1、 先天免疫 第一道防線 適應性免疫 特異性,記憶 免疫, 響應的調節類型 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 先天免疫系統的功能 先天免疫的模式識別先天免疫的模式識別 受體識別模式受體識別模式 PRRs PAMPs 病原體相關分子模式病原體相關分子模式 獨特的微生物產生的物質 e.g. LPS, zymosan, peptidoglycan, doub

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

4、 人類人類T細胞受體細胞受體,連鎖連鎖 特定受體和抗原之間的相互作用導致克隆擴張 T CELLSB CELLS T cell receptor CD4 or CD8 B cell receptor (Immunoglobulin) ANTIGEN PRESENTING CELL (樹突細胞,巨噬細胞、B細胞) 微生物微生物 增殖增殖 增殖增殖 MHC AntigenAntigen 克隆擴張產生效應和記憶細胞 APC T CELL 直接細胞裂解刺激B 細胞 刺激先天免疫系統 效應效應T細胞細胞 記憶記憶T細胞細胞 在他們再次暴露在抗 原反應迅速 B CELL 分泌高親和力抗體 漿細胞漿細胞 記憶

5、記憶B細胞細胞 在他們再次暴露在抗 原反應迅速 先天免疫系統對適應性免疫反應的 發展起關鍵作用 兩種信號需要刺激B細胞和T細胞 Signal 1:抗原 T cells -MHC分子提供的肽 B cells -交聯表面抗原Ig Signal 2:炎癥信號 天生的激活模式識別受體 co-stimulatory Upregulates細胞表面的分子 Upregulates激活細胞因子 在缺乏信號2的情況下信號1導致無效能 先天免疫系統對適應性免疫反應的 發展起關鍵作用 抗原提呈細胞抗原提呈細胞 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:限制對感染的反應 機制包括: n清除感染限制抗原,移除刺激 n表達式的抑制分子 n早期的反應:APC B7 T細胞CD28 Costimulatory n后來回應:APC B7 CTLA4抑制性T細胞 n調節性T細胞(群)采取行動抑制炎癥 控制免疫反應:預防應對自我抗原 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“訓練”成不識別self-antigens 中樞耐受中樞耐受 對self-antigens反應強烈

7、的淋巴細胞在時發展過程中被刪 除 外周耐受外周耐受 n外周self-reactive的淋巴細胞的刪除或無效化 n共刺激缺失 無效 n重復刺激 誘導凋亡 n調節性T細胞行動 多形核細胞多形核細胞 細胞因子細胞因子 細胞因子細胞因子 趨化因子趨化因子 共同刺激共同刺激 先天免疫先天免疫 識別識別 感染感染 APC T CELL 多形核細胞多形核細胞 B CELL 細胞活化細胞活化 細胞補充細胞補充 發展發展 適應適應 免疫免疫 Resolution With Memory 失調失調 不當不當 天生的激活天生的激活 適應缺失適應缺失 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（受體識別模受體識別模 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 效應器效應器 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 細胞因子 CHEMOKINES CYTOKINES SYNOVIUM 滑膜液滑膜液 巨噬細胞巨噬細胞 成纖維細胞成纖維細胞 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模式識別受體與遺傳關 聯 n突變增加

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,一個負調節inflammasome者 nCryopyrin-associated周期綜合征 n家族冷autoinflammatory綜合癥,Muckle- Wells綜合癥,新生兒發病多系統炎性疾病 n突變增加NALP-3 inflammasome活動 NOD2 mutations associated with several diseases Crohns Disease Graft-Versus-Host Disease Blau Syndrome Early-Ons

11、et Sarcoidosis 遺傳相關的其他模式識別受體 SLE PATHOGENESIS n四個因素在狼瘡發病機制中起重要作用 n減少細胞碎片清除 nTLR-stimulated樹突細胞的I型干擾素產生 n損失B細胞和T細胞耐受 n增加對核酸的自體抗體 免疫復合體存入組織,然后導致激活補充與損傷 SLE PATHOGENESIS 減少細胞碎片的清除 單核單核 吞噬系統吞噬系統 正常正常 清除細胞碎片清除細胞碎片,免疫復合體免疫復合體 無共刺激的抗原呈遞無共刺激的抗原呈遞 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細胞和T細胞 增加DAMPS池為PRR的激活 SLE PATHOGENESIS 耐受喪失與自身抗體產生 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 IFN-a,ba,b IFN-a,ba,b TLR3/7/8/9 漿細胞樣樹突狀細胞漿細胞樣樹突狀細胞 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 漿細胞樣樹突狀細胞漿細胞樣樹突狀細胞 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 狼瘡遺傳學狼瘡遺傳學 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,破骨細胞活性 成骨細胞的活性 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破骨細胞破骨細胞activity Possible inhibition of osteoblast activity Synovial血管翳血管翳 erosion 破骨細胞破骨細胞 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 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