Reduced BCMA Signaling Disrupts the BAFF/APRIL Axis and Promotes Inflammatory Cytokine Production by B Cells in Multiple Sclerosis.

Introduction/Rationale: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. While anti-CD20 therapies reduce disease activity, atacicept, a BAFF/APRIL inhibitor, unexpectedly worsened MS. BAFF and APRIL signal through BAFF-R, TACI, and BCMA to regulate B cell survival and function. In EAE, BCMA deficiency disrupted regulatory balance and exacerbated disease, suggesting that BAFF/APRIL signaling supports both protective and inflammatory B cell functions. We therefore investigated how BAFF/APRIL signaling through BCMA modulates disease activity in MS.

Methods: Peripheral blood mononuclear cells from treatment-naïve relapsing-remitting MS patients and healthy controls were analyzed by flow cytometry to quantify B cell subsets and expression of BAFF and APRIL receptors. Serum BAFF, APRIL, and neurofilament light chain levels were measured using OLINK-PEA assays. In vitro cultures assessed cytokine production in transitional and memory B cells after BAFF/APRIL stimulation with or without BCMA blockade.

Results: During relapse, transitional B cells, an IL-10, producing regulatory subset, were markedly reduced compared to remission, accompanied by expansion of class-switched memory B cells. These alterations correlated with low serum BAFF and elevated NfL, indicating disrupted B cell regulation during active disease. Transitional B cells from MS patients showed reduced BCMA expression. Functionally, BAFF and APRIL enhanced IL-10 production via BCMA signaling and limited IL-6 secretion by memory B cells, whereas BCMA blockade disrupted this regulatory balance and increased inflammatory cytokine production.

Conclusion: Together, these findings identify BCMA as a key mediator of BAFF/APRIL-driven regulatory B cell function in MS. Impaired BCMA signaling may disrupt the balance between inflammatory and regulatory B cells, linking altered B cell homeostasis to disease activity. These results highlight BCMA as a potential therapeutic target to restore immune balance without global B cell depletion.