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

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

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