Deciphering the Role of B Cells in Multiple Sclerosis-Towards Specific Targeting of Pathogenic Function

Abstract

B cells, plasma cells and antibodies may play a key role in the pathogenesis of multiple sclerosis (MS). This notion is supported by various immunological changes observed in MS patients, such as activation and pro-inflammatory differentiation of peripheral blood B cells, the persistence of clonally expanded plasma cells producing immunoglobulins in the cerebrospinal fluid, as well as the composition of inflammatory central nervous system lesions frequently containing co-localizing antibody depositions and activated complement. In recent years, the perception of a respective pathophysiological B cell involvement was vividly promoted by the empirical success of anti-CD20-mediated B cell depletion in clinical trials; based on these findings, the first monoclonal anti-CD20 antibody-ocrelizumab-is currently in the process of being approved for treatment of MS. In this review, we summarize the current knowledge on the role of B cells, plasma cells and antibodies in MS and elucidate how approved and future treatments, first and foremost anti-CD20 antibodies, therapeutically modify these B cell components. We will furthermore describe regulatory functions of B cells in MS and discuss how the evolving knowledge of these therapeutically desirable B cell properties can be harnessed to improve future safety and efficacy of B cell-directed therapy in MS.

Keywords: B cell therapies; B cells; anti-CD20; antibodies; antigen presenting cells; experimental autoimmune encephalomyelitis; multiple sclerosis; plasma cells; regulatory B cells.

Figure 1

Molecular and cellular properties of B cells relevant for multiple sclerosis (MS). (a) B cells regulate the activation and differentiation of myeloid antigen presenting cells (APC) and T cells by secretion of distinct pro- and anti-inflammatory cytokines; (b) Antigen-specific B cells act as potent APC to active naive T cells; B cells detect and internalize central nervous system (CNS) antigen via their B cell receptor (BCR) and process them to linearized antigens, which they present to responding T cells in the context of major histocompatibility complex (MHC) class II. The interaction of co-stimulatory molecules on B and T cells along with the secretion of pro-inflammatory cytokines promote the generation of effector T cells; (c) Activated B cells differentiate into plasma cells. Secreted antibodies opsonize rare CNS antigen in the periphery and promote the differentiation of autoreactive T cells; antibody-antigen complexes are recognized by Fc receptors on myeloid APC and trigger internalization, processing and presentation of opsonized antigen to responding T cells. GM-CSF, granulocyte macrophage-colony stimulating factor; TGF, transforming growth factor; IL: interleukin. Green arrow with minus sign: anti-inflammatory, inhibition; Red arrow with plus sign: pro-inflammatory, activation; Black arrow: differentiation; Dashed arrow: processing of antigen.