Memory B Cells Activate Brain-Homing, Autoreactive CD4(+) T Cells in Multiple Sclerosis.
Memory B Cells Activate Brain-Homing, Autoreactive CD4(+) T Cells in Multiple Sclerosis.
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DOI：
10.1016/j.cell.2018.08.011
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发表时间：
2018-09-20
期刊：
影响因子：
64.5
通讯作者：
Martin R
中科院分区：
文献类型：
--
作者：
Jelcic I;Al Nimer F;Wang J;Lentsch V;Planas R;Jelcic I;Madjovski A;Ruhrmann S;Faigle W;Frauenknecht K;Pinilla C;Santos R;Hammer C;Ortiz Y;Opitz L;Grönlund H;Rogler G;Boyman O;Reynolds R;Lutterotti A;Khademi M;Olsson T;Piehl F;Sospedra M;Martin R
多发性硬化症是一种自身免疫性疾病，由遗传因素，特别是HLA-DR 15单倍型和环境风险因素的相互作用引起。这些病因因素如何导致产生自身反应性CD 4 + T细胞库尚不清楚。在这里，我们证明了自身反应性，定义为“自身增殖”的外周血Th 1细胞，是升高携带HLA-DR 15单倍型的患者。记忆B细胞以HLA-DR依赖性方式介导自身增殖。通过抗-CD 20在体外和治疗性体内消耗B细胞有效地降低了T细胞自身增殖。T细胞受体深度测序表明，体外自增殖T细胞富含脑归巢T细胞。使用无偏表位发现方法，我们鉴定了RASGRP 2作为在脑和B细胞中表达的靶自身抗原。这些发现将有助于解决有关多发性硬化症中致病性B-T细胞相互作用的重要问题，并可能开发新的治疗方法。多发性硬化症涉及CD 4 + T细胞和B细胞的自身增殖MS的主要遗传因子HLA-DR 15在自身增殖中起核心作用记忆B细胞驱动Th 1脑归巢CD 4 + T细胞的自身增殖自身增殖T细胞识别在B细胞和脑病变中表达的抗原记忆B细胞驱动自身反应性脑归巢CD 4 + T细胞的增殖，其识别B细胞和多发性硬化症中具有靶向潜力的脑损伤中表达的自身抗原。
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. 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.
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DOI：
10.1093/bioinformatics/btu848
发表时间：
2015-05-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Euesden J;Lewis CM;O'Reilly PF
通讯作者：
O'Reilly PF
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
30.8
作者：
Loh, Po-Ru;Danecek, Petr;Palamara, Pier Francesco;Fuchsberger, Christian;Reshef, Yakir A.;Finucane, Hilary K.;Schoenherr, Sebastian;Forer, Lukas;McCarthy, Shane;Abecasis, Goncalo R.;Durbin, Richard;Price, Alkes L.
通讯作者：
Price, Alkes L.
DOI：
10.1093/bioinformatics/btu014
发表时间：
2014-05-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Durbin R
通讯作者：
Durbin R
DOI：
10.1056/nejmoa0706383
发表时间：
2008-02-14
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hauser, Stephen L;Waubant, Emmanuelle;Smith, Craig H
通讯作者：
Smith, Craig H