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

Authors

Ivan Jelcic, University of Zurich - Switzerland
Faiez Al Nimer, University of Zurich - Switzerland; Karolinska Institutet - Stockholm, Sweden
Jian Wang, University of Zurich - Switzerland
Verena Lentsch, University of Zurich - Switzerland
Raquel Planas, University of Zurich - Switzerland
Ilijas Jelcic, University of Zurich - Switzerland
Aleksandar Madjovski, University of Zurich - Switzerland
Sabrina Ruhrmann, Karolinska Institutet - Stockholm, Sweden
Wolfgang Faigle, University of Zurich - Switzerland
Katrin Frauenknecht, University of Zurich - Switzerland
Clemencia Pinilla, Torrey Pines Institute for Molecular Studies
Radleigh Santos, Torrey Pines Institute for Molecular StudiesFollow
Christian Hammer, Ecole Polytechnique Federale de Lausanne - Switzerland; Swiss Institute of Bioinformatics
Yanneth Ortiz, University of Zurich - Switzerland
Lennart Opitz, Swiss Federal Institute of Technology and University of Zurich
Hans Gronlund, Karolinska Institutet - Stockholm
Gerhard Rogler, University of Zurich - Switzerland
Onur Boyman, University of Zurich - Switzerland
Richard Reynolds, Imperial College London - United Kingdom
Andreas Lutterotti, University of Zurich - Switzerland
Mohsen Khademi, Karolinska Institutet - Stockholm, Sweden
Tomas Olsson, Karolinska Institutet - Stockholm, Sweden
Frederik Piehl, Karolinska Institutet - Stockholm, Sweden
Mireia Sospedra, University of Zurich - Switzerland
Roland Martin, University of Zurich - Switzerland

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

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