医学免疫学教学课件：B lymphocytes and Humoral Immune Response

BlymphocytesandHumoralImmuneResponseChapter9：Blymphocytes1.Bcelldevelopment2.BCellsurfacemarkers3.Bcellsubtypes4.FunctionsofBcellsChapter13Bcell-mediatedhumoralimmuneresponse1.Bcellactivation2.Thelp3.Bcelldifferentiation4.Tcell-independentAgresponse5.GeneralpropertiesofhumoralimmuneresponseContentsBLymphocytes(Bcells)Bcellsareanessentialcomponentoftheadaptiveimmunesystemthatplayalargeroleinthehumoralimmuneresponse.TheprincipalfunctionsofBcellsaretomakeantibodiesagainstantigens,performtheroleofantigen-presentingcells(APCs)andeventuallydevelopintomemoryBcellsafteractivationbyantigeninteraction.Theabbreviation"B",inBcell,comesfromthebursaofFabriciusinbirds,wheretheymature.Inmammals,immatureBcellsareformedinthebonemarrowandresidesinLNandspleen.Bcellsdistributeinblood,lymphoidorgans(lymphnode,spleen,tonsiletc.)andmucosa.About5-15%ofthecirculatinglymphoidpoolareBcellsNaivematureBcellsexitthebonemarrowandmigrateintotheperiphery.IfthesematureBcellsencounterspecificantigen,theybecomeactivatedortolerized.Followingactivation,Ag-specificBcellsdifferentiateintoantibody-formingcells(AFC)ormemoryBcellsinthegerminalcentre.BLymphocytes(Bcells)DevelopmentandmigrationofBcells(Anoverview)4.Bcelldevelopmentiscoupledwithrearrangementofheavy-chainBcelldevelopmentiscoupledwithrearrangementofheavy-chainBcelldevelopmentiscoupledwithrearrangementofheavy-chainBcelldevelopmentiscoupledwithrearrangementofheavy-chain4.Bcelldevelopmentiscoupledwithrearrangementofheavy-chainBcelldevelopmentiscoupledwithrearrangementofheavy-chainBcelldevelopmentiscoupledwithrearrangementofheavy-chain6000heavychainscombinedwith320lightchains1.9X106AbsBcelldevelopmentiscoupledwithrearrangementofheavy-chain6.ImmatureBcellsaretestedforautoreactivitybeforetheyleavethebonemarrow6.ImmatureBcellsaretestedforautoreactivitybeforetheyleavethebonemarrow:ReceptorEditingB-cellsurfacemarkers1.BCRcomplexBCR(mIg):VH,VL----Agbindingsite

matureBcells:mIgMandmIgD.

Function:specificallyrecognizesantigen.

Ig/Ig(CD79a/CD79b):heterodimercytoplasmicdomainscontainITAM.

Function:transducethesignalsthatleadtoBcellactivation.Antigenreceptor-mediatedsignaltransductioninBcellsCD19/CD21/CD81complex

CD21=CR2,C3dR,EBvirusreceptor

CD19/CD21/CD81interactionswithcomplementassociatedwithantigenplayaroleinantigen-inducedB-cellactivation.(2)CD72expressedonBcellsligand:CD100(expressedonB/Tcells)function:carry2ITIMmotifsup-ordown-regulatesBcellactivation2.Co-receptorsTheroleofthecoreceptorinBcellactivation(1)CD40interactswithCD40L(Thcell)

(2)CD80(B7.1),CD86(B7.2)

ExpressedonactivatedBcellsandotherAPCs

(3)ICAM-1（CD54）、LFA-1（CD11α/CD18)：mediatecell-cellinteractionandco-stimulation3.Co-stimulatorymoleculesCD20:functionisunclear.ItissuspectedthatitactsasacalciumchannelinthecellmembraneCD22：InhibitoryreceptorwithITIMmotifCD32(FcRII)：InhibitoryreceptorCytokinereceptorsComplementReceptorsToll-likereceptorsMHC4.Otherreceptors3.SubtypeofBcellsConventionalBcells(B-2cells)B-1cells(expressionofCD5)MarginalBcellsB-2cells:conventionalBcells

RecirculatingfollicularBcells:circulatebetweenLNfolliclesandbloodmIg:IgM,IgDProduceIgG

afterantigenicstimulationinthepresenceofThelpercells

B1cells(CD5+):ManyofthefirstBcellsthatappearduringontogenyexpressCD5,amarkeroriginallyfoundonTcells.(expressmIgM,nomIgD).TheyrespondwelltoTI-AgandmayalsobeinvolvedintheAgprocessingandpresentationtoTcells.

Functions

1.produceanti-bacterialIgMthefirstlineofdefenceagainstmicroorganisms;2.producepolyreactiveAbclearanceofdenaturedselfcomponents;3.produceauto-Ab,therebyparticipatinginthepathogenesisofsomeautoimmunediseases.ComparisonofDifferentBcellsubtypes4.FunctionofBcells1.ProductionofantibodyAbspreventmicroorganismfromentryintocellsandeliminatemicroorganismsbyopsonizationcausingphagocytosis,complementactivationandtoxinneutralization.2.AgpresentationtoTcells3.ImmuneregulationSecretionofcytokines(TNF,IFN,IL-12)→M

,DC,NK,Bcell.Co-stimulationofTcells→Tcellproliferation.Chapter13Bcell-mediatedhumoralimmuneresponse1.Bcellactivation2.Thelp3.Bcelldifferentiation4.Tcell-independentAgresponse5.GeneralpropertiesofhumoralimmuneresponseBcell-mediatedhumoral

immuneresponseHumoralimmunityismediatedbyantibodiesandisthearmoftheadaptiveimmuneresponsethatfunctionstoneutralizeandeliminateextracellularmicrobesandmicrobialtoxins.Itismoreimportantthancellularimmunityindefendingagainstmicrobeswithcapsulesrichinpolysaccharidesandlipids.TD-Ag：Tcell-dependentTI-Ag：Tcell-independentHumoralImmuneresponseismediatedbyantibodymoleculessecretedbyplasmacellsResponsetoTD-Ag1)BcellsrecognizeTD-Aga.BCRdirectlyrecognizesBcellepitopesb.Ig

/Ig

transferthefirstsignalc.Signalingpathwaysd.Effectofcoreceptors(CD21/CD19/CD81)BCR

Signaling

IBCR

Signaling

IITheroleofco-receptors(CD19/CD21/CD81)inBcellactivation2)RoleofThcellsinhumoralimmuneresponsetoTD-AgForaproteinAgtostimulateAbresponse,BcellsandThcellsspecificforthatAgmustcometogetherinlymphoidorgansandinteractinawaythatstimulatesBcellproliferationanddifferentiation.a.ActivationandmigrationofhelperTcellsThcellsthathavebeenactivatedtodifferentiateintoeffectorcellsinteractwithantigen-stimulatedBcellsattheedgesoflymphoidfolliclesintheperipherallymphoidorgans.TheinteractionsofThcellsandBcellsinlymphoidtissues.b.PresentationofAgsbyBcellstoThcellsBcellsthatbindproteinAgsbytheirBCRendocytosetheseAgs,processtheminendosomalvesicles,displayMHCII-peptidesforrecognitionofThcells.BcellsandThcellsrecognizedifferentepitopesofthesameproteinAg.AgpresentationbyBcellstoThcellsc.MechanismsofThcell-mediated

activationofBcellsThcellsthatrecognizeAgpresentedbyBcellsactivateBcellsbyexpressingCD40Landbysecretingcytokines(IL-2,IFN-

,IL-4,IL-5,IL-6,IL-13,etc.).MechanismsofThcell-mediatedactivationofBcellsKeycomponentsofTcellhelpCD40LtriggersCD40->synergizeswithBCRsignalstopromotemitosis;cytokine(e.g.IL4)signalsalsocontributeFasLtriggersFas->BCRsignalingprotectsfromapoptosisTcellderivedcytokinesinfluencedifferentiation,isotypeswitching:IL2,IL6promotedifferentiationIL4->IgG1,IgEIFNg->IgG2a,IgG3TGFbandIL5>IgAManyothermoleculesinvolvedinT-Binteractionse.g.ICAM1/LFA1,ICOS/ICOSL,CD30/CD30L,CD27L/CD27,OX40L/OX40,...KeyRoleofCD40inBcellactivationTCRtriggeringup-regulatesCD40LonTcellCD40signalingpromotesBcellactivationCD40L-deficiency='hyper-IgMsyndrome'(noisotypeswitching,noGerminalCenters)CD40signalingalsoimportantinDC,MØfunctionincreasedexpressionofcellcyclemolecules,survivalmolecules,cytokines,promotesisotypeswitchingd.ThcellsstimulateBcellstoproduceAbsofdifferentheavychainclasses(isotypes)HeavychainclassswitchingisinitiatedbyCD40L-mediatedsignals,andswitchingtodifferentclassesisstimulatedbydifferentcytokines.Igheavychainclass(isotype)switching（蠕虫）Igheavychainclass(isotype)switchingMechanismsofIgheavychainclassswitchinge.AffinitymaturationinAbresponsesAffinitymaturationistheprocessbywhichtheaffinityofAbsproducedinresponsetoaproteinAgincreaseswithprolongedandrepeatedexposuretothatAg.TheincreaseinaffinityisduetopointmutationsintheVregions,andparticularlyintheAg-bindingHVR,oftheAbsproduced.Affinitymaturationoccursinthegerminalcentersoflymphoidfollicles.Affinitymaturationinantibodyresponses–somaticmutationAffinitymaturationinantibodyresponses-SelectionofhighaffinityBcellsTheanatomyofhumoralimmuneresponsesAfractionoftheactivatedBcells,whichareoftentheprogenyofclass-switchedhigh-affinityBcells,donotdifferentiateintoAbsecretorsbutinsteadbecomememoryBcells.GerminalCentersFunction:togenerateBcellsthatproduceantibodieswithincreasedaffinityfortheinducingantigen =>affinitymaturationGerminalCenterReaction:ActivatedBcellsgiverisetoCentroblasts（中心母细胞）-localizeinfollicle,undergorapidcelldivisionandturnonmachinerythatcausessomaticmutationinV-regionsCentroblastsgiverisetoCentrocytes（生发中心细胞）-migratetotheFDC-richregionoftheGerminalCenter-survivalisdependentoninteractionwithFDC-boundAgandpresentationofAgtoTcells-centrocytesthatsuccessfullycompetetobindantigen(e.g.byhavinghigheraffinityBCR)andtoreceiveTcellhelpareselectedandmaydifferentiateintolong-livedplasmacellsormemoryBcellsGerminalCenters3.BcellresponsetoTI-A