Medical Immunology Department of Immunology Yiwei Chu 储以微 ywchu@shmu.edu.cn 2010-7-7 Exam: 9th July (Friday) 8:30-10:30am Inspector: Dr. Lu Qing Dr. Gao Bao 2010-7-7 Department of Immunology Yiwei Chu Wei Xu Rui He Yunlu Lin Qing Lu Xiaowu Hong Bo Gao Haifeng Gao Define of Immunology IMMUNITY ---protection from disease (infectious disease) IMMUNE SYSTEM --- organ, cell, molecule and gene IMMUNE RESPNSE --- response to the foreign substances Define of Immunology IMMUNE FUNCTIONS ---immune defence (infectious disease) --- immune surveillance --- immune homeostasis Define of Immunology IMMUNITY ---protection from disease (infectious disease) IMMUNE SYSTEM --- organ, cell, molecule and gene IMMUNE RESPNSE --- response to the foreign substances Innate and Adaptive Immunity Adaptive Immune Responses Adaptive Immune Responses Cellular Components • Lymphocytes - B, Th, CTL, NKT • Antigen-presenting cells(APCs) - DC, Mj, B • Effector cells - Activated T cells, mononuclear phagocytes Basic Immunology Recognition Activation Effection Ag (antigen) double recognition humural immunity APC double signaling (antigen presenting cell) cellular immunity Chapter 1 Definition of antigen Antigen (Ag) Substances that combine specifically with a B or T cell’s antigen-binding receptors can then induce an immune response are called antigens. Chapter 2 Characteristics of antigen The antigen molecule generally pose two natures, that is (1)immunogenicity (2)antigenicity (1) Antigenic determinants or epitopes 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. Structure of epitopes 1 Conformational epitope Nonsequential polypeptides or polysaccharide on the surface of the molecules, Native conformation, 2 liner epitope A sequential amino acid fragment, Linear determinant, Inside of the antigen molecule (3) hypervarible region (HVR) (complimentarity determining region, CDR) : formation of the Ag binding site Framework region( FR ) : maintaining the 3- dimensional configuration CDR (complimentarity determining region,) 4. Ab-dependent Cell-mediated cytotoxicity, ADCC enhance NK killing Immune Responses to Tumors CONCEPT APCs are immunocytes that can uptake, process and present antigens to other lymphocytes. Professional APCs Dendritic Cells (DCs) Macrophages (M) B Lymphocytes I. Dendritic Cells (DCs) Ralph.M.Steinman, 1973 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) MHC class II molecule combined with peptide What are cytokines? 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 Cytokine actions may be local and systemic Autocrine action Paracrine action act on cytokine-producing cell itself act on a nearby cell circulation Endocrine action act at a distance from the site of infection Chemokines Primary lymphoid organs Secondary lymphoid organs directing migration of leukocytes Blood Tissue inflammation Cellular sources (1) inflammatory stimuli to inflammatory sites (2) Constitutively produced in lymphoid organs Physiologic traffic of lymphocytes through the organs IL-2 • a growth factor for antigen-stimulated T lymphocytes • responsible for T cell clonal expansion after antigen recognition 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 The mechanism of effector function Perforin Granzyme 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 Examples of PAMPs PAMPs Source Principle innate immune response LPS Gram-negative bacteria cell wall Macrophage activation dsRNA Replicating viruses Type I IFN production by infected cells Unmethylated CpG DNA Bacterial DNA Macrophage activation N-formylmethionine Bacteria protein neutrophil and macrophage activation Mannose-rich glycans Microbial glycoproteins or glycolipid phgocytosis opsonization complement activation Patterns recognition receptors (PRRs) Proteins expressed by cells of innate immune system Present on the cell surface, in endosomal vesicles, and in the cytoplasm The subsets of CD4+Th cells How they are induced, What cytokines they produce What effector mechanisms they activate Development of Th1 and Th2 subsets Surface receptor 1) B cell antigen receotor (BCR) BCR/mIgM Membrane Ig (mIg) Mature B cell: mIgM + mIgD BCR-Igα/Igβ complex BCR-Iga/Igb complex 2. BCR coreceptor Help and strengthen the BCR-Ag-signaling 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 JBC 2004;279:31973 BCR-Iga/Igb coreceptor complex B cell epitope B cell activation TCR-CD3 BCR-Iga/b Two-signal activation model for T cells activation co-stimulatory molecules none naive anergy 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 MZ B cells innate immune functions 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 B1 B2/FO B 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 Significance of humoral immunity eliminate extracellular bacterium and toxin eliminate extracellular virus 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 Bcell 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. Early and late event in Ab response to TD antigen 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 Memory B IgG) General Features and Mechanisms Immunologically specific Central tolerance: induced in generative lymphoid organs immature self-reactive lymphocyte The repertoire of mature lymphocytes cannotcannot recognize ubiquitousubiquitous or widely repertoire of mature lymphocytes recognize disseminated self antigens self antigens or widely disseminated T Lymphocyte Tolerance Central T Cell Tolerance Peripheral T cell Tolerance Burnet: Clonal selection hypothesis 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 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. 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 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. 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 Vigorous Weak 57 Classification of Allograft Rejection Host versus graft reaction (HVGR) Conventional organ transplantation Graft versus host reaction (GVHR) Bone marrow transplantation Immune cells transplantation 58 II.Graft versus host reaction (GVHR) Conditions Enough immune competent cells in grafts Immunocompromised host Histocompatability between host and graft differences 59 Hypersensitivity Tissue injury caused by an immune response that is inadequately controlled or inappropriately targeted to host tissues Types of hypersensitivity reactions GELL AND COOMB’S CLASSIFICATION Type I: Type II: Type III: Type IV: Immediate Cytotoxic Immune complex cell mediated or delayed THANK YOU