B-cell types and MS

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frodo
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B-cell types and MS

Post by frodo » Wed Jan 08, 2020 6:39 am

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

https://onlinelibrary.wiley.com/doi/ful ... /ana.25508

Here, we aimed to explore the CNS transmigration capacity of T‐bet(CXCR3)‐expressing B cells and which peripheral triggers are involved in the development of such populations in MS patients. We explored the recruitment of human CXCR3+ B cells to the CNS both ex vivo and in vitro. Furthermore, the susceptibility of blood‐derived B cells from MS patients and healthy individuals to T‐bet–inducing stimuli and how this influences their differentiation into CXCR3+ memory subsets was determined using different T‐cell–based culture systems.

[...]

We here reveal that human CXCR3(T‐bet)+ B cells are a product of T‐ and B‐cell interaction. Anti‐CD20 therapy exerts immediate effects and is assumed to predominantly affect this function of B cells in MS patients. The potential role of CXCR3(T‐bet)+ B cells as prime targets of this therapy is further supported by their abundant CD20 expression, as shown in the current study.

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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‐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.

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