,How to treat autoimmune disease (AID),Li Wang （王莉）, Ph.D. Institute of Immunology PLA, TMMU Tel: 752229 E-mail: ,核心課程“生命科學(xué)綜合” 疾病防治基礎(chǔ),重癥肌無力 Myasthenia gravis,甲亢 hyperthyroidism,類風(fēng)濕性關(guān)節(jié)炎 Rheumatoid arthritis,系統(tǒng)性紅斑狼瘡 Systemic lupus erythematosus,型糖尿病 （Type 1 diabetes）,銀屑病 psoriasis,白癜風(fēng) vitiligo,非我物質(zhì),正免疫應(yīng)答,自我物質(zhì),負(fù)免疫應(yīng)答,免疫耐受,pathogens,tumor,自我物質(zhì),非我物質(zhì),正免疫應(yīng)答,自身免疫病 Autoimmune Disease, AID,負(fù)免疫應(yīng)答（自身耐受）,免疫耐受機(jī)制障礙,autoantibody,autoreactive T cells,autoantigen /self antigens 自身抗原,Autoimmune Disease (AID),定義：自身耐受機(jī)制遭破壞，產(chǎn)生自身抗體和自身反應(yīng)性淋巴細(xì)胞攻擊并破壞自身的正常組織細(xì)胞，機(jī)體出現(xiàn)病理改變和相應(yīng)臨床表現(xiàn) 條件： 高水平的自身抗體和（或）自身反應(yīng)性T細(xì)胞 有明確的自身抗原 （抗原局限或廣泛分布） 用患者血清或淋巴細(xì)胞可使疾病被動轉(zhuǎn)移 可復(fù)制出相似的動物模型 特點(diǎn)： 易感性隨著年齡增加而增加，女性高于男性 遺傳傾向性,甲亢,抗促甲狀腺激素刺激激素受體（TSH receptor）抗體,Autoantibody-mediated dysfunction,重癥肌無力,抗乙酰膽堿受體(AChR)抗體,Autoreacitive T cell and autoantibody mediated damage,Rheumatoid Arthritis 類風(fēng)濕性關(guān)節(jié)炎,Autoantigens in RA,變性IgG (anti-IgG: rheumatoid factors) Type I, II collagen Human Cartilage glycoprotein 39( HC gp-39) Citrullinated fibrinogen HSPs ,抗瓜氨酸化蛋白抗體Anticitrullinated protein antibodies (ACPA)： 重要的RA診斷與預(yù)后指標(biāo),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-22 IL-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,高親和力識別,death,Self tolerance,自身抗原肽-MHC復(fù)合物,中低親和力,無親和力,Potential self-reactive,Foreign antigens,mature T cell,mature T cell,外周,immature T cell,How peripheral autoreactive T cells are generated?,activated?,隱蔽自身抗原,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,被動死亡,活化誘導(dǎo)的細(xì)胞死亡（AICD）,peripheral clonal deletion,Repeated antigen signal,Absent costimulatory signal,How autoreactive T cells are controlled?,胸腺,高親和力識別,death,Self tolerance,Self- reactive,Regulatory T cell,自身抗原肽-MHC復(fù)合物,中低親和力,無親和力,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 細(xì)胞5%10% （1995） Tissue-resident Tregs,功能：免疫調(diào)節(jié)，抑制正應(yīng)答， 維持自身耐受,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,年輕 雄激素 無易感基因 避免微生物感染 清新的環(huán)境 良好的 飲食習(xí)慣 少有組織損傷 好運(yùn)氣,高齡 雌激素 易感基因組合 誘病微生物感染 環(huán)境因素（紫外線 化學(xué)污染等） 不良飲食習(xí)慣 組織損傷 運(yùn)氣不佳,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,2019/8/30,27,可編輯,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,介導(dǎo) 外周組織抗原在胸腺上皮細(xì)胞（TEC）中的異位表達(dá) Aire突變導(dǎo)致T細(xì)胞陰性選擇異常,Autoimmune regulator (Aire),自身免疫增多內(nèi)分泌病變念珠菌病外胚層營養(yǎng)不良 （APECED）, 自身免疫性多種內(nèi)分泌病變,包括甲狀腺及甲狀旁腺功能減退，腎上腺皮質(zhì)衰竭，T1D，性腺衰竭，惡性貧血及自身免疫肝炎 慢性粘膜與皮膚白色念珠菌病 外胚層發(fā)育不良，而且一大部分病人會發(fā)生口腔粘膜鱗狀細(xì)胞癌,罕見人類單基因遺傳性自身免疫疾病,Scurfy 小鼠,Foxp3基因 敲除小鼠,功能：控制CD4+CD25+ Treg的發(fā)育及功能 FOXP3突變 Treg缺失 自身免疫病,叉狀頭/翅膀狀螺旋轉(zhuǎn)錄因子（Foxp3）,Wild type,Scurfy Foxp3 mutation,性聯(lián)免疫失調(diào)綜合征（IPEX）,nature genetics 2001, 27:20-21,特點(diǎn) 早發(fā)性頑固性腹瀉、自身免疫性甲狀腺炎、胰島素依賴性糖尿病、高IgE、嗜酸性粒細(xì)胞升高、腎病、皮疹等，常導(dǎo)致患者在嬰幼兒早期死亡。 機(jī)制：Foxp3 基因突變,Wild-type,Fas-knockout,Fas-FasL介導(dǎo)的AICD是機(jī)體重要的外周免疫耐受機(jī)制，F(xiàn)as基因突變，大量活化的淋巴細(xì)胞可持續(xù)存活，產(chǎn)生淋巴細(xì)胞增生（脾大、淋巴結(jié)腫大）和自身免疫現(xiàn)象,Fas-FasL,自身免疫性淋巴細(xì)胞增生綜合征 Autoimmune lymphoproliferative syndrome (ALPS),特點(diǎn) 淋巴細(xì)胞增生性表現(xiàn)：脾臟腫大； 自身免疫性疾?。鹤陨砻庖咝匀苎载氀?(75%)，免疫性血小板減少癥 (54%)，自身免疫性中性粒細(xì)胞減少癥；其他有腎小球腎炎、多發(fā)性神經(jīng)根炎和皮膚損害(包括蕁麻疹和非特異性皮膚血管炎) 機(jī)制： Fas基因突變,Environment factor for T1D,飲食因素：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,分子模擬,Infectionmolecular mimicry,分子模擬,飲食、應(yīng)激、損傷自身抗原性質(zhì)改變,自身抗原修飾類型： 磷酸化 瓜氨酸化 氧化 乙?；?Current Therapies - 非特異性免疫抑制劑以及抗炎療法 危害：感染、腫瘤的發(fā)生率增加、長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,免疫抑制劑 （Immunosuppressive drugs） -皮質(zhì)類固醇corticosteroids，硫唑嘌呤 azathioprine - slows the proliferation of lymphocytes 環(huán)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 血漿置換 （Plasmapheresis） - removes antigen-antibody complexes for a short- term reduction in symptoms,1. 靶向T/B細(xì)胞的非特異性治療策略,antithymocyte globulin (ATG) anti-CD3 antibody OKT3， humanized FNB mAb OKT3g1ala-ala (teplizumab) retained a combination of rapamycin and anti-IL-2 B-cell-depleting drug rituximab （anti-CD20）,II. Experimental Therapeutic Approaches,體內(nèi)剔除T/B細(xì)胞,阻斷T細(xì)胞共刺激、遷移及細(xì)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 cells aka CD40L: blocking interactions of CD154 on T cells and CD40 on APCs fingolimod (FTY720), a small compound: affecting T-cell trafficking TNF- antagonists Anti-IL-17 mAb Secukinumab： Phase 3 studies in Psoriasis and AS completed,2. 細(xì)胞過繼性治療策略,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）,臨床基于Treg的過繼性治療策略,體外活化和 擴(kuò)增,從病人體內(nèi)分離出部分Treg,回輸入病人 體內(nèi),Treg過繼療法的優(yōu)勢以及存在的問題,優(yōu)勢： 與大多藥物治療相比，Treg過繼轉(zhuǎn)移可以最大程度的降低治療毒性帶來的副作用 向病人回輸Treg之前可以對細(xì)胞的表型和功能進(jìn)行鑒定，并且準(zhǔn)確的控制治療用細(xì)胞的數(shù)量，增強(qiáng)了治療的安全性和可操作性 問題： 這些Treg是否具有靶器官抗原特異性，是否能夠歸巢到局部效應(yīng)靶器官？抗凋亡能力如何？如何獲得抗原特異性Treg？ 體外擴(kuò)增的Treg細(xì)胞是否有恢復(fù)為普通T細(xì)胞的可能 ？ 體內(nèi)輸入大量具有免疫抑制功能的Treg 細(xì)胞，是否會增加感染和腫瘤發(fā)生的機(jī)會 ？,3. Antigen-Specific Therapeutic Approaches,Soluble autoantigens or peptides (oral; i.v.; i.p) Altered peptide li