B細(xì)胞激活1.ppt

B細(xì)胞激活 BCellActivation B細(xì)胞抗原識別受體與信號轉(zhuǎn)導(dǎo)T B細(xì)胞相互作用與B細(xì)胞的增殖分化B細(xì)胞的增殖與分化B細(xì)胞對T細(xì)胞非依賴抗原的應(yīng)答 B細(xì)胞抗原識別受體與信號轉(zhuǎn)導(dǎo) 1 chapternineBCellActivation T細(xì)胞抗原識別信號的轉(zhuǎn)導(dǎo) 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 細(xì)胞骨架重排 免疫突觸 PI PIP3 BCR Ig Ig ITAM 受體交聯(lián) 形成免疫突觸 偶聯(lián)PTK活化 Lyn Fyn Blk ITAM磷酸化 活化 招募胞漿PTK Syk PTK磷酸化 活化 銜接蛋白 BLNK SLP 65 PLC PIP2 DAG IP3 激活PKC 活化鈣調(diào)磷酸酶 活化MAP激酶級聯(lián)反應(yīng) 活化轉(zhuǎn)錄因子 NF B NFAT AP 1 與特異性基因的啟動(dòng)子結(jié)合 啟動(dòng)基因轉(zhuǎn)錄 轉(zhuǎn)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細(xì)胞相互作用與B細(xì)胞的增殖分化 chapternineBCellActivation 2 Ab MTOC microtubule organizingcenter WhenanactivatedhelperTcellencountersanantigen bindingBcell itbecomespolarizedandsecretesIL 4andothercytokinesatthepointofcell cellcontact ContactofTh2cellwithBcell Th2 Th2 B B T細(xì)胞對B細(xì)胞的輔助沒有特異性T細(xì)胞識別B細(xì)胞所提呈抗原是其輔助的前提T細(xì)胞通過CD40L和CK輔助B細(xì)胞時(shí)極化并緊密接觸T B細(xì)胞的相互作用具有特異性但不排除旁鄰輔助 B細(xì)胞的增殖與分化 chapternineBCellActivation 3 B細(xì)胞在淋巴結(jié)的定居 激活 增殖 分化與生發(fā)中心形成體細(xì)胞高頻突變與抗體親和力成熟抗體類別轉(zhuǎn)換漿細(xì)胞 記憶B細(xì)胞與再次應(yīng)答 B細(xì)胞在淋巴結(jié)的定居 激活 增殖 分化與生發(fā)中心形成 HEV 高內(nèi)皮小靜脈 初級淋巴濾泡 次級淋巴濾泡 生發(fā)中心 髓索 HEV highendothelialvenule 高內(nèi)皮細(xì)胞小靜脈 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細(xì)胞功能性亞群的分化 EarlyandlateeventsinhumoralimmuneresponsestoTcell dependentproteinantigens ActivationandmigrationofTandBcells T Bcellinteraction Bdifferentiation Igsecretion isotypeswitching Germinalcenterreaction affinitymaturation memoryBcells Antigen bindingcellsaretrappedintheTcellzoneofthelymphnodetoformaprimaryfocus 原發(fā)灶 B細(xì)胞在淋巴結(jié)的定居 激活 增殖 分化與生發(fā)中心形成 結(jié)構(gòu) 體細(xì)胞高頻突變與抗體親和力成熟 分析抗體重鏈和輕鏈基因核苷酸序列變異性的實(shí)驗(yàn)步驟 1 1000bpvs1 107 1010 T細(xì)胞高頻突變 選擇 Ig親和力成熟 中低親和力 高親和力 Mutationandselectioninmaturationofantibodyaffinity 抗體類別轉(zhuǎn)換 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 弗氏佐劑 IgG immunizationwithaluminiumadjuvant IgED Cytokines B TH2 CD40LCD40 CD28B7 Ck BCR Ig Ig Ag proliferationdifferentiation X linkedhyperIgMsyndromecausedbythedefectiveexpressionofCD40ligandonTcells resultinginnosecondsignalforBcelldifferentiationandisotypeswitching PatientswithX linkedhyperIgMsyndromeareunabletofullyactivatetheirBcells BcellactivationbyTcellsisrequiredbothforisotypeswitchingandfortheformationofgerminalcenters Criticalrolesofcytokinesinisotypeswitchofimmunoglobulin 漿細(xì)胞 記憶B細(xì)胞與再次應(yīng)答 記憶B細(xì)胞 Bm 的一些特點(diǎn) 初次接觸抗原一個(gè)月后產(chǎn)生 Tm五天后產(chǎn)生 并長期存在 Bm誘發(fā)的二次應(yīng)答仍需要已活化Th2的協(xié)助 和初始B細(xì)胞一起參與外周循環(huán) 可聚集在某些外周免疫器官 如脾臟濾泡 淋巴結(jié) 結(jié)合淋巴結(jié) Peyer spatch Bm和初始B細(xì)胞顯示不同的表面標(biāo)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細(xì)胞對胸腺非依賴抗原的應(yīng)答 chapternineBCellActivation 4 TI 1antigensarepolyclonalBcellactivatorsathighconcentrations whereasatlowconcentrationstheyinducedanantigen specificantibodyresponse