Abstract
**Background:** Antibodies directed to proteins containing the non-standard amino acid citrulline, are extremely specific for rheumatoid arthritis (RA). Peptidylcitrulline can be generated by post-translational conversion of arginine residues. This process, citrullination, is catalysed by a group of calcium dependent peptidylarginine deiminase (PAD) enzymes. **Objective:** To investigate the expression and activity of four isotypes of PAD in peripheral blood and synovial fluid cells of patients with RA. **Results:** The data presented here show that citrullination of proteins by PAD enzymes is a process regulated at three levels: *transcription*---in peripheral blood PAD2 and PAD4 mRNAs are expressed predominantly in monocytes; PAD4 mRNA is not detectable in macrophages, *translation*---translation of PAD2 mRNA is subject to differentiation stage-specific regulation by its 3′ UTR, and *activation*---the PAD proteins are only activated when sufficient Ca^2+^ is available. Such high Ca^2+^ concentrations are normally not present in living cells. In macrophages, which are abundant in the inflamed RA synovium, vimentin is specifically citrullinated after Ca^2+^ influx. **Conclusion:** PAD2 and PAD4 are the most likely candidate PAD isotypes for the citrullination of synovial proteins in RA. Our results indicate that citrullinated vimentin is a candidate autoantigen in RA.
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