IFN-β Treatment Requires B Cells for Efficacy in Neuroautoimmunity

IFN-beta remains the most widely prescribed treatment for relapsing remitting multiple sclerosis. Despite widespread use of IFN-beta, the therapeutic mechanism is still partially understood. Particularly, the clinical relevance of increased B cell activity during IFN-beta treatment is unclear. In this article, we show that IFN-beta pushes some B cells into a transitional, regulatory population that is a critical mechanism for therapy. IFN-beta treatment increases the absolute number of regulatory CD19(+)CD24(++)CD38(++) transitional B cells in peripheral blood relative to treatment-naive and Copaxone-treated patients. In addition, we found that transitional B cells from both healthy controls and IFN-beta-treated MS patients are potent producers of IL-10, and that the capability of IFN-beta to induce IL-10 is amplified when B cells are stimulated. Similar changes are seen in mice with experimental autoimmune encephalomyelitis. IFN-beta treatment increases transitional and regulatory B cell populations, as well as IL-10 secretion in the spleen. Furthermore, we found that IFN-beta increases autoantibody production, implicating humoral immune activation in B cell regulatory responses. Finally, we demonstrate that IFN-beta therapy requires immune-regulatory B cells by showing that B celldeficient mice do not benefit clinically or histopathologically from IFN-beta treatment. These results have significant implications for the diagnosis and treatment of relapsing remitting multiple sclerosis.