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Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Self-peptide-dependent autoproliferation (AP) of B and T cells is a key mechanism in MS. Here, we show that pro-inflammatory B-T cell-enriched cell clusters (BTECs) form during AP and mirror features of a germinal center reaction. T-bet+CXCR3+ B cells are the main cell subset amplifying and sustaining their counterpart Th1 cells via interferon (IFN)-γ and are present in highly inflamed meningeal tissue. The underlying B cell activation signature is reflected by epigenetic modifications and receptor-ligand interactions with self-reactive T cells. AP+ CXCR3+ B cells show marked clonal evolution from memory to somatically hypermutated plasmablasts and upregulation of IFN-γ-related genes. Our data underscore a key role of T-bet+CXCR3+ B cells in the pathogenesis of MS in both the peripheral immune system and the CNS compartment, and thus they appear to be involved in both early relapsing-remitting disease and the chronic stage. • Autoproliferation (AP) leads to germinal center-like B-T cell clusters in multiple sclerosis • T-bet+CXCR3+ B cells are strongly enriched in AP and develop into plasmablasts • AP+ CXCR3+ B cells potentiate Th1 responses and form an inflammatory circuit • They are associated with CSF cell counts and spinal cord lesions and found in inflamed meninges Memory B cells activate brain-homing autoreactive T cells in multiple sclerosis. Here, Jelcic et al. demonstrate that self-reactive B and T cells interact within inflammatory B-T cell clusters. We identify T-bet+CXCR3+ B cells to be the main driver in this inflammatory circuit through IFN-γ in both the periphery and inflamed meninges.
Jelčić et al. (Sat,) studied this question.