The rheumatoid arthritis specific Sa antigen is citrullinated vimentin

Background

Antibodies directed at the Sa antigen are highly specific for rheumatoid arthritis (RA) and can be detected in approximately 40% of RA sera. The antigen, a doublet of protein bands of about 50 kDa, is present in placenta and in RA synovial tissue. Although it has been suggested that the Sa antigen is identical to citrullinated vimentin, experimental proof for this has never been published.

Objective

In this study we investigated the precise nature of the Sa antigen.

Methods

Freshly purified Sa antigen from placenta was analyzed by mass spectrometry. Immunoprecipitation and Western blot studies were performed with anti-Sa patient sera, anti-vimentin antibodies and antibodies specifically recognizing citrullinated proteins.

Results and Conclusion

Peptide sequences that were obtained from highly purified Sa antigen were unique to vimentin. Recombinant vimentin, however, was not recognized by anti-Sa reference sera. In vivo, vimentin is subjected to various post-translational modifications, including citrullination. Because antibodies to citrullinated proteins are known to be highly specific for RA, it was investigated whether Sa was citrullinated. Our data show that Sa indeed is citrullinated vimentin. Anti-Sa antibodies thus belong to the growing family of anti-citrullinated protein antibodies, which also includes the well described anti-filaggrin and anti-CCP antibodies. The presence of the Sa antigen in RA synovial tissue, the observations that vimentin is citrullinated in dying human macrophages and that citrullinated vimentin peptides are preferentially presented by HLA-DR4/shared epitope, make Sa a unique autoantigen in RA. Studies on Sa may provide new insights on the potential role of citrullinated synovial antigens and the antibodies directed at them in the pathophysiology of RA.