生命科学基础综合自身免疫病

,How to treat autoimmune disease (AID),Li Wang （王莉）, Ph.D.Institute of Immunology PLA, TMMUTel: 752229E-mail: ,核心课程“生命科学综合” 疾病防治基础,重症肌无力Myasthenia gravis,甲亢hyperthyroidism,类风湿性关节炎Rheumatoid arthritis,系统性红斑狼疮Systemic lupus erythematosus,型糖尿病（Type 1 diabetes）,银屑病psoriasis,白癜风vitiligo,非我物质,正免疫应答,自我物质,负免疫应答,免疫耐受,pathogens,tumor,自我物质,非我物质,正免疫应答,自身免疫病Autoimmune Disease, AID,负免疫应答（自身耐受）,免疫耐受机制障碍,autoantibody,autoreactive T cells,autoantigen /self antigens自身抗原,Autoimmune Disease (AID),定义：自身耐受机制遭破坏，产生自身抗体和自身反应性淋巴细胞攻击并破坏自身的正常组织细胞，机体出现病理改变和相应临床表现条件：高水平的自身抗体和（或）自身反应性T细胞有明确的自身抗原 （抗原局限或广泛分布）用患者血清或淋巴细胞可使疾病被动转移可复制出相似的动物模型特点：易感性随着年龄增加而增加，女性高于男性遗传倾向性,甲亢,抗促甲状腺激素刺激激素受体（TSH receptor）抗体,Autoantibody-mediated dysfunction,重症肌无力,抗乙酰胆碱受体(AChR)抗体,Autoreacitive T cell and autoantibody mediated damage,Rheumatoid Arthritis类风湿性关节炎,Autoantigens in RA,变性IgG (anti-IgG: rheumatoid factors)Type I, II collagenHuman Cartilage glycoprotein 39( HC gp-39)Citrullinated fibrinogenHSPs,抗瓜氨酸化蛋白抗体Anticitrullinated protein antibodies (ACPA)：重要的RA诊断与预后指标,N Engl J Med,1985. 313:353360,Type 1 diabetes,Autoreacitive T cell-mediated damage,-cell antigens specific CD8+/CD4+T cell,Autoantigens in type 1 diabetes,Insulin (Science, 1983)Glutamic Acid Decarboxylase 65 (GAD65) （Nature, 1990)The 60 kDa heat-shock protein (hsp60) (PNAS, 1990)Tyrosine phosphatase (IA-2) (J. Clin. Invest, 1995)The 38 kD islet mitochondrial antigen (Imogen 38) (J. Clin. Invest, 1996)Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) (PNAS, 2003)Preproinsulin (PNAS. 2003)ZnT8 (PNAS, 2007 ) Chromogranin A (Nat Immunol. 2010),The differentiation of autoreactive effector T cells in AID,IFN- ko mouse,AID ,IL-22IL-21,IL-2,Th17 cells play a critical role in the pathogenesis of AID,Sequential recruitment of autoreactive effector T cells in the target organ during inflammation,胸腺,高亲和力识别,death,Self tolerance,自身抗原肽-MHC复合物,中低亲和力,无亲和力,Potential self-reactive,Foreign antigens,mature T cell,mature T cell,外周,immature T cell,How peripheral autoreactive T cells are generated?,activated?,隐蔽自身抗原,How autoreactive T cells are controlled?,clonal anergy,How autoreactive T cells are activated?,A: molecular mimicry,B: bystander activation,C: epitope spreading,Nature Reviews Immunology 2009, 9, 246-258,被动死亡,活化诱导的细胞死亡（AICD）,peripheral clonal deletion,Repeated antigen signal,Absent costimulatory signal,How autoreactive T cells are controlled?,胸腺,高亲和力识别,death,Self tolerance,Self- reactive,Regulatory T cell,自身抗原肽-MHC复合物,中低亲和力,无亲和力,Potential self-reactive,Foreign antigens,mature T cell,mature T cell,外周,immature T cell,activated,active inhibition,How autoreactive T cells are controlled?,Foxp3+,What is regulatory T cells （Treg）?,Regulatory T cells,Effector T cells,natural,induced,CD4+CD25+Foxp3+ Treg ，占外周CD4+T 细胞5%10% （1995）Tissue-resident Tregs,功能：免疫调节，抑制正应答， 维持自身耐受,How do Treg cells work?,Immunology, 2008, 124, 1322,Impaired regulation by CD4+CD25+FOXP3+ regulatory T cells in autoimmune diseases,Nature Reviews Immunology 2010,10: 849-859,Overview of Treg cells in autoimmunity,Nature Reviews Immunology 2010,10: 849-859,抵抗,易感,年轻 雄激素 无易感基因避免微生物感染 清新的环境 良好的 饮食习惯 少有组织损伤 好运气,高龄 雌激素 易感基因组合 诱病微生物感染 环境因素（紫外线 化学污染等） 不良饮食习惯 组织损伤 运气不佳,The factors effecting autoimmune disease,Effect of gender on the prevalence of autoimmune diseases,Genome-Wide Associations Study in Type 1 Diabetes,Modified from Concannon, Rich, Nepom NEJM 360:1646 2009,Genetic Susceptibility for T1D,MHC（HLA） genes,Capacity to present antigens and induce autoreactive T cells activation,Figure 11-23,Association of HLA allotype with autoimmune diseases,Nature reviews Immunol, 2007, 7:645-650,介导 外周组织抗原在胸腺上皮细胞（TEC）中的异位表达Aire突变导致T细胞阴性选择异常,Autoimmune regulator (Aire),自身免疫增多内分泌病变念珠菌病外胚层营养不良 （APECED）, 自身免疫性多种内分泌病变,包括甲状腺及甲状旁腺功能减退，肾上腺皮质衰竭，T1D，性腺衰竭，恶性贫血及自身免疫肝炎 慢性粘膜与皮肤白色念珠菌病 外胚层发育不良，而且一大部分病人会发生口腔粘膜鳞状细胞癌,罕见人类单基因遗传性自身免疫疾病,Scurfy小鼠,Foxp3基因敲除小鼠,功能：控制CD4+CD25+ Treg的发育及功能 FOXP3突变 Treg缺失 自身免疫病,叉状头/翅膀状螺旋转录因子（Foxp3）,Wild type,ScurfyFoxp3 mutation,性联免疫失调综合征（IPEX）,nature genetics 2001, 27:20-21,特点早发性顽固性腹泻、自身免疫性甲状腺炎、胰岛素依赖性糖尿病、高IgE、嗜酸性粒细胞升高、肾病、皮疹等，常导致患者在婴幼儿早期死亡。机制：Foxp3 基因突变,Wild-type,Fas-knockout,Fas-FasL介导的AICD是机体重要的外周免疫耐受机制，Fas基因突变，大量活化的淋巴细胞可持续存活，产生淋巴细胞增生（脾大、淋巴结肿大）和自身免疫现象,Fas-FasL,自身免疫性淋巴细胞增生综合征Autoimmune lymphoproliferative syndrome (ALPS),特点淋巴细胞增生性表现：脾脏肿大；自身免疫性疾病：自身免疫性溶血性贫血 (75%)，免疫性血小板减少症 (54%)，自身免疫性中性粒细胞减少症；其他有肾小球肾炎、多发性神经根炎和皮肤损害(包括荨麻疹和非特异性皮肤血管炎)机制： Fas基因突变,Environment factor for T1D,饮食因素：Bovine milk ？Antibodies to cows milk proteins have been detected in the serum of individuals with T1D感染因素：?Coxsackie B, Rubella, and mumps,分子模拟,Infectionmolecular mimicry,分子模拟,饮食、应激、损伤自身抗原性质改变,自身抗原修饰类型：磷酸化瓜氨酸化氧化乙酰化,Current Therapies- 非特异性免疫抑制剂以及抗炎疗法 危害：感染、肿瘤的发生率增加、长期使用激素的副作用Experimental Therapeutic Approaches - try to target T cells or B cells,How to treat AID？,I. Current Therapies,免疫抑制剂 （Immunosuppressive drugs）-皮质类固醇corticosteroids，硫唑嘌呤 azathioprine- slows the proliferation of lymphocytes环孢菌素A （Cyclosporin A）- blocks signal transduction mediated by the TCR (inhibits only antigen-activated T cells while sparing non-activated ones)胸腺切除（ Thymectomy）- removal of thymus from patients with myasthenia gravis血浆置换 （Plasmapheresis）- removes antigen-antibody complexes for a short- term reduction in symptoms,1. 靶向T/B细胞的非特异性治疗策略,antithymocyte globulin (ATG)anti-CD3 antibody OKT3， humanized FNB mAb OKT3g1ala-ala (teplizumab) retaineda combination of rapamycin and anti-IL-2B-cell-depleting drug rituximab （anti-CD20）,II. Experimental Therapeutic Approaches,体内剔除T/B细胞,阻断T细胞共刺激、迁移及细胞因子,a CTLA4Ig fusion protein: blocking CD28/B7 interactions an LFA-3-Ig fusion protein: blocking the interaction of LFA-3 on APCs with costimulatory molecule CD2 on T cellsaka CD40L: blocking interactions of CD154 on T cells and CD40 on APCsfingolimod (FTY720), a small compound: affecting T-cell traffickingTNF- antagonistsAnti-IL-17 mAb Secukinumab： Phase 3 studies in Psoriasis and AS completed,2. 细胞过继性治疗策略,Mesenchymal stem cells (MSCs)Tolerogenic DCs such as plasmacytoid DCs (pDCs)Tregs（the first U.S. clinical trial of Treg cellular therapy in patients with T1D，ClinicalTrials. gov Identifier NCT01210664）,临床基于Treg的过继性治疗策略,体外活化和扩增,从病人体内分离出部分Treg,回输入病人体内,Treg过继疗法的优势以及存在的问题,优势：与大多药物治疗相比，Treg过继转移可以最大程度的降低治疗毒性带来的副作用向病人回输Treg之前可以对细胞的表型和功能进行鉴定，并且准确的控制治疗用细胞的数量，增强了治疗的安全性和可操作性问题：这些Treg是否具有靶器官抗原特异性，是否能够归巢到局部效应靶器官？抗凋亡能力如何？如何获得抗原特异性Treg？体外扩增的Treg细胞是否有恢复为普通T细胞的可能 ？体内输入大量具有免疫抑制功能的Treg 细胞，是否会增加感染和肿瘤发生的机会 ？,3. Antigen-Specific Therapeutic Approaches,Soluble autoantigens or peptides (oral; i.v.; i.p)Altered