The Elusive B Cell Antigen in Multiple Sclerosis: Time to Rethink CNS B Cell Functions

Although the pivotal role of B cells in the pathogenesis of multiple sclerosis (MS) is well established, their precise functions in disease mechanisms remain incompletely understood. For decades, MS-related B cell research has focused on identifying B cell antigens that could induce pathogenic antibodies contributing to the initiation and maintenance of CNS lesion formation and inflammation. In this review, we conducted a systematic literature search to compile and critically assess proposed antigens with respect to their specificity for MS and the plausibility of findings across different publications. We identified 26 antigens in total. Among these, 15 antigens did not demonstrate high specificity for MS, 9 antigens yielded controversial or contradictory results, and 2 antigens may still be regarded as provisional at the time of our analysis. Based on these findings, a primarily antibody-mediated mechanism driving initial lesion formation is not supported by current evidence, although it cannot be excluded entirely. Instead, a secondary immune response to CNS tissue damage-characterized by local antibody production and alternative B cell functions such as antigen presentation, cytokine secretion and cell-to-cell communication-appears more plausible. Taken together, our review highlights the necessity of expanding B cell-oriented MS research beyond antibody production to include a broader spectrum of B cell functions.