Immune response deepa babin


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Immune response deepa babin

  2. 3. A tribute to A TRIBUTE TO (L-R) 2011 Nobel Prize winners for Physiology or Medicine Bruce A. Beutler, Jules A. Hoffmann , Ralph M. Steinman
  3. 4. Nobel Prize winners <ul><li>Bruce A. Beutler, Jules A. Hoffmann for their discoveries concerning the activation of innate immunity&quot; Ag binds the Toll like receptors in body cells and activates innate immunity-inflammation </li></ul><ul><ul><ul><ul><ul><li>and </li></ul></ul></ul></ul></ul><ul><li>the other half to Ralph M. Steinman &quot;for his discovery of the dendritic cell activates T cell and its role in adaptive immunity&quot; . </li></ul>
  4. 5. The Immune response <ul><li>An immune response is what the immune system does when confronted by an antigen. </li></ul><ul><li>An immune response is an elaborate interplay between antigen, non-specific defenses, and B and T lymphocytes. </li></ul><ul><li>The process involves direct contact (cells, molecules bind to receptors on cell surfaces) and cytokines (messenger molecules) that also bind to receptors on cell surfaces </li></ul>
  5. 6. Immune Response <ul><li>Innate response – by birth, limited in its response (cannot handle too much invasion) </li></ul><ul><li>Adaptive Immune response </li></ul><ul><ul><li>– Matures over person’s lifetime </li></ul></ul><ul><ul><li>– Takes time to start up </li></ul></ul><ul><ul><li>– More effective and very powerful </li></ul></ul><ul><ul><li>– Important Hallmark : MEMORY </li></ul></ul><ul><ul><li>– Complex, involves a network of cells: cytokines, B cells, T cells, antibodies </li></ul></ul>
  6. 7. Adaptive Immune Response <ul><li>2 types </li></ul><ul><ul><li>Humoral/ antibody mediated (AMI) immunity </li></ul></ul><ul><ul><li>Cell mediated immunity (CMI) </li></ul></ul>
  7. 8. Humoral Immunity - Applications <ul><li>Defense against </li></ul><ul><ul><li>most extracellular bacterial pathogens </li></ul></ul><ul><ul><li>viruses that infect through the respiratory or intestinal tracts </li></ul></ul><ul><li>Prevents recurrence of viral infections. </li></ul><ul><li>Takes part in the pathogenesis of Immediate (Types 1, 2 & 3) hypersensitivity & certain autoimmune disorders. </li></ul>
  8. 9. Humoral Immunity <ul><li>Cells taking part in immune response </li></ul><ul><li>- Antigen presenting cells (APCs) </li></ul><ul><li>- B cells & </li></ul><ul><li>- T cells </li></ul><ul><li>Production of antibodies consists of following stages : </li></ul><ul><ul><li>Ag capture & processing by APCs </li></ul></ul><ul><ul><li>Ag presentation </li></ul></ul><ul><ul><li>T H cell activation </li></ul></ul><ul><ul><li>B cell stimulation & differentiation </li></ul></ul><ul><ul><li>Ab production by plasma cells </li></ul></ul>
  9. 10. 1. Antigen Capture & Processing <ul><li>Captured by APCs (macrophages & dendritic cells) – broken down in to small peptides. </li></ul>The immune response begins when a white blood cell called a macrophage encounters a virus and consumes it. Meanwhile, other viruses look for nearby cells to infect.
  10. 11. Next, the macrophage digests the virus and displays pieces of the virus called antigens on its surface. Nearby cells have now become infected by the attacking viruses.
  11. 12. 2. Antigen Presentation <ul><li>Peptides derived from </li></ul><ul><ul><li>Exogenous Ags – presented with MHC class II molecule, recognised by T H cells. </li></ul></ul><ul><ul><li>Endogeous Ags – presented with MHC class I molecule, recognised by T C cells . </li></ul></ul>
  12. 13. Capture, Processing and Presentation of Antigen by an Antigen presenting cell (APC)
  13. 14. This union stimulates the production of chemical substances -- such as interleukin-1 (IL-1) and tumor necrosis factor (TNF) by the macrophage, and interleukin-2 (IL-2) and gamma interferon (IFN-y) by the T cell – that allow intercellular communication
  14. 15. 3. Helper T cell Activation <ul><li>Activation requires 2 signals: </li></ul><ul><ul><li>Combination of TCR with the Ag peptide-MHC class II complex. </li></ul></ul><ul><ul><li>Co-stimulatory signal : combination of B7 on APC & CD28 on the T cell with release of IL-1 . </li></ul></ul><ul><li>Activated T H cells now produce IL-2 which supports the growth of itself & other T cells. </li></ul><ul><li>Also produce IL-4, IL-5 & IL-6 which stimulates the growth & differentiation of B cells into </li></ul><ul><li>- Plasma cells & Memory B cells </li></ul>
  15. 16. KILLER CELLS The killer T cells now begin shooting holes in host cells that have been infected by viruses.
  16. 17. B Cells The antibodies released by the B cells bind to antigens on the surfaces of free-floating viruses. Besides making it easier for macrophages to destroy viruses, this binding signals blood components called complement to puncture holes in the viruses.
  17. 18. Finally, as the infection is brought under control, the activated T and B cells are turned off by suppressor T cells. However, a few &quot;memory cells&quot; remain behind to respond quickly if the same virus attacks again .
  18. 19. 4. B cell activation & differentiation
  19. 21. 5. Ab production <ul><li>Ab production follows a characteristic pattern consisting of : </li></ul><ul><ul><li>Lag Phase – immediate stage following antigenic stimulus during which Ab is not detectable in the circulation. </li></ul></ul><ul><ul><li>Log Phase – steady rise in the titre of Abs. </li></ul></ul><ul><ul><li>Plateau or Steady Phase – equilibrium between Ab synthesis & its catabolism. </li></ul></ul><ul><ul><li>Decline Phase – catabolism exceeds production, fall in Ab titre. </li></ul></ul>
  20. 23. Primary & Secondary Response <ul><li>Primary Response </li></ul><ul><li>Initial contact with the Ag </li></ul><ul><li>Slow, sluggish & short lived. </li></ul><ul><li>Long lag phase. </li></ul><ul><li>Low titres of Ab, does not persist for long. </li></ul><ul><li>IgM – predominant. </li></ul><ul><li>Secondary Response </li></ul><ul><li>Response to subsequent exposure to the same Ag. </li></ul><ul><li>Prompt, powerful & prolonged. </li></ul><ul><li>Short or negligible lag phase. </li></ul><ul><li>Very high levels of Ab, lasts for long periods. </li></ul><ul><li>IgG - predominant </li></ul>
  21. 24. Phases <ul><li>A single injection of an Ag helps in sensitising / priming the immunocompetent cells producing the particular Ab. </li></ul><ul><li>Subsequent injections of an Ag – Boosters – induce effective levels of Ab. </li></ul><ul><li>Hence multiple doses of non living vaccines are administered to achieve effective levels of immunity. </li></ul>
  22. 25. Phases <ul><li>With live vaccines, a single dose is sufficient as multiplication of the organism will provide a continuous stimulus. </li></ul><ul><li>“ Negative Phase” – when an Ag is injected into an animal already carrying the specific Ab in circulation, a temporary fall in the level of Ab occurs due to the combination of Ag with the Ab. It is then followed by a rise in Ab titre. </li></ul>
  23. 26. A B C Negative phase
  24. 27. Cell Mediated Immunity <ul><li>Refers to the specific immune responses that do not involve antibodies. </li></ul><ul><li>CMI response 1 st described by Jenner in 1798. </li></ul><ul><li>1890 - Koch described the exaggerated cutaneous reaction of tuberculous guinea pigs to the I.D. injection of tubercle bacillus – Delayed hypersensitivity (DH). </li></ul><ul><li>DH- skin lesions appear 48-72 hrs after administration of the Ag. </li></ul>
  25. 28. Applications of CMI <ul><li>CMI participates in following immunological functions : </li></ul><ul><li>Delayed hypersensitivity . </li></ul><ul><li>Immunity in infectious diseases caused by obligate & facultative intracellular parasites </li></ul><ul><li>Bacteria – Mycobacteria, Listeria </li></ul><ul><li>Fungi – Histoplasma, Blastomycetes </li></ul><ul><li>Protozoa – Leishmania,Trypanosoma </li></ul><ul><li>Viruses – Measles, Mumps </li></ul>
  26. 29. Applications of CMI <ul><li>Transplantation immunity & graft-versus-host reaction. </li></ul><ul><li>Immunological surveillance & immunity against cancer . </li></ul><ul><li>Pathogenesis of certain autoimmune diseases </li></ul><ul><li>e.g. Thyroiditis </li></ul>
  27. 30. Cells involved in CMI <ul><li>CD8+T cells - recognise antigenic peptides in association with MHC class I molecule on a target cell. </li></ul><ul><li>CD4+T cells - MHC class II restricted, secrete cytokines which help in the growth & differentiation of T lymphocytes. </li></ul>
  28. 34. Scheme of Immune response against T cell dependent Ags
  29. 35. Factors influencing Ab production <ul><li>Genetic factors </li></ul><ul><li>Age </li></ul><ul><li>Nutritional status </li></ul><ul><li>Route of administration of Ag & site of injection </li></ul><ul><li>Size & number of doses </li></ul><ul><li>Multiple Ags </li></ul><ul><li>Adjuvants </li></ul><ul><li>Immunosuppressive agents </li></ul><ul><li>Effect of antibody </li></ul>
  30. 36. 1. Genetic Factors <ul><li>Different individuals within a species show differences in immune response to the same Ag. </li></ul><ul><li>This is determined by the genetic differences. </li></ul><ul><li>Controlled by the gene Ir . </li></ul>
  31. 37. 2. Age <ul><li>Embryo – immunologically immature </li></ul><ul><li>- the developing lymphoid cells come </li></ul><ul><li>into contact with all the tissue Ags of </li></ul><ul><li>the body – Self Tolerance. </li></ul><ul><li>Up to 3-6 mths of age – protection provided by </li></ul><ul><li>maternal Abs. </li></ul><ul><li>B cell responses to most protein Ags develop early. </li></ul><ul><li>Responses to polysaccharides & other Ags develop later, by 2 years of age. </li></ul>
  32. 38. 3. Nutritional Status <ul><li>Protein calorie malnutrition – suppress humoral as well as cell mediated immunity. </li></ul><ul><li>Deficiency of amino acids & vitamins – decrease in Ab synthesis. </li></ul>
  33. 39. 4. Site & Route of Administration of Ag <ul><li>Parenteral – better humoral response. </li></ul><ul><li>Influence the type of Ig produced : </li></ul><ul><li>Oral / Nasal – Ig A </li></ul><ul><li>Inhalation of pollens – Ig E </li></ul><ul><li>Parenteral administration of Ags – Ig G </li></ul><ul><li>Site of administration – relevant with some Ags </li></ul><ul><li>Hepatitis B vaccine – deltoid (highly immunogenic) </li></ul><ul><li>- gluteal (less: paucity of APCs </li></ul><ul><li>in gluteal fat – delays Ag </li></ul><ul><li>presentation) </li></ul>
  34. 40. 5. Size & Number of Doses <ul><li>Ag is effective only above a minimum critical dose. </li></ul><ul><li>Low dose – fails to induce immune </li></ul><ul><li>response. </li></ul><ul><li>High dose – develops tolerance. </li></ul><ul><li>- do not respond to subsequent </li></ul><ul><li>doses of same Ag. </li></ul>
  35. 41. Multiple Ags <ul><li>When 2 or more Ags are administered simultaneously, the effects may vary ; </li></ul><ul><li>Abs produced against different Ags just as though they had been given separately. </li></ul><ul><li>e.g. When 2 bacterial vaccines (typhoid & cholera) are given in a mixed form, the Ab response of one is not influenced by the other. </li></ul>
  36. 42. Multiple Ags <ul><li>Ab response to one or the other Ag may be enhanced or diminished. </li></ul><ul><li>e.g. When toxoids are given with bacterial vaccines (DPT), the response to toxoid is enhanced. </li></ul><ul><li>When 2 toxoids (DT) given together with one in excess, response to other is inhibited . </li></ul>
  37. 43. Adjuvants <ul><li>Any substance that enhances the immunogenicity of an Ag. </li></ul><ul><li>e.g. aluminium hydroxide </li></ul><ul><li>Increase the concentration and persistence of circulating antibody by: </li></ul><ul><ul><li>Increasing the size of Ag - promotes phagocytosis & presentation by macrophages. </li></ul></ul><ul><ul><li>Stimulating the influx of macrophages & other immune cell types to the injection site. </li></ul></ul><ul><ul><li>Promoting local cytokine production </li></ul></ul>
  38. 44. Types of Adjuvants <ul><li>Freund’s incomplete adjuvant : water-in-oil emulsion with protein Ags in water phase. </li></ul><ul><li>Freund’s complete adjuvant : incomplete adjuvant along with a suspension of tubercle bacilli. </li></ul><ul><li>Repository adjuvants – aluminium hydroxide or phosphate. </li></ul><ul><li>Gram negative bacilli (lipopolysaccharide fraction) – Bordetella pertussis – acts as an adjuvant for diphtheria & tetanus toxoid in DPT vaccine. </li></ul>
  39. 45. Immunosuppressive Agents <ul><li>Inhibit immune response – useful in transplantation procedure to prevent graft rejection. </li></ul><ul><li>e.g.corticosteroids,antimetabolites, cyclosporine </li></ul><ul><li>Corticosteroids – depletion of lymphocytes </li></ul><ul><li>-inhibits histamine release & inflammatory process </li></ul><ul><li>Cyclosporine –commonly used for immunosuppression </li></ul><ul><li>- selective inhibition of helper T cell activity </li></ul>
  40. 46. SUPERANTIGENS <ul><li>Class of bacterial toxins (staphylococcal enterotoxins) & retroviral proteins that can activate very large number </li></ul><ul><li>of T cells irrespective of their antigenic specificities. </li></ul><ul><li>Features of super Ags : </li></ul><ul><li>Not processed </li></ul><ul><li>Interact with the MHC class II molecule outside of the peptide - binding groove. </li></ul><ul><li>Bind only to the V β segment of TCR. </li></ul>
  41. 47. Monoclonal Antibodies (mAb) <ul><li>Abs produced by a single clone of cell and directed against a single antigenic determinant are called Monoclonal Antibodies. </li></ul><ul><li>Very useful for diagnostic & research techniques. </li></ul><ul><li>Method for large scale production of mAb was developed by Kohler & Milstein in 1975. </li></ul>
  42. 48. Monoclonal Ab <ul><li>Production is based on Hybridoma technology. </li></ul><ul><li>Hybridomas are somatic cell hybrids produced by fusing Ab forming spleen cells with myeloma cells. </li></ul><ul><li>It retains </li></ul><ul><li>- Ab producing capacity of spleen cell. </li></ul><ul><li>- ability to multiply indefinitely. </li></ul>
  43. 49. ADCC: Antibody Dependent Cell-mediated Cytotoxicity <ul><li>Cytotoxic response is mediated by cells in the presence of Ab. </li></ul><ul><li>Cells carry receptor for the Fc portion of Ig – able to bind Ab coated targets. </li></ul><ul><li>Such cells are also referred to as Killer cells . </li></ul><ul><li>* In the absence of Ab, the same cell could destroy the target by natural killing – NK cells. </li></ul><ul><li>e.g. Eosinophils are very efficient mediators of ADCC against parasitic worms. </li></ul>
  45. 51. TRANSFER FACTOR <ul><li>Transfer of cell mediated immunity </li></ul><ul><li>Nucleopeptide </li></ul><ul><li>Non antigenic </li></ul><ul><li>Stimulate release of lymphokines from sensitised T cells </li></ul><ul><li>Used in CMI deficiency-TB, Lepromatus leprosy,MELANOMA,Wiskott-Aldrich syndrome </li></ul>
  46. 52. Theories of Immune Response <ul><li>Side Chain Theory – Ehrlich (1900) </li></ul><ul><li>Abandoned - Landsteiner demonstrated that Abs can be formed against natural Ags as well as synthetic chemicals. </li></ul><ul><li>Direct Template Theory </li></ul><ul><li>Ag act as a template for Ab synthesis. </li></ul><ul><li>Indirect Template Theory – Burnet & Fenner (1949) </li></ul><ul><li>Entry of an Ag - Incorporation of some of the genes from the antigenic determinant into the genome of Ab producing cells - Heritable changes occur in Ab producing cell </li></ul>
  47. 53. Theories <ul><li>Natural Selection Theory – Jerne (1955) </li></ul><ul><li>Embryonic life – formation of a million diff. Abs (covers full range of Ags) – Natural Abs. </li></ul><ul><li>Entry of an Ag – selective combination with Ab having complementary fit – natural selection of cells forming that particular Ab. </li></ul>
  48. 54. Theories <ul><li>Clonal Selection Theory – Burnet (1957) </li></ul><ul><li>During immunological development, cells capable of reacting with different Ags are formed by somatic mutation. </li></ul><ul><li>Clone of cells having reactivity against self Ags - eliminated – called forbidden clones </li></ul><ul><li>Persistence of forbidden clones or redevelopment in later life – Autoimmunity </li></ul><ul><li>* most widely accepted theory </li></ul>
  49. 55. CYTOKINES <ul><li>Biologically active substances (intercellular messengers) which are </li></ul><ul><li>– produced transiently </li></ul><ul><li>- exert their effects at very low (10 –15 ) conc. & </li></ul><ul><li>- regulate immunological, inflammatory & reparative host responses. </li></ul><ul><li>Includes – Interleukin (product of leucocytes) </li></ul><ul><li>- Interferons </li></ul><ul><li>- Growth factors & others </li></ul>
  50. 56. Features of Cytokines <ul><li>Mediate their actions by binding to specific cell- surface receptors. </li></ul><ul><li>Produced by wide variety of cells like lymphocytes, macrophages, platelets & fibroblasts. </li></ul><ul><li>Cytokines can have </li></ul><ul><li>Paracrine effect – act locally near the producing cells </li></ul><ul><li>Autocrine effect – act directly on the producing cells </li></ul><ul><li>Pleiotropic effect – multiple effects on growth & differentiation of various cell types. </li></ul>
  51. 57. Cytokines: Source & Function Cytokines Source : Immune cells Effects of Cytokines IL-1 Monocytes, macrophages Activation of T & B cells IL-2 T cells Proliferation and/or activation of T & B cells IL-4 T & B cells, mast cells, Activation of B cells, differentiation of Th2 cells IL-6 T cells, macrophages Differentiation of T & B cells IL-10 T & B cells, macrophages Suppression of macrophages, activation of B cells IL-12 B cells, macrophages Differentiation of Th1 cells IFN  Leucocytes Antiviral activity IFN  Fibroblasts IFN  T cells
  52. 58. THANK U