The role of Peptidyl Arginine Deiminase and protein citrullination in the pathogenesis of rheumatoid arthritis

Rheumatoid arthritis (RA) is a common multifactorial inflammatory disorder. It is characterised by a chronic synovial inflammation that destroys the affected joints and causes disability. The molecular basis of RA is largely unknown, but it is clear that the main genetic contribution to RA is by certain DR4 genes in the HLA complex. No environmental factor has been identified. These observations, and the presence of antibodies that target self proteins, indicate that RA may be a “truly” autoimmune disorde r driven by T cells specific for self-peptide-DR4 complexes. The problem with this hypothesis is that self-reactive T cells mostly become tolerant during maturation in the thymus. An intriguing alternative is that rheumatoid joint T cells, rather than nat ive self, recognise modified self-peptides that are not expressed in the thymus and thus not established tolerance to. Strong arguments in favour of this possibility come from recent data on the disease-specific serum autoantibodies in RA. It appears that most of these antibodies, whose production by B cells require specific T cell help, target modified proteins in which post-translational deimination of arginine residues to yield citrulline have occurred. Our ultimate aim it to find out whether the synov ial T cells that provide help to the citrulline-specific B cells also recognise deiminated peptides. To this end we will search for citrullinated peptides in vivo and establish systems for deiminating candidate proteins in vitro using the only human enzym e that can deiminate protein bound arginine; peptidyl arginine deimnase. Identified peptides will ultimately be tested with synovial T cells. This approach should allow better insight into the pathogenesis of RA and contribute to the development of a more specific and safer therapy for the disease. The latter is critically needed as the currently available drugs for RA are non-specific immune suppressors with serious systemic side effects.