某些風濕性疾病的免疫問題課件

1、某些風濕性疾病的免疫問題某些風濕性疾病的免疫問題披露非披露披露非披露提綱簡要回顧免疫學重要概念將這些概念應用于三種風濕性疾病痛風系統(tǒng)性紅斑狼瘡RA提綱簡要回顧免疫學重要概念先天免疫 第一道防線適應性免疫 特異性,記憶免疫, 響應的調節(jié)類型免疫,提高抗微生物活性先天免疫適應性免疫免疫, 響應的調節(jié)類型免疫,提高抗微生物活 先天免疫系統(tǒng) 適應性免疫系統(tǒng)組件補體天然抗體,吞噬細胞肥大細胞上皮細胞、成纖維細胞 B細胞 T細胞進化整個物種系統(tǒng)老整個物種系統(tǒng)新響應的時間早期(0-24小時)后來( 1天)識別廣泛結構常見的微生物群體精細彼此不同的有機體多樣性有限生殖細胞系編碼大生殖細胞系重排記憶 無有 先天

2、免疫系統(tǒng) 適應性免疫系統(tǒng)組件補體 先天免疫 第一道防線ADAPTIVE IMMUNITYSpecificity, MemoryRECRUITS, MODULATES TYPE OF RESPONSERECRUITS, ENHANCES ANTIMICROBICAL ACTIVITY先天免疫ADAPTIVE IMMUNITYRECRUITS, 先天免疫系統(tǒng)的功能病原體去除免疫激活(1) 補體調理作用 -complement(1) 抗原遞傳和共刺激(2) 細胞裂解 -virally infected cells -tumor cells(2) 細胞因子分泌 -T and B cell activa

3、tion -innate immune activation -increased microbial killing(3) 微生物殺滅 -phagocytosis -complement, defensins(3) 趨化因子分泌 -recruitment innate and adaptive immune cells 先天免疫系統(tǒng)的功能病原體免疫(1) 補體先天免疫的模式識別受體識別模式PRRsPAMPs 病原體相關分子模式獨特的微生物產(chǎn)生的物質e.g. LPS, zymosan, peptidoglycan, double-stranded RNADAMPsDANGER-ASSOCIAT

4、ED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受體先天免疫的模式識別受體識別模式PRRsPAMPs 病原體相先天免疫識別模CELL SURFACE核內(nèi)體 細胞質TLR-2 肽聚糖 (Gram(+) bacteria)Heat Shock Protein 70TLR-4脂多糖 (gram(-) bacteria)透明質酸碎片TLR-3 病毒性dsRNAmRNATLR

5、-7病毒ssRNARNATLR-9細菌CpG DNAIgG-Chromatin復合物細胞凋亡誘導蛋白NALP3 NALP-3 Bacterial RNAViral RNA, LPSUric Acid, ATPNOD-1胞壁酰二肽 ?視黃酸誘導基因蛋白I（RIG-I） Viral RNA?病原體相關分子模式 PAMPSDANGER-ASSOCIATED分子模式DAMPS對刺激的響應TNF, proIL-1,IL-6Type I InterferonsTNF, proIL-1,IL-6proIL-1 IL-1RASLEGout先天免疫識別模CELL SURFACE核內(nèi)體 細胞質TLR-INNATE

6、 IMMUNITYFirst Line of Defense適應性免疫 特異性,記憶T cells and B cellsRECRUITS, MODULATES TYPE OF RESPONSERECRUITS, ENHANCES ANTIMICROBICAL ACTIVITYINNATE IMMUNITY適應性免疫RECRUITS, 適應性免疫反應的多樣性107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(qū)分微生物多樣性通過體細胞遺傳基因片段的重組Va1Vann=45Ja1Jann=55Ca人類T細胞受體,連鎖適應性免疫反應的多樣性107年到109個不同的B細胞和T細胞特定受體和抗

7、原之間的相互作用導致克隆擴張T CELLSB CELLST cell receptorCD4 or CD8B cell receptor(Immunoglobulin)ANTIGEN PRESENTING CELL(樹突細胞,巨噬細胞、B細胞)微生物 增殖 增殖 MHCAntigenAntigen特定受體和抗原之間的相互作用導致克隆擴張T CELLSB C克隆擴張產(chǎn)生效應和記憶細胞APCT CELL直接細胞裂解刺激B細胞刺激先天免疫系統(tǒng)效應T細胞記憶T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 記憶B細胞 在他們再次暴露在抗原反應迅速克隆擴張產(chǎn)生效應和記憶細胞APCT

8、 CELL直接細胞裂解刺激先天免疫系統(tǒng)對適應性免疫反應的發(fā)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(lián)表面抗原IgSignal 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(tǒng)對適應性免疫反應的發(fā)展起關鍵作用兩種信號需要刺激先天免疫系統(tǒng)對適應性免疫反應的發(fā)展起關鍵作用抗原提呈細胞 T CELLTCRCD28MicrobeSIGNAL 1MHCMicrobial KillingSIG

9、NAL 2B7Pattern RecognitionReceptorAbatacept(CTLA4-Ig)抑制共同刺激先天免疫系統(tǒng)對適應性免疫反應的發(fā)展起關鍵作用抗原提呈細胞 T控制免疫反應:限制對感染的反應機制包括:清除感染限制抗原,移除刺激表達式的抑制分子早期的反應:APC B7 T細胞CD28 Costimulatory后來回應:APC B7 CTLA4抑制性T細胞調節(jié)性T細胞(群)采取行動抑制炎癥控制免疫反應:限制對感染的反應機制包括: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中樞耐受對self

10、-antigens反應強烈的淋巴細胞在時發(fā)展過程中被刪除外周耐受 外周self-reactive的淋巴細胞的刪除或無效化共刺激缺失 無效重復刺激 誘導凋亡調節(jié)性T細胞行動控制免疫反應:預防應對自我抗原自我分子(蛋白,蛋白多糖等)由多形核細胞 細胞因子 細胞因子 趨化因子 共同刺激 先天免疫識別感染APCT CELL多形核細胞 B CELL細胞活化細胞補充發(fā)展適應免疫ResolutionWithMemory失調不當天生的激活適應缺失耐受Immune Response多形核細胞 細胞因子 細胞因子 趨化因子 共同刺激 先天免疫GOUTDisease of innate immunityUric A

11、cid acts as a DAMP（ DANGER-ASSOCIATED分子模式）NALP-3 inflammasome is the PRR（受體識別模式）Inflammasome activation releases IL-1IL-1 activates the synovium, recruiting neutrophils into the jointGOUTDisease of innate immunityNALP-3 INFLAMMASOMELRRNACHTPYRIN配體傳感齊聚 效應器 NALP-3LRRNACHTPYRINCARDASC半胱天冬酶 (inactive)UR

12、IC ACIDPRO-IL-1IL-1IL-1INFLAMMSOMECASPASE-1(active)NALP-3 INFLAMMASOMELRRNACHTPYRGOUT PATHOGENESISPRO-IL-1IL-1趨化因子細胞因子CHEMOKINESCYTOKINESSYNOVIUM滑膜液巨噬細胞 成纖維細胞PMNPMNPMNPMNPMNPMNPMNPMNPMNPMNPMNPMNNALP-3INFLAMMASOMEIL-1 拮抗劑GOUT PATHOGENESISPRO-IL-1IL-1趨NALP-3模式識別受體與遺傳關聯(lián)突變增加NALP-3 Inflammasomes 活性家族性地中海

13、熱(FMF)在MEFV基因突變,編碼蛋白pyrin,一個負調節(jié)inflammasome者Cryopyrin-associated周期綜合征家族冷autoinflammatory綜合癥,Muckle-Wells綜合癥,新生兒發(fā)病多系統(tǒng)炎性疾病突變增加NALP-3 inflammasome活動NALP-3模式識別受體與遺傳關聯(lián)突變增加NALP-3 InNOD2 mutations associated with several diseasesCrohns DiseaseGraft-Versus-Host DiseaseBlau SyndromeEarly-Onset Sarcoidosis遺傳相

14、關的其他模式識別受體TLR/NLRDisorderTLR2哮喘、急性風濕熱lepromatous麻風病TLR4哮喘、炎癥性腸病TLR10哮喘、濕疹NOD1哮喘、濕疹、炎癥性腸病NALP1白癲風、甲狀腺疾病,愛迪生氏病、類風濕關節(jié)炎、牛皮癬、系統(tǒng)性紅斑狼瘡NOD2 mutations associated withSLE PATHOGENESIS四個因素在狼瘡發(fā)病機制中起重要作用減少細胞碎片清除TLR-stimulated樹突細胞的I型干擾素產(chǎn)生損失B細胞和T細胞耐受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四個因素在狼瘡發(fā)病機制中起重THAN

15、K YOUSUCCESS2022/10/725可編輯THANK YOUSUCCESS2022/10/22SLE PATHOGENESIS 減少細胞碎片的清除單核吞噬系統(tǒng)正常清除細胞碎片,免疫復合體無共刺激的抗原呈遞感染微生物殺滅PRR激活共刺激的抗原呈遞SLE減少清理碎片增加self-antigens池為B細胞和T細胞增加DAMPS池為PRR的激活SLE PATHOGENESIS 減少細胞碎片的清除單核正SLE PATHOGENESIS 耐受喪失與自身抗體產(chǎn)生T cellB cellNORMAL 外周耐受 Weakly self-reactive B and T cells anergic抗原

16、隔離OR Antigens presented without costimulationT cellAPCSLE 耐受喪失 Increaesd stimulatio of self-reactive B and T cells with self-antigens Increased innate activation with self DAMPs increases costimulation Increase autoantibody production to self antigens such as nucleic acidsT cellB cellSLE PATHOGENESI

17、S 耐受喪失與自身抗體產(chǎn)生SLE PATHOGENESIS I型干擾素的響應IFN-a,bIFN-a,bTLR3/7/8/9漿細胞樣樹突狀細胞 VIRAL INFECTION major producers type I interferons viral nucleic acids stimulate TLR3/7/8/9 TLR stimulation leads to type I interferon production Type I interferons potent immune activatorTLR3/7/8/9漿細胞樣樹突狀細胞 nucleic acid contain

18、ing immune complexes stimulate TLR3/7/8/9 TLR stimulation leads to type I interferon production Type I interferons potent immune activator in absence of infectionSLESLE PATHOGENESIS I型干擾素的響應IFNSLE PATHOGENESISMONONUCLEAR PHAGOCYTIC SYSTEMDecreased Clearance Cell DebrisIFN-a,bPLASMACYTOID DENDRITIC C

19、ELLB CELLIncreased Plasmacytoid DC Type I Interferon ProductionIFN-a,bIFN-a,bLoss T and B Cell ToleranceAutoantibody ProductionT CELLSLE PATHOGENESISMONONUCLEAR De狼瘡遺傳學 MONONUCLEAR PHAGOCYTIC SYSTEMIFN-a,bPLASMACYTOID DENDRITIC CELLB CELLIFN-a,bIFN-a,bT CELLDecrease Clearance Cellular Debris Complem

20、ent deficiencies (C1q, C2, C4) SNP in FCGR2ALoss B and T cell Tolerance SNPs associated with B and T cell signaling HLA-DR2 HLA-DR3 PTPN22 BANK1 BLK STAT4Type I Interferon Release Interferon signature in peripheral blood cells of SLE patients Associated with SNPs in IRF5, IRAK1, and STAT4狼瘡遺傳學 MONON

21、UCLEAR IFN-a,bPLASMRA PATHOGENESIS:正常SYNOVIUMSYNOVIAL FLUIDSYNOVIUMSYNOVIAL FIBROBLASTRemodels extracellular matrix, Synthesize lubricin, hyaluronanSYNOVIAL MACROPHAGESentinel cellPhagocytose debrisSYNOVIAL LININGSYNOVIAL SUBLININGBlood VesselsScattered Fibroblasts, Macrophages, Mast CellsBONEFormat

22、ion Resorption(Osteoblasts) (Osteoclasts)CARTILAGEChondrocytesType II Collagen, AggrecanRA PATHOGENESIS:正常SYNOVIUMSYNORA PATHOGENESIS KEY FEATURESsynovium免疫的滲透滑膜增生與肉芽組織形成骨的侵蝕,破骨細胞活性 成骨細胞的活性軟骨被侵蝕RA PATHOGENESIS KEY FEATURESRA PATHOGENESIS 免疫滲透C5aC5aC5aC5aC5aSYNOVIUMSYNOVIAL FLUIDADAPTIVE IMMUNITYINNA

23、TE IMMUNITYT CellsB CellsRheumatoid Factoranti-CCP antibodiesNeutrophilsComplement ActivationMacrophagesImmune ComplexesDendritic CellsMast CellsABATACEPT(CTLA4 Ig)RITUXIMAB(anti-CD20 mAb)RA PATHOGENESIS 免疫滲透C5aC5aC5aRA PATHOGENESIS 滑膜增生SYNOVIUMSYNOVIAL FLUIDC5aC5aC5aC5aC5aSYNOVIUMSYNOVIAL HYPERPLAS

24、IA Increased angiogenesis Synovial lining hyperplasia Lining becomes an invasive tissue mass (pannus) that erodes cartilage and bone Increased synovial macrophages TNF-a Increased synovial fibroblasts IL-6TNF inhibitorsTocilizumab (anti-IL-6R mAb)RA PATHOGENESIS 滑膜增生SYNOVIUMSRA PATHOGENESIS 骨侵蝕SYNOV

25、IUMSYNOVIAL FLUIDC5aC5aC5aC5aC5aSYNOVIUMINCREASED BONE RESORPTION AND EROSION Increased破骨細胞activity Possible inhibition of osteoblast activity Synovial血管翳 erosionTNF inhibitorsDenosumab (anti-RANKL mAb)破骨細胞激活RANKLTNF-aRA PATHOGENESIS 骨侵蝕SYNOVIUMSYRA PATHOGENESIS 軟骨侵蝕SYNOVIUMSYNOVIAL FLUIDC5aC5aC5aC5

26、aC5aSYNOVIUMINCREASED CARTILAGE EROSON Cartilage surface modified by immune complexes, extracellular matrix fragments, enzymatic digestion Inflammatory cytokines inhibit chondrocyte matrix repair Synovial pannus erodes cartilage matrixRA PATHOGENESIS 軟骨侵蝕SYNOVIUMSRA PATHOGENESIS -概述Activation of Syn

27、ovial Tissues by the Immune SystemActivation of the Immune System by Synovial TissuesCYTOKINE AND CHEMOKINE NETWORKSC5aC5aC5aC5aTNF-aIL-6TNF-aIL-17IFN-gIL-17IFN-gTNF-aTNF-aIL-1TNF-aRANKLRA PATHOGENESIS -概述CYTOKINE ANRA PATHOGENESIS -遺傳學Currently identified genetic risk alleles only explain 10-20% of

28、 genetic riskFunction of risk alleles is not knownStrongest risk allele “Shared Epitope”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*1402Most strongly associated with anti-CCP antibodiesMany risk a

29、lleles shared between autoimmune diseasesTNFS14 PADI4 PTPN22FCGR2A STAT4 CD28CTLA4 HLA-DR1 HLA-DR4TNFAIP3 IRF5 CCR6BLK TRAF1 CD40BANK1 PTPN22 ITGAMFCGR2A STAT4 BLKTNFSF4 HLA-DR2 HLA-DR3TNFAIP3 IRF5 IRAK1RA RISK ALLELE SAMPLESLE RISK ALLELE SAMPLERA PATHOGENESIS -遺傳學Currently SUMMARYImmunology Innate

30、 vs. Adaptive Immunity Pattern Recognition Receptors in Innate Immune System Tolerance and Memory in Adaptive Immune SystemGoutInflammasome Activation of IL-1SLELoss of Immune ToleranceInterferon SignatureDefects in Debris ClearanceRAImmune Activation of Synovial TissuesSynovial Activation of Immune

31、 SystemRole of Cytokine NetworksSUMMARYImmunologyQuestion 1Macrophages and neutrophils are cells in the branch of the immune with which of the following characteristics?Found only in vertebratesGenerates immunity to specific pathogensRecognizes conserved microbial patternsDevelopment of response tak

32、es several daysAnswer:C: Recognizes conserved microbial patternsQuestion 1Macrophages and neutINNATE IMMUNITYADAPTIVE IMMUNITYComponentsComplementNatural antibodies, Phagocytic cellsMast cellEpithelia, Fibroblasts B cellsT cellsEvolutionPhylogenetically oldPhylogenetically newerTiming of ResponseEar

33、ly (0-24 hours)Later (1 day)RecognitionBroadStructures common to groups of microbesFineDistinguishes one organism from anotherDiversityLimitedGermline CodedLargeGermline RearrangedMemoryNoYesINNATE IMMUNITYADAPTIVE IMMUNIQuestion 2Inflammasome activation is central to disease pathogenesis in gout an

34、d which of the following diseases?Blau SyndromeCrohns DiseaseMuckle-Wells SyndromePsoriasisSLEAnswer:C: Muckle-Wells SyndromeQuestion 2Inflammasome activatNOD2 mutations associated the following diseasesCrohns Disease, Graft-Versus-Host Disease, Blau Syndrome, Early-Onset SarcoidosisGENETIC ASSOCIAT

35、IONS WITH OTHER PATTERN RECOGNITION RECEPTORSTLR/NLRDisorderTLR2Asthma, acute rheumatic fever, lepromatous leprosyTLR4Asthma, inflammatory bowel diseaseTLR10Asthma, eczemaNOD1Asthma, eczema, inflammatory bowel diseaseNALP1Vitiligo, thyroid disease, Addison disease, RA, psoriasis, SLENALP-3 activatio

36、n associated with goutMutations with NALP-3 or associated proteins associated withFMF, Cryopyrin-Associated Periodic Fever SyndromesNOD2 mutations associated the Question 3Gene profiling of the peripheral blood mononuclear cells has shown that SLE patients have activation of which of the following c

37、ytokine pathways?IFN-aIFN-gIL-1IL-6IL-17Answer:A: IFN-aQuestion 3Gene profiling of thSLE PATHOGENESISMONONUCLEAR PHAGOCYTIC SYSTEMDecreased Clearance Cell DebrisIFN-a,bPLASMACYTOID DENDRITIC CELLB CELLIncreased Plasmacytoid DC Type I Interferon ProductionIFN-a,bIFN-a,bLoss T and B Cell ToleranceAutoantibody ProductionT CELLSLE PATHOGENESISMONONUCLEAR DeQuestion 4The shared epitope risk allele in RA is most directly assoicated with which of the following pathogenic mechanis