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Medical Immunology Department of Immunology Yiwei Chu 储以微 2010-7-7.

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Presentation on theme: "Medical Immunology Department of Immunology Yiwei Chu 储以微 2010-7-7."— Presentation transcript:

1 Medical Immunology Department of Immunology Yiwei Chu 储以微

2 Exam: 9 th July (Friday) 8:30-10:30am Inspector: Dr. Lu Qing Dr. Gao Bao

3 Department of Immunology Rui He Xiaowu Hong Qing Lu Bo Gao Wei Xu Yiwei Chu Haifeng Gao Yunlu Lin

4 IMMUNITY ---protection from disease (infectious disease) IMMUNE SYSTEM --- organ, cell, molecule and gene IMMUNE RESPNSE --- response to the foreign substances Define of Immunology

5 IMMUNE FUNCTIONS ---immune defence (infectious disease) --- immune surveillance --- immune homeostasis Define of Immunology

6 IMMUNITY ---protection from disease (infectious disease) IMMUNE SYSTEM --- organ, cell, molecule and gene IMMUNE RESPNSE --- response to the foreign substances Define of Immunology

7 Innate and Adaptive Immunity

8 Adaptive Immune Responses

9 Cellular Components Adaptive Immune Responses Lymphocytes - B, Th, CTL, NKT Antigen-presenting cells(APCs) - DC, M, B Effector cells - Activated T cells, mononuclear phagocytes

10 Basic Immunology RecognitionActivation Effection Ag (antigen)double recognition humural immunity APCdouble signaling cellular immunity (antigen presenting cell)

11 Antigen (Ag) Chapter 1 Definition of antigen combine specifically induce Substances that combine specifically with a B or T cell’s antigen-binding receptors can then induce an immune response are called antigens.

12 Chapter 2 Characteristics of antigen ( 1 ) immunogenicity ( 2 ) antigenicity The antigen molecule generally pose two natures, that is

13 Antigenic determinants or epitopes are the immunologically active regions of an immunogen that bind to antigen-specific membrane receptors on lymphocytes (TCR/BCR) or to secreted antibodies. (1) Antigenic determinants or epitopes

14 1 Conformational epitope surface Nonsequential polypeptides or polysaccharide on the surface of the molecules, Native conformation Native conformation, 2 liner epitope A sequential amino acid fragment, Linear determinant Linear determinant, Inside Inside of the antigen molecule Structure of epitopes

15 Comparison of epitope of T and B cell T cell epitope B cell epitope Receptor TCR BCR MHC molecule required to display none required processed antigen character liner peptides natural polypeptide,LPS, polysaccharide, organic compound 5~15 amino acids, 5~7 monosaccharide or 5~7 nucleotide Epitope type liner conformational, liner side any on the surface size 8 ~12 amino acids (CD8 + ),12 ~17 amino acids (CD4 + )

16 ( complimentarity determining region, CDR ) : formation of the Ag binding site Framework region ( FR ) : maintaining the 3- dimensional configuration (3) hypervarible region (HVR)

17 ( complimentarity determining region,) CDR

18 4. Ab-dependent Cell-mediated cytotoxicity, ADCC enhance NK killing

19 Immune Responses to Tumors

20 APCs are immunocytes that can uptake, process and present antigens to other lymphocytes. CONCEPT

21 Dendritic Cells (DCs) Dendritic Cells (DCs) Macrophages (M  ) Macrophages (M  ) B Lymphocytes B Lymphocytes Professional APCs

22 Ralph.M.Steinman, 1973 I. Dendritic Cells (DCs)

23 The invariant chain is cleaved to leave a peptide fragment, CLIP, bound to the MHC class II molecule CLIP (class II-associated invariant-chain peptide)

24 MHC class II molecule combined with peptide

25

26

27 Cytokines are polypeptides produced by the cells of innate and adaptive immunity in response to microbes and other antigens as a result of cellular activation. Cytokines initiate their actions by binding to specific membrane receptors on target cells. The cellular responses to most cytokines consist of gene activation, resulting in the expression of new functions and sometimes the proliferation of the target cells What are cytokines?

28 Cytokine actions may be local and systemic Autocrine action Endocrine action circulation act at a distance from the site of infection Paracrine action act on a nearby cell act on cytokine-producing cell itself

29 inflammation Blood Secondary lymphoid organs Primary lymphoid organs Tissue directing migration of leukocytes Chemokines Physiologic traffic of lymphocytes through the organs (1) inflammatory stimuli (2) Constitutively produced in lymphoid organs to inflammatory sites Cellular sources

30 IL-2 a growth factor for antigen-stimulated T lymphocytes responsible for T cell clonal expansion after antigen recognition

31 Natural Killer cells (NK cells)  A type of cytotoxic lymphocytes  The principal physiologic role 1.Defense against infections by viruses and some other intracelluar microbes 2. Rejection of tumors

32 The mechanism of effector function Perforin Granzyme

33 Pathogen-associated molecular patterns (PAMPs)  Small molecular motifs conserved within a class of microbes  Usually essential for survival of the microbes  Recognized by cells of innate immune system  Activate innate immune response

34 PAMPs Source Principle innate immune response LPSGram-negative bacteria Macrophage activation cell wall dsRNAReplicating viruses Type I IFN production by infected cells Unmethylated CpG DNA Bacterial DNA Macrophage activation N-formylmethionineBacteria protein neutrophil and macrophage activation Mannose-rich glycans Microbial glycoproteins phgocytosis or glycolipid opsonization complement activation Examples of PAMPs

35 Patterns recognition receptors (PRRs)  Proteins expressed by cells of innate immune system  Present on the cell surface, in endosomal vesicles, and in the cytoplasm

36 The subsets of CD4+Th cells  How they are induced,  What cytokines they produce  What effector mechanisms they activate

37 Development of Th1 and Th2 subsets

38 Membrane Ig (mIg) Mature B cell : mIgM + mIgD BCR-Igα/Igβ complex BCR/mIgM Surface receptor 1) B cell antigen receotor (BCR)

39 BCR-Ig  /Ig  complex

40 2. BCR coreceptor CD19 B-specific surface marker signal transduction CD21 CR2 , receptor for C3d-bound Ag CD81 BCR - coreceptor ligation induce reversible palmitoylation of CD81 to stabilize the CD19/CD21/CD81 complex Help and strengthen the BCR-Ag-signaling JBC 2004;279:31973

41 B cell activation B cell epitope BCR-Ig  /Ig  coreceptor complex

42 TCR-CD3 BCR-Ig  / 

43 Two-signal activation model for T cells naive activation co-stimulatory molecules anergy none

44 Two-signal activation model for B cells Signal 1 and signal 2 are not simultaneous But in two steps, signal 2 from Th cells Signal 3

45 B-1 cells ( peritoneal cavity ) marginal zone (MZ) B cells ( spleen ) frequent Ag encounter. Secreting essentially germline-encoded, polyreactive natural Abs, respond rapidly and vigorously to pathogens express Toll-like receptors (TLR), provide costimulation to GC B cells important link between the innate and adaptive immunity MZ B cells innate immune functions

46 location mucosal sites spleen, LN Ig-producing way naturally Ag-inductive specificity poly-reactive highly specific Ag TI Ag TD Ag ( polysaccharide ) Ig class Ig M IgG affinity low high B1 B2/FO B

47 Significance of humoral immunity eliminate extracellular bacterium and toxin eliminate extracellular virus

48 Antigen crosslinks mIg(BCR), generating signal 1, which leads to increased expression of class II MHC and costimulatory B7. Antigen–BCR complexes are internalized by receptor-mediated endocytosis and degraded to peptides, which are bound by class II MHC and presented as peptide–MHC complexes. Th cell recognizes Ag–class II MHC and B7-CD28 co-stimulation on B- cell membrane which activates TH cell. Th cell begins to express CD40L. Interaction of CD40 and CD40L provides signal 2. Th cell release large quantities of cytokines( IL-4 ) signal 3 to support the progression of the B cell replication and differentiation.

49 Early events : follicle ( B ) -paracortex ( T ) border, B activation and T-B activation Small amounts of Ab production Late events : At the germinal center Presence of Ag and Th Affinity maturation Ig class switch (IgM IgG) Memory B Early and late event in Ab response to TD antigen

50 General Features and Mechanisms Immunologically specific Immunologically specific Central tolerance: Central tolerance: induced in generative lymphoid organs immature self-reactive lymphocyte The repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens

51 T Lymphocyte Tolerance Central T Cell Tolerance Peripheral T cell Tolerance

52 Burnet: Clonal selection hypothesis

53 Peripheral T cell Tolerance Antigen recognition without adequate costimulation Use CTLA-4 to recognize costimulators on APCs Activation induced cell death (AICD) Regulatory T Lymphocytes Factors that determine the tolerogenicity of self antigens

54 Tumor Antigen Tumor-specific antigen Antigen that are expressed on tumor cells but not on normal cells were called tumor- specific antigens; some of these antigens are unique to individual tumors, whereas others are shared among tumors of the same type.

55 Tumor Antigen Tumor-associated antigen Tumor antigens that are also expressed on normal cells were called tumor-associated antigens; in most cases, these antigens are normal cellular constituents whose expression is aberrant or dysregulated in tumors

56 Evasion of Immune Responses  Class I MHC expression may be down-regulated on tumor cells so that they cannot be recognized by CTLs.  Tumor lose expression of antigen that elicit immune responses.  Tumors may fail to induce CTLs because most tumor cells do not express costimulators or class II MHC molecules.  The products of tumor cells may suppress antitumor immune responses.  Tumor antigens may induces may induce specific immunologic tolerance.

57 57 Difference between Direct Recognition and Indirect Recognition Direct Recognition Indirect Recognition Allogeneic MHC molecule Intact allogeneic MHC molecule Peptide of allogeneic MHC molecule APCs Recipient APCs are not necessary Recipient APCs Roles in rejection Acute rejection Chronic rejection Degree of rejection VigorousWeak

58 58  Host versus graft reaction (HVGR) Conventional organ transplantation  Graft versus host reaction (GVHR) Bone marrow transplantation Immune cells transplantation Classification of Allograft Rejection

59 59 Conditions  Enough immune competent cells in grafts  Immunocompromised host  Histocompatability differences between host and graft II.Graft versus host reaction (GVHR)

60 Hypersensitivity Tissue injury caused by an immune response that is inadequately controlled or inappropriately targeted to host tissues

61 Type I: Immediate Type II:Cytotoxic Type III:Immune complex Type IV:cell mediated or delayed GELL AND COOMB’S CLASSIFICATION Types of hypersensitivity reactions

62 THANK YOU


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