTreg）或诱导性调节T细胞（iTreg）在外周由初始T细胞经多种因素诱导产生，主要包括Tr1和Th3，分别藉助分泌IL-10和TGF-发挥抑制作用。抗原和多种刺激因子55characteristicNatureTregadaptiveTregInductionlocationThymus(periphery),peripheryCD28-B7dependence+-CD25+++-~+Foxp3expression++++AntigenspecificityAuto-antigenTissue-specificAgandexogenousAgmechanismCell-contact,CKindependenceCell-contact,CKdependenceFunctionInhibitARTmediatedResponseInhibitpathologicalresponseExampleCD4+CD25+T,NKT,γδTcellTh1,Th2,Tr1,Th3,CD8+TNaturallyTregandadaptiveTreg无损伤组织损伤自身反应性T细胞切除胸腺切除胸腺CD4＋CD25＋T细胞3H-TdR测定T细胞增殖强度

(cpm×103)0204060CD25-CD25+T细胞T细胞1--1110.510.2510.1

3～5天新生小鼠CD4＋CD25＋nTreg通过抑制CD4+

CD25-自身反应性T细胞对抗自身免疫病的发生LossoffunctionalsuppressionbyCD4+CD25+regulatoryTcellsinpatientswithmultiplesclerosis

VigliettaY,etal:JExpMed2004,199:971-9.CD4+CD25+control

MS

CD4+CD25–

control

MS

Th1和Th2亚群各自藉助分泌的细胞因子和激活的亚群专一性转录因子以调节性T细胞的形式抑制另一亚群的分化

ImmumoregulatoryfunctionofTh1/Th2共刺激

IFN-TNF-CCR5CXCR3IL-4IL-5IL-13CCR3,4,8Th1Th2IL-4pMHCTh

0初始

TIL-4RStat6

IL4Gata3IFNGIFN-RIL-12IL-12RpMHCTCRStat4Stat1

IFNGT-betIL4IL-23IL-23RStat3

IL17IFNG,IL4IL-17IL-17FTh17IL-23IL-12IL-4IFN细胞免疫体液免疫炎症反应IL-17RORtIFN-inhibitsthedevelopmentofTh2andpromotesTh1diferentiationImmunoregulationininnateimmuneresponseRoleofsuppressingreceptorsRoleofregulatoryTcellsRoleoftheidiotypicnetworkRoleofapoptosisRoleofneuroendocrinesystemImmunoregulationamongpopulationContentEpitopeofIgIsotypeThegenesforisotypevariantsarepresentinallhealthymemberofaspecies.(2)AllotypeThisreferstogeneticvariationbetweenindividualswithinaspecies.(3)IdiotypeVariationintheVdomain,particularlyinCDR,producesidiotype.免疫球蛋白的同种型(isotype)、同种异型(allotype)和独特型(idiotype)IsotypeAllotypeIdiotype(Idiotype)NetworkTheory1.Theantigenreceptorsareextremelyheterogeneous.2.Thereareantibodiesthatrecognizetheantigenbindingsites(idiotopes)ofanotherantibody.3.TherearepotentialsimilaritybetweenAb2andoriginalantigen,Ab1andAb3etc.4.Balancebetweenthesepreexistedidiotypeanti-idiotypeantibodiescanbedisturbedwhenoutsideantigensareintroducedintotheimmunesystem.FromclonalselectiontoimmunoregulationAg

AgAb1(Id)Ab2(AId)Ab3完整的Ab分子抗原表位TheidiotypeAbforBCR/TCR利用独特型网络进行免疫干预的两种主要途径A.引入一部分有待清除的Ab1,在体内大量诱导Ab2,由Ab2发挥负向调节作用,抑制体内原有的Ab1，

削弱机体对抗原的特异性应答。B.藉助抗原内影像直接制备Ab1/Ab3,增强机体对抗原的特异性应答。AgAb2增强Ab1Ab1Ab2BAAb3/Ab1Ab1Ab2Ab2削弱Ab1FrequencychangesoftheautoreactiveTcellsinvivoafterTcellvaccinationinaMSpatientImmunoregulationininnateimmuneresponseRoleofsuppressingreceptorsRoleofregulatoryTcellsRoleoftheidiotypicnetworkRoleofapoptosisRoleofneuroendocrinesystemImmunoregulationamongpopulationContentActivation-inducedcelldeath(AICD)Topreventover-expressionoftheactivatedTcellsControlhomeostasisofTcellresponse(1)Fas/FasLanddeathsignaltransduction

evokedbyFasmoleculesDD:deathdomain70aa80aa150

aa

FasL

Fas(receptor)Fas(CD95),atypeImembraneproteinwith325aa(48kD)FasL(Fasligand),atypeIImembraneproteinwith235aasFasLTcellapoptosisinducedbyAICDCaspase级联反应细胞凋亡FasLFasDDDEDPro-caspase-8Pro-caspase-9Caspase-8,9Pro-caspase-3Caspase-3Apaf-1细胞色素C线粒体

射线，药物，细胞因子受体饥饿

胱天蛋白酶

(caspase)

参与Fas

和线粒体相关的细胞凋亡信号转导FADDWTTTTGAG

GAATCTAAGACCTTTTTCGGCTTGTATAAGgld

TTTGAGGAATCTAAGACCCTTTTCGGCTTGTATAAG

CYTTMEXTgld

PheLeulprAsn死亡结构域IleFas

FasLAB自身免疫性淋巴细胞增生综合征自身抗原自身抗原驱动下的淋巴细胞克隆扩增克隆收缩受阻克隆收缩无疾病AICDImmunoregulationininnateimmuneresponseRoleofsuppressingreceptorsRoleofregulatoryTcellsRoleoftheidiotypicnetworkRoleofapoptosisRoleofneuroendocrinesystemImmunoregulationamongpopulationContentAb,cytokineandneuroendocrinesystemImmunoregulationininnateimmuneresponseRoleofsuppressingreceptorsRoleofregulatoryTcellsRoleoftheidiotypicnetworkRoleofapoptosisRoleofneuroendocrinesystemImmunoregulationamongpopulationContent81Immuneresponsegenes(Ir)controlallimmuneresponsesMostofthepolymorphicresiduesinMHCmoleculesresideinthepeptide-bindinggrooveMHCrestrictionAPC-Th,Th-BMHCIICTL-TargetMHCI

1.ControlofimmuneresponsebyMHC82MHCgeneshaveamajorinfluenceonsusceptibilitytoautoimmunediseases______________________________________diseaseHLAallele