Lecture免疫學(xué)概述培訓(xùn)課件

1、Lecture免疫學(xué)概述Lecture免疫學(xué)概述The Origin of Immune ConceptThe term “Immunity” = Latin word “Immunitas” = Protection from legal prosecution (Roman senators)Biological definition = Protection from infectious diseases2.The concept of immunity = existed in ancient Greek & Chinese = the experienced view“天花”又名痘

2、瘡 十六世紀(jì)下半葉（明代隆慶年間1567-1572）正式發(fā)明了人痘接種術(shù)，十七世紀(jì)普遍推廣。2Lecture免疫學(xué)概述The Origin of Immune ConceptThThe 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 cowpo

3、x pus = Protect a young boy from smallpox (Protective immunity)The 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. 1796年，英國(guó)人Edward Jenner發(fā)明牛痘苗預(yù)防天花（cowpox vaccine）。3Lecture免疫學(xué)概述The va

4、ccination against smallpEdward JennerEradication of smallpox200 yearsafter JennerWHO announcesmallpox eradicated1965197019751980Countries withmore than onesmallpox caseper month301504Lecture免疫學(xué)概述Edward JennerEradication of sm4.The concept of “Immunity” developed gradually over time through many scie

5、ntific findings: = Robert Koch (1905 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”研制出多種減毒疫苗（attenuated vaccine）,用于預(yù)防雞霍亂,炭疽桿菌,狂犬病等疾

6、病。Louis Pasteur1880年，雞霍亂弧菌減毒疫苗5Lecture免疫學(xué)概述4.The concept of “Immunity” dVaccines for common infectious diseasesb型流感嗜血桿菌 破傷風(fēng) 百日咳 風(fēng)疹 腮腺炎 麻疹 脊髓灰質(zhì)炎 乙肝 白喉 Still no effective vaccines for many infectious microbes, e.g., HCV, HIV, Dengue virus.etc6Lecture免疫學(xué)概述Vaccines for common infectious細(xì)胞免疫和體液免疫學(xué)派的形成： (

7、19世紀(jì)后葉-20世紀(jì)中葉) 免疫學(xué)重大學(xué)說(shuō)和理論：克隆選擇學(xué)說(shuō)(1957)；免疫網(wǎng)絡(luò)學(xué)說(shuō)(1974) 對(duì)免疫系統(tǒng)的全面認(rèn)識(shí)：發(fā)現(xiàn)各種免疫器官及免疫細(xì)胞Descriptive Science” = “Experimental Science”7Lecture免疫學(xué)概述細(xì)胞免疫和體液免疫學(xué)派的形成： (19世紀(jì)后葉-20世紀(jì)中葉(1) 細(xì)胞免疫學(xué)說(shuō) (cellular immunity) Neutrophil梅契尼可夫1880s- Metchnikoff discovered phagocytic cells that ingest microbes and particlescells con

8、ferred immunity免疫應(yīng)答機(jī)制的研究:8Lecture免疫學(xué)概述(1) 細(xì)胞免疫學(xué)說(shuō) (cellular immunity1. The Discovery of antibody functions in 18972. The Nobel Laureate in Medicine 1908Adopted from Nature Immunology, July 2008 liquid of blood conferred immunity 發(fā)現(xiàn)抗體能清除各種病原微生物或者能中和細(xì)菌毒素。(2) 體液免疫學(xué)說(shuō) (humoral immunity)Paul Ehrlich: One o

9、f the fathers of humoral adaptive immunity9Lecture免疫學(xué)概述1. The Discovery of antibody fQ: Which confers immunity cells or serum?A: Both cells and serum contribute to immunity!10Lecture免疫學(xué)概述Q: Which confers immunity celMacFarlane Burnet （1899-1985） 克隆選擇學(xué)說(shuō)clonal selection theory 體內(nèi)事先就存有能識(shí)別各種抗原的細(xì)胞克隆(clon

10、e)，每一細(xì)胞表面均有對(duì)特定抗原的受體，能與相應(yīng)抗原結(jié)合而識(shí)別它們?？乖淖饔迷谟谶x擇與其相應(yīng)的細(xì)胞克隆與其受體結(jié)合后，引起細(xì)胞的增殖分化，產(chǎn)生免疫應(yīng)答，產(chǎn)生大量抗體（即免疫球蛋白）?？贵w形成理論 -克隆選擇學(xué)說(shuō) 體內(nèi)存在無(wú)數(shù)抗原特異性淋巴細(xì)胞克隆胚胎期與自身成分反應(yīng)的淋巴細(xì)胞被“禁忌”形成耐受出生后淋巴細(xì)胞遇到相應(yīng)抗原發(fā)生特異應(yīng)答，并形成記憶禁忌細(xì)胞突變可導(dǎo)致自身免疫11Lecture免疫學(xué)概述MacFarlane Burnet克隆選擇學(xué)說(shuō) 體內(nèi)事Advances in technology (e.g., Cell culture, Monoclonal Ab, Flow cytometry

11、, Genetic engineeringetc) have facilitated our understanding of the immune system and its functions. “(1)免疫學(xué)理論研究抗體多樣性和特異性的遺傳學(xué)基礎(chǔ) T細(xì)胞抗原受體的基因克隆免疫遺傳學(xué)和MHC限制性的發(fā)現(xiàn)細(xì)胞因子及其受體信號(hào)轉(zhuǎn)導(dǎo)的研究危險(xiǎn)信號(hào)學(xué)說(shuō)(2)免疫學(xué)應(yīng)用研究：基因工程疫苗基因工程制備重組細(xì)胞因子免疫細(xì)胞治療治療性抗體12Lecture免疫學(xué)概述(1)免疫學(xué)理論研究(2)免疫學(xué)應(yīng)用研究：12Lecture免疫（immunity)傳統(tǒng)概念指免除疫病、免除感染，指機(jī)體抗感染的防御能力?，F(xiàn)

12、代概念指機(jī)體對(duì)“自己”或“非己”的識(shí)別并排除“非己”的功能。13Lecture免疫學(xué)概述免疫（immunity)13Lecture免疫學(xué)概述免疫的基本功能功能正常表現(xiàn)（有利）異常表現(xiàn)（有害）免疫防御immune defence抗病原微生物的侵襲超敏反應(yīng)易受感染或免疫缺陷病免疫穩(wěn)定immune homeostasis清除損傷、衰老、死亡細(xì)胞 自身免疫性疾病免疫監(jiān)視immune surveillance清除突變或畸變的惡性細(xì)胞 惡性腫瘤 14Lecture免疫學(xué)概述免疫的基本功能功能正常表現(xiàn)（有利）異常表現(xiàn)（有害）免疫防御抗免疫系統(tǒng) (immune system)：機(jī)體執(zhí)行免疫功能的組織、器官、細(xì)

13、胞和分子構(gòu)成免疫系統(tǒng)。15Lecture免疫學(xué)概述免疫系統(tǒng) (immune system)：機(jī)體執(zhí)行免疫功能的The four kinds of pathogens that cause human disease常見(jiàn)的病原微生物16Lecture免疫學(xué)概述The four kinds of pathogens thOverview of immune responses17Lecture免疫學(xué)概述Overview of immune responses17固有免疫（innate immunity）是機(jī)體抵御病原微生物入侵的第一道防線，并啟動(dòng)和參與適應(yīng)性免疫應(yīng)答。天然免疫（natural im

14、munity)或非特異性免疫(nonspecific immunity)，是個(gè)體出生時(shí)就具有的免疫力，通過(guò)遺傳獲得，是生物在長(zhǎng)期進(jìn)化過(guò)程中逐漸形成的，其針對(duì)外來(lái)異物的范圍廣，反應(yīng)迅速，其應(yīng)答模式和強(qiáng)度不因與病原微生物的反復(fù)接觸而改變。18Lecture免疫學(xué)概述固有免疫18Lecture免疫學(xué)概述固有免疫系統(tǒng)的組成屏障細(xì)胞分子皮膚黏膜屏障：物理、化學(xué)、微生物血-腦屏障、血-胸腺屏障血-胎屏障、氣-血屏障巨噬細(xì)胞、中性粒細(xì)胞、樹(shù)突狀細(xì)胞、T 細(xì)胞、NK細(xì)胞、NKT細(xì)胞、B1細(xì)胞、肥大細(xì)胞、嗜堿性粒細(xì)胞和嗜酸性粒細(xì)胞等?？咕?、溶菌酶、急性期蛋白、補(bǔ)體、細(xì)胞因子和黏附分子、19Lecture免疫學(xué)

15、概述固有免疫系統(tǒng)的組成屏障皮膚黏膜屏障：物理、化學(xué)、微生物巨噬細(xì)Epithelial barriers prevent the entry of microbes20Lecture免疫學(xué)概述Epithelial barriers prevent th固有免疫細(xì)胞 PhagocyteNKILLs（固有樣淋巴細(xì)胞）DC MCBasophil Eosinophil T細(xì)胞 NKT細(xì)胞 B1細(xì)胞Monocyte-macrophageNeutrophil21Lecture免疫學(xué)概述固有免疫細(xì)胞 Phagocyte T細(xì)胞Monocyt肺部巨噬細(xì)胞吞噬大腸桿菌22Lecture免疫學(xué)概述肺部巨噬細(xì)胞吞噬大

16、腸桿菌22Lecture免疫學(xué)概述Phagocytosis by innate immunity23Lecture免疫學(xué)概述Phagocytosis by innate immunit固有性免疫分子指體表分泌液以及血漿和其它體液中能夠識(shí)別或攻擊病原體的可溶性分子?？咕?antimicrobial peptides溶菌酶 lysozyme急性期蛋白(acute phase proteins, APP)脂多糖結(jié)合蛋白（LBP）血清淀粉樣蛋白（SAP）甘露糖結(jié)合蛋白（MBP）C反應(yīng)蛋白等（CRP）補(bǔ)體 細(xì)胞因子和黏附分子24Lecture免疫學(xué)概述固有性免疫分子指體表分泌液以及血漿和其它體液中能夠

17、識(shí)別或攻擊Complement activation pathways 25Lecture免疫學(xué)概述Complement activation pathwaysElie Mechnikoff:The Pioneer of Innate Immunity1. The Discovery of Phagocytes & Phagocytosis2. The Nobel Laureate in Medicine 1908Adopted from Nature Immunology, July 2008 The development of modern Immunology in 20th cent

18、ury mainly centers on understanding the Adaptive Immune System.26Lecture免疫學(xué)概述Elie Mechnikoff:The Pioneer ofCharles A. Janeway, M.D.Yale Univ. The “Renaissance” of innate immunityIn 1989, Janeway = Immune recognition of microbes = Detection of conserved molecular patterns, referred to PAMPs (Pathogen

19、-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 PRRs (Pattern-Recognition Receptors). 4. Innate immunity regulates adaptive immunity27Lecture免疫學(xué)概

20、述Charles A. Janeway, M.D.The “R Julie A. Hoffmann, Ph.D.Strasbourg, FranceThe “Renaissance” of innate immunityIn 1996, Hoffmanns group Toll functions as a PRR in Drosophila28Lecture免疫學(xué)概述 Julie A. Hoffmann, Ph.D.The Key concepts in innate immunity1. The innate immune system mainly recognizes common s

21、tructures shared by classes 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 immunit

22、y 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 dead host cells = Autoimmune diseases29Lecture免疫學(xué)概述Key concepts in innate immunitPattern Lipopolysaccharide (LPS) Lipoteichoic acid Bacterial lipopeptides

23、Peptidoglycan Bacterial DNA (CpG) Flagellin Terminal mannose/fucose Viral DNA (CpG) ssRNA dsRNAPathogen-AssociatedMolecularPatterns(PAMP)是病原微生物（尤其是原核生物）表面存在一些人體所沒(méi)有的，但可為許多相關(guān)微生物所共享、結(jié)構(gòu)恒定、進(jìn)化保守的分子結(jié)構(gòu)。30Lecture免疫學(xué)概述Pattern Lipopolysaccharide (L損傷相關(guān)分子模式（damage-associated molecular patterns，DAMPs）機(jī)體自身細(xì)胞所釋放的內(nèi)

24、源性分子，即內(nèi)源性危險(xiǎn)信號(hào)，來(lái)源于受損或壞死組織和某些激活的免疫細(xì)胞。主要有HMGB1、熱體克蛋白等。31Lecture免疫學(xué)概述損傷相關(guān)分子模式機(jī)體自身細(xì)胞所釋放的內(nèi)源性分子，即內(nèi)源性危險(xiǎn)PAMP vs DAMPSterile inflammationconserved microbial motifs VS non-microbial signals 32Lecture免疫學(xué)概述PAMP vs DAMPSterile inflammat33Lecture免疫學(xué)概述33Lecture免疫學(xué)概述Locations of Different PRRsBody fluids-Soluble PRR

25、sCellular PRRs- Cell surface- Endosomes- Cytosol34Lecture免疫學(xué)概述Locations of Different PRRsBodToll-like Receptors35Lecture免疫學(xué)概述Toll-like Receptors35Lecture免疫M(jìn)yD88-Dependent and independent Signaling36Lecture免疫學(xué)概述MyD88-Dependent and independenNLRs are cytoplasmic bacterial sensors that activate inflamm

26、asomes37Lecture免疫學(xué)概述NLRs are cytoplasmic bacterial1Viral Pattern Recognition Receptors: Signaling and Consequences38Lecture免疫學(xué)概述1Viral Pattern Recognition RecInteraction between innate and& adaptive immunity1. Innate immunity = Ag presentation (by Dendritic cells)2. Adaptive immunity = Ag recognitio

27、n (by T & B lymphocytes)39Lecture免疫學(xué)概述Interaction between innate and適應(yīng)性免疫（adaptive immunity）是機(jī)體獲得性、抗原特異性、抵抗病原微生物感染的高效防御機(jī)制。獲得性免疫（acquired immunity)或特異性免疫(specific immunity)，是個(gè)體出生后，在環(huán)境中受抗原刺激所產(chǎn)生的免疫力，針對(duì)特定抗原，有特異性、多樣性、記憶性和耐受性。1) 特異性，對(duì)某個(gè)特定的異物性抗原能引起特異性免疫應(yīng)答；指抗原特異性。2) 多樣性，機(jī)體可針對(duì)環(huán)境中多種多樣的抗原，分別建立起不同的特異性免疫應(yīng)答；多樣性是特

28、異性產(chǎn)生的基礎(chǔ)。 3) 記憶性，當(dāng)異物抗原再次入侵時(shí)，可產(chǎn)生快而強(qiáng)的再次免疫應(yīng)答效應(yīng)；記憶性淋巴細(xì)胞。4) 耐受性，正常情況下，免疫系統(tǒng)對(duì)自身成分有保護(hù)性的免疫耐受； 40Lecture免疫學(xué)概述適應(yīng)性免疫是機(jī)體獲得性、抗原特異性、抵抗病原微生物感染的高效抗原決定簇Antigenic determinant，AD抗原分子表面具有特殊立體構(gòu)型和免疫活性的化學(xué)基團(tuán)稱為抗原決定簇或抗原決定基。由于抗原決定簇通常位于抗原分子表面，因而又稱為抗原表位(epitope)。 抗原決定簇抗原決定基 抗原表位 抗原決定簇決定抗原的特異性，即決定抗原與抗體發(fā)生特異性結(jié)合的能力（實(shí)際是抗原決定簇與抗體的結(jié)合）。AD

29、的數(shù)目、性質(zhì)和空間構(gòu)象決定抗原特異性抗原以AD與相應(yīng)抗原受體及抗體特異性結(jié)合41Lecture免疫學(xué)概述抗原決定簇Antigenic determinant，AAPC加工處理的抗原種類: 外源性抗原(exogenous antigen): 通過(guò)吞噬或吞飲等作用被APC從細(xì)胞外攝入的抗原，以抗原肽-MHC I I類分子復(fù)合物形式提呈給CD4+T細(xì)胞 。 內(nèi)源性抗原(endogenous antigen): 細(xì)胞內(nèi)合成的抗原，以抗原肽-MHC I類分子復(fù)合物形式提呈給CD8+T細(xì)胞 。 42Lecture免疫學(xué)概述APC加工處理的抗原種類:42Lecture免疫學(xué)概述外源性抗原加工，處理及提呈AP

30、C 攝取的外源性抗原在內(nèi)體中降解成肽，與 MHC類分子(在內(nèi)質(zhì)網(wǎng)合成) 結(jié)合后表達(dá)于細(xì)胞表面。外源性抗原加工中需要 Ii 鏈和 HLA-DM 分子的參與。Ii 鏈 與 MHC類分子的轉(zhuǎn)運(yùn)有關(guān)，并通過(guò) CLIP 封閉 MHC類分子的肽結(jié)合部位，阻止 MHC-類分子在內(nèi)質(zhì)網(wǎng)中與內(nèi)源性抗原肽結(jié)合。HLA-DM 分子促使 CLIP 從 MHC類分子肽結(jié)合區(qū)解離，有利抗原肽與 MHC類分子結(jié)合。 43Lecture免疫學(xué)概述外源性抗原加工，處理及提呈APC 攝取的外源性抗原在內(nèi)體中降內(nèi)源性抗原加工，處理及提呈內(nèi)源性抗原經(jīng)蛋白酶體降解成肽，通過(guò)抗原加工相關(guān)轉(zhuǎn)運(yùn)體(TAP1、TAP2)轉(zhuǎn)運(yùn)進(jìn)入內(nèi)質(zhì)網(wǎng)，與 M

31、HC類分子(在內(nèi)質(zhì)網(wǎng)合成)結(jié)合成肽-MHCI類復(fù)合物，通過(guò)高爾基體表達(dá)于細(xì)胞表面。TAP是內(nèi)質(zhì)網(wǎng)上的異源性二聚體，由TAP-1及TAP-2基因編碼胞漿中蛋白酶體（proteasomes, 核心成分為低分子量多肽LMP細(xì)胞被病毒感染后出現(xiàn)的病毒蛋白，基因突變后產(chǎn)生的腫瘤抗原 44Lecture免疫學(xué)概述內(nèi)源性抗原加工，處理及提呈內(nèi)源性抗原經(jīng)蛋白酶體降解成肽，通過(guò)THE ADAPTIVE IMMUNE RESPONSEAntibody-Mediated Immunity (AMI)Involves B lymphocytes, plasma cells and antibodiesHumoral

32、immunityName 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) moleculesCellular immunity45Lecture免疫學(xué)概述THE ADAPTIVE IMMUNE RESPONSEAnTypes of adaptive immunit

33、y1. 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, bacteriaFor innate immunity, it also include

34、s Humoral & Cellular components for immune defense46Lecture免疫學(xué)概述Types of adaptive immunity1. H1、抗原提呈與識(shí)別階段（感應(yīng)階段）：2、活化、增殖、分化階段（反應(yīng)階段）： T細(xì)胞活化、增殖分化為效應(yīng)T細(xì)胞； B細(xì)胞活化、增殖分化為漿細(xì)胞； 部分細(xì)胞發(fā)育為記憶細(xì)胞。3、效應(yīng)階段： 效應(yīng)T細(xì)胞對(duì)抗原的清除； 漿細(xì)胞分泌抗體清除抗原。免疫應(yīng)答的三個(gè)階段47Lecture免疫學(xué)概述1、抗原提呈與識(shí)別階段（感應(yīng)階段）：免疫應(yīng)答的三個(gè)階段47LOverview of adaptive immune response

35、s48Lecture免疫學(xué)概述Overview of adaptive immune reCELL-MEDIATED IMMUNITY (CMI)Directed against intracellular microorganisms Non-phagocytic cells and phagocytic cellsT-lymphocytes (T cells)Differentiate into effector cells following antigen presentation by antigen presenting cells (APCs)Functional types o

36、f T cellsHelper (CD4 T cells)TH1 and TH2 cellsCytotoxic (CD8 T cells)49Lecture免疫學(xué)概述CELL-MEDIATED IMMUNITY (CMI)DiT cells develop in the thymus50Lecture免疫學(xué)概述T cells develop in the thymus5TSCCD4 RTEDNPre-TCRDPTCRCD4CD8TCRTCRCD8CD4 SPTCRCD4CD4b-selectionPositiveselectionNegative selectionFunctional mat

37、urationTCR-b rearrangementTCR-a rearrangementTCRCD8CD8 SPCD8 RTEDevelopment of ThymocytesDoublenegativeDoublepositiveSinglepositive51Lecture免疫學(xué)概述TSCCD4 RTEDNPre-TCRDPTCRCD4CD8T cells undergo further differentiation in secondary lymphoid tissues after encounter with antigenOnly a small fraction of na

38、ive T cells (mature T 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,

39、 T cells accumulate 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 s

40、ite of infection (CD8 and CD4-TH1 cells).52Lecture免疫學(xué)概述T cells undergo further differT細(xì)胞受體復(fù)合物由TCR和CD3組成。前者識(shí)別和結(jié)合抗原肽, 后者將TCR獲得的抗原信號(hào)傳遞至細(xì)胞內(nèi)。T細(xì)胞對(duì)抗原的識(shí)別 APCT細(xì)胞53Lecture免疫學(xué)概述T細(xì)胞受體復(fù)合物T細(xì)胞對(duì)抗原的識(shí)別 APCT細(xì)胞53Lect信 號(hào)第一信號(hào)第二信號(hào)T細(xì)胞TCR和CD4/CD8 CD28APCMHC-肽復(fù)合物B7(B7.1、B7.2)T細(xì)胞活化的雙信號(hào)刺激 第一信號(hào)：TCR對(duì)MHCII抗原肽復(fù)合物的識(shí)別，CD3分子將第一信號(hào)傳遞到細(xì)

41、胞內(nèi)。 第二信號(hào)：CD28識(shí)別專職APC上的B7分子,又稱協(xié)同刺激信號(hào)。 54Lecture免疫學(xué)概述信 號(hào)第一信號(hào)第二信號(hào)T細(xì)胞TCR和CD28APCMHC-肽55Lecture免疫學(xué)概述55Lecture免疫學(xué)概述Effector T cells 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 (recogniz

42、e MHC class I molecules)CD4 T cellsTH1 helper cells (activate macrophages)TH2 helper cells (induce differentiation of B cells into plasma cells and production of antibodies)Activation (cytokines)(recognize MHC II molecules)56Lecture免疫學(xué)概述Effector T cells In57Lecture免疫學(xué)概述57Lecture免疫學(xué)概述The immune syste

43、m is maintained in a carefully regulated balance between the two polarised control arms, Th1 (cellular immunity) and Th2 (humoral immunity).58Lecture免疫學(xué)概述The immune system is maintaineIn disease states the balance is skewed. multiple sclerosis, rheumatoid arthritis and type I diabetes, have a Th1 bi

44、as, whereas cancer patients have a Th2 bias. 59Lecture免疫學(xué)概述In disease states the balance Th1 and Th2 Cells Do not Represent All CD4+ Cells60Lecture免疫學(xué)概述60Lecture免疫學(xué)概述More T helper subsetsTh3: TGF-producing CD4 T cellsTr1: IL-10-producing CD4 T cellsTh9: IL-9-producing CD4 T cellsTfh: follicular help

45、er T cells, located in the follicular regions of lymph nodes and spleen,follicular Th1/Th2/Th17 cells61Lecture免疫學(xué)概述More T helper subsetsTh3: TGFANTIBODY-MEDIATED (HUMORAL) IMMUNITYDirected against extracellular microorganisms and toxinsB-lymphocytes (B cells)Differentiate into plasma cells which pro

46、duce antibodiesFunction as antigen-presenting cells (APCs)Classification of Antibodies (Immunoglobulins)Immunoglobulin M (IgM)Immunoglobulin G (IgG)Immunoglobulin A (IgA)Immunoglobulin D (IgD)Immunoglobulin E (IgE)62Lecture免疫學(xué)概述ANTIBODY-MEDIATED (HUMORAL) IM 抗體的功能V區(qū)的功能 識(shí)別并特異性結(jié)合抗原 單體（IgG, IgE) 2價(jià) 二聚體

47、(分泌型IgA) 4價(jià) 五聚體(IgM) 10價(jià) 中和效應(yīng) 中和毒素和病毒 與Ag結(jié)合 促吞噬細(xì)胞吞噬 抗體的結(jié)合價(jià) 實(shí)際意義63Lecture免疫學(xué)概述 抗體的功能 抗體的結(jié)合價(jià) 實(shí)際意義63LeC區(qū)的功能 1.激活補(bǔ)體系統(tǒng) Ab(IgM、IgG) + Ag C1q 補(bǔ)體經(jīng)典途徑 IgG4、IgA和 IgE的凝聚物 補(bǔ)體旁路途徑 2.介導(dǎo)免疫細(xì)胞活性 (1)調(diào)理作用（opsonization）：IgG + 抗原(顆粒性) FcR（單核、巨噬細(xì)胞及中性粒細(xì)胞） 促吞噬細(xì)胞吞噬； (2)ADCC：IgG + 抗原(靶細(xì)胞) Fc R（NK 細(xì)胞） 殺傷靶細(xì)胞； (3)介導(dǎo)超敏反應(yīng)：型、型和型超敏

48、反應(yīng)。 3.穿越胎盤和粘膜64Lecture免疫學(xué)概述C區(qū)的功能64Lecture免疫學(xué)概述Antibody-Dependent Cellular Cytotoxicity (ADCC) 65Lecture免疫學(xué)概述Antibody-Dependent Cellular CyTh2與B細(xì)胞的相互作用，獲得第二信號(hào)：協(xié)同刺激信號(hào)CD40-CD40L活化的Th2細(xì)胞分泌細(xì)胞因子及表達(dá)CD40L，輔助B細(xì)胞活化CD79/2第二信號(hào)（Th細(xì)胞信號(hào)） 有二種方式 （1）Th細(xì)胞-B細(xì)胞間接觸作用：CD40L-CD40等 （2）Th細(xì)胞分泌細(xì)胞因子：IL-4、5、6等 胸腺依賴性抗原（TD-Ag）66Le

49、cture免疫學(xué)概述Th2與B細(xì)胞的相互作用，獲得第二信號(hào)：協(xié)同刺激信號(hào)CD40Specificity, Memory, and Homeostasis of Adaptive Immunity67Lecture免疫學(xué)概述Specificity, Memory, and HomeoLecture免疫學(xué)概述培訓(xùn)課件多克隆抗體(polyclonal antibody，PcAb )：采用傳統(tǒng)的免疫方法，將抗原物質(zhì)經(jīng)不同的途徑進(jìn)入動(dòng)物體內(nèi)，經(jīng)數(shù)次免疫后采取動(dòng)物血液，分離出血清，由此獲得的抗血清即為多克隆抗體。用天然的抗原物質(zhì)免疫動(dòng)物，刺激多個(gè)B細(xì)胞克隆所獲得的免疫血清（含多種特異性抗體）。單克隆抗體(

50、Monoclonal Antibody，McAb):由一個(gè)B細(xì)胞分化增殖的子代細(xì)胞產(chǎn)生的針對(duì)單一抗原決定簇的抗體，稱單克隆抗體。由一個(gè)B細(xì)胞克隆產(chǎn)生。識(shí)別一種抗原表位。高度均一（結(jié)構(gòu)、特異性）。雜交瘤技術(shù)制備?；蚬こ炭贵w：利用基因工程技術(shù)來(lái)制備的抗體分子稱為基因工程抗體，是分子水平的抗體。69Lecture免疫學(xué)概述多克隆抗體(polyclonal antibody，PcAb抗體針對(duì)的靶分子作用機(jī)制治療疾病CD3阻斷T細(xì)胞功能預(yù)防腎移植排斥反應(yīng)CD25阻斷IL-2受體預(yù)防腎移植排斥反應(yīng)CD20(或偶聯(lián)核素)誘導(dǎo)腫瘤細(xì)胞凋亡non-Hidgkins淋巴瘤和RACD33(免疫毒素)誘導(dǎo)腫瘤細(xì)胞凋

51、亡急性髓樣白血病CD52誘導(dǎo)腫瘤細(xì)胞凋亡慢性B淋巴細(xì)胞白血病，T細(xì)胞瘤Her2(CD340)抑制和殺傷腫瘤細(xì)胞轉(zhuǎn)移性乳腺癌EGFR抑制腫瘤血管形成轉(zhuǎn)移性結(jié)腸直腸癌和頭頸部腫瘤，非鱗癌、非小細(xì)胞肺癌，對(duì)化療反應(yīng)差的多形性膠質(zhì)細(xì)胞瘤CD41/CD61 (gpIIbIIIa)抑制血小板凝聚預(yù)防冠狀動(dòng)脈血管形成術(shù)中 血栓形成US和EU所批準(zhǔn)的治療性抗體70Lecture免疫學(xué)概述抗體針對(duì)的靶分子作用機(jī)制治療疾病CD3阻斷T細(xì)胞功能預(yù)防腎移 鼠源性單克隆抗體將逐漸被人源化抗體所替代：鼠源性單克隆抗體與人補(bǔ)體成分結(jié)合能力低，CDC作用相應(yīng)較弱，對(duì)腫瘤細(xì)胞的殺傷能力較弱；它與NK等免疫細(xì)胞表面Fc受體親和力

52、弱，介導(dǎo)的 ADCC作用較弱；鼠源抗體在人血循環(huán)中的半衰期短，它發(fā)揮ADCC與CDC作用的時(shí)間較短；鼠單克隆抗體具有免疫原性，宿主易產(chǎn)生抗抗體引起過(guò)敏反應(yīng)?？贵w人源化改造及人源抗體制備71Lecture免疫學(xué)概述 鼠源性單克隆抗體將逐漸被人源化抗體所替代：鼠源性單克隆 人-鼠嵌合抗體：應(yīng)用基因工程技術(shù)將小鼠單克隆抗體的恒定區(qū)用人源抗體恒定區(qū)代替而拼接成嵌合抗體。改型抗體如CDR移植、SDR移植：用鼠單克隆抗體的CDR、SDR移植到人源抗體可變區(qū)，替代人源抗體CDR、SDR。表面氨基酸殘基人源化抗體人源化的主要技術(shù)72Lecture免疫學(xué)概述 人-鼠嵌合抗體：應(yīng)用基因工程技術(shù)將小鼠單克隆抗體的恒

53、定區(qū)用MjmacrophageIL-8Activated T cellaADP56BC58BCNH2COOHIL-2 Cytockines are low-molecular-weight regulatory 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. Cytokine73Lectur

54、e免疫學(xué)概述MjmacrophageIL-8Activated T c Biological effects 74Lecture免疫學(xué)概述 Biological effects 74Lecture免IL-1TNFGM-CSFM-CSFFGFPDGFVEGFIL-12IL-15IL-6LIFOSMChemokinesTGFIL-10IL-11IL-13sTNF-RIL-1raPRO-INFLAMMATORYANTI-INFLAMMATORYCytokine imbalance during inflammation75Lecture免疫學(xué)概述IL-1GM-CSFFGFIL-12IL-6Chemokin 細(xì)胞因子的研究熱點(diǎn)1、新細(xì)胞因子的基因克隆化2、細(xì)胞因子受體的基因克隆化3、細(xì)胞因子信號(hào)轉(zhuǎn)導(dǎo)機(jī)制4、新一代細(xì)胞因子：高活性，多功能，低毒副作用，長(zhǎng)半衰期，高穩(wěn)定性5、細(xì)胞因子作為生物應(yīng)答調(diào)節(jié)劑（BRM）的臨床應(yīng)用6、細(xì)胞因子表達(dá)調(diào)控7、細(xì)胞因子基因治療76Lecture免疫學(xué)概述 細(xì)胞因子的研究熱點(diǎn)76Lecture免疫學(xué)概述Activation of adaptive immunity by innate i