Recent years have substantially broadened our view on the pathogenesis of 
multiple sclerosis (MS). While earlier concepts focused predominantly on T 
lymphocytes as the key cell type to mediate inflammatory damage within central 
nervous system (CNS) lesions, emerging evidence suggests that B lymphocytes may 
play a comparably important role both as precursors of antibody-secreting plasma 
cells and as antigen-presenting cells (APCs) for the activation of T cells. With 
greater appreciation of this pathogenic B-cell function in MS, B-cell-directed 
therapies, and in particular B-cell-depleting monoclonal antibodies targeting 
the CD20 molecule, have gained enormous interest over recent years. Clinical 
trials demonstrated that anti-CD20 treatment, which depletes immature and mature 
B cells but spares CD20 negative plasma cells, rapidly reduces formation of new 
inflammatory CNS lesions. While these findings clearly corroborate a pathogenic 
contribution of B cells, recent experimental but also clinical findings indicate 
that not all B cells contribute in an equally pathogenic manner and that certain 
subsets may in contrast mediate anti-inflammatory effects. In this review, we 
summarize current findings in support of pathogenic B-cell function in MS, 
including the encouraging clinical data which derived from anti-CD20 MS trials. 
Further, we review novel findings suggestive of regulatory properties of B-cell 
subsets which may be collaterally abolished by pan-CD20 depletion. In 
conclusion, we aim to provide an outlook on how this currently differentiating 
concept of pro- and anti-inflammatory B-cell function could be harnessed to 
further improve safety and effectiveness of B-cell-directed therapeutic 
approaches in MS.