Lecture1免疫学概述PPT学习教案

1、会计学1Lecture1免疫学概述免疫学概述3.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)Th

2、e vaccination against smallpoxExudate 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 JennerEradication of smallpox200 yearsafter JennerWHO announcesmallpox eradicated1965197019751980Countries withmore than ones

3、mallpox caseper month301504.The concept of “Immunity” developed gradually over time through many scientific findings: = Robert Koch (1905 Nobel Laureate) = Infectious diseases caused by microorganisms= Louis Pasteur = Vaccines against cholera & rabies= These clinical successes = The search of underl

4、ying mechanism of “Protection of Infectious Diseases”= The development of “Immunology” 5.Advances in technology (e.g., Cell culture, Monoclonal Ab, Flow cytometry, Genetic engineeringetc) have facilitated our understanding of the immune system and its functions. “Descriptive Science” = “Experimental

5、 Science”免疫的基本功能免疫的基本功能功能功能正常表现（有利正常表现（有利）异常表现（有害）异常表现（有害）免疫防御免疫防御immune defenceimmune defence抗病原微生物抗病原微生物的侵袭的侵袭超敏反应超敏反应易受感染或免疫缺陷易受感染或免疫缺陷病病免疫稳定免疫稳定immune immune homeostasishomeostasis清除损伤、衰老清除损伤、衰老、死亡细胞、死亡细胞 自身免疫性疾病自身免疫性疾病免疫监视免疫监视immune immune surveillancesurveillance清除突变或畸变清除突变或畸变的恶性细胞的恶性细胞 恶性肿瘤恶性

6、肿瘤 The four kinds of pathogens that cause human diseaseOverview of immune responses固有免疫固有免疫（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。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

7、接触而改变。固有免疫应答的作用时相：固有免疫应答的作用时相：瞬时固有免疫应答阶段、早期固有免疫应答阶段、适应性免疫应答诱导阶段瞬时固有免疫应答阶段、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固有免疫系统的组成屏障屏障细胞细胞分子分子皮肤黏膜屏障：皮肤黏膜屏障：物理、化学、微生物理、化学、微生物物血血-脑屏障、血脑屏障、血-胸腺屏障胸腺屏障血血-胎屏障、气胎屏障、气-血屏障血屏障巨噬细胞、中性粒细胞、树突状细胞、巨噬细胞、中性粒细胞、树突状细胞、T 细胞、细胞、NK细胞、细胞、NKT细胞、细胞、B1细胞、肥大细胞、嗜碱性粒细胞细胞、肥大细胞、嗜碱性粒细胞和嗜酸性粒细胞等。和嗜

8、酸性粒细胞等。抗菌肽、溶菌酶、急抗菌肽、溶菌酶、急性期蛋白、补体、细性期蛋白、补体、细胞因子和黏附分子、胞因子和黏附分子、Epithelial barriers prevent the entry of microbes PhagocyteNKILLs（固有样淋巴细胞）（固有样淋巴细胞）DC MCBasophil Eosinophil T细胞细胞 NKT细胞细胞 B1细胞细胞Monocyte-macrophageNeutrophil肺部巨噬细胞吞噬大肠杆菌Phagocytosis by innate immunityor DC固有性免疫分子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

9、或攻击病原体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。的可溶性分子。抗菌肽抗菌肽 antimicrobial peptides溶菌酶溶菌酶 lysozyme急性期蛋白急性期蛋白(acute phase proteins, APP)脂多糖结合蛋白（脂多糖结合蛋白（LBP）血清淀粉样蛋白（血清淀粉样蛋白（SAP）甘露糖结合蛋白（甘露糖结合蛋白（MBP）C反应蛋白等（反应蛋白等（CRP）补体补体 细胞因子和黏附分子细胞因子和黏附分子Complement activation pathways Elie Mechnikoff:The Pioneer of Innate Immu

10、nity1. The Discovery of Phagocytes & Phagocytosis2. The Nobel Laureate in Medicine 1908Adopted from Nature Immunology, July 2008 The development of modern Immunology in 20th century mainly centers on understanding the Adaptive Immune System.Charles A. Janeway, M.D.Yale Univ. In 1989, Janeway = Immun

11、e recognition of microbes = Detection of conserved molecular patterns, referred to PAMPs (Pathogen-Associated Molecular Patterns) with features:1. Invariant among a given class of microbes.2. Have essential roles in microbial physiology. 3. Recognized by receptors of the innate immune system, called

12、 PRRs (Pattern-Recognition Receptors). 4. Innate immunity regulates adaptive immunity Julie A. Hoffmann, Ph.D.Strasbourg, FranceIn 1996, Hoffmanns group Toll functions as a PRR in DrosophilaKey concepts in innate immunity1. The innate immune system mainly recognizes common structures shared by class

13、es of microbes, = Pathogen Associated Molecular Patterns (PAMPs), e.g., LPS, Peptidoglycan, Microbial DNA & RNA. 2. Host receptors that recognize PAMPs are called Pattern- Recognition Receptors (PRRs), which are encoded in “Germline” DNA= limited Diversity. 3. Innate immunity not only provide the fi

14、rst line of defenses but link to the program of adaptive immunity.4. PRRs may also recognize components from injured or dead host cells = Autoimmune diseasesPattern Lipopolysaccharide (LPS) Lipoteichoic acid Bacterial lipopeptides Peptidoglycan Yeast and gram+ bacteria Bacterial DNA (CpG) Flagellin

15、Terminal mannose/fucose Viral DNA (CpG) ssRNA dsRNAPathogen-AssociatedMolecularPatterns(PAMP)是病原微生物（尤其是原核是病原微生物（尤其是原核生物）表面存在一些人体所生物）表面存在一些人体所没有的，但可为许多相关微没有的，但可为许多相关微生物所共享、结构恒定、进生物所共享、结构恒定、进化保守的分子结构。化保守的分子结构。损伤相关分子模式损伤相关分子模式（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

16、组织和某些激活的免疫细胞。主要有HMGB1、热体克蛋白等。PAMP vs DAMPSterile inflammationconserved microbial motifs VS non-microbial signals Toll-like ReceptorsLocations of Different PRRsBody fluids-Soluble PRRsCellular PRRs- Cell surface- Endosomes- CytosolSurface receptors of macrophagesMac-1、CR3PRR甘露聚糖凝集素（甘露聚糖凝集素（MBL）C反应蛋白（

17、反应蛋白（CRP）脂多糖结合蛋白（脂多糖结合蛋白（LBP）可溶性：体液和血液可溶性：体液和血液细胞吞噬型：细胞膜细胞吞噬型：细胞膜甘露糖受体（甘露糖受体（MR）清道夫受体（清道夫受体（SR）补体受体（补体受体（CR）Fc受体（受体（FcR）甲酰甲硫氨酰肽受体（甲酰甲硫氨酰肽受体（fMLPR）信号转导型信号转导型细胞膜细胞膜内体、溶酶体内体、溶酶体细胞质细胞质TLR1、2、4、5、6、10、11TLR3、7、8、9NLRs、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、可识别一种或多种多种PAMPs或或DAMPs的识别分子。的识

18、别分子。Diversity of pattern recognition receptorsToll-Like Receptors (TLRs)MyD88-Dependent and independent SignalingNLRs are cytoplasmic bacterial sensors that activate inflammasomesViral Pattern Recognition Receptors: Signaling and ConsequencesInteraction between innate and& adaptive immunity1. Innate

19、 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。染的高效防御机制。获得性免疫（获得性免疫（acquired immunity)或特异性或特异性免疫免疫(specific immunity)，是个体出生后，在环，是个体出生后，在环境中受抗原刺激所产生的免疫力，针对特定抗原境中受抗原刺

20、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。，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。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。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

21、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；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化抗原分子表面具有特殊立体构型和免疫活性的化学基团称为学基团称为抗原决定簇或抗原决定基抗原决定簇或抗原决定基。由于抗由于抗原决定簇通常位于抗原分子表面，因而又称为原决定簇通常位于抗原分子表面，因而又称为抗原表位抗原表位( (epitope) )。 抗原决定簇抗原决定簇抗原决定基抗原决定基 抗原表位抗原表位 抗原决定簇决定抗原的特异性，即决定抗原与抗抗原决定簇决定

22、抗原的特异性，即决定抗原与抗体发生特异性结合的能力体发生特异性结合的能力（实际是抗原（实际是抗原决定簇决定簇与抗体的结合与抗体的结合）。）。ADAD的数目、性质和空间构象决定抗原特异性的数目、性质和空间构象决定抗原特异性抗原以抗原以ADAD与相应抗原受体及抗体特异性结合与相应抗原受体及抗体特异性结合外源性抗原加工，处理及提呈外源性抗原加工，处理及提呈内源性抗原加工，处理及提呈内源性抗原加工，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

23、异源性二聚体，由TAP-1及TAP-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 CD1分子提呈微生物的分子提呈微生物的脂质抗原，脂质抗原，脂质抗原由脂质抗原由CD1分子提呈后激活分子提呈后激活CD1限制性限制性T细胞。细胞。BBCRTTCRTypes of adaptive immunity1. Humoral immunity = Molecules in body fluid, e.g. Antibody (Ab) = Key player = B cells = Target extracell

24、ular microbes & toxins2. Cell-mediated immunity = Key player = T cells = regulate other immune cells = Target intracellular microbes, e.g. viruses, bacteriaFor innate immunity, it also includes Humoral & Cellular components for immune defense3 3、效应阶段：、效应阶段：效应效应T T细胞对抗原的清除；细胞对抗原的清除；浆细胞分泌抗体清除抗原。浆细胞分泌抗

25、体清除抗原。免疫应答的三个阶段Overview of adaptive immune responsesT cells develop in the thymusT cells develop in bone marrow, but in order to mature, they need to migrate to thymus = thymus-(T)-dependent lymphocytesThymus is a primary lymphoid organ located in the upper thorax (chest), just above the heart.Proge

26、nitor (precursor) T cells enter the thymus, where they mature (= produce T cell 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 matureMatur

27、e T cells enter the blood stream, and after infection accumulate in the secondary lymphoid tissues where they are activated. T cell developmentTSCCD4 RTEDNPre-TCRDPTCRCD4CD8TCRTCRCD8CD4 SPTCRCD4CD4b b-selectionPositiveselectionNegative selectionFunctional maturationTCR-b b rearrangementTCR-a a rearr

28、angementTCRCD8CD8 SPCD8 RTEDevelopment of ThymocytesDoublenegativeDoublepositiveSinglepositiveNotch Signal and T-lineage Commitment受体受体: Notch 1-4；胸腺细胞表达；胸腺细胞表达Notch1-3；全部效应由；全部效应由Notch 1介导介导 配体：配体：Dll1，3，4， Jagged 1，2；胸腺上皮细胞表达全部配体；胸腺上皮细胞表达全部配体；Dll4 可能为生理性配体可能为生理性配体 T系定向：系定向：始于始于DN1，完成于，完成于DN3；绝对依赖；

29、绝对依赖Notch1信号信号 APCT细胞细胞 MHC- MHC-B7 CD40 CD58 CD2 信信 号号第一信号第一信号第二信号第二信号T细胞细胞TCR和和CD4/CD8 CD28APCMHC-肽肽复合物复合物B7(B7.1、B7.2)T细胞活化的双信号刺激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。 TH1 helper cells (activate macrophages)TH2 helper cells (induce differentiation of

30、 B 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 skewe

31、d. multiple sclerosis, rheumatoid arthritis and type I diabetes, have a Th1 bias, whereas cancer patients have a Th2 bias. More T helper subsetsTh3: TGF-producing CD4 T cellsTr1: IL-10-producing CD4 T cellsTh9: IL-9-producing CD4 T cellsTfh: follicular helper T cells, located in the follicular regio

32、ns of lymph nodes and spleen,follicular Th1/Th2/Th17 cellsPaul Ehrlich: One of the fathers of humoral adaptive immunity1. The Discovery of Antibody functions2. The Nobel Laureate in Medicine 1908Adopted from Nature Immunology, July 2008 Antibody-Dependent Cellular Cytotoxicity (ADCC) Th2与与B细胞的相互作用，获

33、得第二信号：协同刺激信号细胞的相互作用，获得第二信号：协同刺激信号胸腺依赖性抗原（胸腺依赖性抗原（TD-Ag）Specificity, Memory, and Homeostasis of Adaptive Immunity抗体针对的靶分子抗体针对的靶分子作用机制作用机制治疗疾病治疗疾病CD3阻断阻断T细胞功能细胞功能预防肾移植排斥反应预防肾移植排斥反应CD25阻断阻断IL-2受体受体预防肾移植排斥反应预防肾移植排斥反应CD20(或偶联核素或偶联核素)诱导肿瘤细胞凋亡诱导肿瘤细胞凋亡non-Hidgkins淋巴瘤和淋巴瘤和RACD33(免疫毒素免疫毒素)诱导肿瘤细胞凋亡诱导肿瘤细胞凋亡急性髓样

34、白血病急性髓样白血病CD52诱导肿瘤细胞凋亡诱导肿瘤细胞凋亡慢性慢性B淋巴细胞白血病，淋巴细胞白血病，T细胞瘤细胞瘤Her2(CD340)抑制和杀伤肿瘤细胞抑制和杀伤肿瘤细胞转移性乳腺癌转移性乳腺癌EGFR抑制肿瘤血管形成抑制肿瘤血管形成转移性结肠直肠癌和头颈部肿瘤，转移性结肠直肠癌和头颈部肿瘤，非鳞癌、非小细胞肺癌，对化疗反非鳞癌、非小细胞肺癌，对化疗反应差的多形性胶质细胞瘤应差的多形性胶质细胞瘤CD41/CD61 (gpIIbIIIa)抑制血小板凝聚抑制血小板凝聚预防冠状动脉血管形成术中预防冠状动脉血管形成术中 血栓形成血栓形成US和和EU所批准的治疗性抗体所批准的治疗性抗体抗体针对的靶分

35、子抗体针对的靶分子作用机制作用机制治疗疾病治疗疾病TNFa a阻断阻断TNFa a与受体结合与受体结合RA、银屑病性关节炎、银屑病性关节炎、克隆氏病、强直性脊椎炎克隆氏病、强直性脊椎炎CD11a抑制白细胞黏附抑制白细胞黏附斑状牛皮癣斑状牛皮癣VEGF抑制血管形成抑制血管形成年龄相关性黄斑变性年龄相关性黄斑变性a a4整合蛋白整合蛋白抑制白细胞黏附抑制白细胞黏附多发性硬化症多发性硬化症IgE阻断阻断IgE与与 IgE受体结合受体结合，抑制肥大细胞、，抑制肥大细胞、嗜碱性粒细胞释放介质嗜碱性粒细胞释放介质持续性哮喘持续性哮喘RSVgpF中和病毒中和病毒预防儿童高危期预防儿童高危期RSV感染感染US

36、和和EU所批准的治疗性抗体所批准的治疗性抗体抗体人源化改造及人源抗体制备抗体人源化改造及人源抗体制备抗体人源化的主要技术抗体人源化的主要技术提高抗体提高抗体效应功能效应功能偶联细胞毒物质偶联细胞毒物质双特异性抗体双特异性抗体抗体抗体Fc突变突变改变抗体糖基化改变抗体糖基化细胞内抗体细胞内抗体抗体融合蛋白抗体融合蛋白提高抗体效应功能提高抗体效应功能MjmacrophagemacrophageIL-8Activated Activated T cellT cella aADP56BC58BCNH2COOHIL-2 Cytockines are low-molecular-weight regula

37、tory proteins or glycoproteins secreted by white blood cells and various cells (vascular endothelial cell, epidermic cell and fibroblast ) in body in response to a number of stimuli. Cytokine Biological effects IL-1TNFa aGM-CSFM-CSFFGFPDGFVEGFIL-12IL-15IL-6LIFOSMChemokinesTGFb bIL-10IL-11IL-13sTNF-R

38、IL-1raPRO-INFLAMMATORYANTI-INFLAMMATORYCytokine imbalance during inflammation 细胞因子的研究热点细胞因子的研究热点1、新细胞因子的基因克隆化、新细胞因子的基因克隆化2、细胞因子受体的基因克隆化、细胞因子受体的基因克隆化3、细胞因子信号转导机制、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、新一代细胞因子：高活性，多功能，低毒副作用，长半衰期，高稳定性半衰期，高稳定性5、细胞因子作为生物应答调节剂（、细胞因子作为生物应答调节剂（BRM）的临床应用）的临床应用6、细胞因子表达调控、细胞因子表达调控7、细胞因子基因治疗、细胞因子基因治疗Infections occur when the physical barriers of epithelium are breached, or when pathogens adhere to the epithelium1. Pathogen replication2. Recruitment of neutrophils and macrophages 3. InflammationPathogen adherence to epitheliumPathogens are carried t