浙江大学医学免疫学经典课件免疫9、13-B细胞

LieWang(汪洌）浙江省杭州市浙江大学紫金港校区医学院科研楼A810-814医学院免疫学研究所BlymphocytesandHumoralImmuneResponseThediscoveryofBcellimmunity1954-BruceGlick,OhioStateUniversityStudiesonthefunctionofthebursaofFabricius,alymphoidorganinthecloacalregionofthechickenBursawaslaterfoundtobetheorganinwhichantibodyproducingcellsdeveloped–antibodyproducingcellswerethereaftercalledBcellsMammalsdonothaveabursaofFabriciusTransfermarkedfoetallivercellsOriginofBcellsandorganofBcellmaturationNoMatureBcellsAfterbirth,developmentcontinuesinthebonemarrowNormalbonemarrowDefectivebonemarrowMaturemarkedBcellsinperipheryBcelldevelopmentstartsinthefoetalliverBcelldevelopmentinthebonemarrowBRegulatesconstructionofanantigenreceptorBoneMarrowprovidesaMATURATION&DIFFERENTIATIONMICROENVIRONMENTforBcelldevelopmentEnsureseachcellhasonlyonespecificityBChecksanddisposesofself-reactiveBcellsBExportsusefulcellstotheperipheryBProvidesasiteforantibodyproductionBSecretedFactors-CYTOKINES2.SecretionofcytokinesbystromalcellsBBonemarrowstromalcellsnurturedevelopingBcellsTypesofcytokinesandcell-cellcontactsneededateachstageofdifferentiationaredifferentStromalcell1.Specificcell-cellcontactsbetweenstromalcellsanddevelopingBcellsCell-cellcontactBonemarrowstromalcellMaturingBcellsBBStromalcellBlineagecommitmentHSC(hematopoieticstemcell)MPP(淋巴系髓系多能前体细胞)ELP(earliestlymphocyteprogenitor)ETP(earlyT-lineageprogenitor)CLP(commonlymphoidprogenitor)HSCDevelopmentandmigrationofBcells(Anoverview)StagesofdifferentiationinthebonemarrowaredefinedbyIggenerearrangementBCELLSTAGEIgHGENECONFIGURATIONStemcellEarlypro-BLatepro-BLargepre-BGermlineDHtoJHVHtoDHJHVHDHJHPre-BcellreceptorexpressedIglightchaingenehasnotyetrearrangedBcellreceptorTransientlyexpressedwhenVHDHJHCHmisproductivelyrearrangedIga&IgbsignaltransductionmoleculesCHmHeavychainVHDHJHLightchainVLJLCLVpreBl5Pre-Bcelldevelopmentiscoupledwithrearrangementofheavy-chainBcelldevelopmentiscoupledwithrearrangementofheavy-chainBcelldevelopmentiscoupledwithrearrangementofheavy-chainBcelldevelopmentiscoupledwithrearrangementofheavy-chainBcelldevelopmentiscoupledwithrearrangementofheavy-chainBcelldevelopmentiscoupledwithrearrangementofheavy-chainSplicingofIgMandIgDRNACm1Cm2Cm3Cm4Cd1Cd2Cd3pA1VDJCm1Cm2Cm3Cm4Cd1Cd2Cd3VDJAAARNAcleavedandpolyadenylatedatpA2VDJCmIgMmRNAVDJCdIgDmRNACg1Cg3CdCmVDJCm1Cm2Cm3Cm4Cd1Cd2Cd3DNApA1pA2VDJTwotypesofmRNAcanbemadesimultaneouslyinthecellbydifferentialusageofalternativepolyadenylationsitesandsplicingoftheRNARNAcleavedandpolyadenylatedatpA1AAABcelldevelopmentiscoupledwithrearrangementofheavy-chain6000heavychainscombinedwith320lightchains1.9X106AbsLigationofthepre-Bcellreceptor1.EnsuresonlyonespecifictyofAbexpressedpercellLargePre-BStromalcellUnconfirmedligandofpre-Bcellreceptor2.TriggersentryintocellcycleALLELICEXCLUSIONExpressionofageneononechromosomepreventsexpressionofthealleleonthesecondchromosome1.SuppressesfurtherHchainrearrangement2.Expandsonlythepre-BcellswithinframeVHDHJHjoinsEvidenceforallelicexclusionAllotypescanbeidentifiedbystainingBcellsurfaceIgwithantibodiesa/ab/ba/bYBbYBaYBbYYBabYBaANDALLOTYPE-polymorphismintheCregionofIg–oneallotypeinheritedfromeachparentSuppressionofHchainrearrangementbypre-Bcellreceptorpreventsexpressionoftwospecificitiesofantibodypercell(ReferbacktoDreyer&BennethypothesisinMolecularGeneticsofImmunoglobulinslecturetopic)YYSuppressionofHchaingenerearrangementensuresonlyonespecificityofAbexpressedpercell.AllelicexclusionpreventsunwantedresponsesBSelfantigenexpressedbye.g.braincellsS.aureusYYYBS.aureusYYYYAntiS.aureusAntibodiesAntibrainAbsOneAgreceptorpercellIFthereweretwoAgreceptorspercellYYYYAntiS.aureusAntibodiesPreventsinductionofunwantedresponsesbypathogensAllelicexclusionisneededforefficientclonalselectionAlldaughtercellsmustexpressthesameIgspecificityotherwisetheefficiencyoftheresponsewouldbecompromisedSuppressionofHchaingenerearrangementhelpspreventtheemergenceofnewdaughterspecificitiesduringproliferationafterclonalselectionS.typhiAntibodyS.typhiAllelicexclusionisneededtopreventholesintherepertoireExclusionofanti-brainBcellsi.e.selftoleranceBBOnespecificityofAgreceptorpercellS.aureusAnti-brainIgANDanti-S.aureusIgBBIFthereweretwospecificitiesofAgreceptorpercellAnti-brainIgBBDeletionAnergyORantiS.aureusBcellswillbeexcludedleavinga“holeintherepertoire”BUTBB1.SuppressesfurtherHchainrearrangementLigationofthepre-Bcellreceptor1.EnsuresonlyonespecificityofAbexpressedpercellLargePre-BStromalcellUnconfirmedligandofpre-Bcellreceptor2.Triggersentryintocellcycle2.Expandsonlythepre-BcellswithinframeVHDHJHjoinsLargePre-BLargePre-BLargePre-BLargePre-BLargePre-BLargePre-BLargePre-BLargePre-BLargePre-BLargePre-BProliferationYImmatureBcellLightchainexpressedIgMdisplayedonsurfaceIgMLigationofthepre-BcellreceptortriggersentryintothecellcycleLargepre-BManylargepre-Bcellswithidenticalpre-BreceptorsLargepre-BIntracellularVDJCHchainVL-JLrearrangesProliferationstopsPre-receptornotdisplayedSmallpre-BBYYYYBSmallpre-BcellNoantigenreceptoratcellsurfaceUnabletosenseAgenvironment!!Maybeself-reactive!!ImmatureBcel