Insights into rheumatoid arthritis derived from the Sa immune system

The Sa system is a recently described immune system that has a specificity and positive predictive value of nearly 100% for rheumatoid arthritis (RA) in Asia, Europe and the Americas. Its sensitivity of 30-40% suggests that i t identifies a subset of RA patients. Anti-Sa antibodies are present from d isease onset and are predictive of disease severity. The immune reactants a re plentiful in the target tissue: antigen is present in the synovium, IgG antibody in the fluid. Immunologically, Sa is a hapten-carrier antigen in w hich vimentin is the carrier and citrulline is the hapten. The citrullinati on of vimentin is closely related to apoptosis, and citrullinated vimentin is extremely sensitive to digestion by the ubiquitous calpains. Nevertheles s, Sa is found in only a few cell lines. Calpastatin, the natural specific inhibitor of calpains, is also a RA-associated, albeit non-specific, autoim mune system. Is it possible that calpain-related apoptotic pathways could b e prominent in cells containing Sa? The task is to reconcile the specificit y of Sa/citrullinated proteins in a multifactorial and polygenic disease su ch as RA.