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Ann Neurol. 2019 Aug;86(2):264-278. doi: 10.1002/ana.25508. Epub 2019 Jun 19.

Induction of brain-infiltrating T-bet-expressing B cells in multiple sclerosis.

Author information

1
Department of Immunology, MS Center ErasMS, Erasmus Medical Center, University Medical Center, Rotterdam, the Netherlands.
2
Department of Neurology, MS Center ErasMS, Erasmus Medical Center, University Medical Center, Rotterdam, the Netherlands.
3
Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands.
4
Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
5
Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, the Netherlands.

Abstract

OBJECTIVE:

Results from anti-CD20 therapies demonstrate that B- and T-cell interaction is a major driver of multiple sclerosis (MS). The local presence of B-cell follicle-like structures and oligoclonal bands in MS patients indicates that certain B cells infiltrate the central nervous system (CNS) to mediate pathology. Which peripheral triggers underlie the development of CNS-infiltrating B cells is not fully understood.

METHODS:

Ex vivo flow cytometry was used to assess chemokine receptor profiles of B cells in blood, cerebrospinal fluid, meningeal, and brain tissues of MS patients (n = 10). Similar analyses were performed for distinct memory subsets in the blood of untreated and natalizumab-treated MS patients (n = 38). To assess T-bet(CXCR3)+ B-cell differentiation, we cultured B cells from MS patients (n = 21) and healthy individuals (n = 34) under T helper 1- and TLR9-inducing conditions. Their CNS transmigration capacity was confirmed using brain endothelial monolayers.

RESULTS:

CXC chemokine receptor 3 (CXCR3)-expressing B cells were enriched in different CNS compartments of MS patients. Treatment with the clinically effective drug natalizumab prevented the recruitment of CXCR3high IgG1+ subsets, corresponding to their increased ability to cross CNS barriers in vitro. Blocking of interferon-γ (IFNγ) reduced the transmigration potential and antigen-presenting function of these cells. IFNγ-induced B cells from MS patients showed increased T-bet expression and plasmablast development. Additional TLR9 triggering further upregulated T-bet and CXCR3, and was essential for IgG1 switching.

INTERPRETATION:

This study demonstrates that T-bethigh IgG1+ B cells are triggered by IFNγ and TLR9 signals, likely contributing to enhanced CXCR3-mediated recruitment and local reactivity in the CNS of MS patients. ANN NEUROL 2019;86:264-278.

PMID:
31136008
DOI:
10.1002/ana.25508

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