1、Introduction,IMMUNOLOGY,曹雪濤主編 醫學免疫學第六版 人民衛生出版社 2013 金伯泉主編 醫學免疫學第五版 人民衛生出版社 2008 龔非力主編 醫學免疫學第三版 科學出版社 2009 Abbas A K, et al. Cellular and Molecular Immunology. 7th ed. Elsevier Saunders, 2012 Janeway C A, et al. Immunobiology. 8th ed. Garland Science Publishing, 2012,References,Immunology is on front

2、iers of life sciences Immunology is one of the main pillars for development of basic and clinical medicine Immunology is connected tightly with biotechnology and its industrialization A number of mysteries are under exploration in immunology,Why study Immunology ,Immunology is a difficult,First, the

3、re are lots of details, and sometimes these details get in the way of understanding the concepts. A second difficulty in learning immunology is that there is an exception to every rule. The third difficulty in studying immunology is that our knowledge of the immune system is still evolving,Introduct

4、ion,Concept of Immunity Immune Response Immune Cells Tissues and Organs of the Immune System Immunopathology,Immunity,1.Immunity: refers to all mechanisms used by the body as protection against environmental agents that are foreign to the body. (to recognize and eliminate foreign substances) 2.Agent

5、s:microorganisms (viruses, bacteria etc) and their products, foods, chemicals, pollen, tumor cells, etc. 3.Immune system: immune tissues and organs, immune cells, immune molecules,Introduction,4.Immune response: the coordinated reaction of the molecules and cells in the immune system to a foreign ag

6、ent. Benefits: protect the host from diseases Damaging effects: cause tissue damage 5.Immunology is the study of the ways in which the body defends itself from infectious agents and other foreign substances in its environment,Three functions of immune system: (1) immunologic defence (2) immunologic

7、surveillance (3) immunologic homeostasis,The Danger Model: A RenewedSense of Self,Polly Matzinger,The Self-Nonself Models The Infectious-Nonself (INS) Model The Danger Model,Introduction,Concept of Immunity Immune Response Immune Cells Tissues and Organs of the Immune System Immunopathology Brief hi

8、story of Immune Response,Immune Response,Introduction,Innate immune response natural immune response non-specific immune response Adaptive immune response acquired immune response specific immune response,Innate immunity,It refers to any inborn immunity that is already present the first time a patho

9、gen is encountered. It does not require prior exposure and is not modified significantly by repeated exposures to the pathogen over the life of an individual,Introduction,Innate immune response,Physiological barriers skin mucous membranes Phagocytosis polymorphonuclear leukocytes (PMN) monocytes/mac

10、rophages Natural killer (NK) cell Complement and acute phase proteins,Introduction,The principal mechanisms of innate and adaptive immunity,Innate immunity mechanism of recognition,Pathogen associated molecules patterns(PAMPs）: LPS, DNA, RNA, Protein Danger-associated molecular patterns (DAMPS): DNA

11、, HSP Pattern recognition receptors (PRR): Toll-like receptor(TLR) ,C-lectin recptor(CLR),RIG-I-Like recptor(RLR),NOD-like Receptor(NLR,Toll-like receptor (TLR,TLR,Many different types of blood cells participate in the immune response to microbes: Innate immune cells: “phagocytes” macrophage, neutro

12、phils, dendritic cells Adaptive immune cells: “lymphocytes” T cells, B cells, APC,Innate immune response,Introduction,Innate immune response,Introduction,Although innate immunity can effectively combat many infections, microbes that pathogenic for human have evolved to resist innate immunity. Defens

13、e against these infections are the task of the adaptive immune response, and this is why defects in the adaptive immune system result in increased susceptibility to infections,Adaptive immune response,Adaptive immune response,The T cells and B cells in the body recognize the antigen and, in turn, be

14、come activated. The activated lymphocytes then proliferate and carry out their specific effector functions,Types of adaptive immunity,Two types of adaptive immunity Humoral immunity: mediated by B cells and defense against extracellular microbes. Cell-mediated immunity: mediated by T cells and defen

15、se against intracellular microbes,Cell-mediated immunity: Phagocytosis (cellular eating) cytotoxcity 細胞毒性(cellular killing) Humoral immunity: antibodies: (also called immunoglobulin) proteins secreted by B cells that bind directly and specifically to pathogens. Antibodies target pathogens by marking

16、 them for destruction by other components of the immune system. complement: group of serum proteins that can directly kill pathogens,Immune Effector Mechanisms,2005 Elsevier,Types of adaptive immunity,Adaptive immune response,Introduction,1. The activation of lymphocytes antigen interacts with speci

17、fic receptors: B cell- BCR (B cell receptor): membrane Ig T cell- TCR (T cell receptor), co-stimulatory signal 2. Proliferation and differentiation of lymphocytes B cell-cytokines (IL-4,etc.) T cell-Antigen-TCR; co-stimulatory signal; cytokines(IL-2,IL-7,IL-15) 3. Effector cells and their functions

18、B cell-Antibody; T cell-Th, CTL 4. Memory cells,Adaptive immune response,Introduction,BCR (mIg,TCR,The two-signal requirement for lymphocyte activation. Signal 1 is provided by antigen recognition. Signal 2 is provided by components of the microbes or substances produced during the innate immune res

19、ponse,Adaptive immune response,Introduction,1. The activation of lymphocytes antigen interacts with specific receptors: B cell- BCR (B cell receptor): membrane Ig T cell- TCR (T cell receptor), co-stimulatory signal 2. Proliferation and differentiation of lymphocytes B cell-cytokines 細胞因子(IL-4,etc.)

20、 T cell-Antigen-TCR; co-stimulatory signal共刺激信號; cytokines(IL-2,IL-7,IL-15) 3. Effector cells and their functions B cell-Antibody; T cell-CTL, Th 4. Memory cells,Downloaded from: StudentConsult (on 31 May 2006 05:26 PM,2005 Elsevier,Downloaded from: StudentConsult (on 31 May 2006 05:26 PM,2005 Elsev

21、ier,Links between innate and adaptive immunity,The innate and adaptive immune response,Introduction,Individual B and T cells possess the ability to make a specific receptor (each cell makes a different receptor molecule) Antigen binds to the cell surface receptor and activates the cell Process takes

22、 several days. Effector cells and memory cells are produced. Memory cells can thus be activated faster,Clonal selection theory Frank M. Burnet,The clonal selection hypothesis,The Nobel Prize in Physiology or Medicine 1987 for his discovery of the genetic principle for generation of antibody diversit

23、y,Susumu Tonegawa（利川根進,The genes encoding the antigen receptors of T and B cells are assembled by DNA rearrangement as these cells develop. As a result of V(D)J recombination, every B and T cells expresses a unique version of the antigen receptor,Gene rearrangement of Ig,Introduction,Concept of Immu

24、nity Immune Response Immune Cells Tissues and Organs of the Immune System Immunopathology Brief history of Immune Response,Immune Cells,Introduction,hematopoietic stem cell (HSC,Myeloid progenitor髓系祖細胞,Lymphoid progenitor,Granulocytes (eosinophils嗜酸,neutrophils中性, basophils嗜堿) Monocytes, macrophages

25、 Dendritic cell Erythrocyte紅細胞 Megakaryocyte巨核細胞,T lymphocyte B lymphocyte NK cell Dendritic cell,Most blood cells act to fight infection,Adaptive immunity,Innate immunity,Blood cells lineages,1.Lymphocytes (except NK cells) are wholly responsible for the specific immune recognition of pathogens, so

26、 they initiate adaptive immune responses. 2.Lymphocytes are derived from bone-marrow stem cells. 3.B lymphocytes develop in the bone marrow. T lymphocytes develop in the thymus,Introduction,Lymphocytes,Lymphocytes are extremely heterogeneous in lineage, function and phenotype and are capable of comp

27、lex biologic responses and activities. Lymphocytes are often distinguished by surface proteins that may be identified by panels of monoclonal antibodies單克隆抗體. The standard nomenclature 術語for these proteins is the “CD” (cluster of differentiation) numerical designation,B Lymphocytes,BCR: a surface re

28、ceptor (mIg) specific for a particular antigen B cells plasma cells antibody (the same specificity as the BCR) humoral immunity,Introduction,Ag,secrete,B Lymphocytes,Introduction,TCR: T-cell antigen receptor TCR+ 95% TCR+ 15% 1. Cytotoxic T cells (CTL) 2. helper T cells: Th1, Th2, Th17 3. Regulatory

29、 T cells (Treg) and suppressor T cells (Ts,Introduction,T Lymphocytes,Properties of TH1, TH2, and TH17 subsets of CD4+ helper T cells,Introduction,T Lymphocytes,T lymphocyte,Introduction,T Lymphocytes,Human T-lymphocyte Attacking Fibroblast Tumor Cells,Specialized cells that display antigens to T ce

30、lls and provide second signal. Professional APCs include dendritic cells (DCs), macrophages (M) and B cells,Antigen presenting cells (APC,Macrophage: powerful in antigen processing and destruction, but low in antigen presentation. Dendritic cells (DC): such as Langerhans cell (LC), powerful in antig

31、en processing and presentation,Introduction,Antigen presenting cells,Introduction,Natural killer cells (NK,1. 10-15% of blood lymphocytes, LGL 2. express neither T-cell nor B-cell antigen receptors,Introduction,Phagocytic cells,Monocytes (blood)/Macrophages (tissues) functions: 1. remove particulate

32、 antigens 2. take up, process and present antigenic peptides to T cells distribution: Kupffer cells in the liver microglial cells in the brain,Introduction,Phagocytic cells,Polymorphonuclear granulocytes 1.neutrophils; basophils; eosinophils 2.neutrophils are short-lived phagocytic cells multilobed

33、nucleus; 10-20 m 3.neutrophils have a large arsenal of antibiotic proteins granules: lysosomes; lactoferrin,Introduction,Phagocytic cells,Introduction,Phagocytic cells,Introduction,monocyte,neutrophil,Phagocytic cells,Introduction,eosinophil,neutrophil,Phagocytic cells,Introduction,neutrophil activa

34、ted erythrocyte platelet,Introduction,Concept of Immunity Immune Response Immune Cells Tissues and Organs of the Immune System Immunopathology Brief history of Immune Response,Tissues of the immune system,Primary (or central) lymphoid organs the bone marrow the thymus Secondary (or peripheral) lymph

35、oid organs the spleen lymph nodes Cutaneous and mucosal immune system,Introduction,Generative lymphoid organs: the organs in which T and B lymphocytes mature and become competent to respond to antigens. Peripheral lymphoid organs: the organs in which adaptive immune responses to foreign antigens (su

36、ch as microbes) are initiated,Maturation of lymphocytes. Mature lymphocytes leave the generative lymphoid organs and enter circulation and the peripheral lymphoid organs, where they respond to foreign antigens and from where they recirculate in the blood and lymph,the place in which proliferation of

37、 HSC takes place the place in which development and maturation of B cells occur The lymphoid progenitor cells are transported by circulating blood to the thymus and differentiate into functional T lymphocytes,Introduction,Bone marrow,The thymus,1. Cells: thymic stromal cells (TSC) epithelial cells,

38、monocytes (macrophage), TDC thymocytes T cell (+) 2. Structure: cortex-immature thymocytes medulla-mature thymocytes M, TDC 3. Function: It is the site of T cell maturation/selection; It determines the specificity of the TCR expressed on the T cells released to periphery,Introduction,The lymph node,

39、Human:2-10mm in diameter round and kidney shaped Consists of : cortex (B-cell area) paracortex (T-cell area) central medulla (B-cell area,Introduction,The lymph node,Introduction,Downloaded from: StudentConsult (on 1 June 2006 02:08 PM,2005 Elsevier,The morphology of lymph nodes. The structural orga

40、nization and blood flow in a lymph node. Light micrograph shows a cross-section of a lymph node with numerous follicles in the cortex, some of them contain germinal centers, and the central medulla,180-250g germinal center (B) 1. the white pulp periarterial lymphatic sheath (T) the red pulp (B) 2. f

41、unction: destroy the Ag, aged platelets immune response,Introduction,The spleen,Introduction,The spleen,Downloaded from: StudentConsult (on 1 June 2006 02:08 PM,2005 Elsevier,The morphology of the spleen. A splenic arteriole surrounded by the periarteriolar lymphoid sheath (PALS) and the attached fo

42、llicle containing a prominent germianl center. Light micrograph of a section shows an arteriole with the PALS and a secondary follicle,Within the peripheral lymphoid organs, T cells and B cells are segregated into different anatomic compartments,Downloaded from: StudentConsult (on 31 May 2006 05:26

43、PM,2005 Elsevier,Segregation of T and B cells in different regions of peripheral lymphoid organs. The path by which nave T and B cells migrate to different areas of a lymph node. Immunofluorescence shows that the B cells and T cells locate in the follicles and in the parafollicular cortex, respectiv

44、ely,Mucosal immune system (MIS,1.non-encapsulated lymphoid tissue in the lamina propria and submucosal areas of the gastrointestinal, respiratory and genitourinary tracts. 2. tonsil, appendix, Peyers patches 3. B cell IgA IEL (intraepithelial lymphocytes) Adaptive immune (T cells) 4. function: local

45、 (mucosal) immunity,Introduction,Mucosal-associated lymphoid tissue (MALT,M cells and Production of IgA,M cells: epithelial cells lacking the microvilli, having a deep pocket in the basolateral plasma membrane,Lymphocyte recirculation,Lymphocytes leave the blood via high-walled endothelium of the po

46、st-capillary venules. Lymphocyte trafficking exposes antigen to a large number of lymphocytes,Introduction,Lymphocyte recirculation,Introduction,Recirculation of T cells. Naive T cells migrate from blood through HEV into the T cell areas of a lymph node, where T cells are activated by antigens. Acti

47、vated T cells exit the lymph node, enter bloodstream, and migrate preferentially to peripheral tissues at sites of infection and inflammation, where infectious microbes are eliminated,Introduction,Concept of Immunity Immune Response Immune Cells Tissues and Organs of the Immune System Immunopatholog

48、y Brief history of Immune Response,Immunopathology,Hypersensitivity - overactive immune response Immunodeficiency - ineffective immune response Autoimmunity - inappropriate reaction to self antigens Cancer,Introduction,Concept of Immunity Immune Response Immune Cells Tissues and Organs of the Immune

49、 System Immunopathology Brief history of Immune Response,Brief History of Immunology,1. Empirical Immunology(AD1700-1900) 2. Scientific Immunology(1900-1950s) 3. Modern Immunology(1960s-Present,Documents show that as early as AD 1000, the ancient Chinese custom existed of having children inhale powd

50、ers made from the crusty skin lesions of patients recovering from smallpox,Edward Jenner (1749-1823,Jenner vaccination,Ali Maali,Why Can we eradicate the smallpox,No animal reservoir Lifelong immunity Subclinical cases rare One serotype Effective vaccine Major commitment by governments,Louis Pasteur

51、,Fowl cholera,1879,Pasteurella multocida,狂犬病疫苗 炭疽病疫苗,Scientific Immunology,The Nobel Prize in Physiology or Medicine 1901,Emil von Behring for his work on serum therapy, especially its application against diphtheria, by which he has opened a new road in the domain of medical science and thereby plac

52、ed in the hands of the physician a victorious weapon against illness and deaths,The Nobel Prize in Physiology or Medicine 1905,Robert Koch for his investigations and discoveries in relation to tuberculosis,The Nobel Prize in Physiology or Medicine 1908,Ilya Ilyich Mechnikov and Paul Ehrlich in recog

53、nition of their work on immunity,免疫學系統復雜，常通過多個機制行使功能：俄國科學家Mechnikov識別出了能吞噬入侵細胞的巨噬細胞，而Ehrlich則提出了側鏈理論，指出了對抗入侵者時，血液中的抗體是如何釋放出來的,The Nobel Prize in Physiology or Medicine 1913,Charles Richet in recognition of his work on anaphylaxis,The Nobel Prize in Physiology or Medicine 1930,The Nobel Prize in Phys

54、iology or Medicine 1930 was awarded to Karl Landsteiner for his discovery of human blood groups,Sir Frank Macfarlane Burnet and Peter Brian Medawar for discovery of acquired immunological tolerance,The Nobel Prize in Physiology or Medicine 1960,The Nobel Prize in Physiology or Medicine 1972,Gerald M

55、. Edelman and Rodney R. Porter for their discoveries concerning the chemical structure of antibodies,The Nobel Prize in Physiology or Medicine 1980,Baruj Benacerraf,Jean Dausset and George D. Snell and for their discoveries concerning genetically determined structures on the cell surface that regula

56、te immunological reactions,The Nobel Prize in Physiology or Medicine 1984,Niels K. Jerne, Georges J.F. Khler and Csar Milstein for theories concerning the specificity in development and control of the immune system and the discovery of the principle for production of monoclonal antibodies,The Nobel

57、Prize in Physiology or Medicine 1996,Susumu Tonegawa for his discovery of the genetic principle for generation of antibody diversity,The Nobel Prize in Physiology or Medicine 1996,Peter C. Doherty and Rolf M. Zinkernagel for their discoveries concerning the specificity of the cell mediated immune de

58、fence,The Nobel Prize in Physiology or Medicine 2011 was divided, one half jointly to Bruce A. Beutler and Jules A. Hoffmann for their discoveries concerning the activation of innate immunity and the other half to Ralph M. Steinman for his discovery of the dendritic cell and its role in adaptive imm

59、unity,The Nobel Prize in Physiology or Medicine 2011,Thank you,Antigen（Ag,Chapter,Antigen,1. Concept 2. Immunogenicity and specificity 3. Requirements for immunogenicity 4. Types of antigens 5. Superantigen and adjuvants,KNOWLEDGE POINTS,Concept,1. 抗原Antigen (Ag) the substances that are recognized b

60、y TCR/BCR or antibody and induce a specific immune response. 蛋白質、多糖、脂類、核酸,Antigen,2.Properties of Ag -immunogenicity -immunoreactivity (react with the products of a specific immune response,substances that induce specific immune response,Complete Ags（完全抗原）：have the properties of immunogenicity and i