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

Cell. 2018 Sep 20;175(1):85-100.e23. doi: 10.1016/j.cell.2018.08.011. Epub 2018 Aug 30.

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.

Keywords: B cells; HLA-DR15; RASGRP2; T cell receptor; T cells; autoproliferation; brain; multiple sclerosis; pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantigens / immunology
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / physiopathology
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology*
  • Brain / pathology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / physiology
  • Guanine Nucleotide Exchange Factors / metabolism
  • HLA-DR Serological Subtypes / genetics
  • HLA-DR Serological Subtypes / immunology*
  • Humans
  • Multiple Sclerosis / genetics
  • Multiple Sclerosis / immunology*
  • Multiple Sclerosis / physiopathology
  • Receptors, Antigen, T-Cell
  • Th1 Cells / physiology

Substances

  • Autoantigens
  • Guanine Nucleotide Exchange Factors
  • HLA-DR Serological Subtypes
  • HLA-DR15 antigen
  • RASGRP2 protein, human
  • Receptors, Antigen, T-Cell