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B cell antigen receptor signaling roles in cell development and disease

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BCellAntigenReceptorSignaling:RolesinCellDevelopmentandDiseaseStephenB.Gauld,JosephM.DalPorto,JohnC.Cambier*SignalspropagatedthroughtheBcellantigenreceptor(BCR)arevitalforthedevelopmentandsurvivalofBlymphocytesinboththebonemarrowandtheperiphery.Thesesignalsnotonlyguidematurationandactivationbutalsoaffecttheremovalofpotentiallyself-reactiveBlymphocytes.Interestingly,thesesignalsareknowntobeeitherligand-independent(“tonic”signals)orinducedbyligand(antigen)bindingtotheBCR.WefocusontheproblemsthatoccurinBcelldevelopmentduetodefectsinsignalsemanatingfromtheBCR.Inaddition,wepresenttheBCellAntigenReceptorPathway,anSTKEConnectionsMapthatillustratestheeventsinvolvedinBcellsignaling.

ThesignalspropagatedthroughtheBcellantigenreceptor(BCR)arecentraltoBcelldevelopmentandtheresponsetoantigen.DefectiveBCRsignalingcanresultnotonlyinimpairedBcelldevelopmentandimmu-nodeficienciesbutalsoinapredispositiontoautoimmunity.Science’sSignalTransductionKnowledgeEnvironment(STKE)Connec-tionsMapsarehosttotheBCellAntigenReceptorPathway(http://stke.sciencemag.org/cgi/cm/CMP_6909),whichdepictsanddetailsthegeneral,orcanonical,mechanismsinBcellsignaling(1).TheBCRisamultiproteinstructurecontaininganantigen-bindingcomponentmembraneimmunoglobulin(mIg),whichisproducedfromtherearrangementofimmu-noglobulinheavyandlightchaingenes,noncovalentlyassociatedwithdisulfide-linkedsignaltransducingelementsIg-␣(CD79a)andIg-␤(CD79b)(2).BCRsig-nalingisinitiateduponbindingofantigentomIg,whichinducesreceptoraggregationandsubsequentphosphorylationoftheim-munoreceptortyrosine-basedactivationmotifs(ITAMs)ofIg-␣andIg-␤.BothIg-␣andIg-␤containasingleITAMmotifcomposedoftwotyrosineresidueswithsurroundingconsensussequences(3,4).PhosphorylationofthesetyrosineresiduesbytheSrcfamilykinasesLyn,Fyn,orBlkresultsintherecruitmentofanotherty-rosinekinase,Syk,throughinteractionswithphosphotyrosine-bindingSrchomolo-gy2(SH2)domains(5).SykrecruitmenttoIg-␣/␤facilitatesitsphosphorylation,acti-vation,andinitiationofdownstreamsignal-ingcascades(Fig.1)(6).AnumberofmoleculesthatinteractatornearthereceptorplayessentialrolesinBcelldevelopmentandfunction.BcellsrequiretheexpressionofasurfaceBCRfordevelopmentandsurvival.TheBCRcancomeintheformoffunctionallyrearrangedheavyandlightchainIgmoleculesasfoundonmatureBcellsor,inthecaseofpro–andpre–Bcells,asnascentheavychainscoupledtosurrogatelight-chainpartners(suchas␭5andVpreB)(7).ExpressionofIg-␣andIg-␤isessentialforBCRtransportandsurfaceexpression(8,9);however,thesemoleculesalsofunctioninsignaltransduction,whichcanaffectBcelldevelopment.Mutationofbothtyrosineres-iduesintheITAMofIg-␣blocksBcelldevelopmentatthepro–topre–Bcelltran-sition.InmiceunabletoexpressamatureBCRontheircellsurfaces(RAGϪ/Ϫ),mem-branetargetingofthecytoplasmicdomainsofIg-␣andIg-␤aloneissufficienttopromoteBcelldevelopment(10,11).Thus,signalstransducedbyIg-␣,andpresumablyIg-␤,appeartobeessentialfortheearlystagesofBcelldevelopment(10,12).ManyproteintyrosinekinaseshavevitalrolesindirectingBcelldevelopment.ThetyrosinekinaseLyn,forexample,phosphor-ylatesITAMtyrosineresiduesafterBCRag-gregationbutalsonegativelyregulatesBcellsignaling(13).LynϪ/Ϫmicedisplaynormal

bonemarrowBcelldevelopmentbuthavedifficultyinsustainingamatureperipheralBcellpopulation(14).BcellsthatdoprogresstothematureBcellstageexhibitapredilec-tionforautoreactivity(15,16).Thispheno-typemaybedueinparttoLyn’sadditionalroleinphosphorylationoftheimmunorecep-tortyrosine-basedinhibitorymotifdomains(ITIMs)ofinhibitorycoreceptors,suchasCD22(17).Thus,althoughLyn’sabsencedoesimpedetheprogressionofsignalsthroughtheBCRandmaycontributetoim-pairedsurvivalofmatureBcells,itappearstohaveanonredundantfunctionininhibitorypathwaysthatareimportantforthemainte-nanceoftolerance(18).ThetyrosinekinaseSykisalsocriticalforproperBcelldevelopment(19–21).MicedeficientinSykexhibitanearlyblockinBcelldevelopment,withcellsaccumu-latingatthelatepro–Bcellstage(22,23).UnlikeBcellsofRAGϪ/Ϫmice,which

arrestatasimilarpoint,BcellsofSykϪ/ϪanimalsarecapableofinitiatingIgheavy-chainrearrangementbutprogressnofur-ther,whichsuggeststhatSykisessentialforsignalingthroughtheBCRatthispointindevelopment.TheTecfamilykinasememberBruton’styrosinekinase(Btk)isinvolvedinBcelldevelopment,anditsdysfunctionleadstooftensevereimmunodeficiencies.NaturallyoccurringmutationstoBtkareresponsibleforX-linkedagammaglobulinemia(XLA)inhumansandarelateddeficiencyinmice,xid.

IntegratedDepartmentofImmunology,UniversityofColoradoHealthSciencesCenter,andNationalJewishMedicalResearchCenter,1400JacksonStreet,Den-ver,CO80206,USA.

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B细胞激活

B细胞激活


GTP protein MAPKKKK
MAPKKK MAPKK MAPK
T activation Ras ? Raf Mek Erk
B activation/Stress
Rac,cdc42
Pak
Mekk
Lnkk
Jnk
p38
Transcription factor
Fos
Jun
AP-1
Erk- and Jnk-pathways in MAP kinase-related signaling cascade
After T-cell dependent activation, B cells undergo rounds of mutation and selection for higher affinity, ultimately resulting in high-affinity memory B cells and antibody secreted from plasma cells
chapter nine
B Cell Activation
3
B 细胞的增殖与分化
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
初级 淋巴滤泡 次级 淋巴滤泡
生发中心
MTOC: microtubule-organizing center
B B
Th Th
Contact of Th2 cell with B cell
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
erk信号通路在超抗原seb诱导儿童单个核细胞糖皮质激素抵抗中的作用

erk信号通路在超抗原seb诱导儿童单个核细胞糖皮质激素抵抗中的作用

华中科技大学硕士学位论文ERK信号通路在超抗原SEB诱导儿童单个核细胞糖皮质激素抵抗中的作用姓名：***申请学位级别：硕士专业：儿科学指导教师：***20090501华中科技大学硕士学位论文ERK信号通路在超抗原SEB诱导儿童单个核细胞糖皮质激素抵抗中的作用华中科技大学同济医学院附属同济医院儿科研究生：王凤玉导师：周建华摘要目的建立超抗原金黄色葡萄球菌肠毒素B(SEB) 在体外诱导儿童外周血单个核细胞(PBMCs)对糖皮质激素产生抵抗的模型。

并探讨ERK信号通路在该模型中的作用。

方法：1.密度梯度离心法提取正常儿童外周血单个核细胞（PBMCs）,用10　g/ml 植物血凝素（PHA）或不同浓度（10，100，500，1000ng/ml）金黄色葡萄球菌肠毒素B（SEB）分别刺激培养72h，MTT法检测细胞增殖率，计算刺激指数（SI）。

2.（10-9 －10-6 ）mol/L DEX 分别加入10　g/mlPHA或10 ng/ml，100 ng/ml，500ng/ml SEB 刺激组PBMCs培养72h，通过检测细胞增殖率，判断是否产生激素抵抗。

3.将1　mol/L ERK抑制剂（U0126）或1　mol/LP38MAPK抑制剂（SB203580）分别加入100ng/ml SEB ＋10-6 mol/L DEX组细胞共孵育72h，通过细胞增殖率变化，判断阻滞上述信号途径是否对激素抵抗产生影响。

4. 间接免疫荧光与激光共聚焦显微镜观察不同组别PBMCs 中糖皮质激素受体（GRα）的亚细胞定位，通过计算核浆比，定量反映GRα核转位来说明对激素抵抗的影响及机制。

5. Western-blot 观察100ng/ml SEB刺激组和10　g/ml PHA刺激组ERK活化时程。

结果：1. MTT结果表明, 10－1000ng/ml的浓度范围内SEB与10µg/ml PHA刺激的PBMCs刺激指数（SI）无明显差异。

_型胶原诱导性关节炎遗传易感性及发病机制的研究进展

_型胶原诱导性关节炎遗传易感性及发病机制的研究进展

·46·山西医药杂志2002 年2 月第31 卷第1 期Sh a n x i M ed J , F e b ru a r y 2002, V o l 31, N o. 1·综述·ￊ型胶原诱导性关节炎遗传易感性及发病机制的研究进展西安交通大学医学院(710061) 任峰玲郭雄类风湿关节炎( rh eum a to id a r th r it is, RA ) 是一种以慢性关节病变为主要表现的全身免疫性疾病, 其病变的显著特征是多关节的滑膜组织的慢性炎症, 最终可导致不同程度的关节畸形和功能障碍, 严重影响患者的身心健康及生活质量。

目前, 全世界约有015%～1% 的人口罹患, 我国的患病率大约为014% , 该病的发病原因目前尚不清楚。

胶原诱导性关节炎(co llagen 2induced a r th r it is, C I A) 是指用天然的ￊ型胶原( typ e ￊco llagen , C ￊ) 免疫易感的啮齿类或灵长类动物种系所诱发的多关节的自身免疫性关节炎, 引起与RA 相似的免疫学及组织学损害, 是研究RA 常用的动物模型。

国外对C I A作了大量的研究, 以探求RA 的病因, 发病机制及有效的治疗措施, 现就C I A近5 a 来的病因及发病机制研究作一综述。

1ￊ型胶原与RARA 是一种自身免疫性疾病, 体液免疫与细胞免疫均参与RA 的炎症及组织损伤过程, 其中T 细胞诱导的自身免疫反应在疾病的起始中发挥着重要作用, 但是引发T 细胞反应的初始抗原尚不清楚。

有学者先后提出糖蛋白39 (g lycop ro te in 39, gp 39) [ 1 ] C ￊ, 蛋白多糖(p ro teo g lycan ) 等作为始发反应的自身抗原, 但大量的研究资料表明, C ￊ最有可能是诱发RA 的自身抗原。

其主要研究证据有: ①C ￊ在软骨中大量存在, 而软骨又是易免疫的组织, 处于疾病的活动中心, 且在大多数RA 患者的病变关节中能找到C ￊ特异的IgG 抗体[ 2, 3 ]。

细胞免疫T细胞活化的分子机制

细胞免疫T细胞活化的分子机制


整理ppt
6
Clonal expansion of T cells
整理ppt
7
Antigen-presenting cells are required for T cell activation
整理ppt
8
The initiation of T cell responses to specific antigen requires
Hidehiro整Y理apmptane & William E Paul, 2012 Nature Immunolo30gy
A model for early determination of Teff cell fate versus Tfh cell fate controlled by TCR signal strength
Dual specificity • MHC restriction • Antigen specificity
No signal-transducing functions
整理ppt
11
TCR complex
Composed of TCR and CD3 protein
整理ppt
12
CD3
invariant protein, identical in all T cells regardless of specificity
CD28 on T cells
整理ppt
23
Proliferation
Mediated primarily by an autocrine growth pathway
整理ppt
24
Clonal expansion
The frequency of naïve T cells specific for a given antigen is ~ 1:105-6