Mathematics Faculty Articles

Title

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

Document Type

Article

Publication Date

9-20-2018

Publication Title

Cell

Keywords

Multiple sclerosis, B cells, T cells, Pathogenesis, HLA-DR15, Autoproliferation, Brain, T cell receptor, RASGRP2

ISSN

0092-8674

Volume

175

First Page

85

Last Page

100

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.

Comments

©2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Additional Comments

European Research Council grant #: ERC-2013-ADG 340733; SNF grant #: 3347CO-108792; Swedish Medical Research Council grant #s: 2012-2284, 2014-3077; UK MS Society Tissue Bank grant #: 007/14

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

DOI

10.1016/j.cell.2018.08.011

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