Mathematics Faculty Articles
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.
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
This work is licensed under a Creative Commons Attribution 4.0 International License.
NSUWorks Citation
Jelcic, Ivan; Al Nimer, Faiez; Wang, Jian; Lentsch, Verena; Planas, Raquel; Jelcic, Ilijas; Madjovski, Aleksandar; Ruhrmann, Sabrina; Faigle, Wolfgang; Frauenknecht, Katrin; Pinilla, Clemencia; Santos, Radleigh; Hammer, Christian; Ortiz, Yanneth; Opitz, Lennart; Gronlund, Hans; Rogler, Gerhard; Boyman, Onur; Reynolds, Richard; Lutterotti, Andreas; Khademi, Mohsen; Olsson, Tomas; Piehl, Frederik; Sospedra, Mireia; and Martin, Roland, "Memory B Cells Activate Brain-Homing, Autoreactive CD4+ T Cells in Multiple Sclerosis" (2018). Mathematics Faculty Articles. 286.
https://nsuworks.nova.edu/math_facarticles/286
DOI
10.1016/j.cell.2018.08.011
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/).