Bruton Tyrosine Kinase Inhibition Limits Multiple Sclerosis Disease–Driving Inflammation While Promoting Regulatory B Cells

BACKGROUND AND OBJECTIVES: In multiple sclerosis (MS), a variety of immunosuppressive treatments are available. While effective, these approaches often lead to sustained impairment of essential components of the immune system, posing long-term safety concerns. Consequently, there is a growing interest in alternative therapeutic approaches that selectively limit pathogenic B-cell functions while preserving their physiologic roles. In this study, we investigated the therapeutic potential of inhibiting the enzyme Bruton tyrosine kinase (BTK), a key signaling molecule in both B-cell and myeloid cell activation. METHODS: settings using flow cytometry. RESULTS: In a naïve, healthy environment, evobrutinib promoted the development of regulatory B-cell properties. In various experimental models of CNS demyelination, BTK inhibition limited the differentiation of proinflammatory B cells while supporting their regulatory properties. Beyond modulating B-cell responses, BTK inhibition also attenuated the activation of myeloid cells after Fc receptor-mediated antigen uptake, a process assumed to be of importance in conditions, such as neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein-antibody associated disease. In addition, BTK inhibition was shown to suppress the secretion of proinflammatory cytokines and reduce antigen presentation, further dampening pathogenic immune responses. DISCUSSION: These findings highlight the potential of BTK inhibition as a selective and sustainable immunomodulatory strategy for both B cells and myeloid cells in the context of chronic CNS inflammation. Despite their efficacy, broad-spectrum immunosuppressive therapies often fail to provide targeted immune modulation. By contrast, BTK inhibition promotes regulatory B-cell properties while leaving other B-cell functions intact, providing the basis for its broad use-potentially in combination with established anti-inflammatory agents.