B Cells in the Multiple Sclerosis Central Nervous System: Trafficking and Contribution to CNS-Compartmentalized Inflammation

Abstract

Clinical trial results of peripheral B cell depletion indicate abnormal proinflammatory B cell properties, and particularly antibody-independent functions, contribute to relapsing MS disease activity. However, potential roles of B cells in progressive forms of disease continue to be debated. Prior work indicates that presence of B cells is fostered within the inflamed MS central nervous system (CNS) environment, and that B cell-rich immune cell collections may be present within the meninges of patients. A potential association is reported between such meningeal immune cell collections and the subpial pattern of cortical injury that is now considered important in progressive disease. Elucidating the characteristics of B cells that populate the MS CNS, how they traffic into the CNS and how they may contribute to progressive forms of the disease has become of considerable interest. Here, we will review characteristics of human B cells identified within distinct CNS subcompartments of patients with MS, including the cerebrospinal fluid, parenchymal lesions, and meninges, as well as the relationship between B cell populations identified in these subcompartments and the periphery. We will further describe the different barriers of the CNS and the possible mechanisms of migration of B cells across these barriers. Finally, we will consider the range of human B cell responses (including potential for antibody production, cytokine secretion, and antigen presentation) that may contribute to propagating inflammation and injury cascades thought to underlie MS progression.

Keywords: B cells; central nervous system; meningeal inflammation; multiple sclerosis; trafficking.

Figure 1

Potential MS-relevant B cell responses. (1) B cells can function as efficient antigen-presenting cells (APC) especially in context of cognate B cell:T cell interactions. This may activate pathogenic T cells that in turn contribute to disease propagation. (2) B cells and/or plasma cells have the potential to produce anti-inflammatory cytokines (such as IL-10 and IL-35) but also proinflammatory cytokines (IL-6, LTα, TNFα, and GM-CSF). A lack of balance involving over-propensity of B cells to produce proinflammatory cytokines and their deficient production of anti-inflammatory cytokines has been demonstrated in patients with MS. Such B cell responses within the CNS may contribute to propagating CNS-compartmentalized inflammation. (3) B cells can differentiate into plasmablasts and plasma cells, which can elaborate pathogenic autoantibodies (and possibly also cytokines). (4) Similar to their established roles in normal lymphoid architecture formation, B cells may release factors that contribute to the formation and/or maintenance of persisting immune cell aggregates in the meninges of MS patients.

Figure 2

B cells in different compartments and implication for MS disease activity. (A) Cells of the B cell lineage (including primarily memory B cells, plasmablasts, and plasma cells) are found to persist in the inflamed MS CNS and occupy multiple subcompartments. These include the cerebrospinal fluid (CSF), parenchymal white matter lesions, and collections of immune cells within the meninges, which can be B cell rich. Somatic mutation analysis has demonstrated that the same B cell clones may occupy all three CNS subcompartments. Exactly how and where such clones initially access the CNS and how they communicate across these CNS subcompartments remains largely unknown. (B) The traditional view has held that new MS disease activity is triggered by activation of immune cells in the periphery (possibly triggered by pathogen-associated molecules recognized by cross-reactive T cells; referred to as molecular mimicry) and subsequent trafficking of the activated cells into the CNS (green arrow). However, the demonstration that the CNS clearly has lymphatics that drain into cervical lymph nodes and evidence from somatic mutation analysis indicating bidirectional trafficking of B cells between the CNS and the periphery (with much of the activation and clonal expansion apparently occurring in the periphery) suggests that relapses may also be “invited” from within the CNS (blue arrows). This might occur if proinflammatory B cells exit the chronically inflamed CNS carrying CNS antigens, which they may then present to T cells in the draining cervical lymph nodes with subsequent trafficking of the activated T cells into the CNS.