1. Memory B Cells Activate Brain-Homing, Autoreactive CD4+ T Cells in Multiple Sclerosis.
- Author
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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, Yaneth, Opitz, Lennart, Grönlund, Hans, Rogler, Gerhard, Boyman, Onur, Reynolds, Richard, and Lutterotti, Andreas
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MULTIPLE sclerosis diagnosis , *MULTIPLE sclerosis prevention , *MULTIPLE sclerosis treatment , *CELL proliferation , *AUTOIMMUNE diseases , *DISEASE risk factors - Abstract
Summary 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. Graphical Abstract Highlights • Autoproliferation of CD4+ T cells and B cells is involved in multiple sclerosis • The main genetic factor of MS, HLA-DR15, plays a central role in autoproliferation • Memory B cells drive autoproliferation of Th1 brain-homing CD4+ T cells • Autoproliferating T cells recognize antigens expressed in B cells and brain lesions Memory B cells drive proliferation of self-reactive brain-homing CD4+ T cells, which recognize autoantigens expressed in B cells and in brain lesions with target potential in multiple sclerosis. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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