Jelcic, IvanAl Nimer, FaiezWang, JianLentsch, VerenaPlanas, RaquelJelcic, IlijasMadjovski, AleksandarRuhrmann, SabrinaFaigle, WolfgangFrauenknecht, KatrinPinilla, ClemenciaSantos, RadleighHammer, ChristianOrtiz, YanethOpitz, LennartGronlund, HansRogler, GerhardBoyman, OnurReynolds, RichardLutterotti, AndreasKhademi, MohsenOlsson, TomasPiehl, FredrikSospedra, MireiaMartin, Roland2018-12-132018-12-132018-12-132018-09-2010.1016/j.cell.2018.08.011https://infoscience.epfl.ch/handle/20.500.14299/152748WOS:000445120000016Multiple 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.Biochemistry & Molecular BiologyCell Biologygene-expressionself-antigensantibodieslesionstcrautoimmunityrepertoireshomeostasismechanismsinductiontext::journal::journal article::research article