免疫调节_陈建忠.ppt

1、The immune response is subject to a variety of control mechanisms which serve to restore the immune system to a resting state when the response to a given antigen is no long required. 抗体浓度对抗体产生的调节抗体浓度对抗体产生的调节家兔经抗原免疫后产生特异性抗体，用血清交换人为降低抗体浓度后，可引起抗体产生家兔经抗原免疫后产生特异性抗体，用血清交换人为降低抗体浓度后，可引起抗体产生量的反馈性升高量的反馈性升高,

2、并在到达一定强度后逐渐下降。说明机体可感知自身抗体浓度的变化，并在到达一定强度后逐渐下降。说明机体可感知自身抗体浓度的变化，并自行启动调节机制并自行启动调节机制 Normal anti-infection anti-tumour Abnormal Auto-immune disease Tumour Persisitent infection Allergy SARS patient healthy subjectsevereinflammationreactionin lungnRegulation of innate immunitynImmunoregulation mediated b

3、y Inhibitory ReceptornRegulation by TregnIdiotype networknImmunoregulation by other mechanism A. Regulation of innate immunity1.Feedback Regulation of secretion of inflammatory factor PAMPs (Pathogen associated molecular patterns) are conserved structures among many pathogens. PAMPs are generated by

4、 microbes and not by the host, suggesting that PAMPs are good targets for innate immunity to discriminate between self- and nonself. Furthermore, PAMPs are essential for microbial survival. LPS, CpG DNA，ssRNA，dsRNA, PGN, LTA, HSP, et al. Pattern Recognition Receptors (PRRs) charateristic Few diversi

5、ty Non clonal ditributionImmediate immune response Mambrane PRR:TLR1,2,4,6;MR；SR； Secretory PRR:MBL;CRP;LPB； Cytoplasm RR:TLR3,TLR7/8,TLR9; NLR;RIG-,MDA-5;11固有免疫中针对固有免疫中针对TLR信号转导的负向调节信号转导的负向调节TIR: Toll/IL-1 receptor; ASK1: 凋亡信号调节激酶凋亡信号调节激酶1; IRAK: IL-1受体相关激酶受体相关激酶; MAPK: 丝裂原激活丝裂原激活蛋白激酶蛋白激酶; MyD88: 髓

6、样分化因子髓样分化因子 88; NF- B: 核因子核因子 B; PI 3K: 磷酸肌醇磷酸肌醇 3激酶激酶; PIP2：2磷酸磷脂磷酸磷脂 酰肌醇酰肌醇; PIP3: 3磷酸磷脂酰肌醇；磷酸磷脂酰肌醇；PKB: 蛋白激酶蛋白激酶 B; Rac: 小小G蛋白蛋白; SIGIRR: 单一单一Ig IL-1R相关分子相关分子; ; TIRAP: TIR (Toll/IL-1 受体受体) ) 相关蛋白相关蛋白; ; TRAF6: TNF 受体相关因子受体相关因子6。 炎症细胞因子基因转录TLR4CD14ST2SIGIRRMD2MyD88TIRAPTRAF6SOCS1IRAK1IRAK4NF-BMAP

7、KPKBPI 3K MyD88sIRAK-M受体衔接蛋白信号分子激酶转录因子抑制因子基因转录 激活 抑制Rac1 PIP2 PIP3ASK1TIRTIRA. Regulation of innate immunity1.Regulation by SOCS (suppressor of cytokine signaling)13C蛋白质蛋白质泛素化降解泛素化降解JakStatCISSOCS1 SOCS3JakAJakStatStat胞核胞核DNA细胞因子受体细胞因子受体细胞细胞因子因子SOCS家族部分成员家族部分成员D N端区端区 SH2结构域结构域 SOCS框框胞核胞核B 基因基因X,Y,Z

8、SOCS 基因基因生物学生物学效应效应YpStat 其它其它信号途径信号途径基因转录基因转录Stat细胞因子细胞因子细胞因子受体细胞因子受体磷酸磷酸化化胞核胞核JakYCISSOCS1SOCS2SOCS3pYSOCS 蛋白以负向反馈环路阻抑细胞因子的信号转导蛋白以负向反馈环路阻抑细胞因子的信号转导 14补体成分补体成分C3裂介后产生裂介后产生的相关分子的相关分子C3 C3b C3d C3c C3f C3 转化酶转化酶 I factor I factor+ + H FactorH Factor C3dg C3aiC3b C3g C3转化酶转化酶C3转化酶转化酶Complement regulat

9、ory Protein1516蛋白磷酸化和脱磷酸化分别由蛋白激酶和蛋白磷酸酶促成蛋白质蛋白质 ATP-OH+ ADP+蛋白质蛋白质 O -O-P-O- - | O- -蛋白质蛋白质 O -O-P-O- - | O- -蛋白质蛋白质 -OH + O HO-O-P-O- - | O- -H2O蛋白激酶蛋白激酶 蛋白磷酸酶蛋白磷酸酶 蛋白磷酸化蛋白磷酸化 蛋白脱磷酸化蛋白脱磷酸化PTK and PTPInhibitory receptor mediated regulation17免疫细胞激活性受体和抑制性受体及其作用特点免疫细胞激活性受体和抑制性受体及其作用特点 基因转录 激活激活 抑制抑制Zap

10、-70, SykSHP-1, SHP-2ITAMITIMSrc PTKPTKPTP 磷酸化磷酸化激活性激活性受体受体抑制性抑制性受体受体磷酸化磷酸化脱磷酸化脱磷酸化18 T细胞激活及相关免疫反应中的共信号分子及其受体 家族 配体 受体 ITAM/ITIM Ig-SF B7-1 CD28 ITAM B7-2 CTLA-4 ITIM B7-H1 PD-1 ITIM B7-DC ? B7-H2 ICOS B7-H3 ? HVEM BTLA ITIM TNF CD40L CD40 OX40L OX40 4-1BBL 4-1BB TTAPCAPC1924 hB7CD28AgTCRB7CTLA-4激活信号

11、激活信号 I T I MI TAM抑制信号抑制信号 T细胞细胞CTLA-4对对T细胞激活的反馈调节细胞激活的反馈调节通过两种结构相似但功能相反的协同信号受体CD28 和 CTLA4 调节 T 细胞的激活抗原递呈细胞抗原递呈细胞 T T细胞细胞激活激活 抑制抑制 CD28 CTLA4 抗抗CD28 抗抗CTLA4 (Fab)2 B7 CTLA4-Ig21抑制性受体抑制性受体FcRII-B对抗体产生的反馈性调节对抗体产生的反馈性调节干扰干扰 B 细胞激活的信号转导细胞激活的信号转导 BCR (mIgM)抗BCR抗体Ag-Ab复合物Fc RII-BFc RII-BITIMITIM22BCR (mIg

12、M)抗抗BCR抗体抗体 (Ab2)Fc RII-B ITIM B 细胞激活信号转导受阻细胞激活信号转导受阻抑制性受体抑制性受体FcRII-B对抗体产生的反馈性调节对抗体产生的反馈性调节人人NK细胞主要的抑制性受体和激活性受体细胞主要的抑制性受体和激活性受体24allo-celltumorcellnormalcellvirus-Infectedcell NK NK NK NK+ +kill kill killno killNKs cytotoxic activity depends on activation of the signaling initiated by the ligation

13、of inhibitory receptor with its ligandactivation receptorinhibitory receptor25T CellB cell T cellMast cellNK cellTCR-CD3BCR-Ig/IgV9V2 TCRFcRIKIR-S + DAP12CD94/NKG2C + DAP12NKG2D + DAP10NCR + /FcR1CD16 + /FcR1CTLA-4, PDL-1, BTLAFcRII-B, CD22CD94/NKG2AFcRII-BKIR-LCD94/NKG2AILT2 Cell Activating recepto

14、r Inhibitory receptorActivating receptor and Inhibitory receptor of Immune cellscharacteristicNature Tregadaptive TregInduction locationThymus (periphery),peripheryFoxp3+IL-2 dependence+CD25 +-/+Antigen specificityAuto-antigenTissue-specific Ag and exogenous AgmechanismCell-contact, CK independenceC

15、ell-contact, CK dependenceFunctionInhibit ART mediated ResponseInhibit pathological responseExampleCD4+CD25+TCD4+ Tr1,Th329共刺激共刺激 IFN- TNF- CCR5CXCR3IL-4IL-5IL-13CCR3,4,8Th1Th2IL-4pMHCTh 0初始初始 TIL-4RStat6 IL4Gata3IFNGIFN- RIL-12IL-12RpMHCTCRStat4Stat1 IFNGT-betIL4IL-23IL-23RStat3 IL17IFNG, IL4 IL-17

16、IL-17FTh17IL-23IL-12IL-4IFN 细胞免疫细胞免疫体液免疫体液免疫炎症反应炎症反应IL-17ROR t发挥调节作用的发挥调节作用的Th1和和Th2亚群在功能上的相互拮抗亚群在功能上的相互拮抗Th1和和Th2亚群各自藉助分泌的细胞因子和激活的亚群专一性转录因子以调节亚群各自藉助分泌的细胞因子和激活的亚群专一性转录因子以调节性性T细胞的形式抑制另一亚群的分化细胞的形式抑制另一亚群的分化 33IFN- 逆转逆转Th2极化格局通过激活极化格局通过激活Th1诱导抗胞内菌免疫诱导抗胞内菌免疫 342D. Regulation by idiotypes and anti-idiotyp

17、ic antibodies Antibodies formed against Ag-binding sites of an Ab are called anti-idiotypic antibodies, and are capable of influencing the outcome of an immune response. Id and AId interactions may enhance or suppress Ab responses.(1)Isotype The genes for isotype variants are present in all healthy

18、member of a species.(2) Allotype This refers to genetic variation between individuals within a species.(3) Idiotype Variation in the V domain ,particularly in CDR, produces idiotype.40Idiotype network and antigen internal imageAg Ag Ab1 (Id) Ab2 (AId) Ab3 Ab epitope41利用独特型网络进行免疫干预的两种主要途径利用独特型网络进行免疫干

19、预的两种主要途径AgAb2 增强Ab1Ab1Ab1Ab2BAAb3 / Ab1 Ab1 Ab2 Ab2削弱Ab1Ab11. Activation-induced cell death (AICD) Fas (CD95) and FasL Fas membrane protein is expressed on lymphoid and other cells but is increased in expression with cellular activation. FasL is expressed on activated T cells. Thus, activation of T

20、cells results in the expression of both Fas and FasL. The intracellular portion of the Fas receptor molecule contains death domains, which recruit proteins that lead to the activation of a cascade of proteases which induce apoptosis. Fas-FasL interaction is a major means of mediating AICD in CD4+ T

21、cell.DD:death domain70aa80aa150 aa FasL Fas (receptor)Fas (CD95), a type Imembrane protein with325 aa (48 kD)FasL (Fas ligand), a type II membrane proteinwith 235 aasFasLCaspase:胱天蛋白酶胱天蛋白酶 Major advances have recently been made in mapping the loci which govern susceptibility to the autoimmune diseas

22、e. When the lymphoproliferative (lpr) gene is present in mouse strains, it causes the development of a characteristic clinical syndrome. The mice develop anti-DNA antibodies, rheumatoid factor, circulating IC and glomerulonephritis. 47WT TTT GAG GAA TCT AAG ACC TTT TTC GGC TTG TAT AAGgld TTT GAG GAA

23、 TCT AAG ACC CTT TTC GGC TTG TAT AAG CYT TM EXTgld PheLeulprAsn死亡结构域死亡结构域IleFas FasLAB自身免疫性淋巴自身免疫性淋巴细胞增生综合征细胞增生综合征自身抗原自身抗原自身抗原驱动下的淋巴细胞克隆扩增自身抗原驱动下的淋巴细胞克隆扩增克隆收缩克隆收缩受阻受阻克隆收缩克隆收缩无疾病无疾病AICD Lymphocytes express receptors for many hormones, neurotransmitters and neuropeptides. G. Genetic control of immune response 1. Control of immune response by MHCImmune resp