醫(yī)學(xué)免疫學(xué)課件：08 B cell

淋巴細(xì)胞

第九章醫(yī)學(xué)免疫學(xué)主要內(nèi)容

T淋巴細(xì)胞

B淋巴細(xì)胞

-B細(xì)胞的分化發(fā)育

-B細(xì)胞的表面標(biāo)志

-B細(xì)胞亞群及功能自然殺傷細(xì)胞（NK）B細(xì)胞的發(fā)育

B細(xì)胞在胎肝和骨髓發(fā)育成熟進(jìn)入外周淋巴組織遇到抗原在生發(fā)中心增殖、突變、選擇抗體親和力成熟，Ig類型轉(zhuǎn)化，產(chǎn)生記憶B和漿細(xì)胞產(chǎn)生抗體，介導(dǎo)體液免疫。主要事件*功能性BCR形成（基因重排，骨髓）*陰性選擇（骨髓）*陽性選擇（生發(fā)中心）意義*

功能性BCR形成，BCR多樣性*獲得自身耐受*

BCR與抗體親和力成熟、Ig類型轉(zhuǎn)換、記憶B細(xì)胞和漿細(xì)胞的產(chǎn)生TransferfoetallivercellsOriginofBcellsandorganofBcellmaturationNoMatureBcellsAfterbirth,developmentcontinuesinthebonemarrowNormalbonemarrowDefectivebonemarrowMatureBcellsinperipheryBcelldevelopmentstartsinthefoetalliverB細(xì)胞在骨髓的發(fā)育骨髓為B細(xì)胞發(fā)育提供其成熟與分化的微環(huán)境保證每個B細(xì)胞只有一種特異性B檢查和去除自身反應(yīng)B細(xì)胞B將有用的B細(xì)胞輸出至外周B提供抗體產(chǎn)生的部位BB調(diào)控BCR的形成SecretedFactors-CYTOKINES2.SecretionofcytokinesbystromalcellsBBonemarrowstromalcellsnurturedevelopingBcellsTypesofcytokinesandcell-cellcontactsneededateachstageofdifferentiationaredifferentStromalcell1.Specificcell-cellcontactsbetweenstromalcellsanddevelopingBcellsCell-cellcontactPeripheralStagesofBcelldevelopmentStemCellEarlypro-BcellLatepro-BcellLargepre-BcellSmallpre-BcellImmatureBcellMatureBcellEachstageofdevelopmentisdefinedbyrearrangementsofIgHchaingenes,IgLchaingenes,expressionofsurfaceIg,expressionofadhesionmoleculesandcytokinereceptorsEarlypro-BKitReceptorTyrosinekinaseStemcellfactorCell-boundgrowthfactorVLA-4(Integrin)StemCytokinesandcell-cellcontactsateachstageofdifferentiationaredifferentStromalcellCelladhesionmoleculesVCAM-1(Igsuperfamily)Earlypro-BInterleukin-7receptorStromalcellLatepro-BPre-BInterleukin-7GrowthfactorCytokinesandcell-cellcontactsateachstageofdifferentiationaredifferentEarlyStagesofBCellDevelopmentBonemarrowstromalcellsnurturedevelopingBcells.Bcellmustcontactwithstromalcellsbybindingofadhesionmolecules.ThestromalcellsexpressandsecretgrowthfactorsandcytokinestopromoteBcelldevelopment.B細(xì)胞的發(fā)育

B細(xì)胞在胎肝和骨髓發(fā)育成熟進(jìn)入外周淋巴組織遇到抗原在生發(fā)中心增殖、突變、選擇抗體親和力成熟，Ig類型轉(zhuǎn)化，產(chǎn)生記憶B和漿細(xì)胞產(chǎn)生抗體，介導(dǎo)體液免疫主要事件*功能性BCR形成（基因重排，骨髓）*陰性選擇（骨髓）*陽性選擇（生發(fā)中心）意義*BCR多樣性*獲得自身耐受*

BCR與抗體親和力成熟、Ig類型轉(zhuǎn)換、記憶B細(xì)胞和漿細(xì)胞的產(chǎn)生TheDevelopmentofBCellsNegativeselectionBcellrecognisesnon-selfantigeninperipheryIg-secretingplasmacellDifferentiationintheperipheryYYYYYYYYYBYYYYYYYBYYYYYYYBMatureperipheralBcellPlasmacellsSurfaceSurfaceHighrateGrowthSomaticIsotypeIgMHCIIIgsecretionhypermut’nswitch

HighYes

No

YesYesYes

Low NoYesNoNo

NoBBMatureBcellPlasmacellMenuFBNegativeselectionPositiveselectioninGCPlasmaandBmPro-BcellVDJVJYYYYBImmatureBcellCellsurfaceIgexpressedAbletosenseAgenvironmentCannowbecheckedforself-reactivityAcquisitionofantigenspecificitycreatesaneedtocheckforrecognitionofselfantigensPhysicalremovalfromtherepertoire DELETIONParalysisoffunction ANERGYAlterationofspecificity RECEPTOREDITINGBcellselftolerance:clonaldeletionImmatureBcellrecognisesMULTIVALENTselfAgBClonaldeletionbyapoptosisYYBImmatureBBSmallpre-BSmallpre-BcellassemblesIgYBcellselftolerance:anergyBYYYBAnergicBcellIgDnormalIgMlowImmatureBcellrecognisessolubleselfAgYYBImmatureBBSmallpre-BSmallpre-BcellassemblesIgIgMIgDIgDIgDReceptoreditingArearrangementencodingaselfspecificreceptorcanbereplacedVCDJVVVYBB!!Receptorrecognisesselfantigen!!BApoptosisoranergyYBBEditedreceptornowrecognisesadifferentantigenandcanberecheckedforspecificityCDJVVVVArrestdevelopmentAndreactivateRAG-1andRAG-2RAG:RecombinationactivatinggeneYYYYYYMatureBcellexportedtotheperipheryYYBcellselftolerance:exportofnon-selfreactiveBcellsIgDandIgMnormalIgMIgDIgDIgDIgDIgMIgMIgMImmatureBcelldoesn’trecogniseanyselfAgYYBImmatureBBSmallpre-BSmallpre-BcellassemblesIgBControlOfAnti-SelfBCellsPrimaryFolliclesbecomesecondaryfollicles

whengerminalcentresdevelopDarkzoneLightzoneBTFolliculardendriticcellscaptureantigenonitssurface,presenttoBcellsPositiveSelectioninGerminalCentre1.Bcellsproliferate,somaticallyhypermutatetheirIgVgenes.AFFINITYMATURATION2.Bcells(centrocytes)upregulatesurfaceIg,stopdividingandrecognizeantigenonFDC,receivecostimulatorysignalsfromThcells3.Apoptosisofself-reactive&unselectedcells4.SelectedcellsleavelymphnodeasmemorycellsorplasmacellsBB細(xì)胞的分化發(fā)育過程抗原非依賴期（骨髓）祖B(VDJ/H)

前B(VJ/L;胞漿m)

未成熟B(mIgM)

成熟B(mIgMandmIgD)

陰性選擇（骨髓）未成熟B(IgM)+自身抗原克隆清除或無能

自身耐受抗原依賴期（外周淋巴器官）

成熟B+抗原活化增殖在生發(fā)中心發(fā)育漿細(xì)胞和記憶B陽性選擇（生發(fā)中心）

活化B增殖BCR可變區(qū)體細(xì)胞超頻突變

突變B與FDC表面抗原高親和力結(jié)合

選擇存活

導(dǎo)致BCR及抗體親和力成熟，抗體類型轉(zhuǎn)換，產(chǎn)生漿細(xì)胞和記憶B.

主要內(nèi)容

T淋巴細(xì)胞

B淋巴細(xì)胞

-B細(xì)胞的分化發(fā)育

-B細(xì)胞的表面標(biāo)志

-B細(xì)胞亞群及功能自然殺傷細(xì)胞（NK）

BCRcomplexincreasethesensitivityofBcelltoantigenstimulation.Co-stimulatorymoleculesonBcellsB細(xì)胞的表面標(biāo)志BCR-Igα/Igβ復(fù)合物共受體：CD19、CD21、CD81協(xié)同刺激分子：CD40T細(xì)胞活化共刺激分子：B7-1/2、ICOSL（Tfh)CKR：IL-1R、IL-2R、IL-4R、IL-5R等CR：CR1和CR2FcR:FcgRII絲裂原受體：LPS、PWMMHCI/II

主要內(nèi)容

T淋巴細(xì)胞

B淋巴細(xì)胞

-B細(xì)胞的分化發(fā)育

-B細(xì)胞的表面標(biāo)志

-B細(xì)胞亞群及功能自然殺傷細(xì)胞（NK）CD5TwoBcelllineagesBBcellprecursorBMatureBcellB2cellsPlasmacellYYYYYYYYYPCIgGBYYYYYYYYYYYYYYYYYYYYIgM-nootherisotypesBDistinctBcell

precursor??‘Primitive’BcellsfoundinpleuraandperitoneumB1cells

CD5BYYYYYYYYYYYYYYYYYYYYIgMB-1細(xì)胞的主要生物學(xué)功能-主要識別TI-2抗原的多糖類物質(zhì)，如莢膜多糖，聚合鞭毛素等；-參與對多種細(xì)菌（尤其體腔中）的抗感染免疫；-產(chǎn)生低親和力IgM類的生理性自身抗體，參與對衰老、蛻變自身細(xì)胞的清除；-通過產(chǎn)生IgM類自身抗體參與某些自身免疫病的發(fā)生。B1CellsWithIgMAgRforBacteriaDoNotNeed

TCellHelpBMatureB-2BcellCD5-B-2細(xì)胞的主要生物學(xué)功能-參與體液免疫應(yīng)答：

BC+Ag

在Th輔助下活化增殖分化漿細(xì)胞產(chǎn)生高親和力抗體-抗原提呈：

BC用BCR攝取Ag

處理肽+MHCII

提呈抗原給CD4T細(xì)胞，提供協(xié)同信號-免疫調(diào)節(jié)：活化BC產(chǎn)生多種細(xì)胞因子，參與免疫調(diào)節(jié)YYYYYYIgG脾B細(xì)胞：MZB:TI應(yīng)答，CD9+，不參與LC循環(huán)，血源AgFOB：TD應(yīng)答ComparisonofB-1andB-2cellpropertiesProperty B-1cells B-2cellsVregionrepertoire

Restricted DiverseLocation

Peritoneum/pleura EverywhereRenewal

Selfrenewalinsitu BonemarrowSpontaneousIgproduction High LowIsotypes

IgM IgM/G/A/D/ECarbohydratespecificityYesRarelyProteinspecificity

Rarely YesNeedTcellhelp

No YesSomatichypermutationofIg No HighMemorydevelopment

No YesSpecificity&requirementforTcellhelpsuggestsstrikinglydifferenttypes

ofantigensareseenbyB-1andB-2cells

B細(xì)胞在胚肝開始發(fā)育，出生后在骨髓繼續(xù)發(fā)育。B細(xì)胞發(fā)育：-過程:早B

前B未成熟B成熟B漿細(xì)胞-陰性選擇（在骨髓）：自身耐受-陽性選擇（生發(fā)中心）：抗體親和力成熟，產(chǎn)生漿細(xì)胞和記憶B細(xì)胞B細(xì)胞表面標(biāo)志：BCR復(fù)合物,共受體,共刺激分子(CD40andB7),CKR,CRs,FcR，絲裂原受體和MHCI/IIB細(xì)胞有2類:-CD5+B-1細(xì)胞和CD5-B-2細(xì)胞。B-1細(xì)胞識別糖類抗原，主要產(chǎn)生IgM;-B-2細(xì)胞識別蛋白抗原，產(chǎn)生所有類別的抗體，其應(yīng)答需要T細(xì)胞輔助。

小結(jié)主要內(nèi)容

T淋巴細(xì)胞

B淋巴細(xì)胞

-B細(xì)胞的分化發(fā)育

-B細(xì)胞的表面標(biāo)志

-B細(xì)胞亞群及功能自然殺傷細(xì)胞（NK）NK細(xì)胞NK細(xì)胞表面標(biāo)志NK細(xì)胞的活化受體和抑制性受體NK細(xì)胞的功能

源于骨髓淋巴樣祖細(xì)胞，分布在肝、脾、淋巴結(jié)和外周血，屬于LGL。自然殺傷細(xì)胞(naturalkiller,NK)CellSurfaceMarkersofNKCellsTheabsenceofCD3,butthepresenceofCD16and/orCD56iscurrentlythemostreliablemarkerforNKcellinhuman.NK細(xì)胞NK細(xì)胞表面標(biāo)志NK細(xì)胞的活化受體和抑制性受體NK細(xì)胞的功能

Killerinhibitoryreceptors(KIRs）ThereisthesecondgroupofNKcellreceptorswhicharemembersoftheimmunoglobulinsuperfamilysuchasKIR2D(CD158)andKIR3D.(immunoreceptortyrosineinhibitorymotif)HowdoNKcellsknowwhenacellisandisnotinfectedwithavirus?INANUNINFECTEDCELL,NKR-P1bindhostcellcarbohydrate+vesignaltokilltargetLy49bindsMHCclassI-vesignaloverrulesNKR-P1signalKillingisinhibitedMouseNKcellsKilleractivatingreceptor(KAR)reconizecarbohydrateligands

LIGATIONTRIGGERSKILLINGKillerinhibitoryreceptor(KIR)recognizeselfMHCImoleculeLIGATIONPREVENTSKILLING+-+-Ly49NKR-P1

NKcellsdonotkillnormalcellsTheligationofKIRcandeliveraninhibitorysignaltoNKcellswhichblocktheactivatingsignalfromtheligationofKAR.NKR-P1bindstohostcellcarbohydrateCellsexpresslowlevelsofMHCclassINKR-P1ligationwithnoKIRligationactivatesNKcelltokilltargetcellHowdoNKcellsknowwhenacellisandisnotinfectedwithavirus?InfectedcellsmayexpresslowlevelsofMHCclassI-VirusesinhibitproteinsynthesisofInterferon-inducedMHCclassI-VirusproteinsblockMHCclassIassemblyandtransport-Virusesalterglycosylationofhostcellproteins+-KIRNKR-P1

NKcellscankillabnormalcellsTheligationofKARcandeliveranactivatingsignaltoNKcell,butlackofaninhibitorysignalfromKIR.SotheNKcellisactivatedtokilltargetcell.NK細(xì)胞NK細(xì)胞表面標(biāo)志NK細(xì)胞的活化受體和抑制性受體NK細(xì)胞的功能

NK細(xì)胞的功能抗感染:特別是抗病毒感染抗腫瘤免疫調(diào)節(jié):釋放細(xì)胞因子,如：IFN-g、

IL-1、GM-CSF等

ANKcell(NK)attachedtoatargetcell(TC)NK殺傷靶細(xì)胞的機(jī)制釋放穿孔素和顆粒酶靶細(xì)胞溶解；通過Fas／FasL途徑靶細(xì)胞凋亡；釋放細(xì)胞毒性物質(zhì)（TNF、LT等）；ADCCYYYY

Antibody-dependentcellularcytotoxicity(ADCC)YYYNKFc

RIII(CD16)屬大顆粒淋巴細(xì)胞（LGL）；無特異性TCR；無須抗原致敏即直接殺傷靶細(xì)胞。表面標(biāo)記：CD3-、CD56+、CD16+表面受體：殺傷細(xì)胞活化受體（KAR）殺傷細(xì)胞抑制受體（KIR）主要生物學(xué)功能：抗感染、抗腫瘤、免疫調(diào)節(jié)

自然殺傷細(xì)胞小結(jié)T/B細(xì)胞發(fā)育的陽性和陰性選擇。T、B細(xì)胞的表面標(biāo)志及其功能。小書P68T、B細(xì)胞的亞類及功能。NK細(xì)胞識別靶細(xì)胞的受體及其殺傷靶細(xì)胞的機(jī)制T細(xì)胞發(fā)育:過程:干細(xì)胞

早T前T（DN）DP(雙陽性細(xì)胞)SP（單陽性細(xì)胞）成熟T

（來源于骨髓→在胸腺（thymus）內(nèi)發(fā)育成熟→移行至外周淋巴組織→執(zhí)行特異性細(xì)胞免疫應(yīng)答，參與對TD抗原的體液免疫應(yīng)答。）發(fā)生的主要事件有：①基因重排

功能性TCR形成②陽性選擇（DP細(xì)胞TCR與胸腺皮質(zhì)上皮細(xì)胞表面的MHCI/II類分子以適當(dāng)親和力結(jié)合，分化為CD8/CD4的SP細(xì)胞；不能結(jié)合或高親和力結(jié)合的DP細(xì)胞發(fā)生凋亡）

獲得MHC限制性③陰性選擇（與DC或M提呈的自身肽/MHC復(fù)合物高親和力結(jié)合的SP細(xì)胞，發(fā)生凋亡；而不能識別抗原的SP細(xì)胞則發(fā)育成熟）

獲得對自身抗原的耐受性B細(xì)胞的分化發(fā)育過程一、發(fā)育過程：①B細(xì)胞在胚肝開始發(fā)育，出生后在骨髓繼續(xù)發(fā)育。②抗原非依賴期（骨髓）祖B(VDJ/H)（重鏈重排）

前B(VJ/L;胞漿m)（輕鏈重排）未成熟B(mIgM)

成熟B(mIgMandmIgD)③抗原依賴期（外周淋巴器官）

成熟B+抗原活化增殖在生發(fā)中心發(fā)育漿細(xì)胞和記憶B二、重要事件：①基因重排（骨髓）功能性BCR形成，形成BCR多樣性②陰性選擇（骨髓）未成熟B(IgM)+自身抗原