某些风湿性疾病的免疫问题教学课件

1、 先天免疫 第一道防线 适应性免疫 特异性,记忆 免疫, 响应的调节类型 免疫,提高抗微生物活性 先天免疫 第一道防线 ADAPTIVE IMMUNITY Specificity, Memory RECRUITS, MODULATES TYPE OF RESPONSE RECRUITS, ENHANCES ANTIMICROBICAL ACTIVITY 先天免疫系统的功能 先天免疫的模式识别先天免疫的模式识别 受体识别模式受体识别模式 PRRs PAMPs 病原体相关分子模式病原体相关分子模式 独特的微生物产生的物质 e.g. LPS, zymosan, peptidoglycan, doub

2、le-stranded RNA DAMPs DANGER-ASSOCIATED分子模式分子模式 组织损伤产生、释放的自体分子 e.g. heat shock proteins, matrix fragments, DNA 数量有限的受体 包括叫做TLRs的toll样受体,nod样受体(NLRs),RNA helicases,Dectin,Mannose-binding受体 先天免疫识别模 CELL SURFACE 核内体 细胞质 病原体相关分子模式 PAMPS DANGER-ASSOCIATED分子模式分子模式 DAMPS 对刺激的响应 TNF, proIL-1, IL-6 Type I In

3、terferons TNF, proIL-1, IL-6 proIL-1 IL-1 RA SLE Gout INNATE IMMUNITY First Line of Defense 适应性免疫 特异性,记忆 T cells and B cells RECRUITS, MODULATES TYPE OF RESPONSE RECRUITS, ENHANCES ANTIMICROBICAL ACTIVITY 适应性免疫反应的多样性 n107年到109个不同的B细胞和T细胞的受体,并显著的特异性区分微生 物 n多样性通过体细胞遗传基因片段的重组 Va1Van n=45 Ja1Jan n=55 Ca

4、 人类人类T细胞受体细胞受体,连锁连锁 特定受体和抗原之间的相互作用导致克隆扩张 T CELLSB CELLS T cell receptor CD4 or CD8 B cell receptor (Immunoglobulin) ANTIGEN PRESENTING CELL (树突细胞,巨噬细胞、B细胞) 微生物微生物 增殖增殖 增殖增殖 MHC AntigenAntigen 克隆扩张产生效应和记忆细胞 APC T CELL 直接细胞裂解刺激B 细胞 刺激先天免疫系统 效应效应T细胞细胞 记忆记忆T细胞细胞 在他们再次暴露在抗 原反应迅速 B CELL 分泌高亲和力抗体 浆细胞浆细胞 记忆

5、记忆B细胞细胞 在他们再次暴露在抗 原反应迅速 先天免疫系统对适应性免疫反应的 发展起关键作用 两种信号需要刺激B细胞和T细胞 Signal 1:抗原 T cells -MHC分子提供的肽 B cells -交联表面抗原Ig Signal 2:炎症信号 天生的激活模式识别受体 co-stimulatory Upregulates细胞表面的分子 Upregulates激活细胞因子 在缺乏信号2的情况下信号1导致无效能 先天免疫系统对适应性免疫反应的 发展起关键作用 抗原提呈细胞抗原提呈细胞 T CELL TCR CD28 Microbe SIGNAL 1 MHC Microbial Killin

6、g SIGNAL 2 B7 Pattern Recognition Receptor Abatacept(CTLA4-Ig) 抑制共同刺激抑制共同刺激 控制免疫反应:限制对感染的反应 机制包括: n清除感染限制抗原,移除刺激 n表达式的抑制分子 n早期的反应:APC B7 T细胞CD28 Costimulatory n后来回应:APC B7 CTLA4抑制性T细胞 n调节性T细胞(群)采取行动抑制炎症 控制免疫反应:预防应对自我抗原 自我分子(蛋白,蛋白多糖等)由于免疫耐受都不具免 疫原性，那是它“训练”成不识别self-antigens 中枢耐受中枢耐受 对self-antigens反应强烈

7、的淋巴细胞在时发展过程中被删 除 外周耐受外周耐受 n外周self-reactive的淋巴细胞的删除或无效化 n共刺激缺失 无效 n重复刺激 诱导凋亡 n调节性T细胞行动 多形核细胞多形核细胞 细胞因子细胞因子 细胞因子细胞因子 趋化因子趋化因子 共同刺激共同刺激 先天免疫先天免疫 识别识别 感染感染 APC T CELL 多形核细胞多形核细胞 B CELL 细胞活化细胞活化 细胞补充细胞补充 发展发展 适应适应 免疫免疫 Resolution With Memory 失调失调 不当不当 天生的激活天生的激活 适应缺失适应缺失 耐受耐受 Immune Response GOUT nDiseas

8、e of innate immunity nUric Acid acts as a DAMP（ DANGER- ASSOCIATED分子模式）分子模式） nNALP-3 inflammasome is the PRR（受体识别模受体识别模 式）式） nInflammasome activation releases IL-1 nIL-1 activates the synovium, recruiting neutrophils into the joint NALP-3 INFLAMMASOME LRRNACHTPYRIN 配体传感配体传感齐聚齐聚 效应器效应器 NALP-3 LRRNACH

9、TPYRIN CARD ASC 半胱天冬酶半胱天冬酶 (inactive) URIC ACID PRO-IL-1 IL-1IL-1 INFLAMMSOME CASPASE-1 (active) GOUT PATHOGENESIS PRO-IL-1 IL-1 趋化因子 细胞因子 CHEMOKINES CYTOKINES SYNOVIUM 滑膜液滑膜液 巨噬细胞巨噬细胞 成纤维细胞成纤维细胞 PMN PMN PMN PMN PMN PMN PMN PMN PMN PMN PMN PMN NALP-3 INFLAMMASOME IL-1 拮抗剂拮抗剂 NALP-3模式识别受体与遗传关 联 n突变增加

10、NALP-3 Inflammasomes 活性 n家族性地中海热(FMF) n在MEFV基因突变, n编码蛋白pyrin,一个负调节inflammasome者 nCryopyrin-associated周期综合征 n家族冷autoinflammatory综合症,Muckle- Wells综合症,新生儿发病多系统炎性疾病 n突变增加NALP-3 inflammasome活动 NOD2 mutations associated with several diseases Crohns Disease Graft-Versus-Host Disease Blau Syndrome Early-Ons

11、et Sarcoidosis 遗传相关的其他模式识别受体 SLE PATHOGENESIS n四个因素在狼疮发病机制中起重要作用 n减少细胞碎片清除 nTLR-stimulated树突细胞的I型干扰素产生 n损失B细胞和T细胞耐受 n增加对核酸的自体抗体 免疫复合体存入组织,然后导致激活补充与损伤 SLE PATHOGENESIS 减少细胞碎片的清除 单核单核 吞噬系统吞噬系统 正常正常 清除细胞碎片清除细胞碎片,免疫复合体免疫复合体 无共刺激的抗原呈递无共刺激的抗原呈递 感染感染 微生物杀灭微生物杀灭 PRR激活激活 共刺激的抗原呈递共刺激的抗原呈递 SLE 减少清理碎片 增加self-an

12、tigens池为B细胞和T细胞 增加DAMPS池为PRR的激活 SLE PATHOGENESIS 耐受丧失与自身抗体产生 T cell B cell NORMAL 外周耐受外周耐受 Weakly self-reactive B and T cells anergic 抗原隔离OR Antigens presented without costimulation T cell APC SLE 耐受丧失耐受丧失 Increaesd stimulatio of self-reactive B and T cells with self-antigens Increased innate activa

13、tion with self DAMPs increases costimulation Increase autoantibody production to self antigens such as nucleic acids T cell B cell SLE PATHOGENESIS I型干扰素的响应 IFN-a,ba,b IFN-a,ba,b TLR3/7/8/9 浆细胞样树突状细胞浆细胞样树突状细胞 VIRAL INFECTION major producers type I interferons viral nucleic acids stimulate TLR3/7/8/9

14、 TLR stimulation leads to type I interferon production Type I interferons potent immune activator TLR3/7/8/9 浆细胞样树突状细胞浆细胞样树突状细胞 nucleic acid containing immune complexes stimulate TLR3/7/8/9 TLR stimulation leads to type I interferon production Type I interferons potent immune activator in absence of

15、 infection SLE SLE PATHOGENESIS MONONUCLEAR PHAGOCYTIC SYSTEM Decreased Clearance Cell Debris IFN-a,ba,b PLASMACYTOID DENDRITIC CELL B CELL Increased Plasmacytoid DC Type I Interferon Production IFN-a,ba,b IFN-a,ba,b Loss T and B Cell Tolerance Autoantibody Production T CELL 狼疮遗传学狼疮遗传学 MONONUCLEAR P

16、HAGOCYTIC SYSTEM IFN-a,ba,b PLASMACYTOID DENDRITIC CELL B CELL IFN-a,ba,b IFN-a,ba,b T CELL Decrease Clearance Cellular Debris Complement deficiencies (C1q, C2, C4) SNP in FCGR2A Loss B and T cell Tolerance SNPs associated with B and T cell signaling HLA-DR2 HLA-DR3 PTPN22 BANK1 BLK STAT4 Type I Int

17、erferon Release Interferon signature in peripheral blood cells of SLE patients Associated with SNPs in IRF5, IRAK1, and STAT4 RA PATHOGENESIS:正常SYNOVIUM SYNOVIAL FLUID SYNOVIUM SYNOVIAL FIBROBLAST Remodels extracellular matrix, Synthesize lubricin, hyaluronan SYNOVIAL MACROPHAGE Sentinel cell Phagoc

18、ytose debris SYNOVIAL LINING SYNOVIAL SUBLINING Blood Vessels Scattered Fibroblasts, Macrophages, Mast Cells BONE Formation Resorption (Osteoblasts) (Osteoclasts) CARTILAGE Chondrocytes Type II Collagen, Aggrecan RA PATHOGENESIS KEY FEATURES nsynovium免疫的渗透 n滑膜增生与肉芽组织形成 n骨的侵蚀,破骨细胞活性 成骨细胞的活性 n软骨被侵蚀 RA

19、 PATHOGENESIS 免疫渗透 C5a C5a C5a C5a C5a SYNOVIUM SYNOVIAL FLUID ADAPTIVE IMMUNITYINNATE IMMUNITY T Cells B Cells -Rheumatoid Factor -anti-CCP antibodies NeutrophilsComplement Activation MacrophagesImmune Complexes Dendritic Cells Mast Cells RA PATHOGENESIS 滑膜增生 SYNOVIUM SYNOVIAL FLUID C5a C5a C5a C5a

20、 C5a SYNOVIUM SYNOVIAL HYPERPLASIA Increased angiogenesis Synovial lining hyperplasia Lining becomes an invasive tissue mass (pannus) that erodes cartilage and bone Increased synovial macrophages TNF-a a Increased synovial fibroblasts IL-6 RA PATHOGENESIS 骨侵蚀 SYNOVIUM SYNOVIAL FLUID C5a C5a C5a C5a

21、C5a SYNOVIUM INCREASED BONE RESORPTION AND EROSION Increased破骨细胞破骨细胞activity Possible inhibition of osteoblast activity Synovial血管翳血管翳 erosion 破骨细胞破骨细胞 激活激活 RANKL TNF-a a RA PATHOGENESIS 软骨侵蚀 SYNOVIUM SYNOVIAL FLUID C5a C5a C5a C5a C5a SYNOVIUM INCREASED CARTILAGE EROSON Cartilage surface modified b

22、y immune complexes, extracellular matrix fragments, enzymatic digestion Inflammatory cytokines inhibit chondrocyte matrix repair Synovial pannus erodes cartilage matrix RA PATHOGENESIS -概述 Activation of Synovial Tissues by the Immune System Activation of the Immune System by Synovial Tissues CYTOKIN

23、E AND CHEMOKINE NETWORKS C5a C5aC5a C5a TNF-a a IL-6TNF-a a IL-17 IFN-g g IL-17 IFN-g gTNF-a a TNF-a a IL-1 TNF-a a RANKL RA PATHOGENESIS -遗传学 nCurrently identified genetic risk alleles only explain 10- 20% of genetic risk nFunction of risk alleles is not known nStrongest risk allele “Shared Epitope

24、” Conserved sequence in certain HLA-DR b chains MHC molecules involved in antigen presentation to T cells Examples: DRB*0101, DRB*0401, DRB*0404, DRB*1402 Most strongly associated with anti-CCP antibodies nMany risk alleles shared between autoimmune diseases TNFS14 PADI4 PTPN22 FCGR2A STAT4 CD28 CTL

25、A4 HLA-DR1 HLA-DR4 TNFAIP3 IRF5 CCR6 BLK TRAF1 CD40 BANK1 PTPN22 ITGAM FCGR2A STAT4 BLK TNFSF4 HLA-DR2 HLA-DR3 TNFAIP3 IRF5 IRAK1 RA RISK ALLELE SAMPLESLE RISK ALLELE SAMPLE SUMMARY nImmunology Innate vs. Adaptive Immunity Pattern Recognition Receptors in Innate Immune System Tolerance and Memory in

26、 Adaptive Immune System nGout Inflammasome Activation of IL-1 nSLE Loss of Immune Tolerance Interferon Signature Defects in Debris Clearance nRA Immune Activation of Synovial Tissues Synovial Activation of Immune System Role of Cytokine Networks Question 1 Macrophages and neutrophils are cells in th

27、e branch of the immune with which of the following characteristics? Found only in vertebrates Generates immunity to specific pathogens Recognizes conserved microbial patterns Development of response takes several days Answer: C: Recognizes conserved microbial patterns Question 2 Inflammasome activat

28、ion is central to disease pathogenesis in gout and which of the following diseases? Blau Syndrome Crohns Disease Muckle-Wells Syndrome Psoriasis A. SLE Answer: C: Muckle-Wells Syndrome NOD2 mutations associated the following diseases Crohns Disease, Graft-Versus-Host Disease, Blau Syndrome, Early- O

29、nset Sarcoidosis GENETIC ASSOCIATIONS WITH OTHER PATTERN RECOGNITION RECEPTORS NALP-3 activation associated with gout Mutations with NALP-3 or associated proteins associated with FMF, Cryopyrin-Associated Periodic Fever Syndromes Question 3 Gene profiling of the peripheral blood mononuclear cells ha

30、s shown that SLE patients have activation of which of the following cytokine pathways? IFN-a IFN-g IL-1 IL-6 A. IL-17 Answer: A: IFN-a SLE PATHOGENESIS MONONUCLEAR PHAGOCYTIC SYSTEM Decreased Clearance Cell Debris IFN-a,ba,b PLASMACYTOID DENDRITIC CELL B CELL Increased Plasmacytoid DC Type I Interferon Production IFN-a,ba,b IFN-a,ba,b Loss T and B Cell Tolerance Autoantibody Production T CELL Question 4 The shared epitope risk a