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

• Ivan Jelcic ^[1] ; Faiez Al Nimer ^[1] ; Jian Wang ^[1]
  1. [1] University Hospital Zurich
• Localización: Cell, ISSN 0092-8674, Vol. 175, Nº. 1, 2018, págs. 85-100
• Idioma: inglés
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• Resumen

  • 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.