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

Jamie van Langelaar, Liza Rijvers, Malou Janssen, Annet F. Wierenga-Wolf, Marie-José Melief, Theodora A. Siepman, Helga E. de Vries, Peter-Paul A. Unger, S. Marieke van Ham, Rogier Q. Hintzen, Marvin M. van Luijn

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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.
Original languageEnglish
Pages (from-to)264-278
JournalAnnals of neurology
Issue number2
Publication statusPublished - 1 Aug 2019


  • Adult
  • Aged
  • Animals
  • B-Lymphocytes/metabolism
  • Brain/metabolism
  • Cell Movement/physiology
  • Female
  • Gene Expression
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Multiple Sclerosis/genetics
  • NIH 3T3 Cells
  • Receptors, CXCR3/biosynthesis
  • Young Adult

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