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Transcript
Lecture 24 Immunity Immune System Two functional divisions: 1) Innate (non specific) – first line of defence. 2) Adaptive (specific) – if innate immune response is breached then adaptive response is activated. Components of Immune Response Soluble proteins • Lysozyme • Complement • Interferons Cells • White blood cells (leukocytes). • Granulocytes – neutrophils (70%), eosinophils (1.5%) , basophils (0.5%). • Agranulocytes – monocytes (4%) and lymphocytes T and B cells (24%). (1) Innate Immune Response • Exterior defences – skin, mucosal surfaces, lysozymes. • Phagocytes – monocytes (macrophages) • Natural Killer Cells • Acute Phase Proteins – Complement and Interferons (inflammation). Inflammatory Response • Damaged cells release chemical signals such as histamine, prostaglandins and leukotrienes, that increase capillary blood flow into the affected area. • Increased capillary permeability caused by retraction of the endothelial cells. Enables larger molecules than usual to escape from the capillaries, and thus allows the soluble mediators of immunity to reach the site of inflammation. • In the earliest stages of inflammation, neutrophils are particularly prevalent, but later monocytes and lymphocytes also migrate towards the site of infection. Soluble Factors of DefenceInterferons and Complement • Cells within the body produce two different groups of proteins, interferons and complement. • They help to minimise the damaging effects of viruses and bacteria that do manage to get through the surface barriers. • Interferons are proteins that are produced by cells infected by viruses. In general, they directly help to make uninfected cells more resistant to viral attack and also stimulate the immune system to respond to the viruses. • Complement and complement activation Complement is a group of different plasma proteins (C1 to C9). Complement can be "activated" by the presence of bacteria. Several of the activated complement proteins combine (as Membrane Attack Complexes) to damage bacterial membranes and cause the bacteria to die. Complement • The final five proteins form a membrane attack complex (MAC) that embeds itself into the plasma membrane of the attacker. • Salts enter the invader, facilitating water to cross the membrane, swelling and bursting the microbe. • Complement also functions in the immune response by tagging the outer surface (opsonisation) of invaders for attack by phagocytes. Innate Immune Response INJURY/INFECTION TISSUE DAMAGE INFLAMMATION Mast cell PMN Macrophage PG/LT Platlets, kinins, complement, CRP BLOOD VESSEL HEALING The Adaptive Immune Response • The adaptive immune has two components: 1. Antibody Production – defend against bacteria and viruses. 2. Cell-Mediated Immunity - cells in the body that have been infected by viruses and bacteria, protect against parasites, fungi, and also kill cancerous body cells. Antibodies • Antibodies are proteins that circulate in the blood stream. • The function of antibodies is to recognize substances (proteins, viruses, bacteria, cells etc) as being either SELF or NON-SELF. • The substances that are recognized by antibodies are called ANTIGENS. • NON-SELF ANTIGENS are targeted by antibodies for destruction. . • Two aspects of antibody function that are important in the immunes response: 1. They recognize antigens by binding to a specific 3DIMENSIONAL SHAPE of the antigen. 2. We have the capacity to produce about 100 million DIFFERENT antibodies. This means that we can produce antibodies to substances or viruses that we've never encountered. Antibody Structure • Antibodies consist of two different kinds of protein chains. • LIGHT CHAINS and HEAVY CHAINS. • LIGHT CHAINS have VARIABLE, JOINING and CONSTANT domains. • HEAVY CHAINS have VARIABLE, DIVERSITY, JOINING, and CONSTANT domains. Classes of Antibodies • Antibodies bind to specific antigens in a lockand-key fashion, forming an antigen-antibody complex. • Also known as immunoglobulins (Igs) • There are five classes of immunoglobulins: IgG, IgA, IgD, IgE, and IgM Isotype Placental Binds mast Binds phagocytic Activates Additional transfer cell surfaces cell surfaces complement features – – – + First Ab in development and response IgD – – – – B-cell receptor IgG + – + + Involved in opsonization and ADCC. IgG1, IgG2, IgG3, IgG4. – + – – Involved in allergic responses – – – IgM IgE IgA – Two subclasses; IgA1, IgA2. Also found as dimer (sIgA) in secretions Antibody Structure and Combinatorial Synthesis Provides Antibody Diversity • The number of different genes encoding antibody domains: LIGHT CHAINS Variable Regions ---------------- 300 different types Joining Regions ------------------ 4 different types Constant Regions ---------------- 2 different types • HEAVY CHAINS Variable Regions ---------------- 400 different types Diversity Regions --------------- 20 different types Joining Regions ------------------ 4 different types Constant Regions ---------------- 5 different types • Only Variable, Diversity and Joining regions contribute to antibody diversity. Thus, for light chains there are (300 x 4 = 1200) different possible combinations, for Heavy Chains, there are (400 x 20 x 4 = 32,000) different possible combinations, and in total (1200 x 32,000 = 38,400,000) possible combinations. Cells of Adaptive Immune Response • B-Cells, or B-lymphocytes These are the cells that synthesize and secrete antibodies. • They are of two types: ANTIBODYPRODUCING cells and MEMORY cells. • Memory B-Cells are important because those are the type of cells that are produced when you're vaccinated. They remain in storage and are ready to begin producing antibodies if you are challenged sometime in the future by the same antigen. Cells of Adaptive Immune Response • T-Cells, or T-lymphocytes - there are three types of T-Cells, but we'll only talk about two of them. • HELPER T-CELLS (TH cells) help to turn on the immune response. • KILLER T-CELLS (TC cell) kill viral-infected cells as part of the response. Antibody (Humoral) Response Cell Mediated Response Immunodeficiency Diseases • Result from the lack or failure of one or more parts of the immune system. Genetic disorders, Hodgkin's disease, cancer chemotherapy, and radiation therapy can cause immunodeficiency diseases. • Severe Combined Immunodeficiency (SCID) results from a complete absence of the cell-mediated and antibodymediated immune responses. Affected individuals suffer from a series of seemingly minor infections and usually die at an early age. • Acquired Immunodeficiency Syndrome (AIDS) is currently receiving the most attention among the immunodeficiency diseases. AIDS is a collection of disorders resulting from the destruction of T cells by the Human Immunodeficiency Virus (HIV), a retrovirus. HIV • When HIV replicates in the human T cells, it buds from the T cell plasma membrane encased in a coat derived from the T cell plasma membrane. • HIV selectively infects and kills T helper cells. • The viral RNA is converted into DNA by the enzyme reverse transcriptase; this DNA can become incorporated into a human chromosome for months or years. • When the infected T cell is needed in the immune response, the viral genes are activated and the virus replicates. • The infected cell is destroyed and a new T4 cell infection occurs. • Gradually the number of T4 cells, the master on switch for the immune system, decline. Sites of Activity • Defense mechanisms can take place almost anywhere damage or disease agents can occur. • on the epithelial surfaces of the body • in the interstitial fluid of the connective tissues • ... under epithelial surfaces • ... within organs • in the lymph • in the blood. • The cells involved in the immune response are organised into tissues and organs to perform and function more efficiently. Assignment 7 Q. What is the Major Histocompatibility Complex (MHC) and how is it responsible for organ transplant rejection? The Lymphoid System • Primary lymphoid organs – bone marrow and thymus. • Secondary lymphoid organs – lymph nodes small bean shaped organs (back of throat, under armpit, groin area), tonsils, adenoids, the spleen. Primary Lymphoid Organs • Bone marrow contains tissue that produces lymphocytes. B-lymphocytes (B-cells) mature in the bone marrow. • T-lymphocytes (T-cells) mature in the thymus gland. The thymus secretes a hormone, thymosin, that causes pre-T-cells to mature (in the thymus) into T-cells. Secondary Lymphoid Organs • Lymph nodes are areas of concentrated lymphocytes and macrophages. • The spleen is similar to the lymph node except that it is larger and filled with blood. The spleen serves as a reservoir for blood, and filters or purifies the blood and lymph fluid that flows through it. • If the spleen is damaged or removed, the individual is more susceptible to infections. Immunity to Bacteria • Bacteria are usually dealt with by phagocytosis. • Bacteria have adapted and evolved mechansims to a) avoid phagocytosis – capsule. b) avoid digestion – cell wall. c) damage phagocyte – exotoxins. Immunity to Viruses • Viruses are smaller, unable to replicate outside the host cell. • Different viruses affect different cell types. (E.g Epstein-Barr virus infects B cells via a specific receptor called CR2. • There are different phases of viral infection :– i) typical infection starts with local invasion of an epithelial cell surface – IgA and IFN. ii) followed by systemic spread or viraemia – antibodies. iii) replication in target organs – complement, cells, antibodies, IFN • Interferons stimulate virally infected cells to make a protein that blocks viral mRNA transcription. Immunity to Fungi • Normally only cause superficial infections. • Spores entering through lungs can cause serious systemic infection. • Survival mechanisms are similar to those of bacteria