Targeting B cells in the treatment of multiple sclerosis: recent advances and remaining challenges

Abstract

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.

Keywords: B cell; Multiple sclerosis; anti-CD20; antibody; cellular subsets; experimental autoimmune encephalomyelitis; immune phenotyping; intrathecal; therapy.

Figure 1.

The role of B cells in multiple sclerosis. B cells act as (a) potent producers of regulating cytokines, (b) antigen-presenting cells (APCs) for the activation of T cells and (c) precursors of antibody-secreting plasma cells. FcR, Fc receptor; IFNγ, interferon γ; IL-6/10, interleukin 6/10; mAPC, myeloid APC; TNF, tumor necrosis factor.