The Immune System Biological mechanisms that defend an organism must be 1. triggered by a stimulus upon injury or pathogen attack 2. able to counteract the injury or invasion 3. able to recognise foreign material, distinguish self from non self Vertebrates have even more advanced immune systems that can 4. recognise specific kinds of foreign material 5. form a memory of previously encountered pathogens These are classified as the Innate and Adaptive Immune Responses Innate Immunity
Barriers exist for all external surfaces Skin * cells are resistant to damage * physically difficult to penetrate * cells are constantly being replaced * coated with acidic secretions (ph 3-5) * sweat contains lysozyme which digest bacterial cell walls Digestive Tract * saliva contains digestive enzymes * stomach contains hydrochloric acid and digestive enzymes Innate Immunity
Barriers exist for all external surfaces Respiratory and Urogenital tracts * mucous traps pathogens * cilia in the respiratory tract sweeps out mucous Normal Flora * symbiotic microbes that normally live on our body * may prevent pathogens from seeking entry * usually beneficial Blood Clotting * Platelets promote clotting to reinforces a breached surface Innate Immunity
Barriers can be breached Foreign invaders may enter * through damaged surfaces (eg. cuts to skin) * because they can survive in a harsh environment (eg. Hepatitis A through digestive tract) Hepatitis A Virus Generic chemical signals produced by pathogens or damaged cells leads to a response from white blood cells, or leukocytes. Innate Immunity
Non-Specific Responders to Invasion Neutrophils * phagocytose any foreign material at the invasion site * constitute 60-70% of all leukocytes Macrophages * slower to arrive * larger and more effective at phagocytosis * release cytokines (WBC cytokine mediators are sometimes called interleukins) Natural Killer (NK) Cells * attack virally infected or cancerous cells * release perforins that puncture membrane and burst cells Innate Immunity
Aiding the Response Complement * 20 types of protein * circulates blood and interstitial fluid Complement System/Cascade * may attack the cell walls of bacterial or fungal cells (causing lysis) * may coat the foreign invader- flagging it for phagocytosis * stimulate the greater activity in phagocytes * recruit more leukocytes to the area Innate Immunity
Managing the Response Mast Cells * release histamine in response to complement activation * allergic (hypersensitivity) responses are caused by too much histamine being released Inflammation * is initiated by histamine release and macrophage cytokine production * characterised by pain, heat, redness, swelling * symptoms are the result of increased blood flow and vascular permeability * the result is the greater recruitment of WBCs to the site of infection Innate Immunity
Managing the Response Fever * in addition to local inflammation a more extensive infection can trigger fever * leads to an elevated body temperature * increases the rate of phagocytosis * accelerates the actions of protein defenses * inhibits the growth of some pathogens. * speed up cellular repair by increasing the metabolic rate of cells Fever is a broad response * it affects the whole body * severe, prolonged fever can damage host tissues. Innate Immunity
Non-specific Viral Defense Interferons * are proteins secreted by virally infected cells * signal healthy neighbouring cells to produce compounds that interfere with viral replication Innate Immunity
When Innate Immunity Isn't Enough Sometimes pathogens * exhibit resistance to innate immune mechanisms * multiply too rapidly to be overcome Adaptive immune responses * target specific pathogens * are powerful and highly efficient Adaptive Immunity
Identifying a Threat Lymphocytes * are a special group of leukocytes * include B cells which develop in the bone marrow * include T cells which mature in the thymus * are found in the lymphatic system when they are not activated * each one expresses many receptor proteins on their cell surface Recognition * Receptors recognise foreign material- typically a specific surface molecule on a pathogen * Recognition triggers lymphocyte activation * Any molecule that triggers this adaptive response is called an antigen Adaptive Immunity
Receptor Specificity Receptors * Possess a binding site that binds an antigen of a specific conformation * Any particular B or T cell will express receptors that bind a single antigen * In an individual vertebrate there are millions of lymphocytes each expressing receptors with a different binding site. B cell receptor T cell receptor Question If only one, or a few, lymphocytes in an organism's body will recognise a specific antigen, how can these few cells mount an effective response? Adaptive Immunity
Generating the Responders Clonal Selection * A lymphocyte receptor recognises an antigen * The lymphocyte undergoes rapid division * resulting in many daughter cells with identical receptors * Thus, only the cell with the correct receptor will be selected to produce clones. * The cells produced by clonal selection differentiate into different roles. Exception: B cells must both recognise antigen and be activated by a helper T cell before being activated for division Adaptive Immunity: Clonal Selection
Generating the Responders NOTE: The clonal selection mechanism actually affects the lymphocyte receptors of both B cells and T cells VCE textbooks only refer to clonal selection as a mechanism for generating antibody receptors in B cells. Adaptive Immunity: Clonal Selection
B cell clones may differentiate into B Plasma Cells * secrete antibodies into the blood, lymph, and interstitial fluid * these antibodies bind to the antigen (thereby coating the pathogen) * Humoral immunity refers to this process because it concerns the fluids, or humors of the body. B Memory cells * do not participate in the immune attack * remain in the body * enable a more rapid response if the same antigen is encountered again Adaptive Immunity: Clonal Selection
B Cell Receptors: Immunoglobulin Proteins The antigen receptors of B cells belong to a family of proteins called immunoglobulins (Ig). Typically we refer to these as antibodies Antibodies have * a Y shape * 2 identical, short chains * 2 identical long heavy chains Classes * Antibodies come in different classes which have different effects * These include IgM, IgG, IgA, IgE Each chain has both a constant region and a variable region. The variable regions contribute to the binding site. Adaptive Immunity
T cell clones may differentiate into T Helper Cells (TH) * activate B cells and the adaptive immune response * assist other WBCs in the immune response * release chemicals that can attract more WBCs to an infection site Cytotoxic T Cells (TC) * destroy virally infected, or cancerous, host cells by apoptosis T Memory Cells * do not participate in the immune attack * remain in the body * enable a more rapid response if the same antigen is encountered again Cell-mediated immunity refers to T cells mediating an adaptive response Adaptive Immunity: Clonal Selection
T Cell Receptors & MHC T cell receptors can only recognise antigen that is presented by MHC marker molecules. Found in most vertebrates, these marker molecules are encoded by a set of genes called the Major Histocompatibility Complex MHC molecules are constantly in the process of binding short peptide fragments (8-10 amino acids) from the host cell and presenting them as antigen on the surface. These peptide fragments come proteins the are digested in either the cytosol (MHC I) or in endocytic vesicles (MHC II) Adaptive Immunity
MHC Presentation: Class I and Class II * CD8 and CD4 refer to the receptors of TC cells and TH cells respectively Adaptive Immunity
MHC Presentation: Class I and Class II MHC Class I Molecules * are found on all nucleated cells * display peptide fragments * allow specific cytotoxic T cells to identify cells that are infected by intracellular microbes or viruses MHC Class II molecules * are only expressed on professional Antigen Presenting Cells (APCs) * APCs travel to the lymph nodes to present their MHC-peptide structures * APCs include Dendritic cells, Macrophages, and B cells * Specific TH cells activate B cells via MHC II presentation Dendritic cells Adaptive Immunity
T Cell Activation Thus, specific T cells can only be activated for clonal selection via TCR binding with an antigen presenting MHC molecule (sometimes referred to as TCR MHC restriction). Once this has occurred, the adaptive immune response will properly begin. Adaptive Immunity
Responding to Threat APCs present antigen via MHC class II markers to T cells in lymph nodes T cells are activated and begin to divide and differentiate. TH cell clones go looking for a B cell that has processed the same antigen TC cell clones begin to attack infected cells expressing antigen via MHC class I markers Memory T cell clones are generated TH cells activate B cells via MHC II markers stimulating division B plasma cell clones begin secreting antigen-specific antibodies Memory B cell clones are generated Antibodies bind antigen and coat (opsonise) the pathogen Adaptive Immunity
Antibody Effects Antibody binding may serve to * neutralise toxins (eg. Antivenoms) * prevent pathogens from binding at mucosal surfaces * increase vulnerability to phagocytes * activate complement * induce the release of cytoxic products from macrophages, NK cells, and eosinophils Eosinophils Thus the Adaptive Response also amplifies the Innate Response. Adaptive Immunity
Measuring the Adaptive Immune Response Antibody concentration reflects primary and secondary immune responses to antigen After first infection it takes about 2 weeks for antibodies to be generated in significant levels. After a second infection with the same antigen the adaptive immune response is swifter and more pronounced. Adaptive Immunity
Genetic Origins of Receptor Diversity Question: Where does lymphocyte receptor diversity originate from? Answer: Random DNA recombination of receptor genes in the lymphocytes as they develop in the bone marrow. Question: Doesn't random recombination leads to the development of receptors that recognise self molecules? Answer: Yes. When immature lymphocytes bind to normal self cells they either self-destruct or become permanently inactivated. It is estimated that as many as 90% of developing lymphocytes are eliminated this way before they can fully mature. Adaptive Immunity