疫基础绪论医学医药.ppt

现代免疫学基础及进展 第一章 概述, 序言 简述未列入专章论述的重要概念 衔接大学本科免疫学教学,Chapter 1: An Overview,1、 简史 2、 免疫系统和免疫学 3、 免疫系统的识别能力：抗原识别 抗原 固有免疫及适应性免疫对抗原的识别 4、免疫系统的反应能力：免疫应答 免疫细胞的各种受体 信号转导和基因的转录激活 5、免疫系统的自我感知能力：免疫调节 感知网络和感知元件 免疫应答的反馈调控 6、免疫系统的记忆能力：免疫记忆 免疫记忆的特征 记忆性淋巴细胞的分化与维持,免疫学在人类和烈性传染病 作斗争中发展起来,1,Violent infectious diseases as disasters for mankind: yellow fever, plaque, cholera, smallpox, flu,Sixty million died in the epidemic of smallpox in Europe in 18 century,Prophylactic infection by variolation to prevent smallpox in ancient China, 人痘接种 (variolation）的 正式记载，最早见于明朝 隆庆年间 (15671572 )。 当时的诊所已设有专门的 痘科和种痘师。 两种主要的人痘接种法： - 鼻苗法 旱苗法 水苗法 浆苗法 - 痘衣法,张琰：种痘心法，1741年,下苗时选入钵，用杵研细。加水再研， 入和苗丹少许，以微有红色为度，不可太 多。再研极和。干湿所得，大约苗新宜润， 苗久宜干；天寒用温水，天热用凉水。随 取木棉絮一丸如豆大，泡透仍挹干，先展 钵底苗浆，再收杵上苗浆。然后令孩 子向明，左手拈起苗丸，塞入鼻孔，男左 女右。,国初，人多畏种痘、至朕得种痘方， 诸子女皆以种痘得无恙。今四十九旗 俱命种痘，凡所种者皆得善愈。尝记,初 种豆时，年老人尚以为怪。朕坚意为之， 遂全此千万人之生者，岂偶然耶？,康熙：庭训格言（1689年）,皇祖母 ( 博尔济吉特),顺治 （福临）,康熙 （玄烨）,1637-1661 1653-1722,人痘接种（viriolation）,1688年（康熙27年）俄国派人来华学种痘； 1718年 英驻土尔其公使夫人Montagu将人痘接 种带往英国； 1722年 Boston医生马瑟在北美推广种痘； 1752年医宗金鉴传入日本，带去种痘法； 1777年 华盛顿命令美国全军将士种痘。,法国思想家伏尔泰（Voltare, 1694-1778） 在他著名的著作哲学通讯中说: “我听说100年来中国人一直有此习惯 （指人痘接种），这是被认为世界上最聪 明、最讲礼貌的一个民族作出的伟大先例 和榜样。倘若我们在法国曾实施种痘， 也许会挽救千千万万人的生命。”,Edward Jenner (1749-1823),牛痘接种 （vaccination with cowpox）,James Philips was the first case vaccinated with cowpox by Dr. Edward Jenner on May 14, 1796,The vaccination with cowpox in Europe in nineteen century,France army : 23 400 (no smallpox vaccination) Prussian army : 278 (with smallpox vaccination),An example for evaluation of cowpox vaccination,Victims of smallpox during the Prussian-France War in 1870,Louice Pasteur watching Joseph Meister receive the rabies vaccine* (狂犬病 疫苗),* wood engraving, LIllustration, 29:836, 1885,Robert Koch discovered Mycobacterium tuberculosis, by which Calmette-Guerin vaccine (卡介苗) was developed for prevention of Tuberculosis,application of antitoxins against diphtheria (白喉抗毒素),Emil Adolph von Behring (1854-1917),Should Dr. H. Mahler, Director-General of WHO in 1980, thank Emperor Kang-Xi?, In eradication of smallpox, either variolation or vaccination with cowpox depends on “combat poison with poison”, an excellent idea originally came from ancient China. This is an example that the idea with creativity would be a motive force to push science forward. A The exploration of the mechanisms underlying the vaccina- tion in control of infectious diseases opened an era for immu- nology developing.,免疫系统与免疫学,2, 免疫系统 免疫器官：中枢和外周 免疫细胞：固有免疫和适应性免疫 免疫分子：以结构区分和以功能区分,Immune system,Organs and tissues central: bone marrow, thymus peripheral: lymph node, spleen, mucosal-associated lymphoid tissue Immunocytes in innate immunity: M, NK, DC, granulocyte, etc in adapted immunity: lymphocyte Immunological molecules Classified based on structure cytokines/chemokines and their receptors complements and their regulatory molecules differentiation antigens (CD antigen) adhesion molecules products of TCR, BCR, MHC genes Classified based on function molecules in immunocyte differentiation molecules in inflammation; molecules in antigen-recognition and costimulation molecules in signal transduction for immunocyte activation molecules in apoptosis and cell death,Immune system,Immune: free of infectious disease 1 Immunity: the state of protection against foreign organisms or substances (antigens) Immunology: A discipline for: - study on structures and functions of the immune system; - study on mechanisms by which organisms are free from infection with no undesirable consequences of immune responses; - discrimination of self and non-self. -, 免疫学：分辨自身和非己的学科 Immunology, A discipline for discrimination of self and non-self,WHAT IS the SELF ? The materials encoded by genes in germ-line; The materials encountered by the immune system at early stages of its development, The materials encountered by the immune system at the early stage of its development could be regarded as SELF.,Dizygotic cattle twins fused at the placentae,图1-6 新生动物皮肤移植实验 通过脾细胞注射，在新生期获得对棕色品系小鼠免疫耐受的白色品系小鼠，成年后可接受该棕色鼠的皮肤移植物，但排斥另一黄色小鼠的皮肤移植物。右侧照片所示为实际实验的结果，可见带有棕色毛的皮肤移植物生长良好。（照片自文献xx）,新生动物皮肤移植实验 通过脾细胞注射，在新生期获得对棕色品系小鼠免疫耐受的白色品系小鼠，成年后可接受该棕色鼠的皮肤移植物，但排斥另一黄色小鼠的皮肤移植物。右侧照片所示为实际实验的结果，可见带有棕色毛的皮肤移植物生长良好。,The imbalance of self-nonself discrimination causes diseases,self,nonself,Treatment of nonself as self,Nomal (well discrimination of self-nonself),Treatment of self as nonself,TUMOR, INFECTION,AUTOIMMUNE DISEASE,unable to clean nonself,kill “innocent,THREE FUNCTIONS OF IMMUNE SYSTEM immune defense - anti-infection homeostasis - immune regulation, autoimmunity immune surveillance - anti-tumors,免疫防御、内环境稳定、免疫监视,Immune system organs and tissues immunocytes Immunological molecules Immune response innate immunity adapted immunity Immunopathology, immune responses in diseases hypersensitivity and anaphylaxis anti-infection immunology autoimmune diseases immunodeficiency disease tumor immunology transplantation immunology,Immunology course,第27章,第812章,第1318章,免疫系统的识别能力,3, 抗原、免疫原和抗原表位 抗原和免疫原 决定免疫原性的因素 抗原表位：T 表位和 B 表位 固有免疫和适应性免疫对抗原的 识别,Immunogen Materials able to induce specific humoral and/or cellular immune responses Antigen (Ag) Materials able to specifically combine the products of the immune responses,Immunogenicity 1 An attribution of inducing specific humoral and/or cellular immune responses Antigenicity An attribution of combining the products of the immune responses,Ab, BCR, TCR,新问题,诱导固有免疫应答的分子 (PAMP/DAMP) 一般 不产生抗体，不激活淋巴细胞 (不出现BCR/TCR), 因而具有免疫原性而不显示一般意义上的抗原性。,低分子量的半抗原（hepton）单独不能诱发抗 体应答，但可以与抗体结合。因而半抗原不具有 免疫原性而显示抗原性。,能诱导固有免疫和适应性免疫应答的物质为免疫原。,Factors that influence immunogenicity,Those determined by properties of antigen 1) Foreignness and phylogenetic distance 2) Molecular size: MW 100 kD 3) Chemical composition and heterogeneity 4) Susceptibility to antigen processing and presentation Those contributed by biological system 1) Genetic background of the host 2) Antigen dosage and route of administration 3) Adjuvants Materials unable to change the immunogenicity of an antigen but are able to enhance hosts response to it.,poly-lysine glutamic acid,immunogenicity + ,poly-alanine tyrosine,Factors that influence immunogenicity,Those determined by properties of antigen 1) Foreignness and phylogenetic distance 2) Molecular size: MW 100 kD 3) Chemical composition and heterogeneity 4) Susceptibility to antigen processing and presentation Those contributed by biological system 1) Genetic background of the host 2) Antigen dosage and route of administration 3) Adjuvants Materials unable to change the immunogenicity of an antigen but are able to enhance hosts response to it.,蛋白质抗原激活 T 细胞的能力取决于能否被 MHC 分子结合并递呈 来自同一抗原的14条人工合成肽结合MHC分子的能力(A) 和经MHC分子递呈后激活Th细胞的 能力(B) 之间高度相关。图中部上方为APC表面MHC分子接纳抗原肽形成pMHC示意图；下方 为TCR识别pMHC，并在共刺激信号作用下使Th细胞激活。激活以细胞组织强度表示。 C：两 端锚着于MHC分子中的抗原九肽分子中部凸起处为TCR识别的T表位。,Factors that influence immunogenicity,Those determined by properties of antigen 1) Foreignness and phylogenetic distance 2) Molecular size: MW 100 kD 3) Chemical composition and heterogeneity 4) Susceptibility to antigen processing and presentation Those contributed by biological system 1) Genetic background of the host 2) Antigen dosage and route of administration 3) Adjuvants Materials unable to change the immunogenicity of an antigen but are able to enhance hosts response to it.,强直型脊柱炎（ankylosing spondylitis, AS）,10年,10年,10年,100 80 60 40 20 0 20 （RR）,354 376 90 98 55 109 213 270,HLA-B27 positive（） relative risk,Oriental Caucasoid Black Arabian Indian Singapore,AS,control,The subject with HLA-B27 allele is highly susceptible to ankylosing spondylitis (AS),抗原剂量和进入途径, Antigen dosages and induction of tolerance (immunological unresponsiveness) Repeated administration stimulates a more strong immune response (booster) Administration route: intravenous: antigen spleen subcutaneous: antigen local lymph nodes,佐剂（adjuvant）,一类可与抗原混合共同进行免疫的物质。 佐剂通常不改变抗原的免疫原性,但可以提高 机体的应答能力,增强对抗原的免疫应答强度。, Prolong antigen persistence Enhance co-stimulatory signals Induce granuloma formation Stimulate lymphocyte proliferation nonspecifically,Antigen epitopes (表位) and their recognition by T cells and B cells, Epitope (determinants) is a special part of antigen molecule responsible for recognition and binding by BCR (antibody) or TCR. The recognition specificity of BCR (antibody) and TCR is directed to the epitope (s) instead of the whole antigen molecule. T cell and B cell usually recognize different epitopes on same antigen molecule. There are T cell epitope (s) and B cell epitope (s) for an antigen molecule.,抗原分子以其 B 细胞表位与抗体分子的抗原结合部位发生互补性结合 A. 抗原-抗体复合物的立体构象。B. 采用电脑技术将抗原和抗体分子分开，可见抗原和抗体分子的相互作用仅发生在抗原分子的B细胞表位和抗体分子的抗原结合部位之间，两者呈现结构互补。,抗原的连续表位 (continuous epitope) 和构象 表位 (conformational epitope),antigen,antibody,conformational epitope,continuous epitope,antibody, 适应性免疫主要通过淋巴细胞表面抗原受体 识别蛋白质抗原 抗原TCR及BCR 固有免疫主要通过非淋巴细胞的模式识别受 体识别病原体相关非蛋白质抗原 PAMPPRR PAMP (pathogen-associated molecular pattern)： 病原体相关分子模式 PRR (pattern recognition receptor): 模式识别受体,免疫系统的反应能力,4, 免疫细胞的各种受体 受体分子启动的信号转导 固有免疫应答和适应性免疫应答 适应性免疫中的重要概念,免疫细胞的各种受体 抗原识别受体 TCR/BCR PRR 共信号分子受体 免疫球蛋白 Fc 受体 其它,B细胞和T细胞抗原识别受体及相关分子的比较,属于PRR的Toll样受体 (TLR) : 基本结构与分类,Co-signal molecules and their receptors in T cell activation and the related immune responses ligand receptor ITAM/ITIM Ig-SF B7-1 CD28 ITAM B7-2 CTLA-4 ITIM B7-H1 PD-1 ITIM B7-DC ? B7-H2 ICOS B7-H3 ? HVEM BTLA ITIM 1 Adh mol CD2 LFA-3 LFA-1 ICAM-1 TNF CD40L CD40 OX40L OX40 4-1BBL 4-1BB,T,T,APC,APC,共信号分子 及其受体,FcRII-B对抗体产生的反馈性调节,免疫球蛋白 Fc受体 (FcR),蛋白质的磷酸化和脱磷酸化,受体分子启动的信号转导,免疫细胞信号转导途径模式图 受体识别抗原之后，通过分子间聚合（此处未画）或本身及相关分子胞内段，使蛋白酪氨酸激酶（PTK）激活，后者藉助多种衔接蛋白（adopter）激活蛋白丝氨酸苏氨酸激酶，活化胞质中的转录因子，使之转位到细胞核与相应顺式作用元件结合。当各种转录因子到位，基因开始转录。,Innate immunity（固有免疫/天然免疫）, The early phases of the host response to infection, which is also developed in early stages of phylogeny Rapid response to various microbes essentially in same way；No antigen specificity Presence in all individuals at all times and exits prior to exposure to antigen,固有免疫应答和适应性免疫应答,模式识别受体（PRR）中的 Toll样受体（TLR） 结构：I 型跨膜糖蛋白。胞外段 包含多个富含亮氨酸重复体， 结合 PAMP；胞内段为 TIR 结 构域，参与信号转导。 分布：主要表达于 M 和 DC。 识别配体：PAMP 和 DAMP。 功能：结合配体后实施胞内信号转导。,在不同层次感知非己PAMP成份的TLR、NLR及RLR Toll样受体（TLR)、NOD样受体（NLR）与RIG-I 样受体（RLR) 分别在细胞膜外、内体 腔中及胞质溶胶内以相似的亮氨酸重复序列结构域（LRR) 感知PAMP和DAMP的不同成份。,病原体相关分子模式 (pathogen-associated molecular pattern, PAMP) 病原微生物及其细胞壁等特有的结构，真核细胞不具有。 如脂多糖 (LPS)、类脂、肽聚糖 (PGN)、脂磷壁酸 (LTA)、 脂阿拉伯甘露聚糖 (LAM)、脂蛋白、寡核苷酸 CpG。,PAMP组成成分相对单一，可纳入为数不多的结构范畴； PAMP有其共性，可以为多种病原体所共有； PAMP结构属病原体赖以生存因而变化较少的组份，对此病原体很难以 突变改变其组成与结构。有利于固有免疫对其发挥作用。,糖,Activation,Damaged or dying cells,Secreted from stressed cells,Degradation of tissue matrix,protease,PWN,DAMP,PRR,Immunocytes,Signal transduction,损伤相关分子模式 damage-associated molecular pattern (DAMP),Innate immunity,Adaptive/acquired immunity （适应性免疫/获得性免疫）, Defense functions acquired after birth by exposure to infectious agents 1 Main features： 1 - Specificity: Exact discrimination of distinct antigen 1 - - Diversity： Recognition structures of lympho- cytes are highly heterogeneous 1 - Memory： Enhanced response to re-exposure to the same antigen,Important concepts in adaptive immunity, Humoral and cellular (cell-mediated) immune response Host defense mediated by antibodies or lymphocytes Primary and secondary immune response Active and passive immunization Immunity induced by exposure to pathogen (vaccine) or acquired by receiving antibodies and/or activated lymphocytes Three phases in immune responses Input phase: recognition of antigen Central phase: activation of lymphocytes Output phase: elimination of antigen by effectors,Important concepts in adaptive immunity, Humoral and cellular (cell-mediated) immune response Host defense mediated by antibodies or lymphocytes Primary and secondary immune response Active and passive immunization Immunity induced by exposure to pathogen (vaccine) or acquired by receiving antibodies and/or activated lymphocytes Three phases in immune responses Recognition phase: recognition of antigen Activation phase: activation and differentiation of lymphocytes Effector phase: elimination of antigen by effectors,体液免疫和细胞免疫 中的二次应答 A. 抗体产生的二次增强应答。B. 同种异型皮肤二次移植诱导的加速排 斥。两类二次对初次致 敏的抗原，表明体液和 细胞免疫二次应答皆显 示抗原特异性。,Important concepts in adaptive immunity, Humoral and cellular (cell-mediated) immune response Host defense mediated by antibodies or lymphocytes Primary and secondary immune response Active and passive immunization Immunity induced by exposure to pathogen (vaccine) or acquired by receiving antibodies and/or activated lymphocytes Three phases in immune responses Recognition phase: recognition of antigen Activation phase: activation and differentiation of lymphocytes Effector phase: elimination of antigen by effectors,Important concepts in adaptive immunity, Humoral and cellular (cell-mediated) immune response Host defense mediated by antibodies or lymphocytes Primary and secondary immune response Active and passive immunization Immunity induced by exposure to pathogen (vaccine) or acquired by receiving antibodies and/or activated lymphocytes Three phases in immune responses Recognition phase: recognition of antigen Act