That Obscure Object of Desire: In systemic lupus erythematosus B-cell activating factor/B-lymphocyte stimulator is targeted both by the immune system and by physicians

Abstract

Systemic lupus erythematosus (SLE) is characterized by autoantibodies that mediate tissue injury. However, the pathogenesis of SLE remains poorly understood and available therapeutic approaches are not fully satisfactory. Belimumab, a monoclonal antibody that neutralizes B-cell activating factor (BAFF), was the first drug approved to treat SLE in more than 50 years. However, it is not labelled for use in severe lupus nephritis. Recently, a novel high-throughput multiplex protein microarray platform to profile circulating immunoglobulin G (IgG) autoantibodies in SLE patients identified IgG autoantibodies against several cytokines and growth factors at higher titres in SLE patients than in controls. The presence of autoantibodies to BAFF was validated in a subset of SLE patients by enzyme-linked immunosorbent assay. Low levels of anti-BAFF autoantibodies were also present in healthy controls. The association of anti-BAFF reactivity to clinical features and response to therapy was not addressed. However, preliminary data suggested an association to an interferon- responsive mRNA signature, itself associated with severity. Functional studies disclosed a neutralizing activity of autoantibodies against BAFF. These findings raise new questions regarding the role of BAFF in SLE and the functional and therapeutic significance of anti-BAFF and anti-cytokine autoantibodies.