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

Ivan Jelcic, Faiez Al Nimer, Jian Wang, Verena Lentsch, Raquel Planas, Ilijas Jelcic, Aleksandar Madjovski, Sabrina Ruhrmann, Wolfgang Faigle, Katrin Frauenknecht, Clemencia Pinilla, Radleigh Santos, Christian Hammer, Yaneth Ortiz, Lennart Opitz, Hans Grönlund, Gerhard Rogler, Onur Boyman, Richard Reynolds, Andreas LutterottiMohsen Khademi, Tomas Olsson, Fredrik Piehl, Mireia Sospedra, Roland Martin

Research output: Contribution to journalArticlepeer-review

312 Scopus citations

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. Memory B cells drive proliferation of self-reactive brain-homing CD4+ T cells, which recognize autoantigens expressed in B cells and in brain lesions with target potential in multiple sclerosis.

Original languageEnglish (US)
Pages (from-to)85-100.e23
JournalCell
Volume175
Issue number1
DOIs
StatePublished - Sep 20 2018
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2018 The Authors

Keywords

  • B cells
  • HLA-DR15
  • RASGRP2
  • T cell receptor
  • T cells
  • autoproliferation
  • brain
  • multiple sclerosis
  • pathogenesis

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