Autoimmunity - Basic Immunology

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

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

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