期刊
CELL
卷 175, 期 1, 页码 85-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2018.08.011
关键词
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资金
- European Research Council [ERC-2013ADG 340733]
- Clinical Research Priority Program MS (CRPPMS) of the University of Zurich (UZH)
- Swiss National Science Foundation (SNF) Sinergia grant UnmetMS
- SwissMSsociety
- Swedish Society for Medical Research
- Swedish Foundation for MS Research
- Stavros Niarchos Foundation
- SNF [3347CO-108792]
- Swedish Medical Research Council [2012-2284, 2014-3077]
- Knut and Alice Wallenberg Foundation
- Swedish Brain Foundation
- MAUS foundation
- Multiple Sclerosis National Research Institute
- NEURO Sweden
- UK MS Society Tissue Bank [007/14]
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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