Conversion of arginyl to citrullyl residues (citrullination) is essential for the formation of the
epitopes recognized by
rheumatoid arthritis (RA)-associated
autoantibodies to citrullinated
proteins (ACPA). ACPA are secreted by plasma cells of the rheumatoid synovial tissue where their major target, citrullinated
fibrin, is abundant. Although numerous arguments suggest that ACPA play an important role in RA, their pathological relevance remains to be established. In the present study, we assessed the immunogenicity and arthritogenicity of complete
Freund's adjuvant-emulsified autologous citrullinated (C-rFBG) or non-citrullinated (NC-rFBG)
fibrinogen in Lewis (LEW) and Brown-Norway rats, which exhibit drastic differences in their susceptibility to induced
autoimmune diseases. NC-rFBG induced no antibody response. In contrast, a single injection of C-rFBG induced an
IgG response directed mainly to citrullinated determinants of rFBG. However, all rat strains remained devoid of clinical and histological signs of
arthritis up to 3 months after C-rFBG inoculation. Next, in LEW rats, we tested whether autoimmunity to C-rFBG could aggravate acute ankle
arthritis triggered by
intra-articular injection of
incomplete Freund's adjuvant (IFA). However, such
arthritis evolved identically in the presence or absence of anti-C-rFBG
autoantibodies. However, IFA-injected joints were devoid of citrullinated
fibrin deposits. Therefore, citrullination allows breakdown of immunological tolerance but the autoimmune response developed is not spontaneously arthritogenic. Whether or not it can aggravate
arthritis with citrullinated
fibrin deposits remains to be evaluated.