Memory B Cells Activate Brain-Homing, Autoreactive CD4+ T Cells in Multiple Sclerosis

Cell
Ivan JelcicRoland Martin

Abstract

Multiple sclerosis is an autoimmune disease that is caused by the interplay of genetic, particularly the HLA-DR15 haplotype, and environmental risk factors. How these etiologic factors contribute to generating an autoreactive CD4+ T cell repertoire is not clear. Here, we demonstrate that self-reactivity, defined as "autoproliferation" of peripheral Th1 cells, is elevated in patients carrying the HLA-DR15 haplotype. Autoproliferation is mediated by memory B cells in a HLA-DR-dependent manner. Depletion of B cells in vitro and therapeutically in vivo by anti-CD20 effectively reduces T cell autoproliferation. T cell receptor deep sequencing showed that in vitro autoproliferating T cells are enriched for brain-homing T cells. Using an unbiased epitope discovery approach, we identified RASGRP2 as target autoantigen that is expressed in the brain and B cells. These findings will be instrumental to address important questions regarding pathogenic B-T cell interactions in multiple sclerosis and possibly also to develop novel therapies.

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Datasets Mentioned

BETA
PRJEB19652
PRJEB23143

Methods Mentioned

BETA
flow cytometry
ELISA
leukaphereses
density gradient centrifugation
FCS
genotyping
FACS
electrophoresis
chip
PCR

Software Mentioned

Viewer
FlowJo
Scaffold
R
MASCOT
bioconductor package edgeR
iVIEW
PRSice
EAGLE2
Spice

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