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Introduction to Cellular Immunology Dr. Colin R.A. Hewitt [email protected] Movie credits: The movies of cells are used with the permission of Dr. James A. Sullivan of Cells Alive http://www.cellsalive.net/ © [email protected] 2000. Slide 1/43 The purpose of this preliminary lecture is to remind students of the immunology learnt in the second year, and introduce key concepts that are required for a full understanding of the later lectures To use the lecture, click on the projection screen icon below , then just click your way through the presentation. Don’t forget to try the online multiple choice questions at the end to find your strengths and weaknesses © [email protected] 2000. Slide 2/43 What you should know by the end of this lecture The basic terms used in immunology The characteristics and interdependence of adaptive and innate immunity The names and functions of cells in the immune system The structure and function of peripheral lymphoid organs The purpose of lymphocyte recirculation How cells communicate in the immune system and how this is tested How the clonal distribution of antigen receptors in the immune system allows for diverse recognition, self tolerance and memory That the compartments invaded by pathogens require different effector mechanisms of immunity. © [email protected] 2000. Slide 3/43 History & impact of immunology on human health Koch’s Kohler & Milstein Postulates Monoclonal Abs Metchnikoff Phagocytosis Müller Jenner Wright Miller Bacteria Vaccination Antisera T cells Jansen Microscope 1600 1700 1800 1900 2000 1955 30 Countries with more than one smallpox case 15 per month 200 years WHO announce after Jenner smallpox eradicated 0 1965 1970 1975 © [email protected] 2000. 1980 Slide 4/43 Why study immunology now? Infectious diseases Mechanisms of pathogenicity Vaccine development Diseases caused by a disturbed immune system ALLERGY: Immune responses to innocuous materials e.g. ASTHMA AUTOIMMUNITY: Anti-self immunity e.g. MULTIPLE SCLEROSIS GRAFT REJECTION: Immune responses to TRANSPLANTED TISSUE IMMUNODEFICIENCY: Defects in immune responses e.g. SCID Manipulation of immunity to treat disease IMMUNOSUPPRESSION: Treatment of immune diseases IMMUNOREGULATION: Immunotherapeutic interventions © [email protected] 2000. Slide 5/43 Reminder of basic immunological terms ANTIGENS (Ag) are substances recognised by • ANTIBODIES (Immunoglobulin, Ig, Ab) and • T LYMPHOCYTES (T CELLS) Antibodies are made by B LYMPHOCYTES (B CELLS) T cells help B cells make antibodies: T HELPER (Th) cells T cells kill infected cells T CYTOTOXIC (CTL) © [email protected] 2000. Slide 6/43 Immune responses Barriers Invasion & infection Innate immunity + + Skin & Mucous membranes rapidly regenerating surfaces, peristaltic movement, mucociliary escalator, vomiting, flow of urine/tears, coughing Cellular and humoral defences lysosyme, sebaceous/mucous secretions, stomach acid, commensal organisms,complement proteins, phagocytosis, NK cells Inflammation Adaptive immunity Cellular and humoral defences Antibodies, cytokines, T helper cells, cytotoxic T cells © [email protected] 2000. Slide 7/43 Adaptive immunity Immunity established to adapt to infection • Learnt by experience • Confers pathogen-specific immunity • Enhanced by second exposure • Has memory • Uses cellular and humoral components • Is poorly effective without innate immunity Antibodies reflect infections to which an individual has been exposed- diagnostic for infection © [email protected] 2000. Slide 8/43 Innate immune response Inbuilt immunity to resist infection • Present from birth • Not antigen-specific • Not enhanced by second exposure • Has no memory • Uses cellular and humoral components • Is poorly effective without adaptive immunity Also involved in the triggering and amplification of adaptive immune responses © [email protected] 2000. Slide 9/43 Leucocytes Adaptive and innate immunity depends upon LEUCOCYTES Innate immunity is mediated largely by GRANULOCYTES Adaptive immunity mediated by LYMPHOCYTES The growth, development and activities of granulocytes and lymphocytes are interconnected and often co-operative. © [email protected] 2000. Slide 10/43 Lymphocyte Adaptive immunity Macrophage Phagocytosis Monocyte Ag presentation Neutrophil PMN Cells Of The Immune System Common lymphoid progenitor Phagocytic Anti-bacterial Eosinophil Anti-parasite immunity Basophil ?Protection of mucosal surfaces? Mast cell Protection of mucosal surfaces © [email protected] 2000. Pluripotent haemopoietic stem cell Myeloid progenitor Slide 11/43 Lymphocyte subsets CLP T CELLS B CELLS Common lymphoid precursor T Th Activate B cells and macrophages T HELPER CELLS CTL Kill virusinfected cells CYTOTOXIC T LYMPHOCYTES © [email protected] 2000. B PC Produce antibodies PLASMA CELLS Slide 12/43 Look for some excellent low power images and electron micrographs of the cells at the following site: http://www-medlib.med.utah.edu/WebPath/webpath.html •Resting Lymphocyte •Activated Lymphocyte •Plasma cell •T and B cells are morphologically identical Movie: Cytotoxic T- lymphocyte killing target (click on this link) © [email protected] 2000. Slide 13/43 Look for some excellent low power images and electron micrographs of the cells at the following site: http://www-medlib.med.utah.edu/WebPath/webpath.html •Erythrocyte (Red blood cell) •Blood monocyte •Platelet (thrombocyte) •Tissue macrophage Movie: Human macrophage ingesting Candida albicans (click on this link) © [email protected] 2000. Slide 14/43 Look for some excellent low power images and electron micrographs of the cells at the following site: http://www-medlib.med.utah.edu/WebPath/webpath.html •Neutrophil Movie: Chemotaxis of human neutrophils (click on this link) © [email protected] 2000. Slide 15/43 © [email protected] 2000. Slide 16/43 Look for some excellent low power images and electron micrographs of the cells at the following site: http://www-medlib.med.utah.edu/WebPath/webpath.html •Eosinophil •Basophil •Neutrophil •Lymphocyte •Monocyte © [email protected] 2000. Slide 17/43 Lymphocyte antigen receptors Until the 1960’s, lymphocytes had no known function. Lyc T and B cells are essentially inactive until they encounter antigen. T and B cells express ANTIGEN RECEPTORS B T The B cell antigen receptor is a membrane-bound antibody SURFACE IMMUNOGLOBULIN The T cell antigen receptor IS NOT membrane bound antibody but a distinct molecule T CELL ANTIGEN RECEPTOR Each antigen receptor binds to a different antigen Each cell has only one antigen specificity © [email protected] 2000. Slide 18/43 Lymphoid organs Organised tissue in which lymphocytes interact with non lymphoid cells Sites of maturation & initiation of adaptive immune responses CENTRAL LYMPHOID ORGANS PERIPHERAL LYMPHOID ORGANS Central lymphoid organs: THYMUS – T cell maturation BONE MARROW – B cell maturation Peripheral lymphoid organs: LYMPH NODES SPLEEN WHITE PULP MUCOSAL-ASSOCIATED LYMPHOID TISSUE T and B cell activation Antigen trapping © [email protected] 2000. Slide 19/43 Lymph node 4. Germinal centre (site of intense B cell proliferation) 5. Medullary cords (Macrophage & plasma cell area) 3. Secondary lymphoid follicle 6. Efferent lymphatic vessel 2. Primary Lymphoid follicle (B cell area) Paracortical (T cell) area Artery Vein 1. Afferent lymphatic vessel. Lymph, cells & Ag drained from tissues enters here Medullary sinus © [email protected] 2000. Slide 20/43 Look for an excellent image of a sectioned lymph node at the following site: http://www-medlib.med.utah.edu/WebPath/webpath.html © [email protected] 2000. Slide 21/43 Look for an excellent image of a germinal centre at the following site: http://www-medlib.med.utah.edu/WebPath/webpath.html © [email protected] 2000. Slide 22/43 Spleen white pulp Transverse section Marginal sinus B cell corona Red pulp Germinal centre Marginal zone Periarteriolar lymphocytic sheath (PALS) – T cell area Central arteriole © [email protected] 2000. Slide 23/43 Look for an excellent image of a sectioned spleen at the following site: http://www-medlib.med.utah.edu/WebPath/webpath.html © [email protected] 2000. Slide 24/43 Lymphocyte recirculation NAIVE LYMPHOCYTES enter blood, are seeded to the peripheral lymphoid organs and recirculate Cells & antigens from a site of infection are trapped in draining lymphoid tissue. Cells proliferate and re-enter the RECIRCULATING LYMPHOCYTE POOL to re-seed the peripheral lymphoid organs © [email protected] 2000. Slide 25/43 Look for an excellent images of Wuchereria bancrofti and elephantiasis at the following site: http://www-medlib.med.utah.edu/WebPath/webpath.html © [email protected] 2000. Slide 26/43 How immune cells communicate: SOLUBLE MEDIATORS Infection CYTOKINES & CHEMOKINES Phagocyte activation Diverse collection of soluble proteins made by cells that affect the behaviour of other cells. The balance & level of cytokines and chemokines secreted affects the outcome of the response INFLAMMATION Early events involve endothelial cells and result in the accumulation of fluid, plasma proteins & leucocytes. Later events involve the activation and maturation of lymphocytes and other granulocytes. © [email protected] 2000. Slide 27/43 Bio-assay of cytokines in vitro Activation of M in vitro Test for effect on other cells Cytokine secretion Remove cytokine containing supernatant +/Which cytokine? © [email protected] 2000. Slide 28/43 Specificity of cytokine bioassays Test for a characteristic effect on other cells e.g. interleukin-1 Induces proliferation in thymocytes Include an antibody that blocks interleukin-1 + + IL-1 absent - IL-1 present © [email protected] 2000. Slide 29/43 How immune cells communicate: CELL-CELL CONTACT Peripheral lymphoid tissues trap antigen-containing phagocytic cells and concentrate cells together to promote cell-cell contact. Cell-cell contact occurs at many stages of immune responses. Killing CTL Target cell T Y Antigen presentation B T Ab production Accessory cell activation © [email protected] 2000. Slide 30/43 Cell surface molecules mediate cell-cell contact Resting cells Activated cells Expression and level of expression controls cell-cell adhesion Activation can induce expression. Cell adhesion, migration, antigen specificity, antigen presentation, costimulation, helper function, effector function. Cell surface molecules influenced by activation include cytokine receptors. © [email protected] 2000. Slide 31/43 Bio-assay of cell cell contact requirements in vitro Physically separate cells with permeable membrane T T T T T T Include a blocking anti-MHC molecule antibody T T T T + Due to cytokine or cell-cell contact? T T - - Not due to a cytokine MHC molecules important Which cell surface molecule? + MHC molecules not important © [email protected] 2000. Slide 32/43 Clonal nature of the adaptive immune response Each lymphocyte expresses a single antigen receptor specificity. There are millions of lymphocytes in the body, and thus millions of different antigen receptors. Each naive lymphocyte bearing a unique receptor is the progenitor of a genetically identical CLONE of daughter cells. PROBLEM: The CLONAL DISTRIBUTION of antigen receptors means that lymphocytes of a particular specificity will be too infrequent to mount an effective response. A process akin to natural selection, CLONAL SELECTION raises the clonal frequency of cells with a particular antigen specificity © [email protected] 2000. Slide 33/43 Clonal selection theory: MacFarlane Burnet 1957 Each lymphocyte bears a single type of receptor of unique specificity. Antigen interaction leads to lymphocyte activation. Daughter cells bear identical antigen specificity to the parent cell. © [email protected] 2000. Slide 34/43 Clonal selection induces proliferation and increases effector cell frequency No. of cells with useful specificity Threshold of protective effector function No. of cell divisions © [email protected] 2000. Slide 35/43 Clonal nature of adaptive immune response allows for removal of harmful cells !!!!Cells specific for self antigen!!!! Opportunity to remove harmful specificity at an early stage of development IMMUNOLOGICAL TOLERANCE Antigen receptors recognising self antigens can be individually purged from the antigen receptor REPERTOIRE before clonal expansion © [email protected] 2000. Slide 36/43 Clonal nature of adaptive immune response allows for immunological memory 2° response to antigen A Antibody titre 1° response to antigen B 1° response to antigen A 4 8 12 A 16 20 64 68 72 Days A B Lymphocyte proliferation to Ag A Lymphocyte apoptosis © [email protected] 2000. Lymphocyte proliferation to Ag B Slide 37/43 Immune effector mechanisms against extracellular pathogens & toxins NEUTRALISATION ` ` Y ` Adhesion to host cells blocked Toxin release blocked Prevents invasion Prevents toxicity ` Y NEUTRALISING ANTIBODIES © [email protected] 2000. Slide 38/43 Effector mechanisms against extracellular pathogens OPSONISATION Bacteria in extracellular space + Ab OPSONISATION Fc receptor binding © [email protected] 2000. Phagocytosis Slide 39/43 Effector mechanisms against extracellular pathogens COMPLEMENT Bacteria in plasma Lysis + Ab & COMPLEMENT Opsonisation Complement & Fc receptor binding © [email protected] 2000. Phagocytosis Slide 40/43 Effector mechanisms against intracellular pathogens CYTOXICITY CTL CTL CTL Viral infection Lethal hit © [email protected] 2000. Target cell death Slide 41/43 Effector mechanisms against intracellular bacteria MACROPHAGE ACTIVATION Inflammatory T cell Cytokines Th Resting Macrophage Th Activated macrophage Activation of killing mechanisms © [email protected] 2000. Slide 42/43 Summary: Reminder of 2nd year immunology Characteristics and components of adaptive and innate immunity Peripheral lymphoid organs & lymphocyte recirculation Intercellular communication by cytokines and cell-cell contact Clonal selection: Ag recognition, self tolerance and memory Effector mechanisms NOW TRY THE MULTIPLE CHOICE QUESTIONS (click on this link) © [email protected] 2000. Slide 43/43