B细胞激活1.ppt

B细胞激活 BCellActivation B细胞抗原识别受体与信号转导T B细胞相互作用与B细胞的增殖分化B细胞的增殖与分化B细胞对T细胞非依赖抗原的应答 B细胞抗原识别受体与信号转导 1 chapternineBCellActivation T细胞抗原识别信号的转导 pathwayA pathwayB pathwayC PKC calcineurin MAPkinase PIP2DAG IP3Ras GDPRas GTP Ca2 Raf PLC Sos NF AT OCT NF B AP 1 NF AT OCT PKC Grb 2 I B NF B NF B NF AT NF AT p c Junc Fos AKT B7CD28 PI3 K LAT SLP 76 ZAP 70 Peptide MHCTCR LckFyn CD45CD4 PTPdomains Y505 p ITAM ITAM Yp Yp NUCLEUS CELLMEMBRANE IL 2gene Yp Yp Yp GSK3 Gads NCK 细胞骨架重排 免疫突触 PI PIP3 BCR Ig Ig ITAM 受体交联 形成免疫突触 偶联PTK活化 Lyn Fyn Blk ITAM磷酸化 活化 招募胞浆PTK Syk PTK磷酸化 活化 衔接蛋白 BLNK SLP 65 PLC PIP2 DAG IP3 激活PKC 活化钙调磷酸酶 活化MAP激酶级联反应 活化转录因子 NF B NFAT AP 1 与特异性基因的启动子结合 启动基因转录 转位 GEF Vav CD81 TAPA 1 CD19Y Erk andJnk pathwaysinMAPkinase relatedsignalingcascade Pak Raf Mekk Mek Lnkk Erk Jnk Fos Jun AP 1 Ras Rac cdc42 TactivationBactivation Stress GTPproteinMAPKKKKMAPKKKMAPKKMAPK Transcriptionfactor p38 T B细胞相互作用与B细胞的增殖分化 chapternineBCellActivation 2 Ab MTOC microtubule organizingcenter WhenanactivatedhelperTcellencountersanantigen bindingBcell itbecomespolarizedandsecretesIL 4andothercytokinesatthepointofcell cellcontact ContactofTh2cellwithBcell Th2 Th2 B B T细胞对B细胞的辅助没有特异性T细胞识别B细胞所提呈抗原是其辅助的前提T细胞通过CD40L和CK辅助B细胞时极化并紧密接触T B细胞的相互作用具有特异性但不排除旁邻辅助 B细胞的增殖与分化 chapternineBCellActivation 3 B细胞在淋巴结的定居 激活 增殖 分化与生发中心形成体细胞高频突变与抗体亲和力成熟抗体类别转换浆细胞 记忆B细胞与再次应答 B细胞在淋巴结的定居 激活 增殖 分化与生发中心形成 HEV 高内皮小静脉 初级淋巴滤泡 次级淋巴滤泡 生发中心 髓索 HEV highendothelialvenule 高内皮细胞小静脉 SLC secondarylymphoidchemokine forreceptorCCR7onTcellandDCMIP 3 macrophageinflammationprotein 3 forreceptorCCR7BLC Blymphocytechemokine forreceptorCXCR5onBcell Thecellularorganizationofalymphoidorgan whichisorchestratedbychemokines naiveCD4T Th0 Th2 Th1 Stat1T bet Gata3 IL 12 IL 4 IL 12R 1 2IFN R1 IFN R2 cIL 4R IFN TNF IL 2 IL 4IL 5IL 13 CCR3 4 8CCR7 CxCR3 CCR5 Stat4 Stat6 AgMHC costimulation ROR t IL 17IL 17F Stat3 IL 23 Il 23RIL 12R 1 Th17 IFN CD4T细胞功能性亚群的分化 EarlyandlateeventsinhumoralimmuneresponsestoTcell dependentproteinantigens ActivationandmigrationofTandBcells T Bcellinteraction Bdifferentiation Igsecretion isotypeswitching Germinalcenterreaction affinitymaturation memoryBcells Antigen bindingcellsaretrappedintheTcellzoneofthelymphnodetoformaprimaryfocus 原发灶 B细胞在淋巴结的定居 激活 增殖 分化与生发中心形成 结构 体细胞高频突变与抗体亲和力成熟 分析抗体重链和轻链基因核苷酸序列变异性的实验步骤 1 1000bpvs1 107 1010 T细胞高频突变 选择 Ig亲和力成熟 中低亲和力 高亲和力 Mutationandselectioninmaturationofantibodyaffinity 抗体类别转换 Neutrolization Opsonization C activation complement Threeeffectivefunctionsofspecificanti bodies Isotypeswitchtakesplaceduringthesecondresponseofantibodies Immunoglobulinlevelsinnewborninfantsfalltolowlevelsaroundsixmonthsofage Molecularmechanismsofheavychainisotypeswitching Mainfactorsresponsibleforisotypeswitchingofantibodies A Antigenproperties solubleantigens IgG1 polysachrideantigens IgM alsoIgG2 IgG3 wormantigens IgEB ExpressionofCD40onBcells inductionofsecondsignal mutationofCD40L expressiondeficiency failureofisotypeswitch X linkedhyperIgMsyndromeC Administrationroutesofantigensintobodyandadjuvants oraladministration mucosalimmunization IgA subcutaneousorintramuscularinjection IgG immunizationwithFreudadjuvant 弗氏佐剂 IgG immunizationwithaluminiumadjuvant IgED Cytokines B TH2 CD40LCD40 CD28B7 Ck BCR Ig Ig Ag proliferationdifferentiation X linkedhyperIgMsyndromecausedbythedefectiveexpressionofCD40ligandonTcells resultinginnosecondsignalforBcelldifferentiationandisotypeswitching PatientswithX linkedhyperIgMsyndromeareunabletofullyactivatetheirBcells BcellactivationbyTcellsisrequiredbothforisotypeswitchingandfortheformationofgerminalcenters Criticalrolesofcytokinesinisotypeswitchofimmunoglobulin 浆细胞 记忆B细胞与再次应答 记忆B细胞 Bm 的一些特点 初次接触抗原一个月后产生 Tm五天后产生 并长期存在 Bm诱发的二次应答仍需要已活化Th2的协助 和初始B细胞一起参与外周循环 可聚集在某些外周免疫器官 如脾脏滤泡 淋巴结 结合淋巴结 Peyer spatch Bm和初始B细胞显示不同的表面标志 Acomparisonofna veandmemoryBcells1PropertyNa veBcellMemoryBcell1MembranemarksimmunoglobulinIgM IgDIgM IgG IgA IgEcomplementreceptorlowhighAnatomiclocationspleenBM lymphnode spleenLifespanshort livedlong livedRecirculationyesyesReceptoraffinitylowerhigherduetoaffinitymaturationAdhesionmoleculesICAM 1lowhigh Whylong livedaretheantigen specificmemorylymphocyteclones A Persistenceofretainedantigens boundtoiccosomesoffolliculardendriticcells mightbecrucial B Therearecross reactionbetweenthenewlyenteringantigensandtheantigenoriginallysensitizingthememorycells C Cytokinessuchasthoseproducedeitherconstitutivelyorduringthecourseofantigen specificimmuneresponsescouldberesponsiblefordividingofmemorycellstomaintainthememorycellclonesinanantigen non specificmanner Possiblemechanismsformaintenanceoftheantigen sensitizedmemorycells AntigencanberetainedwithinfolliculardendriticcellsforalongtimeinaformofAg Abcomplex antigen B细胞对胸腺非依赖抗原的应答 chapternineBCellActivation 4 TI 1antigensarepolyclonalBcellactivatorsathighconcentrations whereasatlowconcentrationstheyinducedanantigen specificantibodyresponse