Autoimmunity against Fibrinogen Mediates Inflammatory Arthritis in Mice

Abstract

Rheumatoid arthritis (RA) is an autoimmune synovitis characterized by the presence of anticitrullinated protein Abs, although the exact targets and role of anticitrullinated protein autoimmunity in the pathogenesis of RA remain to be defined. Fibrinogen, which can be citrullinated, has recently emerged as a candidate autoantigen. To determine whether autoimmunity against fibrinogen can mediate inflammatory arthritis, we immunized a variety of common mouse strains with fibrinogen and found that DBA/1 and SJL mice developed an inflammatory and erosive arthritis. Mice with fibrinogen-induced arthritis (FIA) possess fibrinogen-reactive T cells that produce the proinflammatory cytokines IL-6, IL-17, TNF-α, and IFN-γ. FIA can be adoptively transferred with either plasma or fibrinogen-specific T cells from diseased mice. Mice with FIA possess rheumatoid factor, circulating immune complexes, and anticyclic citrullinated peptide Abs, all of which are characteristic of human RA. These observations demonstrate that fibrinogen is arthritogenic in mice and that the pathogenesis of FIA is mediated by both autoantibodies and fibrinogen-reactive T cells.

Transglutaminase factor XIII promotes arthritis through mechanisms linked to inflammation and bone erosion

“…Multiple studies have directly implicated the primary fXIIIA substrate fibrin(ogen) in the pathogenesis of inflammatory arthritis. 8,[21][22][23][24] These data also support the concept that fXIIIA contributes to arthritis pathogenesis through distinct fibrinogen-dependent inflammatory processes and through altered osteoclast function-mediated mechanisms.…”

Citrullinated mouse collagen administered to DBA/1J mice in the absence of adjuvant initiates arthritis

“…With an increased understanding of their potential role in disease pathogenesis, citrullinated proteins have been evaluated as immunogens in the presence of FCA [4][5][6]13]. These studies showed that there was a slight increase in immune responses towards the injected immunogen, and a slight increase in joint damage reflected in the ankle.…”

“…In the last decade autoantibodies to citrullinated protein antigens (ACPA) and/or peptides have been used as diagnostic tools and have been implicated in the disease process [1]. A number of citrullinated proteins have been implicated as playing a central role in disease pathogenesis; including, filaggrin, fibrin, fibrinogen, vimentin, alpha enolase, collagen, and even peptidylagrinine deiminase (PAD), the enzyme responsible for the post-translational modification of arginine into citrulline [2][3][4][5][6][7][8][9].…”

Neutrophil Activation Promotes Fibrinogen Oxidation and Thrombus Formation in Behçet Disease

“…Recent studies have provided evidence that fibrinogen plays a multifaceted role in inflammatory responses and autoimmunity. 18,19 The ability of fibrinogen to participate in the inflammatory response depends on its specific interaction with integrins, the leukocyte cell surface adhesion receptors. M2 (CD11b/CD18, Mac-1) and X2 (CD11c/CD18, p150,95) are the main fibrinogen receptors and are expressed on neutrophils, monocytes, macrophages and several subsets of lymphocytes.…”