医学免疫学课件：第十三章 B细胞介导的免疫应答

第十三章B细胞介导的免疫应答Chapter13Bcellmediatedimmuneresponse教学大纲要求：1.掌握B细胞对TD抗原的免疫应答2.了解B细胞对TI抗原的应答3.掌握体液免疫应答产生抗体的一般规律

概述（overview）体液免疫应答：

抗体存在于体液；B细胞介导的免疫是由B细胞分泌的抗体介导的特异性免疫；B细胞在周围淋巴器官激活。BCR与抗原结合产生第一激活信号，BCR与共刺激受体的交联加强B细胞的活化。B细胞的完全激活需

要活化的Th细胞辅助。

活化的B细胞经过高频突变和同种型转化后分化成产生抗体的浆

细胞和记忆细胞。B细胞识别的抗原分为T细胞依赖性抗原（TD-Ag）和T细胞非依

赖性抗原（TI-Ag）B2细胞介导T细胞依赖性抗原的免疫反应，需要Th（Th2）细胞

的辅助。B1细胞介导T细胞非依赖性抗原的免疫反应。

第一节B细胞对TD-Ag的免疫应答

SectiononeBcellresponsetoTDantigensT细胞依赖性抗原的特征（CharacteristicsofTD-Ag）:Mostnative,largemoleculesProteinAg.AdiverseepitopesincludingTcellandBcellepitope,inducecellmediatedandhumoralimmunity,bothneedThcellsparticipation.StimulateBcelltoproducehighaffinityantibodiesProduceimmunememory.B细胞对抗原的识别1.BCR对抗原的识别与TCR不同：①不仅能识别蛋白抗原，还能识别多肽、核酸、多糖、脂类及小分子化合物。BCRcomplexAgITAMAg（BCR）ITAM②可特异性识别完整抗原的天然构象或抗原降解所暴露表位的空间构象。③识别的抗原无需经APCs的加工和处理，也不受MHC限制。2.BCR是B细胞识别特异性抗原的受体，B细胞的识别抗原与BCR结合产生两个相互关联的作用:①BCR特异性结合抗原，产生B细胞活化的第一信号；②BCR特异性结合的抗原被B细胞内化，经加工处理成pMHCII，提呈给Th细胞识别，活化的Th表达CD40L，与B细胞表面的CD40结合，产生B细胞活化的第二信号。

bindingofBCRandAg

signalbetookbyspecificreceptor-mediatedendocytosis,activateprocessing,BcellpeptidesbindwithMHCIImoleculespMHCIIcomplexproliferationpresentingdifferentiationTcellsBcellscanrecognisenativeantigensdirectlyYYYYYYYBProliferationandantibodyproductionCross-linkingofsurfacemembraneIgYBYBYBYBYBYBYBYYBThAntigenprocessingandpresentationbyBlymphocytes二.B细胞活化需要的信号B细胞的活化与T细胞相似，需要双信号；B细胞活化后的信号转导途径也与T细胞相似。

①B细胞活化的双信号(DualsignalofBcellactivation）

Firstsignal:antigensignalBCR--determinantonthesurfaceofAgBCR交联

firstsignalIgα/IgβtransductenterBcellsupregulateMHCIIandB7expressionBcellsselfactivation.Secondsignal:co-stimulatorysignalTheCD40onBcellsbindstoCD40LonactivatedThcellsfullactivationofBcells.②B细胞活化过程中与Th细胞的相互作用BcellsinteractwithTcellsviacapturing,processingantigentoformandpresentingpeptide-MHCIImolecules.a)B细胞对Th细胞的作用--BCRbindingwithantingencapturedandprocessedbyBcells(asaAPCs)presentingpeptide-MHCIImoleculesfirstsignalThcells.--BCRbindingwithantingenactivateBcellsupregulateB7expressioncombiningwithCD28onThcellssecondsignalactivateThcells.b)Th细胞对B细胞的作用

(ThcellshelpactivationofBcells)--activatedThcellsinducedtoexpressCD40LcombinewithCD40onBcellssecondsignalfullactivationofBcells.--activatedThcellssecreteIL4,IL5,IL-6enhanceproliferationanddifferentiationofBcell,andinduceIgisoformswitch.BcellsasaAPCscannotactivateNaïveTcells.③细胞因子的作用：

活化的T细胞产生的细胞因子，通过活化的B细胞表面的细胞因子受体诱导B细胞增殖和分化。③B活化辅助受体及其他辅助分子的作用--CD19/CD21/CD81(co-receptor)combinewithC3dgonAgandBCRsignalviaCD19enterBcellsenhanceactivationofBcells.--interactionbetweenotheradhesionmoleculesonBandThcells(e.g.LFA3-CD2,ICAM-1-LFA-1,LFA-3-LFA-1,MHCII-CD4)tightenadhesionofBandThcellsenhanceBcellsactivation.④B细胞活化信号的转导gBcell

第一信号转导:与T相似，但：--firstsignalisfromBCRcombinationwithaspecificantigenandtransductedviaIgα-Igβ

--earlyPTKsactivatedbyBCRcrosslinkareBlk,FynandLyn,theyactivateSyk(notZAP-70).--activatedSykactivateRassignalpathway--transcriptedgenesareNF-AT,NF-κBandCREB(cyclic-AMPresponseelement/Bcells).第二信号转导SecondsignaltransductionsecondsignalRasMAPKTFa三、B细胞的增值和终末分化

ActivatedBcellwhichexpressCKRcytokineThcellshelpantibodyplasmacellsmemoryBcells①②

一）活化B细胞的分化途径：

activatedBcellsThcellshelppartofBcellsmigratemostofBcells

medullaofPeripheralprimaryfolliclelymphoidorgansdifferentiateproliferatetoformPlasmacellssecretegerminalcenterIgM(secondaryfollicle)differentiateimmediateimmuneresponseplasmacells(inearlyimmuneresponse)secretehighaffinityIgbonemarrow二）B细胞分化的抗原依赖期抗原非依赖期;

抗原依赖期.

三）B细胞增殖生成生发中心

BcellstouchantigeninjunctionregionofmigrateTcellandBcellprimaryfollicleproliferatePrimarygerminalcentereffectofmicroenviroment(follicleDCs,Thcells)secondarygerminalcenter四)体细胞高频突变及抗体亲和力成熟和阳性选择--thehypermutationoflymphocytoblastingerminalcenterissecondarymutationofBcellgenes,itleadBcellstoproducehighaffinityantibody.--thefeaturesofsomatichypermutation:Somatichypermutationispointmutation,andmainlyconcentratedinCDRofVregion,particularlyinCDR3.Thefrequencyofthispointmutationisveryhigh,about0.1%.thispointmutationonlyoccursinrearrangedVgenes.thispointmutationofIgGiseasiertooccursthanthatofIgM.thispointmutationdependsonantigenselection.--affinitymaturationistheprocessbywhichBcellsproduceantibodieswithincreasedaffinityforspecificantigenduringthecourseofanimmuneresponse.ItinvolvesthehelpofThcellsandinteractionofCD40L-CD40.b)ItistheresultsofsomatichypermutationofIggenesandthesurvivalofBcellsthatsecretehighaffinityantibodies.--positiveselectionofBcellsoccursaftersomatichypermutation.MostofBcellscloneswilldiebyamechanismcalled

apoptosisbecausetheyexpress,evendonotexpress,BCRwithloweraffinityor;afewclonessurviveduetoexpressinganti-apopoticproteins.五)免疫球蛋白类别转换或同种型转换(Immunoglobulinclassswitchingorisotypeswitching)isabiologicalmechanismthatchangesaBcell'sproductionofantibodyfromoneclasstoanother,forexample,fromanisotypecalledIgMtoanisotypecalledIgG.Duringthisprocess,theconstantregionportionoftheantibodyheavychainischanged,butthevariableregionoftheheavychainstaysunchanged.Sincethevariableregiondoesnotchange,classswitchingdoesnotaffectantigenspecificity.Instead,theantibodyretainsaffinityforthesameantigens,butcaninteractwithdifferenteffectormolecules.classswitchingonlyoccursinTD-Agresponse.Bcellsundergoclassswitchingwithantigens,CD40andcytokinesinvolved.体细胞高频突变：生发中心B淋巴母细胞的轻链和重链V基因可发生高频率的点突变。抗体亲和力成熟：指机体正常存在的一种免疫功能状态的现象，在体液免疫中，再次应答所产生抗体的平均亲和力高于初次免疫应答。Ig的类型转换：

B细胞接受抗原刺激后首先合成IgM，随后在多种因素影响下可表达IgG、IgA或IgE，但其Ig的可变（V）区不发生改变，这种可变区相同而Ig的类型发生变化的过程称为Ig的类型转换或同种型转换。六）浆细胞的形成--是终末分化的B细胞，能分泌大量的特异性抗体；--不再表达BCR和MHCII分子，不与抗原起反应，也失去了与Th相互作用的能力。七)记忆B细胞的产生--aftersurvivingingerminalcenter,mostofBcellsdifferentiateintotheplasmacells,alsocalledeffectorBcellswhichproducetheantibodies.Therestpersistasthememorycellsthatleavegerminalcenterintoperipherallymphoidorgansandcanrecirculateandsurviveforyears,orevenalifetime.

--memoryBcellsoverexpressCD44inadditiontotheexpressionofCD27.第二节B细胞对TI-Ag的应答

SectiontwoBcellresponsetoTIantigensCharacteristicsofTI-Ag:simplestructure.polysaccharide,lipopolysaccharide.activateBcellswithoutThcellshelp.recognizedonlybyB1cells.mainlyproducelowaffinityIgM.classifiedintoTI-1antigensandTI-2antigens一、B细胞对TI-1抗原的应答1）TI-1Agmajorlybelongtocomponentofcellwallofbacteria,e.g.LPSwhichactivateB1cellsviaTLR4andBCR.2）almostofB1cellsexpressTLR4,onlyfewofB1cellshavespecificBCRforLPS.3）TI-1Ag不仅能与BCR结合，还能通过丝裂原（mitogen）成分与B1细胞上的丝裂原受体结合，引起B1细胞的增值和分化。①TI-1Agcontainmitogen.②TI-1AgofhighconcentrationcaninducepolyclonalBcellsactivationviacombinationofmitogenanditsreceptor,whichistherecognizationofBCR-independentforepitopesofantigen.③TI-1AgoflowconcentrationonlyactivateB1cellcloneswithspecificantigenreceptorinwhichmitogenbindtoitsreceptortoactasasecondarysignalinvolve.4）B1cellsthatareactivatedonlybyTI-1AgcannotbeinducedtoproduceIgisotypeswicth,affinitymaturation,andmemoryBcells.Thymus-independent(TI)-1antigenscanactivateBcellswithoutT-cellhelpNoMemory,noclassswitching二、B细胞对TI-2抗原的应答）

TI-2Agmajorlybelongpolysaccharide(includingcellwallofbacteriaandcapsulepolysaccharide),bacterialflagellaproteinandPoliomyelitisvirus.TI-2AgonlyactivatematureB1cellsviaBCRcrosslinkinducedbyrepeat

epitopes.TI-2Agishighrepeat

epitopeswhichdonotcontainmitogenandcannotinducepolyclonalBcellsactivation.TI-2Agisnoteasytobedegradedbyproteases.TI-2AgactivateB1cellswithouthelpofThcell,butcytokinesproducedbyactivatedTcellscanenhanceB1cellsresponseandinduceIgisotypeswicth.三、B细胞对TI抗原应答的意义①PlayimportantroleindefenseagainstextracellularmicrobeinfectionbecauseitcanrapidlysetupwithoutthehelpofThcellsandsensitizationofB1cellsbeforespecificimmuneresponseinducedbyB2cellsoccurs.②Playanimportantroleindefenseagainstbacteriawithcapsulepolysaccharidebecauseitcanphagocytoseanddigestbacteriawithcapsulepolysaccharideviaantibodymediatedopsonificationandinducespecificcell-mediatedimmuneresponse.四、B细胞对TD抗原和TI抗原应答的不同

第三节抗体产生的一般规律

SectionthreeGeneralrulesofantibodyproduction一、初次应答的特点:1.潜伏期(lagphase):持续数小时至数周；其长短取决于抗原的性质、进入机体的途径、所用的佐剂及宿主的状态。2.对数期（logphase):

血清中抗体量呈指数增长，抗体量增长速度取决于抗原的剂量和性质。3.平台期（plateauphase):血清中抗体浓度基本维持在一个相当稳定的较高水平，到达平台期的时间、平台的高度及持续时间依抗原而异，持续数天或数周；4.下降期（declinephase):

血清抗体中抗体的浓度因其被降解或与抗原的结合而被清除慢慢下降，持续数天至数周。二、再次应答的特点:①潜伏期短，约为初次应答的一半；②血清抗体浓度增加快，快速到达平台期，平台高；③抗体维持时间长；④诱发再次应答所需抗原剂量小；

⑤主要产生高亲和力的IgG，而初次应答主要产生低亲和力的IgM。⑥再次应答参与反应的B细胞与初次应答不同：

Cellsinvolvedinprimaryimmuneresponse--naïveBcellsandThcells.Cellsinvolvedinsecondaryimmuneresponse--memoryBcellsandThcells.⑦再次应答参与反应的机制与初次应答不同：ThecauseforshortlagphaseofsecondaryimmuneresponseincludsagreatnumberofmemoryBcellsenhancethechancethatBcellsencounterantigens.MemoryBcellshavebeenexposedtoantigens.MemoryBcellsexpresshighlevelofadhesionmoleculessothattheyareeasytobeactivatedbyAPCs.SecondaryimmuneresponseproduceshighlevelandlongLifespanofantibodiesbe