B10 Cell Frequencies and Suppressive Capacity in Myasthenia Gravis Are Associated with Disease Severity.

John S Yi,Lisa D Hobson-Webb,Karissa Gable,Janice M Massey,Kristina Balderson,Kent J Weinhold,Melissa A Russo,Shruti M Raja,Vern Juel,Jeffrey T Guptill

doi:10.3389/fneur.2017.00034

John S Yi, Lisa D Hobson-Webb + Show 8 more

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https://doi.org/10.3389/fneur.2017.00034

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Abstract

Myasthenia gravis (MG) is a T cell-dependent, B cell-mediated disease. The mechanisms for loss of self-tolerance in this disease are not well understood, and recently described regulatory B cell (Breg) subsets have not been thoroughly investigated. B10 cells are a subset of Bregs identified by the production of the immunosuppressive cytokine, interleukin-10 (IL-10). B10 cells are known to strongly inhibit B- and T-cell inflammatory responses in animal models and are implicated in human autoimmunity. In this study, we examined quantitative and qualitative aspects of B10 cells in acetylcholine receptor autoantibody positive MG (AChR-MG) patients and healthy controls. We observed reduced B10 cell frequencies in AChR-MG patients, which inversely correlated with disease severity. Disease severity also affected the function of B10 cells, as B10 cells in the moderate/severe group of MG patients were less effective in suppressing CD4 T-cell proliferation. These results suggest that B10 cell frequencies may be a useful biomarker of disease severity, and therapeutics designed to restore B10 cell frequencies could hold promise as a treatment for this disease through restoration of self-tolerance.

Highlights

Autoimmune myasthenia gravis (MG) is regarded as a T cell-dependent, B cell-mediated disease
Investigations of other immune regulatory mechanisms in the disease are scant, but initial evidence in murine studies suggest that B cells with regulatory function play an important role in Abbreviations: AChR, acetylcholine receptor; Breg, regulatory B cell; LPS, lipopolysaccharide; MG, myasthenia gravis; MMT, manual muscle testing; PBMC, peripheral blood mononuclear cell; PMA, phorbal 12-myristate 13-acetate; Th1, type 1 T helper; TLR, toll-like receptor; Tregs, regulatory T cells
We examined IL-10 expression after 5, 24, and 48 h of stimulation with rCD40L and CpG, and for the last 5 h, the cells were restimulated with PMA and ionomycin along with brefeldin A (BFA)

Summary

Introduction

Autoimmune myasthenia gravis (MG) is regarded as a T cell-dependent, B cell-mediated disease. Investigations of other immune regulatory mechanisms in the disease are scant, but initial evidence in murine studies suggest that B cells with regulatory function play an important role in Abbreviations: AChR, acetylcholine receptor; Breg, regulatory B cell; LPS, lipopolysaccharide; MG, myasthenia gravis; MMT, manual muscle testing; PBMC, peripheral blood mononuclear cell; PMA, phorbal 12-myristate 13-acetate; Th1, type 1 T helper; TLR, toll-like receptor; Tregs, regulatory T cells. Lower frequencies or defective regulatory B cells (Bregs) have been associated with lupus, multiple sclerosis, MG, and transplantation [13,14,15,16,17,18,19] These studies demonstrate the difficulty of studying Bregs because the phenotype used to identify Bregs varied between investigative groups. The most accepted measurement of Bregs’ suppressive function is through the production of interleukin-10 (IL-10) [6, 20, 21]

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