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 indicate that certain B cells infiltrate the 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, CSF, 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 clinically effective drug natalizumab prevented the recruitment of CXCR3high IgG1+ subsets, corresponding to their increased ability to cross CNS barriers in vitro. Blocking of IFN‐γ reduced the transmigration potential and antigen‐presenting cell function of these cells. IFN‐γ‐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 IFN‐γ and TLR9 signals, likely contributing to enhanced CXCR3‐mediated recruitment and local reactivity in the CNS of MS patients.
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