Memory B Cells Activate Brain-Homing, Autoreactive CD4+ T Cells in Multiple Sclerosis
Multiple sclerosis, B cells, T cells, Pathogenesis, HLA-DR15, Autoproliferation, Brain, T cell receptor, RASGRP2
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.
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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.