1、免疫学概述,The Origin of Immune Concept,The term “Immunity” = Latin word “Immunitas” = Protection from legal prosecution (Roman senators)Biological definition = Protection from infectious diseases 2. The concept of immunity = existed in ancient Greek & Chinese = the experienced view,“天花”又名痘疮,中国从宋朝起用人痘接种预
2、防天花,The medical view of immunity = Edward Jenner (1796)Observation = Milkmaids generally get No SmallpoxHypothesis = Pus from vaccinia (cowpox) = Protect milkmaids from smallpox Test = Inoculate materials from cowpox pus = Protect a young boy from smallpox (Protective immunity),The vaccination again
3、st smallpox,Exudate from a cowpox pustule on the hand of milkmaid Sarah Nelmes was inserted into scratches on the arms of James Phipps, May 14, 1796.,Edward Jenner,Eradication of smallpox,4. The concept of “Immunity” developed gradually over time through many scientific findings: = Robert Koch (1905
4、 Nobel Laureate) = Infectious diseases caused by microorganisms= Louis Pasteur = Vaccines against cholera & rabies= These clinical successes = The search of underlying mechanism of “Protection of Infectious Diseases”= The development of “Immunology” Advances in technology (e.g., Cell culture, Monocl
5、onal Ab, Flow cytometry, Genetic engineeringetc) have facilitated our understanding of the immune system and its functions. “Descriptive Science” = “Experimental Science”,免疫（immunity)传统概念指免除疫病、免除感染，指机体抗感染的防御能力。现代概念指机体对“自己”或“非己”的识别并排除“非己”的功能。,免疫的基本功能,免疫系统 (immune system)：机体执行免疫功能的组织、器官、细胞和分子构成免疫系统。,T
6、he four kinds of pathogens that cause human disease,常见的病原微生物,Overview of immune responses,固有免疫 （innate immunity）是机体抵御病原微生物入侵的第一道防线，并启动和参与适应性免疫应答。天然免疫（natural immunity)或非特异性免疫(nonspecific immunity)，是个体出生时就具有的免疫力，通过遗传获得，是生物在长期进化过程中逐渐形成的，其针对外来异物的范围广，反应迅速，其应答模式和强度不因与病原微生物的反复接触而改变。,固有免疫应答的作用时相： 瞬时固有免疫应答阶
7、段、早期固有免疫应答阶段、适应性免疫应答诱导阶段,固有免疫系统的组成,屏障细胞分子,皮肤黏膜屏障：物理、化学、微生物 血-脑屏障、血-胸腺屏障 血-胎屏障、气-血屏障,巨噬细胞、中性粒细胞、树突状细胞、T 细胞、NK细胞、NKT细胞、B1细胞、肥大细胞、嗜碱性粒细胞和嗜酸性粒细胞等。,抗菌肽、溶菌酶、急性期蛋白、补体、细胞因子和黏附分子、,Epithelial barriers prevent the entry of microbes,固有免疫细胞,Phagocyte NK ILLs（固有样淋巴细胞）DC MC Basophil Eosinophil, T细胞NKT细胞B1细胞,Monocy
8、te-macrophage Neutrophil,肺部巨噬细胞吞噬大肠杆菌,Phagocytosis by innate immunity,Leukocyte recruitment to sites of inflammation,or DC,固有性免疫分子,指体表分泌液以及血浆和其它体液中能够识别或攻击病原体的可溶性分子。,抗菌肽 antimicrobial peptides 溶菌酶 lysozyme 急性期蛋白(acute phase proteins, APP) 脂多糖结合蛋白（LBP） 血清淀粉样蛋白（SAP） 甘露糖结合蛋白（MBP） C反应蛋白等（CRP） 补体 细胞因子和黏附分
9、子,Complement activation pathways,Elie Mechnikoff:The Pioneer of Innate Immunity,1. The Discovery of Phagocytes & Phagocytosis 2. The Nobel Laureate in Medicine 1908,Adopted from Nature Immunology, July 2008,The development of modern Immunology in 20th century mainly centers on understanding the Adap
10、tive Immune System.,Charles A. Janeway, M.D. Yale Univ.,The “Renaissance” of innate immunity,In 1989, Janeway = Immune recognition of microbes = Detection of conserved molecular patterns, referred to PAMPs (Pathogen-Associated Molecular Patterns) with features:1. Invariant among a given class of mic
11、robes. 2. Have essential roles in microbial physiology. 3. Recognized by receptors of the innate immune system, called PRRs (Pattern-Recognition Receptors). 4. Innate immunity regulates adaptive immunity,Julie A. Hoffmann, Ph.D. Strasbourg, France,The “Renaissance” of innate immunity,In 1996, Hoffma
12、nns group Toll functions as a PRR in Drosophila,Key concepts in innate immunity,1. The innate immune system mainly recognizes common structures shared by classes of microbes, = PathogenAssociated Molecular Patterns (PAMPs), e.g., LPS, Peptidoglycan, Microbial DNA & RNA. 2. Host receptors that recogn
13、ize PAMPs are called Pattern-Recognition Receptors (PRRs), which are encoded in “Germline” DNA= limited Diversity. 3. Innate immunity not only provide the first line of defenses but link to the program of adaptive immunity.4. PRRs may also recognize components from injured or deadhost cells = Autoim
14、mune diseases,Pathogen- Associated Molecular Patterns (PAMP),是病原微生物（尤其是原核生物）表面存在一些人体所没有的，但可为许多相关微生物所共享、结构恒定、进化保守的分子结构。,损伤相关分子模式 （damage-associated molecular patterns，DAMPs）,机体自身细胞所释放的内源性分子，即内源性危险信号，来源于受损或坏死组织和某些激活的免疫细胞。主要有HMGB1、热体克蛋白等。,PAMP vs DAMP,Sterile inflammation,conserved microbial motifs VS
15、non-microbial signals,Toll-like Receptors,Locations of Different PRRs,Body fluids -Soluble PRRsCellular PRRs - Cell surface- Endosomes- Cytosol,Surface receptors of macrophages,Mac-1、CR3,PRR,甘露聚糖凝集素（MBL） C反应蛋白（CRP） 脂多糖结合蛋白（LBP）,可溶性：体液和血液,细胞吞噬型：细胞膜,甘露糖受体（MR） 清道夫受体（SR） 补体受体（CR） Fc受体（FcR） 甲酰甲硫氨酰肽受体（fML
16、PR）,信号转导型,细胞膜内体、溶酶体细胞质,TLR1、2、4、5、6、10、11,TLR3、7、8、9,NLRs、RLRs、ALRs,固有免疫细胞表面、内体、溶酶体、细胞质中、可识别一种或多种PAMPs或DAMPs的识别分子。,Diversity of pattern recognition receptors,Toll-Like Receptors (TLRs),MyD88-Dependent and independent Signaling,NLRs are cytoplasmic bacterial sensors that activate inflammasomes,1,Vira
17、l Pattern Recognition Receptors: Signaling and Consequences,Interaction between innate and & adaptive immunity,1. Innate immunity = Ag presentation (by Dendritic cells)2. Adaptive immunity = Ag recognition (by T & B lymphocytes),适应性免疫 （adaptive immunity）,是机体获得性、抗原特异性、抵抗病原微生物感染的高效防御机制。获得性免疫（acquired
18、immunity)或特异性免疫(specific immunity)，是个体出生后，在环境中受抗原刺激所产生的免疫力，针对特定抗原，有特异性、多样性、记忆性和耐受性。1) 特异性，对某个特定的异物性抗原能引起特异性免疫应答；指抗原特异性。 2) 多样性，机体可针对环境中多种多样的抗原，分别建立起不同的特异性免疫应答；多样性是特异性产生的基础。 3) 记忆性，当异物抗原再次入侵时，可产生快而强的再次免疫应答效应；记忆性淋巴细胞。 4) 耐受性，正常情况下，免疫系统对自身成分有保护性的免疫耐受；,抗原决定簇 Antigenic determinant，AD,抗原分子表面具有特殊立体构型和免疫活性的
19、化学基团称为抗原决定簇或抗原决定基。由于抗原决定簇通常位于抗原分子表面，因而又称为抗原表位(epitope)。抗原决定簇抗原决定基 抗原表位抗原决定簇决定抗原的特异性，即决定抗原与抗体发生特异性结合的能力（实际是抗原决定簇与抗体的结合）。,AD的数目、性质和空间构象决定抗原特异性 抗原以AD与相应抗原受体及抗体特异性结合,T细胞表位和B细胞表位,T细胞表位：TCR识别 必须经降解加工处理后才能被T细胞识别线性决定簇 B细胞表位：BCR识别或抗体识别并结合直接识别构象决定簇或线性决定簇,抗原提呈细胞 (antigen-presenting cell, APC),是指能摄取, 加工处理抗原, 并将
20、抗原信息提呈给淋巴细胞的一类免疫细胞，在机体免疫应答过程中发挥重要作用。 此类细胞能辅助和调节T细胞、B细胞识别抗原并对其产生应答，故又称为辅佐细胞(accessory cell)，简称A细胞。,APC加工处理的抗原种类:外源性抗原(exogenous antigen): 通过吞噬或吞饮等作用被APC从细胞外摄入的抗原，以抗原肽-MHC I I类分子复合物形式提呈给CD4+T细胞 。内源性抗原(endogenous antigen): 细胞内合成的抗原，以抗原肽-MHC I类分子复合物形式提呈给CD8+T细胞 。,外源性抗原加工，处理及提呈,APC 摄取的外源性抗原在内体中降解成肽，与 MHC
21、类分子(在内质网合成) 结合后表达于细胞表面。外源性抗原加工中需要 Ii 链和 HLA-DM 分子的参与。Ii 链 与 MHC类分子的转运有关，并通过 CLIP 封闭 MHC类分子的肽结合部位，阻止 MHC-类分子在内质网中与内源性抗原肽结合。HLA-DM 分子促使 CLIP 从 MHC类分子肽结合区解离，有利抗原肽与 MHC类分子结合。,内源性抗原加工，处理及提呈,内源性抗原经蛋白酶体降解成肽，通过抗原加工相关转运体(TAP1、TAP2)转运进入内质网，与 MHC类分子(在内质网合成)结合成肽-MHCI类复合物，通过高尔基体表达于细胞表面。 TAP是内质网上的异源性二聚体，由TAP-1及TA
22、P-2基因编码胞浆中蛋白酶体（proteasomes, 核心成分为低分子量多肽LMP,细胞被病毒感染后出现的病毒蛋白，基因突变后产生的肿瘤抗原,脂类抗原的CD1分子提呈,CD1分子：非经典MHC I类分子，30%同源性。提呈抗原：提呈糖脂或脂类抗原，供CD1限制性T细胞识别,CD1分子提呈微生物的脂质抗原，脂质抗原由CD1分子提呈后激活CD1限制性T细胞。,Adaptive immunity,Main effectors: Antibody T cell receptors,B,BCR,THE ADAPTIVE IMMUNE RESPONSE,Antibody-Mediated Immunit
23、y (AMI) Involves B lymphocytes, plasma cells and antibodies Humoral immunity Name derives from antibodies found in body fluids (humors - old medical term) Cell-Mediated Immunity (CMI) Involves T lymphocytes, antigen-presenting cells and MHC (major histocompatibility complex) molecules Cellular immun
24、ity,Types of adaptive immunity,1. Humoral immunity = Molecules in body fluid,e.g. Antibody (Ab)= Key player = B cells = Target extracellular microbes & toxins2. Cell-mediated immunity = Key player = T cells = regulate other immune cells = Target intracellular microbes, e.g. viruses, bacteria,For inn
25、ate immunity, it also includes Humoral & Cellular components for immune defense,1、抗原提呈与识别阶段（感应阶段）： 2、活化、增殖、分化阶段（反应阶段）：T细胞活化、增殖分化为效应T细胞；B细胞活化、增殖分化为浆细胞；部分细胞发育为记忆细胞。 3、效应阶段：效应T细胞对抗原的清除；浆细胞分泌抗体清除抗原。,免疫应答的三个阶段,Overview of adaptive immune responses,CELL-MEDIATED IMMUNITY (CMI),Directed against intracellul
26、ar microorganisms Non-phagocytic cells and phagocytic cellsT-lymphocytes (T cells) Differentiate into effector cells following antigen presentation by antigen presenting cells (APCs)Functional types of T cells Helper (CD4 T cells) TH1 and TH2 cells Cytotoxic (CD8 T cells),T cells develop in the thym
27、us,T cells develop in bone marrow, but in order to mature, they need to migrate to thymus = thymus-(T)-dependent lymphocytes Thymus is a primary lymphoid organ located in the upper thorax (chest), just above the heart. Progenitor (precursor) T cells enter the thymus, where they mature (= produce T c
28、ell receptors). Mature T cells leave the thymus and enter the secondary lymphoid tissues, where they become activated after exposure to antigen.,T cells develop in bone marrow and then migrate to thymus where they mature,Mature T cells enter the blood stream, and after infection accumulate in the se
29、condary lymphoid tissues where they are activated.,T cell development,TSC,CD4 RTE,TCR,TCR,CD8,CD4,b-selection,Positive selection,Negative selection,Functional maturation,TCR-b rearrangement,TCR-a rearrangement,CD8 RTE,Development of Thymocytes,Double negative,Double positive,Single positive,Notch Si
30、gnal and T-lineage Commitment,受体: Notch 1-4；胸腺细胞表达Notch1-3；全部效应由Notch 1介导配体：Dll1，3，4， Jagged 1，2；胸腺上皮细胞表达全部配体；Dll4可能为生理性配体T系定向：始于DN1，完成于DN3；绝对依赖Notch1信号,T cells undergo further differentiation in secondary lymphoid tissues after encounter with antigen,Only a small fraction of naive T cells (mature T
31、 cells before they encounter antigen) survives the positive and negative selection, and leaves the thymus. Mature naive T cells can re-circulate between blood and lymphoid tissues for many years (in contrast to B cells, which have shorter life span). In secondary lymphoid tissues, T cells accumulate
32、 in T cell areas, where they become activated by their specific antigens. Encounter with antigen induces the final stage of T cell development: their differentiation into effector T cells. Some effector T cells stay in the lymphoid tissues (CD4-TH2 cells), while others migrate to site of infection (
33、CD8 and CD4-TH1 cells).,T细胞受体复合物由TCR和CD3组成。前者识别和结合抗原肽, 后者将TCR获得的抗原信号传递至细胞内。,T细胞对抗原的识别,APC,T细胞,CD molecules associated with reco-gnition,adhesion and activation of T cell, MHC-, MHC-, B7,CD40, CD58, CD2,T细胞活化的双信号刺激第一信号：TCR对MHCII抗原肽复合物的识别，CD3分子将第一信号传递到细胞内。 第二信号：CD28识别专职APC上的B7分子,又称协同刺激信号。,Effector T c
34、ells,In contrast to terminally differentiated B cells (plasma cells), there are several types of terminally differentiated effector T cells.CD8 T cells Cytotoxic T cells (recognize MHC class I molecules)CD4 T cells,TH1 helper cells (activate macrophages) TH2 helper cells (induce differentiation of B
35、 cells into plasma cells and production of antibodies),Activation (cytokines),(recognize MHC II molecules),The immune system is maintained in a carefully regulated balance between the two polarised control arms, Th1 (cellular immunity) and Th2 (humoral immunity).,In disease states the balance is ske
36、wed. multiple sclerosis, rheumatoid arthritis and type I diabetes, have a Th1 bias, whereas cancer patients have a Th2 bias.,Th1 and Th2 Cells Do not Represent All CD4+ Cells,More T helper subsets,Th3: TGF-producing CD4 T cells Tr1: IL-10-producing CD4 T cells Th9: IL-9-producing CD4 T cells Tfh: fo
37、llicular helper T cells, located in the follicular regions of lymph nodes and spleen,follicular Th1/Th2/Th17 cells,ANTIBODY-MEDIATED (HUMORAL) IMMUNITY,Directed against extracellular microorganisms and toxinsB-lymphocytes (B cells) Differentiate into plasma cells which produce antibodies Function as
38、 antigen-presenting cells (APCs)Classification of Antibodies (Immunoglobulins) Immunoglobulin M (IgM) Immunoglobulin G (IgG) Immunoglobulin A (IgA) Immunoglobulin D (IgD) Immunoglobulin E (IgE),Paul Ehrlich: One of the fathers of humoral adaptive immunity,1. The Discovery ofAntibody functions2. The
39、Nobel Laureate in Medicine 1908,Adopted from Nature Immunology, July 2008,抗体的功能V区的功能 识别并特异性结合抗原单体（IgG, IgE) 2价二聚体(分泌型IgA) 4价五聚体(IgM) 10价中和效应 中和毒素和病毒与Ag结合 促吞噬细胞吞噬,抗体的结合价,实际意义,C区的功能1.激活补体系统Ab(IgM、IgG) + Ag C1q 补体经典途径 IgG4、IgA和 IgE的凝聚物 补体旁路途径 2.介导免疫细胞活性(1)调理作用（opsonization）：IgG + 抗原(颗粒性) FcR（单核、巨噬细胞及中性
40、粒细胞） 促吞噬细胞吞噬；(2)ADCC：IgG + 抗原(靶细胞) Fc R（NK 细胞） 杀伤靶细胞；(3)介导超敏反应：型、型和型超敏反应。3.穿越胎盘和粘膜,Antibody-Dependent Cellular Cytotoxicity (ADCC),Th2与B细胞的相互作用，获得第二信号：协同刺激信号,CD40-CD40L,活化的Th2细胞分泌细胞因子及表达CD40L，辅助B细胞活化,第二信号（Th细胞信号） 有二种方式（1）Th细胞-B细胞间接触作用：CD40L-CD40等（2）Th细胞分泌细胞因子：IL-4、5、6等,胸腺依赖性抗原（TD-Ag）,活化的B细胞增殖与分化活化B细
41、胞 浆细胞 产生抗体原始淋巴滤泡分裂增殖，形成 生发中心（一周左右）,Specificity, Memory, and Homeostasis of Adaptive Immunity,体液免疫应答一般规律,多克隆抗体(polyclonal antibody，PcAb )：采用传统的免疫方法，将抗原物质经不同的途径进入动物体内，经数次免疫后采取动物血液，分离出血清，由此获得的抗血清即为多克隆抗体。用天然的抗原物质免疫动物，刺激多个B细胞克隆所获得的免疫血清（含多种特异性抗体）。单克隆抗体(Monoclonal Antibody，McAb):由一个B细胞分化增殖的子代细胞产生的针对单一抗原决定簇
42、的抗体，称单克隆抗体。 由一个B细胞克隆产生。 识别一种抗原表位。 高度均一（结构、特异性）。 杂交瘤技术制备。基因工程抗体：利用基因工程技术来制备的抗体分子称为基因工程抗体，是分子水平的抗体。,US和EU所批准的治疗性抗体,US和EU所批准的治疗性抗体,鼠源性单克隆抗体将逐渐被人源化抗体所替代：鼠源性单克隆抗体与人补体成分结合能力低，CDC作用相应较弱，对肿瘤细胞的杀伤能力较弱；它与NK等免疫细胞表面Fc受体亲和力弱，介导的 ADCC作用较弱；鼠源抗体在人血循环中的半衰期短，它发挥ADCC与CDC作用的时间较短；鼠单克隆抗体具有免疫原性，宿主易产生抗抗体引起过敏反应。,抗体人源化改造及人源抗
43、体制备,人-鼠嵌合抗体：应用基因工程技术将小鼠单克隆抗体的恒定区用人源抗体恒定区代替而拼接成嵌合抗体。改型抗体如CDR移植、SDR移植：用鼠单克隆抗体的CDR、SDR移植到人源抗体可变区，替代人源抗体CDR、SDR。表面氨基酸残基人源化,抗体人源化的主要技术,提高抗体效应功能,macrophage,Activated T cell,a,A,D,P56 B C58,B,C,NH2,COOH,IL-2,Cytockines are low-molecular-weight regulatory proteins or glycoproteins secreted by white blood ce
44、lls and various cells (vascular endothelial cell, epidermic cell and fibroblast ) in body in response to a number of stimuli.,Cytokine,Biological effects,Cytokine imbalance during inflammation,细胞因子的研究热点1、新细胞因子的基因克隆化 2、细胞因子受体的基因克隆化 3、细胞因子信号转导机制 4、新一代细胞因子：高活性，多功能，低毒副作用，长半衰期，高稳定性 5、细胞因子作为生物应答调节剂（BRM）的临
45、床应用 6、细胞因子表达调控 7、细胞因子基因治疗,Infections occur when the physical barriers of epithelium are breached, or when pathogens adhere to the epithelium,Pathogen replication Recruitment of neutrophils and macrophages Inflammation,Pathogen adherence to epithelium,Pathogens are carried to the closest lymph node w
46、here they stimulate specific T- and B-cells Production of specific antibodies = Adaptive immunity,Innate immunity,Adaptive immunity,Activation of adaptive immunity by innate immunity,Time course of primary infection in healthy individuals, and people who lack immune or adaptive immunity,In the absen
47、ce of innate immunity, there is also no adaptive immunity,Infection is cleared from the body by combined actions of innate and adaptive immunity,T Cells maitain the homostasis of innate inflammation,Pathogen Danger signal,Lymphocyte,INNATE IMMUNITY,ADAPTIVE IMMUNITY,PROTECTION,IMMUNOPATHOLOGY,Failur
48、e of the immune system,1. Ineffective response- Immunodeficiency2. Overactive response- Hypersensitivity 3. Auto-reactive response - Autoimmunity,免疫的基本功能,免疫学研究的主要内容,基础免疫学研究 免疫系统的形成机制、免疫器官与免疫细胞组成以及不同种类免疫细胞和亚群的形成过程与相互之间调控机制。 抗原的结构特性与免疫识别、免疫应答的关系与机制。 免疫细胞感受外界危险信号、识别抗原的物质结构基础。 天然免疫应答的细胞与分子机制。 获得性免疫应答的细胞
49、与分子机制。 免疫耐受及免疫负相调控的方式与机制。 免疫效应分子的结构、功能与作用机制。 免疫细胞的功能调控及其信号转导机制。 免疫细胞的迁移触发、迁移过程与定居机制。 免疫记忆形成的细胞与分子机制。,临床免疫学研究和应用 围绕着重大疾病如感染性疾病、肿瘤、自身免疫性疾病与过敏性疾病以及器官移植排斥等的发生发展机制、诊断与病程的动态观察和预后分析、治疗与预防措施开展应用性研究。 肿瘤免疫逃逸机制与肿瘤防治新方法的设计以及肿瘤早期特异性免疫诊断如何提高,急性感染与免疫病理现象,慢性感染与免疫耐受现象(例如机体为何不能有效识别、清除HBV 感染而导致慢性乙肝) ,器官移植排斥的预警与免疫药物和免疫调节控制,自身免疫性疾病的诊断与治疗等 免疫学技术的研究和应用 疫苗、单克隆抗体、基因工程、细胞因子和免疫抑制药物等相关的免疫学技术的发展与应用,免疫学研究的前沿热点,天然免疫识别机制与信号转导研究 炎性复合体的研究 免疫细胞的分化及新型亚群功能的研究 免疫记忆的研究 免疫治疗的研究 microRNA参与免疫细胞的分化发育及免疫应答调控 表观遗传学在免疫细胞分化及疾病发生中的作用机制 系统生物学与免疫学研究的结合 免疫系统与免疫应答过程的可视化研究,
