Functional analysis of BAFF, APRIL and their receptors, and the study of their role in the pathogenesis of autoimmune disease

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Objective. To investigate the role of BAFF, APRIL and their receptors in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).Results. By exon-specific PCR/SSCP, we identified a novel polymorphism, P21R, in BR3 gene. P21R is located in the cystein-rich domain of BR3, a specific receptor for BAFF, and could be functionally important. To investigate the reverse-signal through membrane BAFF, we constructed cDNA for membrane BAFF, which was not cleaved by furin convertase, by site-directed mutagenesis. Expression of membrane BAFF was observed on transfected Jurkat cells by flow cytometry. When we analyzed the expression of BR3, TACI and BCMA on each peripheral B cell subset by flow cytometry, BR3 was highly expressed on naive B cells while BCMA was highly expressed on plasmablasts. The number of plasmablasts was increased in patients with SLE. Synovial fibroblast-like cells synthesized APRIL when they were cultured in the presence of TNF-a and IFN-y. BCMA-Ig, which was common receptor for BAFF and APRIL, but not BR3-Ig, receptor for BAFF, inhibited the proliferation of synovial fibroblast-like cells in the presence of TNF-α and IFN-γ.Conclusions. These data suggest that BCMA has important role in the survival of plasmablasts in SLE patients. APRIL is associated with the proliferation of synovial fibroblast-like cells in autocrine fashon. APRIL and BAFF could be a therapeutic target in the treatment of autoimmune disease.