CLONING OF FOLLISTATIN-RELATED PROTEIN AS A NOVEL AUTOANTIGEN IN SYSTEMIC RHEUMATIC DISEASES

In an attempt to identify autoantigens of synovium in rheumatoid arthr itis (RA), we constructed lambda phage expression cDNA libraries from synovium and screened them by IgG purified from synovial fluids, both of which were derived from RA patients. As a result of this unique com bination of the libraries and probes, we cloned follistatin-related pr otein (FRP) as a novel autoantigen in systemic rheumatic diseases. FRP is a secreted protein containing a similar amino acid sequence to fol listatin, an inhibitor of activin. FRP was first cloned as a transform ing growth factor-beta 1-inducible protein (called TSC-36) from a mous e osteoblastic cell line and was suggested to have some roles in the n egative regulation of cellular growth, Immunoblotting analyses detecte d synovial fluid and serum anti-FRP antibodies of IgG class more frequ ently in HA than any other systemic rheumatic diseases and controls. S ynovial fluid anti-FRP antibodies appeared in 44% of HA (n = 18) and n one of osteoarthritis (OA) (n = 15) patients. Serum antibodies were de tected in 30% of RA (n = 67), 17% of systemic sclerosis (n = 18), 10% of systemic lupus erythematosus (n = 51) and Sjogren's syndrome (n = 1 0), and none of polymyositis/dermatomyositis (n = 13) patients and hea lthy subjects (n = 30), These antibodies recognized an EC domain, an e xtracellular Ca2+ binding module. In anti-FRP antibody-positive HA pat ients, serum C-reactive protein level and erythrocyte sedimentation ra te were more elevated than negative patients (P < 0.05 and P < 0.01, r espectively). FRP gene expression was higher in RA than OA synovium (P < 0.05), However, there was no difference between these groups in the amount of synovial FRP, suggesting its elevated turnover in RA, As fo llistatin inhibits activin, FRP might inhibit some growth factor-like molecule. Detection of anti-FRP antibodies, possibly having disease-pr omoting effects as the blocking antibodies, could be one of the marker s for clinical evaluation of systemic rheumatic diseases.