Balancing Act: The Dual Roles of BAFF in Systemic Lupus Erythematosus

In systemic lupus erythematosus (SLE) and other autoimmune diseases, B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) play critical roles through three receptors, i.e., BAFF-Receptor (BAFF-R), transmembrane activator and calcium-modulator and cyclophilin ligand (CAML) interactor (TACI), and B-cell maturation antigen (BCMA), promoting the survival of self-reactive B cells and supporting their differentiation into antibody-producing cells. Several biologic therapies with anti-BAFF and anti-BAFF/APRIL agents induce profound suppression of immunoglobulin production and B-cell survival with variable safety profiles. While belimumab has demonstrated significant improvement of overall disease activity in clinical trials, some cases of de novo lupus nephritis have been reported suggesting a potential lack of protection in certain cases. The sustained reduction in B cell populations expressing regulatory markers, alongside a rapid decline in IL-10 levels following belimumab initiation, suggests that BAFF may have a previously underappreciated role in supporting the development or function of regulatory B cells (Bregs). Given the complex receptor interactions of BAFF and APRIL, as well as the heterogeneous phenotype of regulatory B cells and their different mechanisms for regulating the immune response, the involvement of BAFF in regulatory immune responses remains difficult to fully elucidate. This review explores the current evidence on the anti-BAFF/APRIL therapies and examines the unresolved question of whether BAFF exerts a context-dependent role in supporting regulatory B cell function.