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首页> 外文期刊>Diabetes >A Type I Interferon Transcriptional Signature Precedes Autoimmunity in Children Genetically at Risk for Type 1 Diabetes
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A Type I Interferon Transcriptional Signature Precedes Autoimmunity in Children Genetically at Risk for Type 1 Diabetes

机译：I型干扰素转录特征优先于遗传上具有1型糖尿病风险的儿童自身免疫

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摘要

Diagnosis of the autoimmune disease type 1 diabetes (T1D) is preceded by the appearance of circulating autoantibodies to pancreatic islets. However, almost nothing is known about events leading to this islet autoimmunity. Previous epidemiological and genetic data have associated viral infections and antiviral type Ⅰ interferon (IFN) immune response genes with T1D. Here, we first used DNA microarray analysis to identify IFN-p-inducible genes in vitro and then used this set of genes to define an IFN-inducible transcriptional signature in peripheral blood mononuclear cells from a group of active systemic lupus erythematosus patients (n = 25). Using this predefined set of 225 IFN signature genes, we investigated the expression of the signature in cohorts of healthy controls (n = 87), patients with T1D (n = 64), and a large longitudinal birth cohort of children genetically predisposed to T1D (n = 109; 454 microarrayed samples). Expression of the IFN signature was increased in genetically predisposed children before the development of autoantibodies (P = 0.0012) but not in patients with established T1D. Upregulation of IFN-inducible genes was transient, temporally associated with a recent history of upper respiratory tract infections (P = 0.0064), and marked by increased expression of SIGLEC-1 (CD169), a lectin-like receptor expressed on CD14~+ monocytes. DNA variation in IFN-inducible genes altered T1D risk (P = 0.007), as exemplified by IFIH1, one of the genes in our IFN signature for which increased expression is a known risk factor for disease. These findings identify transient increased expression of type Ⅰ IFN genes in preclinical diabetes as a risk factor for autoimmunity in children with a genetic predisposition to T1D.
机译：在诊断自身免疫性疾病1型糖尿病（T1D）之前，会出现针对胰岛的循环自身抗体。然而，关于导致这种胰岛自身免疫的事件几乎一无所知。先前的流行病学和遗传学数据已将病毒感染和抗病毒Ⅰ型干扰素（IFN）免疫应答基因与T1D相关。在这里，我们首先使用DNA微阵列分析在体外鉴定IFN-p诱导基因，然后使用这组基因在一组活跃的系统性红斑狼疮患者的外周血单核细胞中定义IFN诱导的转录特征（n = 25）。我们使用这套预定义的225个IFN签名基因集，研究了该签名在健康对照组（n = 87），T1D患者（n = 64）和大量遗传易患T1D的儿童的纵向出生队列中的表达（n = 87）。 n = 109； 454个微阵列样品）。在患有自身抗体的遗传易感儿童中，IFN标记的表达增加（P = 0.0012），但在已确诊的T1D患者中则没有。 IFN诱导型基因的上调是短暂的，在时间上与最近的上呼吸道感染史相关（P = 0.0064），并以SIGLEC-1（CD169）（CD14〜+单核细胞表达的一种凝集素样受体）的表达增加为标志。 。 IFN诱导基因中的DNA变异改变了T1D风险（P = 0.007），例如IFIH1，这是我们IFN标记中的一种​​基因，其表达增加是已知的疾病危险因素。这些发现确定了临床前糖尿病患者中Ⅰ型IFN基因的瞬时表达增加是T1D遗传易感儿童自身免疫的危险因素。

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  • 来源
    《Diabetes》 |2014年第7期|2538-2550|共13页
  • 作者

    Ricardo C. Ferreira; Hui Guo; Richard M.R. Coulson; Deborah J. Smyth; Marcin L. Pekalski; Oliver S. Burren; Antony J. Cutler; James D. Doecke; Shaun Flint; Eoin F. McKinney; Paul A. Lyons; Kenneth G.C. Smith; Peter Achenbach; Andreas Beyerlein; David B. Dunger; David G. Clayton; Linda S. Wicker; John A. Todd; Ezio Bonifacio; Chris Wallace; Anette-G. Ziegler;

  • 作者单位

    JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.;

    JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.;

    JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.,Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, U.K.;

    JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.;

    JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.;

    JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.;

    JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.;

    JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.,The Australian E-Health Research Centre, Royal Brisbane and Women's Hospital, Queensland, Australia,The Commonwealth Scientific and Industrial Research Organisation (CSIRO) Preventative Health Flagship, victoria, Australia,CSIRO Mathematics and Information Sciences, Macquarie University, New South Wales, Australia;

    Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, U.K.;

    Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, U.K.;

    Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, U.K.;

    Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, U.K.;

    Institute of Diabetes Research, Helmholtz Zentrum Muenchen, Neuherberg, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universitaet Muenchen, Munchen, Germany;

    Institute of Diabetes Research, Helmholtz Zentrum Muenchen, Neuherberg, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universitaet Muenchen, Munchen, Germany;

    Department of Paediatrics, School of Clinical Medicine, University of Cambridge,Cambridge, U.K.;

    JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.;

    JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.;

    JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.;

    CRTD-DFG Research Center for Regenerative Therapies Dresden and Paul Langer-hans Institute Dresden, Technische Universitaet Dresden, Dresden, Germany;

    JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.;

    Institute of Diabetes Research, Helmholtz Zentrum Muenchen, Neuherberg, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universitaet Muenchen, Munchen, Germany;

  • 收录信息 美国《科学引文索引》(SCI);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 入库时间 2022-08-18 03:46:20

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