BLyS--an essential survival factor for B cells: basic biology, links to pathology and therapeutic target

A paradigm shift in our understanding of autoimmune disease pathology is underway; B cells are now considered to play a central role in disease pathogenesis. Targeting B cells may prove to be an effective route for the development of novel therapeutics. BLyS, a member of the TNF family of cytokines, is an essential survival factor for B cells. Constitutive BLyS overexpression in mice leads to an autoimmune phenotype similar to lupus nephritis. Clinically, BLyS is elevated in patients with systemic autoimmune diseases including rheumatoid arthritis and systemic lupus erythematosus. BLyS ablation results in a block of B cell development in which mature B cells are absent. BLyS binds to three receptors, BR3, TACI and BCMA. Analysis of the receptors suggests that the major pro-survival signals are mediated by BR3, while TACI is involved in negative signaling. BCMA is required for survival of long-lived plasma cells. BLyS signaling results in upregulation of anti-apoptotic bcl-2 family members. In animal models of autoimmune disease, BLyS antagonists reduce disease severity and delay disease progression. BLyS is an attractive target for antagonism in autoimmune diseases. Multiple approaches are being taken to antagonize BLyS including a fully human antibody and soluble BLyS receptors. These approaches are currently being tested in clinical trials.