Autoimmunity - Basic Immunology

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A basic course in immunology focusing on autoimmunity and the current biologic treatments in rheumatoid arthritis

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Autoimmunity - Basic Immunology

  1. 1. 1<br />Être ou ne pas être...<br />The Immune system dilema<br />Sam Khalil, PhD<br />
  2. 2. The immune system<br />
  3. 3. Innate and Acquired Immunity<br />
  4. 4. Vasodilatation<br />Inflammation – Innate immunity<br />1<br />Actual Inflammatory response<br />2<br />Inflammatory mediators<br />2<br />1<br />3<br />3<br />Vascular permeability and dilation<br />4<br />4<br />Neutrophil and macrophage chemotaxis<br />5<br />6<br />5<br />Antigen <br />Removed<br />Phagocytosis<br />6<br />Proinflammatory cytokine release<br />
  5. 5. Communication via cytokines<br />
  6. 6. Inflammatory disease / Autoimmunity<br />The Immune Response<br /><ul><li>Cognitive phase</li></ul> Cells recognize the presence of foreign antigen<br /><ul><li>Activation phase:</li></ul> Immune cells expand to mount an attack<br /><ul><li>Effector phase:</li></ul> Immune cells perform functions to eliminate antigen<br /><ul><li>Normalisation phase:</li></ul> Numbers of immune cells diminish following destruction of the antigen<br />
  7. 7. Chronic inflammation<br />Actual Inflammatory response<br />Inflammatory mediators<br />Chronic Inflammation<br />Vascular permeability and dilation<br />Innate Immunity<br />Adaptive Immunity<br />Macrophages <br />+ <br />Lymphocytes recruited<br />Neutrophil and macrophage chemotaxis<br />Phagocytosis<br />Proinflammatory cytokine release<br />Antigen <br />Remains<br />
  8. 8. The adaptive immune system<br />http://www.biolegend.com/pop_pathway.php?id=88<br />
  9. 9. The adaptive immune system<br />http://www.biolegend.com/pop_pathway.php?id=88<br />
  10. 10. Innate Immunity <br />Key step to antigen<br />recognition<br />Adaptive Immunity<br />RECOGNIZE ONLY<br />FOREIGN <br />ANTIGENS<br />
  11. 11. Antigen Presenting Cell<br />
  12. 12. Antigenic peptide<br />Front view<br />Top view<br />Side view<br />MHC class II molecules<br />
  13. 13. MHC class II molecules<br />Not any peptide<br />will fit in the groove but multiple possibilities per molecule<br />(20-24 aa)<br />Some peptide will have a better “fit” in one isotype vs the other<br />
  14. 14. MHC<br />peptide<br />T-Lymphocytes<br />TCR<br />
  15. 15. T-cell receptor<br />5x1015 combinations<br />How to select only the ones that do not react with self antigens?<br />
  16. 16. Thymus<br />5x1015 combinations<br />2x107 combinations<br />
  17. 17. Autoimmunity<br />
  18. 18. Rheumatoid arthritis<br />
  19. 19. Genetic<br />Onset of<br />Autoimmunity<br />Environmental<br />Inflammation &<br />Bone Erosion<br />CCP<br />RA Timeline<br />Birth<br />Pre-clinical<br />Clinical Symptoms<br />Adult Life<br />
  20. 20. Genetic<br />Genetic Factors in RA<br />Genetic Factors have a substantial impact on susceptibility to RA<br />McGregor et al. Arthritis Rheum, 43:30-37<br />Birth<br />
  21. 21. Genetic<br />Genetic Factors in RA<br />Strongest Associations:<br />HLA-DRw4 alleles<br />Birth<br />
  22. 22. Genetic<br />Antigenic Peptide<br />Genetic Factors in RA<br />HLA-DRw4 alleles<br />Shared Epitope (SE)<br />Birth<br />Imboden J. Annu. Rev. Pathol. Mech. Dis. 2009. 4:417-434<br />
  23. 23. Genetic<br />Onset of<br />Autoimmunity<br />Environmental<br />Inflammation &<br />Bone Erosion<br />CCP<br />RA Timeline<br />Birth<br />Pre-clinical<br />Clinical Symptoms<br />Adult Life<br />
  24. 24. BREAKTHROUGH IN RA<br />Autoimmunity to citrullinated protein antigens has specificity for RA and identifies a clinically and genetically distinct form of RA<br />Environmental<br />70% of RA patients are anti-CCP+<br />Environmental Factors in RA<br />Adult Life<br />
  25. 25. Environmental<br />Environmental Factors in RA<br />Process exist constitutively and occurs in healthy individuals.<br />Citrullinated proteins are found in sites of inflammation including joints but are not specific to RA<br />Adult Life<br />However the loss of tolerance is the event specific for RA<br />
  26. 26. Environmental<br />Environmental Factors in RA<br />Adult Life<br />
  27. 27. Production of<br />anti-CCP antibodies<br />Genetic<br />Environmental<br />Citrullinated Peptide<br />Combination of Genetic & Environmental factors<br />HLA-DRw4 alleles<br />Shared Epitope (SE)<br />Birth<br />Adult Life<br />27<br />27<br />
  28. 28. Combination of Genetic & Environmental factors<br />Annu. Rev. Immunol. 2008. 26:651–75<br />
  29. 29. Genetic<br />Onset of<br />Autoimmunity<br />Environmental<br />Inflammation &<br />Bone Erosion<br />Observed up to 10 years<br />before onset of disease*<br />CCP<br />RA Timeline<br />+<br />=<br />Therefore <br />Joint inflammation is not a requirement for the development of anti-CCP antibodies<br />Birth<br />Pre-clinical<br />Clinical Symptoms<br />Adult Life<br />* Klareskog et al. Ann Rheum Dis 2004; 63(Suppl II): ii28-ii33<br />
  30. 30. Pathologic inflammatory response<br />?<br />Annu. Rev. Immunol. 2008. 26:651–75<br />
  31. 31. Chronic rheumatoid arthritis<br />Annu. Rev. Immunol. 2008. 26:651–75<br />
  32. 32. Chronic inflammation<br />Actual Inflammatory response<br />Inflammatory mediators<br />Chronic Inflammation<br />Vascular permeability and dilation<br />Innate Immunity<br />Adaptive Immunity<br />Macrophages <br />+ <br />Lymphocytes recruited<br />Neutrophil and macrophage chemotaxis<br />Phagocytosis<br />Proinflammatory cytokine release<br />Antigen <br />Remains<br />
  33. 33. Pathogenesis of RA<br />J. Clin. Invest. 118:3537–3545 (2008). doi:10.1172/JCI36389<br />
  34. 34. Current Biologic agents in RA<br />Infliximab<br />Adalimumab<br />Golimumab<br />CertolizumabPegol<br />Etanercept<br />Ustekinumab<br />Tocilizumab<br />Abatacept<br />Rituximab<br />Infliximab<br />Adalimumab<br />Rituximab<br />Adapted from Chan et al. Nature Reviews Immunology, May 2010; v10; p301-316<br />
  35. 35. Current Biologic agents in RA<br />-<br />-<br />-<br />-<br />Abatacept<br />Rituximab<br />Tocilizumab<br />Anti-TNF<br />Anakinra<br />-<br />-<br />Nature Reviews Rheumatology 5, 531-541 (October 2009)<br />
  36. 36. Genetic Susceptibility<br />(HLA-DRw4)<br />Inflammation<br />Cytokines<br />Pathways<br />Citrullination of antigens in the joints<br />Bone Erosion<br />Environment<br />(e.g Smoking)<br />Immune Complexes Activation of the complement<br />Summary<br />Anti-CCP antibodies<br />Insult in the joints<br />
  37. 37. Genetic Susceptibility<br />(HLA-DRw4)<br />Inflammation<br />Cytokines<br />Pathways<br />Citrullination of antigens in the joints<br />Bone Erosion<br />Environment<br />(e.g Smoking)<br />Immune Complexes Activation of the complement<br />Summary<br />Anti-CCP antibodies<br />Insult in the joints<br />?<br />
  38. 38. 38<br />QUESTIONS ?<br />http://www.samkhalil.ca<br />

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