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

Jonatan Leffler; Stephanie Trend; Natalie C Ward; Georges E Grau; Simon Hawke; Scott N Byrne; Allan G Kermode; Martyn A French; Prue H Hart

doi:10.3389/fimmu.2022.812317

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

Front Immunol. 2022 Feb 16:13:812317. doi: 10.3389/fimmu.2022.812317. eCollection 2022.

Authors

Jonatan Leffler¹, Stephanie Trend^{1

2}, Natalie C Ward³, Georges E Grau⁴, Simon Hawke⁴, Scott N Byrne^{4

5}, Allan G Kermode^{2

6}, Martyn A French^{7

8}, Prue H Hart¹

Affiliations

¹ Telethon Kids Institute, University of Western Australia, Perth, WA, Australia.
² Centre for Neuromuscular and Neurological Disorders, Perron Institute for Neurological and Translational Science, University of Western Australia, Perth, WA, Australia.
³ Dobney Hypertension Centre, Medical School, University of Western Australia, Perth, WA, Australia.
⁴ School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
⁵ Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Westmead, NSW, Australia.
⁶ Institute for Immunology and Infectious Disease, Murdoch University, Perth, WA, Australia.
⁷ School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia.
⁸ Immunology Division, PathWest Laboratory Medicine, Perth, WA, Australia.

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.

Keywords: B cells; BAFF; Epstein Barr virus; IgA; flow cytometry; memory B cells; multiple sclerosis; short chain fatty acids.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

B-Cell Activation Factor Receptor* / genetics
B-Cell Activation Factor Receptor* / metabolism
Epstein-Barr Virus Infections* / complications
Epstein-Barr Virus Infections* / immunology
Herpesvirus 4, Human
Humans
Immunoglobulin A
Immunoglobulin M
Memory B Cells* / metabolism
Multiple Sclerosis* / immunology
Multiple Sclerosis* / metabolism

Substances

B-Cell Activation Factor Receptor
Immunoglobulin A
Immunoglobulin M