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11/28/12 MICROBIOLOGY LECTURE 8 IMMUNOLOGY 2 PROF T.J. FOSTER ANTIGEN PRESENTATION CLONAL SELECTION INDUCTION OF ANTIBODY SYNTHESIS Lymphatic System Antigens brought by macrophages from site of infection to lymph nodes Bone marrow & thymus. Generate white blood cells 1 11/28/12 Antigenic Determinants. Epitopes A single protein has many different epitopes on its surface [slide from lecture 7] Antigen presentation by macrophages & other antigen presenting cells Clonal selection Cell division Immature cells Lymphoid tissue Differentiation Long lived. In lymphoid tissue Short-lived Y 2 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y 3 Y Y Y Y YY Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y 11/28/12 11/28/12 THE PRIMARY RESPONSE LYMPHOID TISSUE Y Y Y Y Y Y Y Y Y Y Y Y CLONAL SELECTION Y Y Y Y Y Y Y Y Y Y differentiation Y Y ANTIGEN PRESENTATION Memory cells Y Y Y YY Y PLASMA CELLS short-lived B LYMPHOCYTES Retained in lymphoid tissue Y Y Antibody synthesis ANTIGEN PRESENTATION CLONAL SELECTION THE IMMATURE B LYMPHOCYTE WITH THE APPROPRIATE ANTIGEN-BINDING DETERMINANT DISPLAYED ON ITS SURFACE IS SELECTED ACTIVATED TO DIVIDE AND DIFFERENTIATE PLASMA CELLS THAT SYNTHESIZE ANTIBODIES ARE SHORT-LIVED MEMORY CELLS REMAIN IN LYMPHOID TISSUE THERE ARE MANY DUPLICATE COPIES OF THE ORIGINAL B CELL PRIMARY & SECONDARY RESPONSES SECONDARY PRIMARY Antibody concentration in blood First exposure Second exposure Months, years later 7 14 21 28 Time (days) 4 11/28/12 THE SECONDARY RESPONSE B cells Y Y Y Y CLONAL SELECTION • quicker • more B cells for specific antigens Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y PLASMA CELLS Y Y differentiation Y ANTIGEN PRESENTATION B LYMPHOCYTES Y LYMPHOID TISSUE Y Memory cells Y Y Y YY Y Y Y Antibody synthesis IMMUNOLOGICAL MEMORY • LONG-LIVED, PROTECTIVE • VACCINATION – PRIMARY RESPONSE WITHOUT SUFFERING SYMPTOMS OF DISEASE – FIRST EXPOSURE TO DISEASE GIVES SECONDARY RESPONSE T CELLS T Helper Cells TH Antigen Presentation to B cells Cytotoxic T Cells TC Kill host cells that are infected with viruses and intracellular bacteria. Kill some cancer cells 5 11/28/12 ANTIGEN PRESENTATION Humoral Immunity MHC II-Antigen complex recognized by one subset of T cell Many types with different specificities. ANTIGEN PRESENTATION Requires CD4 on TH to promote binding TH Intermediate between presenting cell and B cell ANTIGEN PRESENTATION Antigen binding determinant on surface. Internalized by endocytosis Presented on surface by MHC II 6 11/28/12 HUMORAL IMMUNE RESPONSE Proliferation & differentiation triggered by cytokines Secreted Ig binds same antigen epitope as the receptor on the Immature B cell ACTIVATION OF B CELL summary of key points in previous diagrams B cells carry surface-located antibody that recognizes specific antigen Antigen is endocytosed and presented on surface in MHCII TH cell carries a TCR that recognizes MHCII-antigen complex TH secretes IL-2 which stimulates B cell division and differentiation into PLASMA cells and MEMORY cells Plasma cells secrete antibody specific for antigen Cell-Mediated Immunity A dendritic cell is another type of antigen-presenting cell 7 11/28/12 ANTIGEN PRESENTATION MHCI - on all cell types. Presents fragment of intracellular pathogen (bacteria or virus) CD8+ T Cell CYTOTOXIC T CELLS T cell population with TCR that recognizes MHCI-antigen complex amplified CD4 Activated cytotoxic T cell seeks infected cells. Secretes perforin protein Membrane damage. Lysis Recognizes MHC-I antigen complex on surface ACTIVE IMMUNITY Stimulation of body’s immune system NATURAL • INFECTION ARTIFICIAL • VACCINATION – Stimulates immune response & immunological memory without symptoms 8 11/28/12 Passive Immunity Transfer or administration of antibodies NATURAL – FOETUS – MILK receives maternal IgG contains IgA ARTIFICIAL – TETANUS ANTITOXIN (horse) – RABIES ANTIBODIES (human) – POOLED IgG (human non-enriched/ enriched with anti-Hepatitis B) Active Immunization Vaccines • Toxoid – Inactivated toxin • Chemical • Genetic (formaldehyde) (non-toxic mutant / fragment) • Killed Whole cell / inactivated virus • Subunit – Purified component of cell / virus • Live-attenuated – Bacteria or virus CURRENTLY USED VACCINES : BACTERIA PATHOGENIC BACTERIUM DISEASE VACCINE Mycobacterium tuberculosis Tuberculosis Live BCG. Non- Corynebacterium diphtheria Diphtheria Clostridium tetani Tetanus pathogenic mutant of M.bovis Toxoid chemically inactivated toxin. Loss of toxicity retains antigenicity Toxoid Bordetella pertussis Whooping cough Toxoid + Surface proteins Neisseria menigitidis C Meningitis MenC polysaccharide capsule Haemophilus influenzae Meningitis Hib polysaccharide capsule 9 11/28/12 Vaccine for Cholera. Killed whole cells + enterotoxin B subunit Y Y Stimulates secreted IgA antibody on mucosal intestinal surface YY Lumen of intestine microvilli Columnar epithelial cells Immunity in Vaccinated Individual or Convalescent microvilli Columnar epithelial cells Enterotoxin 5 B, 1 A subunits Y Lumen of intestine Y Antibodies to pilus & outer membrane protein block bacterial attachment Anti CtxB blocks toxin Binding to GM1 A A Specific receptor on surface of cell for B subunit 10 11/28/12 This lecture covers the induction of the immune response. Fragments of antigens are processed after destruction of the pathogen by a macrophage or dendritic cells. A fragment binds to the MHCII receptor which migrates to the cell surface. The MHCII-peptide complex is recognized by a specific T cell receptor (of which there are many). Binding is facilitated by the surface protein CD4 ( the HIV receptor). The macrophage secretes a chemical messenger called interleukin 1 which stimulates the T cell to divide and form two populations: memory T cells that remain until the next infection and active T helper cells that engage a B cell that bears a surface-located antibody molecule that reacts with the antigen. It becomes internalized and is then presented on the surface in the MHCII complex. This is recognized by the T cell receptor which originally bound to the MHCII-antigen complex on the macrophage. The T cell secretes interleukin 2 which stimulates the B cell to divide and differentiate into antibody-secreting plasma cells. Many undifferentiated B cells remain in the lymphoid tissue as Memory Cells. This process is termed CLONAL SELECTION and results in IMMUNOLOGICAL MEMORY. Upon a subsequent exposure, antigen presentation and clonal selection occur more efficiently. This allows the immune response to develop before symptoms of disease occur. Vaccination generates a primary response without development of symptoms of illness. Another aspect of cell-mediated immunity are killer T cells. These are stimulated by exposure to host cells infected with intracellular viruses and bacteria (eg Salmonella typhi). The intracellular microbes/viruses cannot be recognized by immunoglobulin. The Tc cell recognizes an infected cell because the latter displays protein fragments of the replicating virus in its MHCI receptor which are recognized by the Tc cell’s TCRs. This stimulates the release of the membrane damaging protein perforin which kills the infected cell. There are several different types of vaccine currently used in Ireland to combat infectious disease caused by bacteria and viruses. Toxoids are chemically modified forms of a toxin. Toxoid vaccines are effective when the symptoms of disease are caused by a toxin. (Diphtheria & tetanus vaccines are toxoids & the whooping cough vaccine contains a toxoid). Live-attenuated vaccines have been weakened by multiple rounds of culture in the laboratory. The tuberculosis vaccine BCG is a live-attenuated form of Mycobacterium bovis that is sufficiently closely related to M. tuberculosis to give immunity. Several virus vaccines are live-attenuated variants. Subunit vaccines comprise components of the bacterial (or viral) surface. They have a protective antigen but lack toxic components such as lipopolysaccharide endotoxin of Gram negative bacteria. The new improved Whooping Cough vaccine comprises purified surface protein antigens (and a toxoid). Another type of subunit vaccine comprises capsular polysaccharides (Haemophilus influenzae b, Streptococcus pneumoniae and Nessieria menigitidis C) coupled to a protein to make them more immunogenic. 11