MCD Immunology Alexandra Burke-Smith 1. Introduction to Immunology Professor Charles Bangham ([email protected]) 1. Explain the importance of immunology for human health. The immune system What happens when it goes wrong? persistent or fatal infections allergy autoimmune disease transplant rejection What is it for? To identify and eliminate harmful “non-self” microorganisms and harmful substances such as toxins, by distinguishing ‘self’ from ‘non-self’ proteins or by identifying ‘danger’ signals (e.g. from inflammation) The immune system has to strike a balance between clearing the pathogen and causing accidental damage to the host (immunopathology). Basic Principles The innate immune system works rapidly (within minutes) and has broad specificity The adaptive immune system takes longer (days) and has exisite specificity Generation Times and Evolution Bacteria- minutes Viruses- hours Host- years The pathogen replicates and hence evolves millions of times faster than the host, therefore the host relies on a flexible and rapid immune response Out most polymorphic (variable) genes, such as HLA and KIR, are those that control the immune system, and these have been selected for by infectious diseases 2. Outline the basic principles of immune responses and the timescales in which they occur. IFN: Interferon (innate immunity) NK: Natural Killer cells (innate immunity) CTL: Cytotoxic T lymphocytes (acquired immunity) 1 MCD Immunology Alexandra Burke-Smith Innate Immunity Acquired immunity Depends of pre-formed cells and molecules Depends on clonal selection, i.e. growth of T/B cells, release of antibodies selected for antigen specifity Fast (starts in mins/hrs) Slow (starts in days) Limited specifity- pathogen associated, i.e. Highly specific to foreign proteins, i.e. antigens recognition of danger signals Cells involved: Cells involved : - Neutrophils (PMN) - T lymphocytes - Macrophages - B lymphocytes - Natural killer (NK) cells - Dendritic cells - Eosinophils - Basophils/mast cells Soluble factors involved Soluble factors involved - Acute-phase proteins - Antibodies - Cytokines - Complement Stimulates the acquired immune response Innate Immunity Anatomical barriers - Skin as a mechanical barrier- keeps out 95% of household germs while IN TACT - Mucus membrane in respiratory and GI tract traps microbes - Cilial propulsion on epithelia cleans lungs of invading microorganisms Physiological barriers - Low PH - Secretion of lysozyme, e.g. in tears - Interferons - Antimicrobial peptides - Complement; responsible for lysing microorganisms Acute-phase inflammatory response An innate response to tissue damage Rise in body temperature, i.e. the fever response This is followed by increased production of a number of proteins (acute-phase proteins), mainly by the liver. Includes: - C-reactive protein - Serum amyloid protein - Mannan-binding lectin C-reactive protein and serum amyloid protein bind to molecules found on the cell wall of some bacteria and fungi- pattern recognition Mannan-binding lectin binds to mannose sugar molecules which are not often found on mammalian cells These molecules are non-specific, but direct phagocytes e.g. macrophages to identify and ingest the infectious agent Cytokines Small proteins that carry messages from one cell to another E.g. to stimulate activation or proliferation of lymphocytes “kick-start”acquired immune response Send messages to other cells, e.g. to kill or secrete 2 MCD Immunology Alexandra Burke-Smith Cells of the innate immune system Granular leukocytes Natural Killer (NK) cells - Identify and kill virus-infected and tumour cells - Complex recognition system- recognise HLA molecule of virus infected cell or tumour, and kill them Macrophages - Mononuclear phagocytes - To main functions: 1. “garbage disposal” - 2. Present foreign cells to immune system Granulocytes Neutrophils Eosinophils Basophils Poluymorphonuclear Bi-lobed nucleus neutrophils (PMN): multi- lobed nucleus 50-70% of circulating WBC 1-3% of circulating WBH <1% of circulating WBC Phagocytic Not phagocytic- release granules containing histamines, serotonin, prostaglandins Required for immune Important in Th2 responses- response to parasites, kick starting acquired helminths and allergic immune reponse responses 3. Define the terms antigen, antibody, B lymphocyte, T lymphocyte, primary and secondary immune responses, and innate and acquired immunity. Acquired/Adaptive Immunity Characteristics Antigen specific Can form memory Requires priming- specific cells help to start the acquired immune response Cellular Immunity: T and B cells Humoral immunity: antibodies Antigens are glycoprotein molecules which react with antibodies or T cells. However not all antigens can induce an immune response in the host: those that can are termed immunogens Antibody molecules can be found in the blood stream and the body fluids and bind specifically to particular molecules termed antigens. They are the acquired component of the humoral immune response.The most basic antibody molecule is bivalent- with two antigen binding sites. Immunoglobulins IgG - 75% of our serum - Crosses placenta, therefore important in protecting newborns - Long serum hal-life - Part of secondary immune respons 3 MCD Immunology Alexandra Burke-Smith - Bivalent- two identical antigen binding sites IgM - 10% of total serum Ig - Complex of 5 linked bivalent monomeric antibodies, therefore 10 identical binding sites- multivalent - Star-like shape - Important in primary immune response - Slightly lower affinity to antigens compared to IgG, which is compensated for by number of binding sites IgA - 2 basic monomers; dimer with secretory piece - Found in body secretions, e.g. mucus membranes in GI tract - Contains a secretory component which protects it from digestive enzymes IgE - Involved in allergic response and the response to helminths - Binds to basophils and mast cells - Triggers release of histamines IgD - Complete function not known A particularly antibody ‘recognizes’ an antigen because that antibody’s binding site it complementary to the EPIPTOPE (region approx 6 amino acids long) on the antigen. This forms the basis of the specificity of antigen recognition. How does an antibody kill a virus? Four important mechanisms: 1. Binds to the virus and prevents attachment to the cell 2. Opsonisation: virus-antibody complex is recognised and phagocytosed by macrophage 3. Complement- mediated lysis of enveloped viruses: cascade of enzymes in the blood which leads to the destruction of cell membranes, and the destruction of the viral envelope 4. Antibody-dependant cell-mediated cytotoxicity (ADCC) mediated by NK-like cells (see earlier for explanation) Cells of the acquired immune system Lymphocytes Agranular leukocytes 20-40% of the circulating WBC 99% of the cells in lymphatic circulation T (thymus-derived) cells - Helper T cells: recognize antigen, help B cells to make antibodies and T cells to kill - Cytotoxic T cells: poisonous to cells,kill cells infected by viruses and intracellular bacteria B (bone marrow-derived) cells - Make antibodies - Have insoluble antigen-binding receptor on its surface. In fact have multiple clones of this receptor; monoclonal antibodies NK (natural killer) cells - See earlier in notes Each subset has distinct cell-surface molecules, e.g. CD4 on helper T-cell which is the receptor for HIV molecules Lymphocyte precursors are produced in the haematopoietic tissue in the bone marrow 4 MCD Immunology Alexandra Burke-Smith T cells are then transported to the thymus, where they undergo THYMAL EDUCATION. Here 95-99% get destroyed as they have the potential to recognise host cells 4. Outline the role of clonal selection in immune responses. Lymphocyte antigen receptors B cell antigen receptor is a membrane-bound antibody, i.e. surface immunoglobulin which binds intact antigens; recognises surface of protein, therefore antigen must be in native conformation Expressed on the T cell surface are 2 protein chains (alpha and beta) which together make the t cell antigen receptor (TCR). This binds to digested antigen fragments. Each antigen receptor binds to an epitope on a different antigen, and is unique to a cell. There are many copies of the receptor on the cell surface The T-cell antigen receptor (TCR) Recognizes complex of antigen peptide and HLA (MHC) molecule HLA (Human leukocyte antigen) binds to little fragments of the pathogen, transports them to the surface so they can be recognized, e.g. so a virus cannot hide inside a host cell. Combination of short peptide from microorganism + HLA = recognition by TCR MHC denotes the Major Histocompatibility Complex (also known as HLA) Generation of clonal diversity in lymphocytes During B and T cell development, random genetic recombinations occur within each cell among multiple copies of immunoglobulin genes (B cells) or TCR genes (T cells). There are parallel genes, but they undergo random splicing and recombination which leads to a large repertoire of antigen receptors These processes generate the diversity of clones of lymphocytes: each clone is specific to a different antigen. Primary Immune Response: clonal selection A typical antigen is recognized by 1 in ~105 naive T cells 98% of T cells are in the lymph circulation and organs; 2% in blood. Antigen binds to surface receptor on the B cell (Ig) or the T cell (TCR) and causes selective expansion of that clone. The receptors which bind with highest affinity to the antigen are selected for, outcompete