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

作者：Ivan Jelčić, Faiez Al Nimer, Jian Wang, Verena Lentsch, Raquel Planas, Ilijas Jelčić, Aleksandar Madjovski, Sabrina Ruhrmann, Wolfgang Faigle, Katrin Frauenknecht, Clemencia Pinilla, Radleigh G. Santos, Christian Hammer, Yaneth Ortiz, Lennart Opitz, Hans Grönlund, Gerhard Rogler, Onur Boyman, Richard Reynolds, Andreas Lutterotti, Mohsen Khademi, Tomas Olsson, Fredrik Piehl, Mireia Sospedra, Roland Martinꝉ · 发表于：Cell · 年份：2018 · DOI：10.1016/j.cell.2018.08.011 · 被引用次数：526 · 研究领域：T-cell and B-cell Immunology、Immunotherapy and Immune Responses、Monoclonal and Polyclonal Antibodies Research

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.