Abstract
Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system that results in demyelination of axons, inefficient signal transmission and reduced muscular mobility. Recent findings suggest that B cells play a significant role in disease development and pathology. To further explore this, B cell profiles in peripheral blood from 28 treatment-naive patients with early MS were assessed using flow cytometry and compared to 17 healthy controls. Conventional and algorithm-based analysis revealed a significant increase in MS patients of IgA+ memory B cells (MBC) including CD27+, CD27- and Tbet+ subsets. Screening circulating B cells for markers associated with B cell function revealed a significantly decreased expression of the B cell activation factor receptor (BAFF-R) in MS patients compared to controls. In healthy controls, BAFF-R expression was inversely associated with abundance of differentiated MBC but this was not observed in MS. Instead in MS patients, decreased BAFF-R expression correlated with increased production of proinflammatory TNF following B cell stimulation. Finally, we demonstrated that reactivation of Epstein Barr Virus (EBV) in MS patients was associated with several phenotypic changes amongst MBCs, particularly increased expression of HLA-DR molecules and markers of a T-bet+ differentiation pathway in IgM+ MBCs. Together, these data suggest that the B cell compartment is dysregulated in MS regarding aberrant MBC homeostasis, driven by reduced BAFF-R expression and EBV reactivation. This study adds further insights into the contribution of B cells to the pathological mechanisms of MS, as well as the complex role of BAFF/BAFF-R signalling in MS.
Highlights
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by inflammation, demyelination and neuronal damage [1]
To identify Clinically isolated syndrome (CIS)- or MS-specific B cell profiles in blood, three custom-made flow cytometry panels were used (Supplementary Tables 2, 3). These contained antibodies to a set of core markers (Supplementary Table 2) to identify transitional, naive, marginal zone-like (MZ-like), memory B cells (MBC), double negative (DN) and plasmablast (PB) B cell subsets
In the current study we have examined the circulating MBC compartment of early MS patients compared to controls
Summary
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by inflammation, demyelination and neuronal damage [1]. A major drawback of anti-CD20 therapy is that multiple B cell subsets are depleted and their long-term use may have adverse effects on the generation and maintenance of antibodies and memory B cells (MBCs) after infections or vaccinations, as exemplified by responses to SARSCoV-2 vaccines [4]. Autoantibodies have been reported in MS patients, and extrafollicular immunoglobulin (Ig) deposits in the CNS are common and may contribute to disease progression [5] They are unlikely to be responsible for the rapid improvement in pathology following anti-CD20 therapy. This suggests that antibody-independent functions of B cells are likely 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]. As studies in mice have suggested that T-bet+ B cells are potent antigen-presenting cells for T cells and capable of producing Th1 cytokines, IFN-g and IL-12 [10, 15], it has been proposed that T-bet+ MBCs are preferentially recruited to the CNS of patients with MS and act as antigen presenting cells for pathogenic T cells [2]
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