ImmunoChip study implicates antigen presentation to T cells in narcolepsy.
ImmunoChip study implicates antigen presentation to T cells in narcolepsy.
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DOI：
10.1371/journal.pgen.1003270
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Mignot E
中科院分区：
文献类型：
--
作者：
Faraco J;Lin L;Kornum BR;Kenny EE;Trynka G;Einen M;Rico TJ;Lichtner P;Dauvilliers Y;Arnulf I;Lecendreux M;Javidi S;Geisler P;Mayer G;Pizza F;Poli F;Plazzi G;Overeem S;Lammers GJ;Kemlink D;Sonka K;Nevsimalova S;Rouleau G;Desautels A;Montplaisir J;Frauscher B;Ehrmann L;Högl B;Jennum P;Bourgin P;Peraita-Adrados R;Iranzo A;Bassetti C;Chen WM;Concannon P;Thompson SD;Damotte V;Fontaine B;Breban M;Gieger C;Klopp N;Deloukas P;Wijmenga C;Hallmayer J;Onengut-Gumuscu S;Rich SS;Winkelmann J;Mignot E
最近在鉴定易感基因和环境暴露方面的进展为发作性睡病/下丘脑泌素（食欲素）缺乏的感染后自身免疫基础提供了广泛的支持。我们使用定制的基因分型阵列（ImmunoChip）对1，886名下丘脑泌素缺乏性发作性睡病患者和10，421名对照者中与其他自身免疫性和炎症性疾病相关的基因座进行了基因分型，所有这些患者都是欧洲血统。位于6号染色体人类白细胞抗原（HLA）区域外的三个位点与疾病风险显著相关。除了在T细胞受体α（TRA）中的强信号外，在另外两个发作性睡病基因座，组织蛋白酶H（CTSH）和肿瘤坏死因子（配体）超家族成员4（TNFSF 4，也称为OX 40 L）中的变体获得了全基因组意义。这些发现强调了HLA II类抗原呈递给T细胞在这种自身免疫性疾病的病理生理学中的重要性。虽然现在有广泛的共识，发作性睡病-下丘脑泌素缺乏症是由下丘脑泌素细胞的高度特异性自身免疫攻击引起的，但关于潜在的自身免疫过程的启动和进展却知之甚少。我们利用了独特的高密度基因分型平台（免疫芯片），旨在研究已知对自身免疫性和炎症性疾病重要的基因变异。我们对近2000例发作性睡病病例和10，000例对照的研究强调了HLA DQB 1 * 06：02和T细胞受体α基因的重要作用，并涉及两个额外的基因，组织蛋白酶H和TNFSF 4/OX40 L，在疾病发病机制中。这些发现特别重要，因为这些编码的蛋白质在抗原加工、呈递和T细胞应答中具有关键作用，并且它们表明免疫突触处的特异性相互作用构成了疾病的途径。因此，对这些基因和编码蛋白的进一步研究可能揭示导致这种高度选择性和独特的自身免疫性疾病的机制。
Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease. While there is now broad consensus that narcolepsy-hypocretin deficiency results from a highly specific autoimmune attack on hypocretin cells, little is understood regarding the initiation and progression of the underlying autoimmune process. We have taken advantage of a unique high-density genotyping platform (the ImmunoChip) designed to study variants in genes known to be important to autoimmune and inflammatory diseases. Our study of nearly 2000 narcolepsy cases compared to 10,000 controls underscored important roles for HLA DQB1*06:02 and the T cell receptor alpha genes and implicated two additional genes, Cathepsin H and TNFSF4/OX40L, in disease pathogenesis. These findings are particularly important, as these encoded proteins have key roles in antigen processing, presentation, and T cell response, and they suggest that specific interactions at the immunological synapse constitute the pathway to the disease. Further studies of these genes and encoded proteins may therefore reveal the mechanism leading to this highly selective and unique autoimmune disease.
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DOI：
10.1007/978-0-387-89520-8_6
发表时间：
2009-01-01
期刊：
THERAPEUTIC TARGETS OF THE TNF SUPERFAMILY
影响因子：
--
作者：
Gough, Michael J.;Weinberg, Andrew D.
通讯作者：
Weinberg, Andrew D.
影响因子：
30.8
作者：
Barrett, Jeffrey C.;Clayton, David G.;Concannon, Patrick;Akolkar, Beena;Cooper, Jason D.;Erlich, Henry A.;Julier, Cecile;Morahan, Grant;Nerup, Jorn;Nierras, Concepcion;Plagnol, Vincent;Pociot, Flemming;Schuilenburg, Helen;Smyth, Deborah J.;Stevens, Helen;Todd, John A.;Walker, Neil M.;Rich, Stephen S.
通讯作者：
Rich, Stephen S.
影响因子：
3.7
作者：
Bühling F;Kouadio M;Chwieralski CE;Kern U;Hohlfeld JM;Klemm N;Friedrichs N;Roth W;Deussing JM;Peters C;Reinheckel T
通讯作者：
Reinheckel T
影响因子：
30.8
作者：
Hallmayer, Joachim;Faraco, Juliette;Mignot, Emmanuel
通讯作者：
Mignot, Emmanuel
影响因子：
11.2
作者：
Han, Fang;Lin, Ling;Mignot, Emmanuel
通讯作者：
Mignot, Emmanuel