Human ISG15 and USP18 Deficiencies Underlying Type I Interferonopathies

项目摘要 I型干扰素（IFN）是具有明确定义的抗病毒活性的细胞因子。虽然有益的影响， 干扰素是有据可查的，很明显，干扰素也有深刻的有害影响，人类 健康其中失调的IFN引起病理学的病症统称为I型干扰素病。 孟德尔I型干扰素病，如Aicardi-Goutières综合征（AGS）和 脊椎软骨瘤病（SPENCD）展示了IFN活性的组成性上调如何导致 神经和自身免疫疾病病理学。 我们最近发现了11名患有孟德尔I型干扰素病的儿童。 在遗传学上，我们发现6名儿童完全缺乏ISG 15，5名儿童完全缺乏USP 18。 缺陷这些缺陷是影响IFN负调控的第一遗传缺陷 反应ISG 15和USP 18缺陷个体在其血液中存在升高的IFN刺激基因 细胞，增加对病毒感染的抵抗力，但也有神经和自身免疫表现，类似 AGS和SPENCD。该建议是围绕ISG 15和USP 18是基本的假设建立的。 控制对I型IFN应答的应答性和持续时间的因素。 为了解决这个假设，我们 建议在体外、离体和体内研究这11例罕见患者的分子、免疫学和 以确定这些基因在调节IFN途径和抗性中的功能意义 人类的病毒感染。 更深入地了解IFN的分子调控将使我们更好地了解IFN的分子调控机制。 这些缺陷背后的病理生理学，并将奠定基础的药物开发， 管理持续的炎性病症和/或增加的抗病毒应答。

Project Summary Type I Interferons (IFNs) are cytokines with well-defined anti-viral activities. While beneficial effects of IFNs are well documented, it has become clear that IFNs also have profound detrimental effects to human health. Disorders where dysregulated IFNs cause pathology are collectively termed type I Interferonopathies. Mendelian type I Interferonopathy disorders like Aicardi–Goutières syndrome (AGS) and spondyloenchondromatosis (SPENCD) showcase how constitutive upregulation of IFN activity can lead to neurologic and autoimmune disease pathology. We have recently identified eleven children presenting with Mendelian type I Interferonopathy. Genetically, we discovered six children with complete ISG15 deficiency and five children with complete USP18 deficiency. These deficiencies are the first genetic defects affecting the negative regulation of the IFN response. ISG15 and USP18 deficient individuals present with elevated IFN stimulated genes in their blood cells, increased resistance to viral infections, but also with neurologic and autoimmune manifestations, similar to AGS and SPENCD. This proposal is built around the hypothesis that ISG15 and USP18 are the essential factors controlling responsiveness to and duration of type I IFN responses.  To address this hypothesis we propose to study these eleven rare patients in vitro, ex vivo, and in vivo at the molecular, immunological, and clinical levels to determine the functional significance of these genes in regulating IFN pathway and resistance to viral infections in humans. Deeper understanding of molecular regulation of IFN will allow us to better understand the pathophysiology behind these deficiencies and will lay the ground for development of medicines aiding management of persistent inflammatory disorders and/or increased anti-viral responses.