自身耐受和免疫异常与免疫介导的炎症性疾病教学提纲.ppt

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1、自身耐受和免疫异常与免疫介导的炎症性疾病免疫调节的重要性免疫调节的重要性 避免正常抗感染免疫应答过程中出现过量淋巴避免正常抗感染免疫应答过程中出现过量淋巴细胞活化造成组织损伤。细胞活化造成组织损伤。防止不适当的抗自身抗原的免疫应答（防止不适当的抗自身抗原的免疫应答（“自身自身耐受耐受”）。）。免疫调控机制失调会诱发免疫介导的炎症性疾免疫调控机制失调会诱发免疫介导的炎症性疾病。病。免疫调节的方式免疫调节的方式 免疫耐受免疫耐受 中枢性耐受中枢性耐受 外周性耐受外周性耐受 免疫细胞调节免疫细胞调节 调节性调节性T T细胞作用细胞作用免疫耐受免疫耐受定义定义:淋巴细胞接触抗原后被诱导的针对该抗原的特

2、淋巴细胞接触抗原后被诱导的针对该抗原的特异性不应答。该种抗原被称为异性不应答。该种抗原被称为耐受原耐受原。意义意义:所个体均存在针对自身抗原的耐受性（称所个体均存在针对自身抗原的耐受性（称自身自身耐受耐受）。打破自身耐受就会引起自身免疫性疾）。打破自身耐受就会引起自身免疫性疾病。病。治疗价值：诱导耐受可用于预防移植排斥、治治疗价值：诱导耐受可用于预防移植排斥、治疗自身免疫性和变态反应性疾病。疗自身免疫性和变态反应性疾病。自身免疫自身免疫自身免疫与自身免疫病：自身免疫与自身免疫病：自身免疫：抗自身抗原的免疫应答。自身免疫：抗自身抗原的免疫应答。自身免疫病：自身免疫应答对机体造成病理性自身免疫病：

3、自身免疫应答对机体造成病理性损伤。损伤。此种疾病通常被分类为此种疾病通常被分类为“免疫介导的炎症性免疫介导的炎症性疾病疾病”。总体特点总体特点:发生机制发生机制:易感基因易感基因+环境诱发环境诱发全身性和器官特异性全身性和器官特异性The principal fate of lymphocytes that recognize self antigens in the generative organs is death(deletion),BUT:Some B cells may change their specificity(called“receptor editing”)Some C

4、D4 T cells may differentiate into regulatory(suppressive)T lymphocytesCentral and peripheral toleranceFrom Abbas,Lichtman and Pillai.Cellular and Molecular Immunology 6th ed,2007Consequences of self antigen recognition in thymusFrom:Abbas&Lichtman,Cellular&Molecular Immunology 5th ed 2003APCTCRT cel

5、lT cellCD28 ActivatedActivatedT cellsT cellsAPCTCRFunctionalunresponsivenessNormal T cellresponseAnergy Apoptosis(activation-inducedcell death)APCDeletion APC Block inactivationSuppression RegulatoryT cellPeripheral toleranceOff signalsActivatedActivatedT cellT cellT cell anergy“Activation-induced c

6、ell death”:death of mature T cells upon recognition of self antigensFrom Abbas and Lichtman.Basic Immunology 2nd ed,2006Both pathways cooperate to prevent reactions against self Regulatory T cells From Abbas,Lichtman and Pillai.Cellular and Molecular Immunology 6th ed,2007T Regulatory Cell Propertie

7、sPropertyNatural Treg(nTreg)Induced Treg(iTreg)-Tr1Induced Treg(iTreg)-Th3DevelopmentThymusPeriphery(MALT)Periphery(MALT)PhenotypeCD4+CD25+CD127lowCD4+CD25-CD4+CD25+from CD25-precursorsOther Associated MarkersCTLA-4+GITR+Foxp3+CD45RBlowFoxp3-CD25low-variableCD45RBlowFoxp3+SuppressionContact-,Granzym

8、e-B dependent,makes TGF betaIL-10 mediatedTGF beta mediatedTarget CellsAPC and Effector T CellsEffector T CellsUnknownCD28 InvolvementThymic development and maintenance in peripheryUnnecessary for development or functionUnnecessary for development or functionin vivo RoleSuppression of autoreactive T

9、 cells，and dendritic cellsMucosal immunity,inflammatory responseMucosal immunity,inflammatory responsein vitro ExpansionTCR/CD28 stimulation and IL-2CD3,IL-10,Retinoic AcidCD3,TGF betaPeripheral(adaptive,inducible)regulatory T cellsDevelop from mature CD4 T cells that are exposed to persistent antig

10、en in the peripheryMay be generated in all immune responses,to limit collateral damage Can be induced in vitro(stimulation of CD4 T-cells in presence of TGF +IL-2)What factors determine the balance of effector cells and Treg?Signals for the generation and maintenance of regulatory T cells Antigen re

11、cognition,with or without inflammation?TGF-(source?)Interleukin-2(originally identified as T cell growth factor;major function is to control immune responses by maintaining functional Treg;works via Stat5)Low levels of B7:CD28 costimulation Transcription factor Foxp3Many activated T cells(not only T

12、reg)may transiently express Foxp3cellular therapy with Regulatory T cells?Some autoimmune diseases are associated with defective generation or function of Tregs or resistance of effector cells to suppression by TregsWill cellular therapy with ex vivo expanded Treg become a reality?Therapeutic goal:s

13、elective induction or activation of Treg in immune diseasesImmune-mediated inflammatory diseasesChronic diseases with prominent inflammation,often caused by failure of tolerance or regulationRA,IBD,MS,psoriasis,many othersAffect 2-5%of people,incidence increasingMay result from immune responses agai

14、nst self antigens(autoimmunity)or microbial antigens(Crohns disease?)May be caused by T cells and antibodiesMay be systemic or organ-specificPathogenesis of autoimmunitySusceptibility genesEnvironmental trigger(e.g.infections,tissue injury)Failure ofself-toleranceActivation ofself-reactive lymphocyt

15、esImmune responses against self tissuesPersistence of functionalself-reactive lymphocytesGenetics of autoimmunityHuman autoimmune diseases are complex polygenic traitsIdentified by genome-wide association mappingSingle gene mutations are useful for pathway analysisSome polymorphisms are associated w

16、ith multiple diseasesMay control general mechanisms of tolerance and immune regulationOther genetic associations are disease-specificMay influence end-organ damageNOD2:polymorphism associated with 25%of Crohns diseaseMicrobial sensorPTPN22:commonest autoimmunity-associated gene;polymorphism in RA,SL

17、E,othersPhosphataseCD25(IL-2R):associated with MS,others;genome-wide association mappingRole in TregsGenetics of autoimmunity:recent successes of genomicsInfections and autoimmunityInfections trigger autoimmune reactionsClinical prodromes,animal modelsAutoimmunity develops after infection is eradica

18、ted(i.e.the autoimmune disease is precipitated by infection but is not directly caused by the infection)Some autoimmune diseases are prevented by infections(type 1 diabetes,multiple sclerosis,others?-increasing incidence in developed countries):mechanism unknownThe“hygiene hypothesis”卫生假说的内容卫生假说的内容

19、卫生假说指出，过敏性疾病的发病率不断上卫生假说指出，过敏性疾病的发病率不断上升与现代生活方式有关。高水平的生活环境和卫升与现代生活方式有关。高水平的生活环境和卫生条件同过敏性疾病发生的危险性增加密切相关。生条件同过敏性疾病发生的危险性增加密切相关。由于暴露于环境中微生物及其产物机会的减少，由于暴露于环境中微生物及其产物机会的减少，这些环境因素对过敏性疾病的预防潜能无论在质这些环境因素对过敏性疾病的预防潜能无论在质还是量方面都不能足够存在，结果导致免疫系统还是量方面都不能足够存在，结果导致免疫系统功能失衡，过敏性疾病发生。因此说，过敏性疾功能失衡，过敏性疾病发生。因此说，过敏性疾病的发生是基于患

20、者同环境因素之间复杂相互作病的发生是基于患者同环境因素之间复杂相互作用的结果。用的结果。The nature of the disease is determined by the type of dominant immune responseTh1 response:inflammation,autoantibody production;autoimmune diseasesTh2 response:IgE+eosinophil-mediated inflammation;allergic reactionsTh17 response:acute(and chronic?)inflamm

21、ation;increasingly recognized in immune-mediated diseasesTh1 cells(IFN-)Th2 cells(IL-4,IL-5)Th17 cells(IL-17)Nave CD4T cellCD4 subsets:generation and function Regulatory T cellsIFN-,IL-12:T-bet,Stat4IL-4:GATA3,Stat6TGF-+IL-6:ROR t,Stat3TGF-IL-2:Foxp3,Stat5Host defense:many microbesSystemic and organ

22、-specific autoimmune diseasesHost defense:helminthsAllergic diseasesHost defense:fungi,bacteria Organ-specific autoimmune diseases Immunological diseases tend to be chronic and self-perpetuating,because The initiating trigger can often not be eliminated(self antigen,commensal microbes)The immune sys

23、tem contains many built-in amplification mechanisms whose normal function is to optimize our ability to combat infections“Epitope spreading”“Molecular minicry”Amplification loop in cell-mediated immunityCytokines are powerful amplifiers of immune reactions After a microbial infection,activa-ted micr

24、obe-speci-fic TH1(mTH1)cells migrate to the infected organ.A.Molecular mimicry.B.Epitope spre-ading.C.Bystander activation.D.Cryptic antigen.Pathogenesis of organ-specific autoimmunityCurrent therapies target late stages of the reaction(lymphocyte activation,inflammation).Ultimate goal should be to

25、tackle the underlying cause and restore control of the abnormally directed response Treatment of autoimmune disease(contd)Reduce inflammation TNF-alpha blockers(RA,Crohns dis.,psoriasis)e.g.,Enbrel,Remicade,Humira IL-1 receptor antagonist(RA)Abs against IL6R and IL-15R Statins,shown to lower CRP(RA,

26、MS)Rituxin=monoclonal Ab=anti-CD20Eliminates B cells in non-Hodgkins lymphoma(maybe also RA,and other Ab-mediated autoimmune diseases)Possible experimental approachesT cell vaccines(against activated Ag-specific T cells)Interfere with antigen presentation(anti-MHC)Monoclonal antibodies against a variety of target antigensOral induction of tolerance(MS)So far,efforts have been more successfulin mice than humans此课件下载可自行编辑修改，仅供参考！此课件下载可自行编辑修改，仅供参考！感谢您的支持，我们努力做得更好！谢谢感谢您的支持，我们努力做得更好！谢谢