自身耐受和免疫异常与免疫介导炎症性疾病

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,自身耐受和免疫调节异常与免疫介导的炎症性疾病,吕昌龙,中国医科大学免疫研究所,Activation,Effector T cells,Normal: reactions against pathogens,Inflammatory,disease, e.g. reactions against self,Tolerance,Regulatory T cells,No response to self,Controlled response to pathogens,Balancing lymphocyte activation and control,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（“自身耐受”）。,免疫调控机制失调会诱发免疫介导的炎症性疾病。,免疫调节的方式,免疫耐受 中枢性耐受,外周性耐受,免疫细胞调节 调节性T细胞作用,免疫耐受,定义:,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,耐受原,。,意义:,所个体均存在针对自身抗原的耐受性（称,自身耐受,）。打破自身耐受就会引起自身免疫性疾病。,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。,自身免疫,自身免疫与自身免疫病：,自身免疫：抗自身抗原的免疫应答。,自身免疫病：自身免疫应答对机体造成病理性损伤。,此种疾病通常被分类为“免疫介导的炎症性疾病”。,总体特点:,发生机制: 易感基因 + 环境诱发,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 CD4 T cells may,differentiate into,regulatory (suppressive),T lymphocytes,Central and peripheral tolerance,From Abbas, Lichtman and Pillai. Cellular and Molecular Immunology 6th ed, 2007,Consequences of self antigen recognition in thymus,From: Abbas & Lichtman, Cellular & Molecular Immunology 5th ed 2003,APC,TCR,T cell,CD28,Activated,T cells,APC,TCR,Functional,unresponsiveness,Normal T cell,response,Anergy,Apoptosis,(activation-induced,cell death),APC,Deletion,APC,Block in,activation,Suppression,Regulatory,T cell,Peripheral tolerance,Off signals,Activated,T cell,T cell anergy,“Activation-induced cell death”: death of mature,T cells upon recognition of self antigens,From Abbas and Lichtman. Basic Immunology 2nd ed, 2006,Both pathways cooperate to prevent reactions against self,Regulatory T cells,From Abbas, Lichtman and Pillai. Cellular and Molecular Immunology 6th ed, 2007,T Regulatory Cell Properties,Property,Natural Treg (nTreg),Induced Treg (iTreg) - Tr1,Induced Treg (iTreg) - Th3,Development,Thymus,Periphery (MALT),Periphery (MALT),Phenotype,CD4,+,CD25,+,CD127,low,CD4,+,CD25,-,CD4,+,CD25,+,from CD25,-,precursors,Other Associated Markers,CTLA-4,+,GITR,+,Foxp3,+,CD45RB,low,Foxp3,-,CD25,low-variable,CD45RB,low,Foxp3,+,Suppression,Contact-, Granzyme-B dependent, makes TGF beta,IL-10 mediated,TGF beta mediated,Target Cells,APC and Effector T Cells,Effector T Cells,Unknown,CD28 Involvement,Thymic development and maintenance in periphery,Unnecessary for development or function,Unnecessary for development or function,in vivo,Role,Suppression of autoreactive T cells，and dendritic cells,Mucosal immunity, inflammatory response,Mucosal immunity, inflammatory response,in vitro,Expansion,TCR/CD28 stimulation and IL-2,CD3, IL-10, Retinoic Acid,CD3, TGF beta,Peripheral (adaptive, inducible) regulatory T cells,Develop from mature CD4 T cells that are exposed to persistent antigen in the periphery,May 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 recognition, 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 Foxp3,Many activated T cells (not only Treg) may transiently express Foxp3,cellular 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 Tregs,Will cellular therapy with ex vivo expanded Treg become a reality?,Therapeutic goal:,selective induction or activation of Treg in immune diseases,Immune-mediated inflammatory diseases,Chronic diseases with prominent inflammation, often caused by failure of tolerance or regulation,RA, IBD, MS, psoriasis, many others,Affect 2-5% of people, incidence increasing,May result from immune responses against self antigens (autoimmunity) or microbial antigens (Crohns disease?),May be caused by T cells and antibodies,May be systemic or organ-specific,Pathogenesis of autoimmunity,Susceptibility genes,Environmental trigger,(e.g. infections,tissue injury),Failure of,self-tolerance,Activation of,self-reactive,lymphocytes,Immune responses against self tissues,Persistence of functional,self-reactive lymphocytes,Genetics of autoimmunity,Human autoimmune diseases are complex polygenic traits,Identified by genome-wide association mapping,Single gene mutations are useful for pathway analysis,Some polymorphisms are associated with multiple diseases,May control general mechanisms of tolerance and immune regulation,Other genetic associations are disease-specific,May influence end-organ damage,NOD2,:,polymorphism associated with 25% of Crohns disease,Microbial sensor,PTPN22,:,commonest autoimmunity-associated gene; polymorphism in RA, SLE, others,Phosphatase,CD25 (IL-2R,):,associated with MS, others; genome-wide association mapping,Role in Tregs,Genetics of autoimmunity: recent successes of genomics,Infections and autoimmunity,Infections trigger autoimmune reactions,Clinical prodromes, animal models,Autoimmunity develops after infection is eradicated (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 unknown,The “hygiene hypothesis”,卫生假说的内容,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，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者同环境因素之间复杂相互作用的结果。,The nature of the disease is determined by the type of dominant immune response,Th1 response: inflammation, autoantibody production; autoimmune diseases,Th2 response: IgE+eosinophil-mediated inflammation; allergic reactions,Th17 response: acute (and chronic?) inflammation; increasingly recognized in immune-mediated diseases,Th1 cells (IFN-,g,),Th2 cells (IL-4, IL-5),Th17 cells (IL-17),Nave CD4,T cell,CD4 subsets: generation and function,Regulatory T cells,IFN-, IL-12:,T-bet, Stat4,IL-4:,GATA3, Stat6,TGF-,+ IL-6:ROR,t, Stat3,TGF-,IL-2:,Foxp3, Stat5,Host defense: many microbes,Systemic and organ-specific,autoimmune diseases,Host defense: helminths,Allergic diseases,Host 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 system 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 immunity,Cytokines are,powerful,amplifiers of,immune reactions,After a microbial infection, activa-ted microbe-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 autoimmunity,Current therapies,target late stages,of the reaction (lymphocyte activation,inflammation).,Ultimate goal should,be to 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, MS),Rituxin = monoclonal Ab = anti-CD20,Eliminates B cells in non-Hodgkins,lymphoma (maybe also RA, and other,Ab-mediated autoimmune diseases),Possible experimental approaches,T cell vaccines,(against activated Ag-specific T cells),Interfere with antigen presentation (anti-MHC),Monoclonal antibodies against a,variety of target antigens,Oral induction of tolerance (MS),So far, efforts have been more successful,in mice than humans,