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
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
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
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 ?