Memory B Cells in Multiple Sclerosis: Emerging Players in Disease Pathogenesis

Abstract

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Once thought to be primarily driven by T cells, B cells are emerging as central players in MS immunopathogenesis. Interest in multiple B cell phenotypes in MS expanded following the efficacy of B cell-depleting agents targeting CD20 in relapsing-remitting MS and inflammatory primary progressive MS patients. Interestingly, these therapies primarily target non-antibody secreting cells. Emerging studies seek to explore B cell functions beyond antibody-mediated roles, including cytokine production, antigen presentation, and ectopic follicle-like aggregate formation. Importantly, memory B cells (Bmem) are rising as a key B cell phenotype to investigate in MS due to their antigen-experience, increased lifespan, and rapid response to stimulation. Bmem display diverse effector functions including cytokine production, antigen presentation, and serving as antigen-experienced precursors to antibody-secreting cells. In this review, we explore the cellular and molecular processes involved in Bmem development, Bmem phenotypes, and effector functions. We then examine how these concepts may be applied to the potential role(s) of Bmem in MS pathogenesis. We investigate Bmem both within the periphery and inside the CNS compartment, focusing on Bmem phenotypes and proposed functions in MS and its animal models. Finally, we review how current immunomodulatory therapies, including B cell-directed therapies and other immunomodulatory therapies, modify Bmem and how this knowledge may be harnessed to direct therapeutic strategies in MS.

Circulating Memory B Cells in Early Multiple Sclerosis Exhibit Increased IgA+ Cells, Globally Decreased BAFF-R Expression and an EBV-Related IgM+ Cell Signature

“…This suggests that antibody-independent functions of B cells are likely also important in MS, including antigen presentation to CD4 + T cells and/or induction of “auto proliferative” Th1 CD4 + T cells ( 6 ), possibly facilitated by the HLA-DR15 gene variant ( 7 ). While uncertainty remains about which MBC subpopulations and functions might mediate these effects ( 8 ), one population that has emerged as being of particular interest is MBCs expressing the T-box family transcription factor (T-bet), the activity of which results in Th1-skewed immune responses and enhances control of infections by viruses and other intracellular pathogens ( 9 , 10 ). Early reports highlighted that some MS patients exhibit an expansion of “age-associated B cells” including double negative (IgD - /CD27 - ) B cells as well as CD21 low B cells ( 11 ), which are now recognised to be primarily T-bet + MBCs ( 10 ).…”

Identification of a novel role for matrix metalloproteinase-3 in the modulation of B cell responses in multiple sclerosis

“…In this context, it has been shown that memory B cells can function as potent antigen presenting cells (APCs) ( 50 ) with proinflammatory tendencies including their capacity to express high levels of proinflammatory cytokines including GM-CSF, TNF-α and lymphotoxin ( 51 ). Class-switched memory B cells not only populate the cerebrospinal fluid (CSF) of MS patients ( 52 ) but are also found within the brain parenchyma ( 53 ) with studies demonstrating that the increased accumulation of class-switched memory B cells in the CSF also correlates with the intrathecal synthesis of IgG ( 54 – 56 ).…”

What Have Failed, Interrupted, and Withdrawn Antibody Therapies in Multiple Sclerosis Taught Us?

“…The example of tabalumab illustrates the complex nature of B cell involvement in MS and emphasizes the important role of Bmem in MS immunopathology [ 73 , 78 , 79 ].…”

“…The clinical study on tabalumab illustrates the complex nature of B cell actions and effects on the autoimmune system [ 69 ] and highlights the importance of memory B cells (Bmem) as central players in the MS immunopathogenesis [ 73 , 78 , 79 ]. Bmem display diverse effector functions including cytokine production, antigen presentation, and serving as antigen-experienced precursors to antibody-secreting cells [ 78 ].…”