Autoantibodies in primary Sjogren's syndrome are directed against proteasomal subunits of the alpha and beta type

Objective. The proteasome subunit HC9 (alpha 3) has recently been identifie d as a major target of the humoral autoimmune response in patients with aut oimmune myositis and systemic lupus erythematosus. Since B cell hyperreacti vity is a common feature of systemic autoimmune diseases, patients with pri mary Sjogren's syndrome (SS) and other control groups were investigated to evaluate the significance of autoantibodies against the proteasome. Methods. Analyses of autoantibodies directed against the 20S proteasome wer e performed using enzyme-linked immunosorbent assay, immunoblot, and 2-dime nsional electrophoresis. Forty-three patients with primary SS, 47 patients with rheumatoid arthritis including 9 with secondary SS, 19 patients with g astrointestinal tumors, and 80 healthy controls were tested for antiproteas ome antibodies. Results. Antiproteasome antibodies were detected in 39% of patients (17 of 43) with primary SS. In contrast, only 1 of 47 patients with rheumatoid art hritis showed positive reactivity (P < 0.001). Serum samples from 19 tumor patients (P < 0.003) and 80 healthy controls (P < 0.001) were serologically negative. Moreover, immunoblotting and 2-dimensional analysis of the antip roteasome response revealed a polyspecific recognition pattern in 7 patient s with primary SS. Different proteasomal subunits of the alpha and beta typ e, including subunits that carried the proteolytic active sites, were recog nized by the patients' sera. Conclusion. The humoral antiproteasome response in primary SS, in contrast to its secondary form, is characterized by an extensive recognition pattern of several subunits, indicating a polyspecific B cell activation against t he 20S proteasome. Moreover, proteolytically active beta-type subunits, whi ch are important for the generation of major histocompatibility complex cla ss I-restricted antigens, appear to be targets of the autoimmune response. The data indicate that the proteasome itself may stand on a cross point of pathways that links mechanisms of the immune defense with features of syste mic autoimmunity.