Immunoglobulin class-switched B cells form an active immune axis between CNS and periphery in multiple sclerosis

Abstract

In multiple sclerosis (MS), an exchange of lymphocytes, in particular B cells, between the central nervous system (CNS) and periphery is believed to be required for the maintenance of active disease. Therapeutic monoclonal antibodies that prevent lymphocytes from crossing the blood-brain barrier (BBB) or induce near-complete peripheral B cell depletion rapidly mitigate MS disease activity. Using next-generation sequencing technology, we recently found that clonally related B cells exist in the cerebrospinal fluid (CSF) and peripheral blood (PB) of MS patients, establishing the existence of an immune axis across the BBB. However, it remains unclear which subpopulations of the highly diverse peripheral B cell compartment share antigen-specificity with intrathecal B cell repertoires, and whether their antigen stimulation occurs on both sides of the BBB. To address these questions, we combined flow cytometry sorting of PB B cell subsets with deep immune repertoire sequencing of CSF and PB B cells. Immunoglobulin (IgM and IgG) heavy chain variable (VH) region repertoires of five PB B cell subsets from MS patients (n=8) were compared with their CSF Ig-VH transcriptomes. In 6 of 8 patients, we identified peripheral CD27+IgD−memory B cells, CD27hiCD38hi plasma cells/plasmablasts, or CD27−IgD− B cells providing an immune connection to the CNS compartment. Pinpointing Ig class-switched B cells as key component of the immune axis thought to contribute to ongoing MS disease activity strengthens the rationale of current therapeutic strategies and may lead to more targeted approaches.

Clonal relationships of CSF B cells in treatment-naive multiple sclerosis patients

“…We previously showed that clonally related B cells are present in CSF and PB of MS patients (7,8,10). Here, we were interested in the clonal relationships between B cell subsets in untreated MS CSF and PB.…”

“…Multiple features of intrathecal B cells, such as the presence of memory B cells, short-lived plasmablasts (12), and plasmablasts and plasma cells sharing the same B cell receptors (13), and the accumulation of somatic hypermutations (SHM) in Ig genes, support the participation of B cells in the CNS in antigen-directed immunity. Compared with peripheral blood (PB) or immune organs, B cell receptor diversity in cerebrospinal fluid (CSF) is generally limited, suggesting selective recruitment and/or survival of B cell populations in the MS CNS (8,10,14).…”

“…B cell repertoires in the periphery and CNS are closely linked in MS and other CNS autoimmune diseases, such as neuromyelitis optica, suggesting that disease-relevant B cell networks interact on both sides of the blood-brain barrier (7)(8)(9)(10)(11). Multiple features of intrathecal B cells, such as the presence of memory B cells, short-lived plasmablasts (12), and plasmablasts and plasma cells sharing the same B cell receptors (13), and the accumulation of somatic hypermutations (SHM) in Ig genes, support the participation of B cells in the CNS in antigen-directed immunity.…”

Targeting B cells in relapsing–remitting multiple sclerosis: from pathophysiology to optimal clinical management

“…Different studies investigated the VH repertoire in the peripheral blood, cervical lymph nodes, meninges, CNS parenchyma and CSF [Von Budingen et al 2012;Palanichamy et al 2014a;Stern et al 2014]. A common observation of all studies were overlapping clonal B-cell populations common to peripheral and CNS compartments.…”

Mapping the effects of vitamin D in multiple sclerosis

“…Clonally related B cells in MS have been found both in the CNS and the peripheral blood compartment, implying that they are able to exchange across the blood-brain barrier [127] . Although B cells belonging to the bi-compartmental clusters were shown by Palanichamy et al to be IgG class-switched B cells, which probably undergo somatic hypermutation both in the secondary lymphoid tissues and in the CNS, no conclusions could be drawn regarding the origin of antigen stimulation in this study [128] . Other recent findings, however, point to the secondary lymphoid tissues as the initial site of B cell activation [129] .…”