B cells in multiple sclerosis: connecting the dots

Abstract

Over the past two decades B cells have increasingly moved into the spotlight in multiple sclerosis (MS) research. This interest was fuelled by growing understanding and acceptance of pathological involvement of B cells and antibodies in MS. Data derived from animal models of MS, human histopathological studies, and analyses of B cells in the peripheral blood and cerebrospinal fluid (CSF) have permitted the integration of B cells in our overall picture of MS immunopathogenesis. The as yet strongest direct evidence for a central role of B cells in MS autoimmunity was the demonstration that peripheral B cell depletion leads to a rapid decline of disease-activity in MS. While lending formidable impact to peripheral blood B cells as mediators of disease activity, the effects of anti-CD20 treatment also seemingly challenged the paradigm of a role of antibodies in targeted central nervous system (CNS) myelin destruction. This review shall attempt to provide an overview of our current understanding of B cell and antibody mediated mechanisms relevant to MS. We will include findings from, both, human studies, and animal models to highlight the complexity of B cell function as it pertains to MS. B cells appear to be effective drivers of inflammatory activity in MS by way of a diverse toolset of cellular functions. These functions appear to be closely linked to B cells that can be found in the periphery. However, by serving as the source of antibodies, B cells offer a direct humoral response that may target the CNS and lead to tissue specific destruction. Therefore, B cells participate in MS pathogenesis on both sides of the blood-brain barrier.

Figure

This schematic summarizes current thinking about the development and migration of disease-relevant B cells and their functions in MS as described in this review article. The numbers in the figure correspond to the respective paragraphs in the “Functional Aspects” section. Upon leaving the bone marrow (BM) mature naïve B cells undergo antigen-training and affinity maturation in peripheral germinal centers (GC). During affinity maturation, immunoglobulin genes can become significantly mutated by somatic hypermutation (SHM). Which antigens drive the development of MS-relevant B cells remains controversial, but a number of possible candidates have been identified (see text). Following antigen training in the GC B cells undergo class-switch recombination and enter the CD27+ memory B cell compartment from which they can be rapidly activated to become antibody producing plasma cells or plasma blasts (1.). Memory B cells will persist and can act as efficient antigen-presenting cells (2.) to activate potentially CNS-reactive T cells. Activated CNS-reactive lymphocytes will cross the blood brain barrier (BBB) and establish perivascular infiltrates. Here, and at other sites, B and T cells reside in close proximity, which could allow for further in situ activation of inflammatory cells. The perivascular CNS parenchyma is likely the first site behind the BBB at which B and T cells will reside. Evidence exists for the formation of lymphoid follicle-like structures in the meninges (5.). In the cerebrospinal fluid, clonally expanded B cells and plasma cells can be identified, with the latter having been demonstrated to produce clonal IgG (oligoclonal bands, OCB). Overall, a vivid exchange of B cells appears to take place between the different compartments behind the BBB; it is likely that these different compartments (i.e. perivascular infiltrates, lymphoid follicle-like structures, CSF) support different aspects of B cell involvement in MS immunopathogenesis. At present, it remains unknown whether there is a two-way communication of B cell clones between the periphery and the CNS, or whether migration of B cells into the CNS is a unidirectional process (see ‘?’ in figure). In addition to the APC function, regulatory functions (3.) and T cell activation via non-antigen specific bystander B cell activation (4.) have been shown to be of relevance in MS.