Evaluation of: Matsushita T, Yanaba K, Bouaziz JD et A: Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J. Clin. Invest. 118(10), 3420-3430 (2008). B lymphocytes have several potentially relevant roles in the pathogenesis of multiple sclerosis and have become increasingly important targets for therapy. Beyond the production of antimyelin antibodies, these roles may include antigen presentation, cytokine production and the establishment of ectopic lymphoid tissue in the CNS compartment, which could provide a local inflammatory stimulus driving the chronic progressive stages of the disease. B cells may also have important roles as regulatory cells, especially through the production of anti-inflammatory cytokines such as IL-10. In the study by Matushita et al., the impact of B-cell depletion by an anti-CD20 monoclonal antibody was studied in the animal model of experimental autoimmune encephalomyelitis (EAE). Timing of drug administration had a dramatic impact on outcome: depletion preceding EAE induction resulted in an increase in disease severity, in comparison with suppression when the drug was administered after the appearance of clinical signs. This phenomenon was not related to a decrease in antibody levels; instead, it was explained by a preferential effect of anti-CD20 on a regulatory B-cell population whose function was crucial in initial stages of the disease. In summary, these results further expand our knowledge of the importance of B cells in EAE and, potentially, multiple sclerosis, and highlight the complex and often paradoxical results of immunotherapy in autoimmune disorders.