B cell maturation and its dysregulation in autoimmunity

Abstract

B cell development in mouse bone marrow depends critically upon control of cell production by proliferation and cell loss by apoptosis. Although proliferative factors that modulate B cell production have been extensively studied, much less is known of the factors that regulate the selection of B cells during their development. Our previous studies on normal and gene-modified have identified various intrinsic and extrinsic signals that can trigger or inhibit B cell apoptosis. Recent studies have revealed the implication of dysregulated lymphocyte apoptosis in various disorders including autoimmunity. The TNF cytokine superfamily plays a crucial role in immune regulation by modulating lymphocyte proliferation and apoptosis. We have found that B cell activating factor (BAFF), a member of TNF family cytokines, is critically involved in promoting B cell survival and autoantibody production in mice with collagen-induced arthritis (CIA). Moreover, we have demonstrated that administration of BAFF protein in vivo has potent effects on enhancing the generation of long-lived plasma cells and production of autoantibodies, leading to increased disease severity in arthritic mice. To determine the therapeutic effect of BAFF gene silencing in vivo, we have shown that peri-articular injection of lentivirus expressing shRNA for BAFF gene silencing provides a long-term suppression of arthritic development in CIA mice, which identifies BAFF as a valuable gene-silencing target potentially for the effective treatment of rheumatoid arthritis. Thus, our findings have contributed to a fuller understanding of B cell maturation process and its dysregulation under autoimmune conditions.