Human ISG15 and USP18 Deficiencies Underlying Type I Interferonopathies

项目摘要 I型干扰素(IFN)是具有明确抗病毒活性的细胞因子。虽然这样做的好处 IFN有很好的记录，但很明显，IFN对人类也有深远的有害影响 健康。调节失调的干扰素引起的疾病统称为I型干扰素病。 孟德尔I型干扰素病，如艾卡迪-古蒂埃综合征(AGS)和 脊柱软骨瘤病(SPENCD)展示了干扰素活性的结构性上调如何导致 神经学和自身免疫性疾病病理学。 我们最近发现有11名儿童患有孟德尔I型干扰素病。 在遗传学上，我们发现6名儿童完全缺乏ISG15，5名儿童完全缺乏USP18 缺乏症。这些缺陷是影响干扰素负调控的第一个基因缺陷。 回应。ISG15和USP18缺陷者血液中干扰素刺激基因水平升高 细胞，对病毒感染的抵抗力增强，但也有神经系统和自身免疫的表现，类似 致AGS和SPENCD。这一建议建立在ISG15和USP18是基本的假设之上 控制I型干扰素应答和持续时间的因素。为了解决这一假设，我们 建议从分子、免疫学、体内外等方面对这11例罕见患者进行研究。 临床水平确定这些基因在调节干扰素途径和耐药性中的功能意义 人类中的病毒感染。 深入了解干扰素的分子调控将使我们更好地理解 这些缺陷背后的病理生理学，并将为开发有助于 持续炎症性疾病的管理和/或增加的抗病毒反应。

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.