The broad, long-range objective of this proposal is to identify pathogenic autoantigens in and to develop diagnostics and therapeutics for rheumatoid arthritis (RA). Recent studies identified citrullinated fibrin as a candidate autoantigen in RA, and native fibrinogen was previously described as a candidate autoantigen. Citrullination (deimination) results from the conversion of peptidyl-arginine to peptidyl-citrulline by peptidyl arginine deiminase (PAD). To assess B cell reactivity against fibrinogen in RA we synthesized overlapping native and citrulline-substituted peptides representing the a- and b- chains of fibrinogen for inclusion on synovial protein microarrays. Synovial mircroarray analysis demonstrated autoantibodies targeting epitopes derived from predominantly native, and to a lesser extent citrullinated, fibrinogen in 20% of RA patients. Based on these results we developed a fibrinogen-induced arthritis (FIA) mouse model using native human fibrinogen as the immunizing antigen. Mice with FIA exhibit erythema and swelling encompassing the digits and midfoot, and histophathology demonstrates mononuclear cell infiltrates and synoviocyte proliferation. In this model we demonstrate strong T cell reactivity to native fibrinogen. Synovial protein microarray analysis demonstrated strong autoreactive B cell responses to epitopes representing native fibrinogen, and spreading to citrullinated fibrinogen, gp39 and collagen type V. We propose to investigate the mechanisms underlying FIA including the role of T cells, antibodies and immune complexes in mediating arthritis (Aims 1 and 2). We also propose to apply synovial micoarrays to survey autoantibody reactivity against native and citrullinated fibrinogen in established and pre-disease serum samples derived from RA patients (Aim 3). Our overriding hypothesis is that native and/or citrullinated fibrinogen/fibrin is a pathogenic autoantigen in RA, and that autoimmunity against fibrinogen/fibrin defines a molecular subtype of RA (representing approximately 20% of RA patients). Relevance to public health: RA affects 0.6% of the world population, yet the triggering antigens remain poorly understood. We propose to investigate the potential role for the clotting protein fibrinogen as a pathogenic autoantigen in RA. The success of the proposed studies could lead to development of novel diagnostic tests and therapeutics for RA. ? ? ?
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