Induction of brain‐infiltrating T‐bet–expressing B cells in multiple sclerosis. Issue 2 (19th June 2019)

• Record Type: Journal Article
• Authors: van Langelaar, Jamie; Rijvers, Liza; Janssen, Malou; Wierenga‐Wolf, Annet F.; Melief, Marie‐José; Siepman, Theodora A.; de Vries, Helga E.; Unger, Peter‐Paul A.; van Ham, S. Marieke; Hintzen, Rogier Q.; van Luijn, Marvin M.
• Is Part Of: Annals of neurology. Volume 86:Issue 2(2019)
• Page Start: 264
• Page End: 278
• Publication Date: 2019-06-19
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.25508
• Languages: English
• ISSNs: 0364-5134

Abstract

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 CXCR3 high 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‐bet high 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