某些風(fēng)濕性疾病的免疫問題教學(xué)課件

1、 先天免疫 第一道防線 適應(yīng)性免疫 特異性,記憶 免疫, 響應(yīng)的調(diào)節(jié)類型 免疫,提高抗微生物活性 先天免疫 第一道防線 ADAPTIVE IMMUNITY Specificity, Memory RECRUITS, MODULATES TYPE OF RESPONSE RECRUITS, ENHANCES ANTIMICROBICAL ACTIVITY 先天免疫系統(tǒng)的功能 先天免疫的模式識(shí)別先天免疫的模式識(shí)別 受體識(shí)別模式受體識(shí)別模式 PRRs PAMPs 病原體相關(guān)分子模式病原體相關(guān)分子模式 獨(dú)特的微生物產(chǎn)生的物質(zhì) e.g. LPS, zymosan, peptidoglycan, doub

2、le-stranded RNA DAMPs DANGER-ASSOCIATED分子模式分子模式 組織損傷產(chǎn)生、釋放的自體分子 e.g. heat shock proteins, matrix fragments, DNA 數(shù)量有限的受體 包括叫做TLRs的toll樣受體,nod樣受體(NLRs),RNA helicases,Dectin,Mannose-binding受體 先天免疫識(shí)別模 CELL SURFACE 核內(nèi)體 細(xì)胞質(zhì) 病原體相關(guān)分子模式 PAMPS DANGER-ASSOCIATED分子模式分子模式 DAMPS 對(duì)刺激的響應(yīng) 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 適應(yīng)性免疫 特異性,記憶 T cells and B cells RECRUITS, MODULATES TYPE OF RESPONSE RECRUITS, ENHANCES ANTIMICROBICAL ACTIVITY 適應(yīng)性免疫反應(yīng)的多樣性 n107年到109個(gè)不同的B細(xì)胞和T細(xì)胞的受體,并顯著的特異性區(qū)分微生 物 n多樣性通過(guò)體細(xì)胞遺傳基因片段的重組 Va1Van n=45 Ja1Jan n=55 Ca

4、 人類人類T細(xì)胞受體細(xì)胞受體,連鎖連鎖 特定受體和抗原之間的相互作用導(dǎo)致克隆擴(kuò)張 T CELLSB CELLS T cell receptor CD4 or CD8 B cell receptor (Immunoglobulin) ANTIGEN PRESENTING CELL (樹突細(xì)胞,巨噬細(xì)胞、B細(xì)胞) 微生物微生物 增殖增殖 增殖增殖 MHC AntigenAntigen 克隆擴(kuò)張產(chǎn)生效應(yīng)和記憶細(xì)胞 APC T CELL 直接細(xì)胞裂解刺激B 細(xì)胞 刺激先天免疫系統(tǒng) 效應(yīng)效應(yīng)T細(xì)胞細(xì)胞 記憶記憶T細(xì)胞細(xì)胞 在他們?cè)俅伪┞对诳?原反應(yīng)迅速 B CELL 分泌高親和力抗體 漿細(xì)胞漿細(xì)胞 記憶

5、記憶B細(xì)胞細(xì)胞 在他們?cè)俅伪┞对诳?原反應(yīng)迅速 先天免疫系統(tǒng)對(duì)適應(yīng)性免疫反應(yīng)的 發(fā)展起關(guān)鍵作用 兩種信號(hào)需要刺激B細(xì)胞和T細(xì)胞 Signal 1:抗原 T cells -MHC分子提供的肽 B cells -交聯(lián)表面抗原Ig Signal 2:炎癥信號(hào) 天生的激活模式識(shí)別受體 co-stimulatory Upregulates細(xì)胞表面的分子 Upregulates激活細(xì)胞因子 在缺乏信號(hào)2的情況下信號(hào)1導(dǎo)致無(wú)效能 先天免疫系統(tǒng)對(duì)適應(yīng)性免疫反應(yīng)的 發(fā)展起關(guān)鍵作用 抗原提呈細(xì)胞抗原提呈細(xì)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 控制免疫反應(yīng):限制對(duì)感染的反應(yīng) 機(jī)制包括: n清除感染限制抗原,移除刺激 n表達(dá)式的抑制分子 n早期的反應(yīng):APC B7 T細(xì)胞CD28 Costimulatory n后來(lái)回應(yīng):APC B7 CTLA4抑制性T細(xì)胞 n調(diào)節(jié)性T細(xì)胞(群)采取行動(dòng)抑制炎癥 控制免疫反應(yīng):預(yù)防應(yīng)對(duì)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“訓(xùn)練”成不識(shí)別self-antigens 中樞耐受中樞耐受 對(duì)self-antigens反應(yīng)強(qiáng)烈

7、的淋巴細(xì)胞在時(shí)發(fā)展過(guò)程中被刪 除 外周耐受外周耐受 n外周self-reactive的淋巴細(xì)胞的刪除或無(wú)效化 n共刺激缺失 無(wú)效 n重復(fù)刺激 誘導(dǎo)凋亡 n調(diào)節(jié)性T細(xì)胞行動(dòng) 多形核細(xì)胞多形核細(xì)胞 細(xì)胞因子細(xì)胞因子 細(xì)胞因子細(xì)胞因子 趨化因子趨化因子 共同刺激共同刺激 先天免疫先天免疫 識(shí)別識(shí)別 感染感染 APC T CELL 多形核細(xì)胞多形核細(xì)胞 B CELL 細(xì)胞活化細(xì)胞活化 細(xì)胞補(bǔ)充細(xì)胞補(bǔ)充 發(fā)展發(fā)展 適應(yīng)適應(yīng) 免疫免疫 Resolution With Memory 失調(diào)失調(diào) 不當(dāng)不當(dāng) 天生的激活天生的激活 適應(yīng)缺失適應(yīng)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（受體識(shí)別模受體識(shí)別模 式）式） nInflammasome activation releases IL-1 nIL-1 activates the synovium, recruiting neutrophils into the joint NALP-3 INFLAMMASOME LRRNACHTPYRIN 配體傳感配體傳感齊聚齊聚 效應(yīng)器效應(yīng)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 趨化因子 細(xì)胞因子 CHEMOKINES CYTOKINES SYNOVIUM 滑膜液滑膜液 巨噬細(xì)胞巨噬細(xì)胞 成纖維細(xì)胞成纖維細(xì)胞 PMN PMN PMN PMN PMN PMN PMN PMN PMN PMN PMN PMN NALP-3 INFLAMMASOME IL-1 拮抗劑拮抗劑 NALP-3模式識(shí)別受體與遺傳關(guān) 聯(lián) n突變?cè)黾?/p>

10、NALP-3 Inflammasomes 活性 n家族性地中海熱(FMF) n在MEFV基因突變, n編碼蛋白pyrin,一個(gè)負(fù)調(diào)節(jié)inflammasome者 nCryopyrin-associated周期綜合征 n家族冷autoinflammatory綜合癥,Muckle- Wells綜合癥,新生兒發(fā)病多系統(tǒng)炎性疾病 n突變?cè)黾覰ALP-3 inflammasome活動(dòng) NOD2 mutations associated with several diseases Crohns Disease Graft-Versus-Host Disease Blau Syndrome Early-Ons

11、et Sarcoidosis 遺傳相關(guān)的其他模式識(shí)別受體 SLE PATHOGENESIS n四個(gè)因素在狼瘡發(fā)病機(jī)制中起重要作用 n減少細(xì)胞碎片清除 nTLR-stimulated樹突細(xì)胞的I型干擾素產(chǎn)生 n損失B細(xì)胞和T細(xì)胞耐受 n增加對(duì)核酸的自體抗體 免疫復(fù)合體存入組織,然后導(dǎo)致激活補(bǔ)充與損傷 SLE PATHOGENESIS 減少細(xì)胞碎片的清除 單核單核 吞噬系統(tǒng)吞噬系統(tǒng) 正常正常 清除細(xì)胞碎片清除細(xì)胞碎片,免疫復(fù)合體免疫復(fù)合體 無(wú)共刺激的抗原呈遞無(wú)共刺激的抗原呈遞 感染感染 微生物殺滅微生物殺滅 PRR激活激活 共刺激的抗原呈遞共刺激的抗原呈遞 SLE 減少清理碎片 增加self-an

12、tigens池為B細(xì)胞和T細(xì)胞 增加DAMPS池為PRR的激活 SLE PATHOGENESIS 耐受喪失與自身抗體產(chǎn)生 T cell B cell NORMAL 外周耐受外周耐受 Weakly self-reactive B and T cells anergic 抗原隔離OR Antigens presented without costimulation T cell APC SLE 耐受喪失耐受喪失 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型干擾素的響應(yīng) IFN-a,ba,b IFN-a,ba,b TLR3/7/8/9 漿細(xì)胞樣樹突狀細(xì)胞漿細(xì)胞樣樹突狀細(xì)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 漿細(xì)胞樣樹突狀細(xì)胞漿細(xì)胞樣樹突狀細(xì)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 狼瘡遺傳學(xué)狼瘡遺傳學(xué) 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免疫的滲透 n滑膜增生與肉芽組織形成 n骨的侵蝕,破骨細(xì)胞活性 成骨細(xì)胞的活性 n軟骨被侵蝕 RA

19、 PATHOGENESIS 免疫滲透 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 骨侵蝕 SYNOVIUM SYNOVIAL FLUID C5a C5a C5a C5a

21、C5a SYNOVIUM INCREASED BONE RESORPTION AND EROSION Increased破骨細(xì)胞破骨細(xì)胞activity Possible inhibition of osteoblast activity Synovial血管翳血管翳 erosion 破骨細(xì)胞破骨細(xì)胞 激活激活 RANKL TNF-a a RA PATHOGENESIS 軟骨侵蝕 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 -遺傳學(xué) 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