Basic Immunology


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Basic Immunology

  1. 1. Basic Immunology Dr Russell Watkins
  2. 5. INTRODUCTION <ul><li>Immunology is the study of host defence mechanisms. </li></ul><ul><li>Immunity is the ability of the host to protect itself against foreign organisms. </li></ul><ul><li>The immune system comprises the tissues, cells & molecules which mount the immune response . </li></ul>
  3. 6. Coagulation Cascade Fibrinolytic Cascade Kinin Cascade Thrombin Plasmin Kallikrein Plasma Fibrinogen Complement Cascade MAC Bradykinin Fibrin XIIa PCV Cellular mediators
  4. 7. Immunology <ul><li>Natural (‘innate’) immune system </li></ul><ul><ul><li>Skin, tears, saliva, mucus, acids </li></ul></ul><ul><ul><li>Property of all living creatures </li></ul></ul><ul><li>Adaptive (‘acquired’) immune system </li></ul><ul><ul><li>Specialist cells, cytokines, antibodies </li></ul></ul><ul><ul><li>Specific and has ‘memory’ </li></ul></ul><ul><ul><li>Specialised mucosal lymphoid tissue </li></ul></ul>
  5. 11. INTRODUCTION <ul><li>Immunogenicity is the capacity to induce an immune response by foreign, complex, high molecular weight compounds </li></ul><ul><li>Antigenicity is the ability to bind to Ig or immune cells; an immune response need not result </li></ul><ul><li>Haptens </li></ul>
  6. 12. INTRODUCTION <ul><li>Epitopes </li></ul><ul><ul><li>aka antigenic determinants </li></ul></ul><ul><li>Immunological cross-reactivity </li></ul><ul><ul><li>the sharing of epitopes by different substances </li></ul></ul><ul><ul><li>toxoids & immunisation </li></ul></ul>
  7. 13. THE INNATE IMMUNE SYSTEM <ul><ul><li>Synonyms are the natural or native immune system </li></ul></ul><ul><ul><li>Rapidly mobilised first line of defence </li></ul></ul><ul><ul><li>Not dependent on prior exposure to a foreign invader </li></ul></ul><ul><ul><li>Non-specific </li></ul></ul><ul><ul><li>May not be sufficient to prevent foreign material persisting in the host </li></ul></ul>
  8. 14. THE INNATE IMMUNE SYSTEM <ul><li>Innate immunity comprises: </li></ul><ul><ul><li>physicochemical barriers </li></ul></ul><ul><ul><li>molecules normally present in body fluids e.g. lysozyme, complement, antiproteases </li></ul></ul><ul><ul><li>phagocytic & cytotoxic cells such as neutrophils, macrophages, natural killer cells </li></ul></ul>
  9. 16. THE INNATE IMMUNE SYSTEM <ul><li>The “Respiratory Burst” </li></ul><ul><ul><li>aka the “oxidative burst” </li></ul></ul><ul><ul><li>membrane-bound NADPH system produces </li></ul></ul><ul><ul><ul><li>superoxide radicals </li></ul></ul></ul><ul><ul><ul><li>hyperchlorous acid </li></ul></ul></ul><ul><ul><ul><li>H 2 O 2 </li></ul></ul></ul><ul><ul><ul><li>chloramines </li></ul></ul></ul>
  10. 17. THE INNATE IMMUNE SYSTEM <ul><li>A reliable means of protecting the host in the first instance against many extracellular organisms </li></ul><ul><li>It is a property of every living organism </li></ul><ul><li>Unable to deal with all intracellular organisms (e.g protozoa, viruses & certain bacteria are not killed) </li></ul>
  11. 18. THE ACQUIRED IMMUNE SYSTEM <ul><li>Specific & has immunologic memory </li></ul><ul><li>Dedicated immune cells - the lymphoid cells (lymphocytes) </li></ul><ul><li>Molecules that specifically counteract antigens (antibodies or immunoglobulins) </li></ul><ul><li>Specific immune systems associated with barrier surfaces e.g. MALT, GALT </li></ul><ul><li>Lymphocyte secreted cytokines </li></ul>
  12. 19. T-LYMPHOCYTES <ul><li>Cell-mediated immunity especially intracellular organisms, protozoa & fungi </li></ul><ul><li>Graft rejection </li></ul><ul><li>Immune surveillance of neoplasia </li></ul><ul><li>70-80% of total lymphocytes </li></ul><ul><li>Long-lived memory cells </li></ul><ul><li>Activity is by cytokine production </li></ul>
  13. 20. T-LYMPHOCYTES <ul><li>T h - CD4+: Respond to antigen in association with MHC Class II </li></ul><ul><li>T c - CD8+: Respond to antigen presented via MHC Class I </li></ul><ul><li>Antigen MUST be peptide </li></ul><ul><li>T dth </li></ul><ul><li>T s </li></ul>
  14. 21. T-LYMPHOCYTES <ul><li>CD4+ cells recognize antigens that have been taken up by antigen presenting cells which present antigen fragments on the cell surface </li></ul><ul><li>CD8+ cells recognise cells infected with virus, which they then kill </li></ul>
  15. 22. T-LYMPHOCYTES <ul><li>CD4 (T h ) cells interact directly with other cells by releasing cytokines to control development of the immune response </li></ul><ul><li>Two types of T h cell </li></ul><ul><ul><li>T h -1 cells activate macrophages to destroy material phagocytosed </li></ul></ul><ul><ul><li>T h -2 cells help B-cells make antibody </li></ul></ul>
  16. 23. B-LYMPHOCYTES <ul><li>Specialised for the production of immunoglobulins after differentiation into plasma cells </li></ul><ul><li>Controls pyogenic bacteria </li></ul><ul><li>Prevents blood-borne infections </li></ul><ul><li>Neutralise toxins </li></ul><ul><li>12% of total lymphocytes </li></ul>
  17. 24. B-LYMPHOCYTES <ul><li>Can respond to peptide, carbohydrate & glycolipids </li></ul><ul><li>Usually require T-cell help to respond to antigen (interleukins) but can also recognise antigen directly through surface Ig </li></ul><ul><li>B cells mature & proliferate in lymph nodes </li></ul>
  18. 25. B-LYMPHOCYTES <ul><li>B-cells process & present antigen via surface MHC class II </li></ul><ul><li>Responses are antigen-specific but effects are not specific - mainly via complement </li></ul>
  19. 26. IMMUNOGLOBULINS <ul><li>The 5 classes of Ig are: </li></ul><ul><ul><li>IgM </li></ul></ul><ul><ul><li>IgA </li></ul></ul><ul><ul><li>IgD </li></ul></ul><ul><ul><li>IgG </li></ul></ul><ul><ul><li>IgE </li></ul></ul>
  20. 27. IMMUNOGLOBULINS <ul><li>4-chain structure </li></ul><ul><ul><li>2 light chains </li></ul></ul><ul><ul><li>2 heavy chains </li></ul></ul><ul><li>Chains linked by disulphide bonds </li></ul><ul><li>Chains are coiled into “domains” </li></ul><ul><ul><li>110 amino acids </li></ul></ul><ul><ul><li>stabilised by intrachain disulphide bond </li></ul></ul>
  21. 29. IMMUNOGLOBULINS <ul><li>Terminal regions of H & L chains are the variable regions </li></ul><ul><li>The variable region is the site where Ig combines with antigen </li></ul><ul><li>This region’s variability is responsible for wide range of antigen specificity </li></ul>
  22. 30. IMMUNOGLOBULINS <ul><li>The other domains are the constant regions which are similar within isotypes of Ig </li></ul><ul><li>Using enzymes, a number of Ig fragments have been identified. Important ones are: </li></ul><ul><ul><li>F ab </li></ul></ul><ul><ul><li>F c </li></ul></ul>
  23. 31. IMMUNOGLOBULINS <ul><li>F c regions formed from H chains & determine isotype & so biological function </li></ul><ul><li>Hinge region also has effect on function </li></ul><ul><li>These functions are distinct from antigen binding </li></ul>
  24. 32. IMMUNOGLOBULINS <ul><li>IgG </li></ul><ul><ul><li>neutralises toxins </li></ul></ul><ul><ul><li>activates complement </li></ul></ul><ul><ul><li>opsonisation </li></ul></ul><ul><ul><li>able to cross placenta (only Ig that can) </li></ul></ul>
  25. 33. IMMUNOGLOBULINS <ul><li>IgA </li></ul><ul><ul><li>monomeric & dimeric forms </li></ul></ul><ul><ul><li>dimeric = “secretory IgA” - found in secretions </li></ul></ul><ul><ul><li>important antiviral Ig </li></ul></ul>
  26. 35. IMMUNOGLOBULINS <ul><li>IgM </li></ul><ul><ul><li>pentameric </li></ul></ul><ul><ul><li>good agglutinator </li></ul></ul><ul><ul><li>good at activating complement </li></ul></ul>
  27. 37. IMMUNOGLOBULINS <ul><li>IgD </li></ul><ul><ul><li>true function unknown </li></ul></ul><ul><ul><li>appears to be involved in B-cell differentiation </li></ul></ul>
  28. 38. IMMUNOGLOBULINS <ul><li>IgE </li></ul><ul><ul><li>parasitic infections </li></ul></ul><ul><ul><li>F c portion binds to mast cells </li></ul></ul><ul><ul><li>triggers mast cell degranulation </li></ul></ul>
  29. 41. T- & B-LYMPHOCYTES <ul><li>T- & B-cells recognise the antigen, proliferate in response to it, & migrate back to the site of injury </li></ul><ul><li>There they release cytokines that attract effector cells (cytotoxic T-cells, activated macrophages, committed B-cells) </li></ul>
  30. 43. THE ACQUIRED IMMUNE SYSTEM <ul><li>CD System </li></ul><ul><ul><li>WBCs are distinguished according to groups of molecules they express on their surfaces - mostly “CD” molecules </li></ul></ul><ul><ul><li>>130 CD molecules identified </li></ul></ul><ul><ul><li>may be lineage specific or shared between different cell types </li></ul></ul><ul><ul><li>may only appear during cell development or only when activated </li></ul></ul>
  31. 45. THE ACQUIRED IMMUNE SYSTEM <ul><li>MHC expression </li></ul><ul><ul><li>Class I molecules expressed on all nucleated cells </li></ul></ul><ul><ul><li>Class II molecules expressed on a small group of antigen presenting cells </li></ul></ul><ul><ul><li>Class II molecules may also be induced to be expressed on other cells during immune reactions by interferon-  </li></ul></ul>
  32. 46. THE ACQUIRED IMMUNE SYSTEM <ul><li>Cytokines are short-range, multifunctional, short-acting mediators of cellular activities, especially within the immune system </li></ul><ul><li>Released primarily by activated T-cells & other immune and non-immune cells. </li></ul>
  33. 47. THE ACQUIRED IMMUNE SYSTEM <ul><li>There are 4 major classes of cytokines </li></ul><ul><ul><li>interleukins (IL-1 to IL-12) </li></ul></ul><ul><ul><li>interferons (IF-  , IF-  & IF-  ) </li></ul></ul><ul><ul><li>colony stimulating factors (CSFs) </li></ul></ul><ul><ul><li>tumour necrosis factors (TNF-  & TNF-  ) </li></ul></ul>
  34. 48. NATURAL KILLER CELLS <ul><li>Natural Killer (NK) cells: </li></ul><ul><ul><li>classed as part of the lymphoid system but have no differentiating surface markers </li></ul></ul><ul><ul><li>they are particularly effective against virus-infected & tumour cells </li></ul></ul><ul><ul><li>also called large granular lymphocytes </li></ul></ul>
  35. 49. ANTIGEN PRESENTING CELLS <ul><li>Examples of APCs are: </li></ul><ul><ul><li>macrophages </li></ul></ul><ul><ul><li>B-cells </li></ul></ul><ul><ul><li>dendritic cells </li></ul></ul><ul><li>Macrophages & B-cells recognise antigen through the Ig molecule </li></ul><ul><li>Dendritic cells process & present antigen to naïve T-cells via MHC Class II </li></ul>
  36. 50. THE ACQUIRED IMMUNE SYSTEM <ul><li>Macrophages </li></ul><ul><ul><li>long-lived </li></ul></ul><ul><ul><li>widespread distribution </li></ul></ul><ul><ul><li>they express receptors for Ig & activated complement components which they use to take up immune complexes </li></ul></ul>
  37. 51. ANTIGEN PRESENTING CELLS <ul><li>Antigen Presenting Cells (APCs): </li></ul><ul><ul><li>normally, initiation of the acquired immune response does not take place at the site of injury or penetration of foreign organisms </li></ul></ul><ul><ul><li>antigen is taken up by APCs at the site of inflammation & transported to regional lymph nodes &/or spleen where it is presented to T- & B-cells </li></ul></ul>
  38. 53. THE ACQUIRED IMMUNE SYSTEM <ul><li>Macrophages & B-cells are involved in the perpetuation of the immune response </li></ul><ul><li>Dendritic cells are implicated in the initiation of the immune response </li></ul>
  39. 54. THE ACQUIRED IMMUNE SYSTEM <ul><ul><li>Antigen specificity is the single most important aspect of the acquired immune system (mediated by lymphocytes) </li></ul></ul><ul><ul><li>Each clone of a lymphoid cell responds only to a single antigen </li></ul></ul><ul><ul><li>T-cells deal with surface bound antigen (usually cell associated) </li></ul></ul><ul><ul><li>B-cells deal with soluble (extracellular) antigen </li></ul></ul>
  40. 55. THE ACQUIRED IMMUNE SYSTEM <ul><li>Specific immunity is termed humoral when antibodies are involved in removing the antigen </li></ul><ul><li>It is termed cell-mediated when T-cells & macrophages are involved </li></ul>
  41. 57. THE ACQUIRED IMMUNE SYSTEM <ul><ul><li>Immunity after infection is termed active immunity (because the host has responded actively to the stimulus) </li></ul></ul><ul><ul><li>Immunity may be transferred passively by antibodies or cells (breast milk, vaccination) </li></ul></ul><ul><ul><li>Vaccination may be passive (using Ig) or active (using antigen or attenuated organism) </li></ul></ul>
  42. 58. THE ACQUIRED IMMUNE SYSTEM <ul><li>The development of acquired immunity begins with a primary immune response : </li></ul><ul><ul><li>an afferent phase involving APCs </li></ul></ul><ul><ul><li>T-cell transformation from a resting to an active state </li></ul></ul><ul><ul><li>an effector phase - induction of other cells (B-cells & macrophages) by active T-cells </li></ul></ul>
  43. 59. THE ACQUIRED IMMUNE SYSTEM <ul><ul><li>The primary immune response is accompanied by the appearance of antigen-specific T-cells & Ig-secreting B-cells </li></ul></ul><ul><ul><li>The secondary immune response : </li></ul></ul><ul><ul><ul><li>on second (& subsequent) exposure to the same antigen, antigen-specific memory T- & B-cells are recruited much sooner & more efficiently </li></ul></ul></ul><ul><ul><ul><li>Ig levels are consequently much higher </li></ul></ul></ul>
  44. 61. INNATE & ACQUIRED IMMUNITY <ul><ul><li>Extracellular foreign antigen is normally cleared by the innate immune system, with some assistance from B-cell activity </li></ul></ul><ul><ul><li>Intracellular foreign antigen is handled by the acquired immune system in which self & foreign antigen are jointly recognised </li></ul></ul><ul><ul><li>All cellular defence mechanisms involve interactions of cell surface molecules (receptors) with complementary molecules (ligands) </li></ul></ul>
  45. 62. COMPLEMENT <ul><li>The complement system </li></ul><ul><ul><ul><li>comprises at least 9 plasma proteins & some regulatory factors, that mediate several functions of the inflammatory process </li></ul></ul></ul><ul><ul><ul><li>synthesised by macrophages or hepatocytes </li></ul></ul></ul><ul><ul><ul><li>usually circulate as inactive proenzymes </li></ul></ul></ul><ul><ul><ul><li>heat labile (c.f. Ig is heat stable) </li></ul></ul></ul>
  46. 63. COMPLEMENT <ul><li>Complement pathways </li></ul><ul><ul><li>Cascade of sequential activation converts each proenzyme into its active state & amplifies the response. </li></ul></ul><ul><ul><li>Two main pathways: </li></ul></ul><ul><ul><ul><li>“ Classical” pathway - bound IgG, IgM </li></ul></ul></ul><ul><ul><ul><li>“ Alternative” pathway - certain antigens (LPS, endotoxin, IC) </li></ul></ul></ul>
  47. 64. COMPLEMENT <ul><li>Functions </li></ul><ul><ul><li>opsonisation, chemotaxis, immune adherence (MAC) </li></ul></ul><ul><ul><li>acceleration of acute inflammation </li></ul></ul><ul><ul><li>immune cytolysis </li></ul></ul><ul><ul><li>virus neutralisation </li></ul></ul>