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,*,*,免疫调节、免疫失调与自身免疫病,Immunoregulation,，,Immunodysregulation and Autoimmune Disorders,2024/11/19,免疫调节、免疫失调与自身免疫病Immunoregulatio,1,Part I,Concept of Immunohomeostasis,Part II,Immunological Tolerance,Part III,Immunoregulation and Immunodysregulation,Part IV,Mechanisms of Autoimmune Diseases,Contents,2024/11/19,Part I Concept of Immunohom,2,Part I,Concept of Immunohomeostasis,免疫平衡的概念,2024/11/19,Part I Concept of Immunohomeo,3,Two systems(innate and adaptive),Organs and connecting network,Different lineage of cells,Numerous T and B cell clones with unique Ag specificity,Has to be able to distinguish self from non-self,Complexity of the Immune System,2024/11/19,Two systems(innate and adapti,4,Stay in harmony with self-antigens and tissues of the host,Maintain appropriate magnitude when responding to foreign Ags challenge,1 Defend against infectious microorganisms,A properly coordinated(regulated)immune system will:,2024/11/19,Stay in harmony with self-anti,5,Combination of good genes,Good luck,Regulation,Immune homeostasis,免疫细胞的调亡,免疫细胞的不断更新,免疫耐受的维持,免疫记忆的传递,免疫分子的平衡,2024/11/19,Combination of good genesGood,6,Immuno-imbalance,Hypersensitivity,Overreaction to,foreign substances,Athma,Hayfever,Contact hypersensitivity,2024/11/19,Immuno-imbalanceHypersensitivi,7,Immuno-imbalance,Immunodeficiency,Frequent infection,Immunodeficiency,unable to control infection,Frequent infection with various pathogens,2024/11/19,Immuno-imbalance Immunodeficie,8,SLE,Rheumatoid Arthritis,Diabetes,AS,Immuno-imbalance,Autoimmunity,Attack of self-antigens,Autoimmunity,Autoimmune diseases,2024/11/19,SLE Immuno-imbalanceAutoimmuni,9,Part II,Immunological tolerance,免疫耐受,2024/11/19,Part II Immunological toleran,10,2,-1,中枢免疫耐受,免疫系统无时无刻不与许许多多的自身抗原发生直接的接触，免疫系统的淋巴细胞并不因此而被激活并对自身抗原发生免疫反应。这种现象被称作,自身免疫耐受,。自身免疫耐受是通过中央和外周免疫耐受来实现和维持的。,胸腺细胞的阴性选择,B,细胞在骨髓中的克隆清除,2024/11/19,2-1 中枢免疫耐受 2023/8/5,11,固有免疫识别受体与适应性免疫识别受体的区别,适应性免疫识别受体的多样性产生机制,基因重排,随机性与独立性,质量控制步骤,2024/11/19,固有免疫识别受体与适应性免疫识别受体的区别2023/8/5,12,2-2,外周免疫耐受,T,细胞免疫耐受,B,细胞免疫耐受,淋巴细胞循环限制,2024/11/19,2-2 外周免疫耐受 T 细胞免疫耐受2023/8/5,13,非专职,APC,诱导初始,T,细胞进入免疫失能状态,T,细胞外周免疫耐受,2024/11/19,非专职APC诱导初始 T 细胞进入免疫失能状态T 细胞外周免,14,T-B,细胞之间的协作限制,B,BCR,TCR,T-B,细 胞 经 典 活 化 途 径,外来抗原,MHC II,Th,辅 助,2024/11/19,T-B 细胞之间的协作限制 BBCRTCRT-B 细,15,B,BCR,TCR,T-B,细 胞 免 疫 耐 受,自身抗原,MHC II,活性封闭,T,细胞,协作限制是维持,B,细胞耐受的主要机制之一,2024/11/19,BBCRTCRT-B 细 胞 免 疫 耐 受自身抗原,16,Part III,Immunoregulation and dysregulation,免疫调节与免疫失调,2024/11/19,Part III 免疫调节与免疫失调2023/8/5,17,调节性,T,细胞是主动维持自身免疫耐受的关键细胞,Th1/Th2/Th17,细胞之间的相互调节,细胞因子的免疫调节作用,(IL-2,IL-10,TGF-,b,),淋巴细胞,(,活化,),状态的自身调节机制,(ITIM,LAIRE,AICD),神经内分泌系统对免疫系统的调节作用,2024/11/19,调节性T细胞是主动维持自身免疫耐受的关键细胞2023/8/,18,经典实验,-1,主动维持免疫耐受的专职调节性,T,细胞,2024/11/19,经典实验-1主动维持免疫耐受的专职调节性 T 细胞202,19,Anti-CD25-PE,Before depletion,After depletion,Anti-CD4-FITC,5-10%,2024/11/19,Anti-CD25-PEBefore depletionAf,20,Normal mouse,CD4,+,T cells eliminated CD25,+,cells,T cell-deficient mouse,Autoimmune diseases,thyroid,stomach,salivary gland,Langerhans islets,adrenal glands,ovaries,testes,经典实验,-2,2024/11/19,Normal mouseCD4+T cells eli,21,2024/11/19,2023/8/5,22,CD4,+,CD25,+,Tregs:,A naturally occurring unique lineage of regulatory T cells,Comprise 5-10%of peripheral CD4 T cells in human and mice,Capable of maintaining self tolerance in vivo,Characterized by expression of,CD4,and,CD25,on surface,FOXP3,in the nucleus,Require activation and cell contact to repress proliferation of,CD4,+,CD25,-,T cells in vitro,CD4,Effectors,Regulators,2024/11/19,CD4+CD25+Tregs:CD4Effecto,23,调节抗原特异性免疫应答,抑制天然免疫应答,调节肿瘤免疫,抑制病毒特异性免疫应答（,HIV,为例）,抑制各种自身免疫性疾病（,RA,，,MS,等）,The“miracle”CD4,+,CD25,+,Tregs:,2024/11/19,调节抗原特异性免疫应答The“miracle”CD4+C,24,B,10,10,CD8,10,10,CD4,10,10,Peripheral Lymphocyte Repertoire,在,CD25,+,Treg,细胞之前的免疫学理论,Immunization,CD4,B,Abs,CD8,Th1,Th2,Th3,CTL,2024/11/19,B,1010CD8,1010CD4,1010Perip,25,B,10,10,CD8,10,10,CD4,10,10,Peripheral Lymphocyte Repertoire,新的假说,-,CD25,Treg,+,-,-,CD25,+,10,9,Immunization,CD4,B,CD8,2024/11/19,B,1010CD8,1010CD4,1010Perip,26,IPEX,I,mmune deficiency/dysregulation,P,olyendocrinopathy,E,nteropathy,(Often have Ab against gut epithelium),X,-linked inheritance,2024/11/19,IPEXImmune deficiency/dysre,27,CD25,FOXP3,IPEX Normal,2024/11/19,CD25FOXP3IPEX,28,FOXP3,Mutations,Zn-finger,FKH(DNA binding),Zip,ATG,A38S,C424Y,R397W,R397W,R397L,delGA(TGA)1317-1318,delT(TGA)13115-1316,I363V,F371C,A,g,G,+4A,g,G,A384T,A384T,A384T,A384T,R347P,del251E,C565T splicing,C565T splicing,L76,frameshift,1 2 3 4 5 6 7 8 9 10 11 PolyA,2024/11/19,FOXP3 Mutations Zn-finger,29,Immuno-dysregulation,Autoimmunity,Immunodeficiency,Hypersensitivity,Leukemia and lymphoma,2024/11/19,Immuno-dysregulationAutoimmuni,30,Mechanisms of autoimmune disorders,自身免疫疾病发病原理,Part IV,2024/11/19,Mechanisms of autoimmune disor,31,自身免疫病,是免疫系统对宿主自身抗原发生正性应答、造成其组织或器官的病理性损伤、影响其生理功能、并最终导致各种临床症状的结果。,2024/11/19,自身免疫病 是免疫系统对宿主自身抗原发生,32,证实自身抗体或自身反应性,T,细胞的存在；,找到自身抗原；,用该自身抗原免疫动物能够诱发同样的自身,免疫病；,通过被动转移实验证实抗体或者,T,细胞的致,病能力。,确认自身免疫病的条件,2024/11/19,证实自身抗体或自身反应性T细胞的存在；确认自身免疫病的,33,2024/11/