Clinical and pathogenic significance and its therapeutic application of anti-calpastatin antibodies in rheumatoid arthritis

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We found novel autoantibodies to calpastatin, natural inhibitor for calcium-dependent cycteine proteinase (calpain), in patients with rheumatoid arthritis (RA). Since calpain is thought to be one of neutral proteinases that may be involved in joint destruction and inflammation process, the production of autoantibodies to its inhibitor protein, calpastatin, might be associated with pathogenic mechanisms of RA. In this study, we intended to examine 1) the domain reactivity of autoantibodies using the expression products from the full-length cDNA encoding for human calpastatin, 2) the inhibitory activity of calpastatin by patient autoantibodies, and 3) the effect of calpain inhibitors for arthritis model animals.Patient sera showed a variety of reactivity among the five domains of calpastatin (domains L, I, II, III, IV and V), and the reactive patterns tended to correlate to the diseases. RA sera predominantly reacted domains I and II. 81% of sera from RA patients reacted at least one domain, whereas 46%, 32% and 43% were reacted in sera from SLE, scleroderma and myositis, respectively.IgG from RA patient sera containing anti-calpastatin antibodies suppressed the calpain inhibitory activity of calpastatin domain fusion proteins in dose-dependent manner. 5 of 11 (45%) IgG from RA sera recovered more than 40% of calpain activity of at least one domain, whereas IgG from SLE and normal controls did not inhibited the function of calpastatin domains.Among the various calpain inhibitors, calpeptin suppressed significantly the development of type II collagen-induced rat arthritis. Calpeptin-treated rats showed less synovial infiltration and less cartilage destraction than untreated rats.These results suggest that anti-calpastatin antibodies may be useful as a novel marker of RA, and may be closely associated with pathogenic mechanisms of RA. Moreover, our results lead to a new strategy of treatment.