FcγRIIb Expression Is Decreased on Naive and Marginal Zone-Like B Cells From Females With Multiple Sclerosis.

Stephanie Trend,Martyn A French,Ingrid Teige,Allan G Kermode,Björn Frendéus,Prue H Hart,Jonatan Leffler

doi:10.3389/fimmu.2020.614492

Abstract

B cells are critical to the development of multiple sclerosis (MS), but the mechanisms by which they contribute to the disease are poorly defined. We hypothesised that the expression of CD32b (FcγRIIb), a receptor for the Fc region of IgG with inhibitory activities in B cells, is lower on B cell subsets from people with clinically isolated syndrome (CIS) or MS. CD32b expression was highest on post-naive IgM+ B cell subsets in healthy controls. For females with MS or CIS, significantly lower CD32b expression was identified on IgM+ B cell subsets, including naive and IgMhi MZ-like B cells, when compared with control females. Lower CD32b expression on these B cell subsets was associated with detectable anti-Epstein Barr Virus viral capsid antigen IgM antibodies, and higher serum levels of B cell activating factor. To investigate the effects of lower CD32b expression, B cells were polyclonally activated in the presence of IgG immune complexes, with or without a CD32b blocking antibody, and the expression of TNF and IL-10 in B cell subsets was assessed. The reduction of TNF but not IL-10 expression in controls mediated by IgG immune complexes was reversed by CD32b blockade in naive and IgMhi MZ-like B cells only. However, no consequence of lower CD32b expression on these cells from females with CIS or MS was detected. Our findings highlight a potential role for naive and marginal zone-like B cells in the immunopathogenesis of MS in females, which requires further investigation.

Highlights

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS) characterised by episodes of inflammation that result in demyelination
There were no significant differences between controls and patients with clinically isolated syndrome (CIS) or MS in total B cell frequencies, or in any B cell subset frequencies (%peripheral blood mononuclear cells (PBMC); Figure 3A)
We report for the first time that total B cells, and in particular naive B cells and IgMhi marginal zone (MZ)-like B cells from females with CIS or MS, express lower levels of CD32b compared with healthy control females

Summary

Introduction

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS) characterised by episodes of inflammation that result in demyelination. Despite many attempts to characterise the Ig found in and around MS lesions and in cerebrospinal fluid, a common autoantigen target in MS has not been identified, suggesting that understanding autoantigen-independent Ig production and/or B cell responses may be a more pragmatic way to assess the associations of Ig with MS pathology. Therapies that deplete B cells or prevent their entry to the CNS have improved clinical outcomes for people with relapsing-remitting (RR)MS, which is attributed to effects on peripheral memory B cells (MBC) [6]. Given the importance of B cells for innate responses to novel pathogens and for contributing to serological memory through differentiation of MBC into plasma cells, total depletion of B cells may leave individuals with MS receiving anti-CD20 therapy vulnerable to infections [11, 12]. The complexity of the B cell compartment in MS warrants further detailed examination with a view to developing more targeted therapies that do not result in global B cell losses

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