Human ISG15 and USP18 Deficiencies Underlying Type I Interferonopathies

项目摘要 I型干扰素（IFN-1）具有有效的抗病毒和炎症特性。然而，在这方面， 我们和其他人已经表明，这些细胞因子的炎症效应可能对 人体健康由IFN-1长期作用引起的疾病统称为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）是严重的神经系统，自身炎症和 由IFN-1的永久诱导引起的自身免疫性疾病。 我们最近描述了20多名患有孟德尔I型干扰素病的儿童。 在遗传学上，我们已经证明这些疾病是由于ISG 15或USP 18的完全或部分缺陷造成的。 这些缺陷影响IFN-I应答的下调。缺乏ISG 15或USP 18的个体 在他们的血细胞中有高水平的IFN-1刺激的基因产物，对病毒感染有高水平的抵抗力， 而且还有神经学、自身炎症和自身免疫表现，类似于AGS和SPENCD的表现。这 一个建议是建立在假设这些缺陷的发病机制是由IFN-I反应驱动 在特定的组织中，这些反应可以用于开发新的治疗方法。我们计划 为了通过在体外、离体和体内在分子，免疫学， 和组织特异性水平，以确定其在IFN-1途径调节和抗性中的功能意义 人类的病毒感染。 我们对IFN-I分子调节的理解的提高应该有助于阐明 这些缺陷的病理生理学，为开发新的治疗方法铺平了道路， 持续的炎症性疾病和增强抗病毒反应。

Project Summary Type I interferons (IFN-Is) have well-documented potent antiviral and inflammatory properties. However, we and others have shown that the inflammatory effects of these cytokines can have detrimental effects on human health. Disorders caused by the prolonged effects of IFN-Is are collectively known as type I interferonopathies. Mendelian type I interferonopathies, such as Aicardi–Goutières syndrome (AGS) and spondyloenchondromatosis (SPENCD) are prime examples of severe neurologic, autoinflammatory and autoimmune diseases caused by the perpetual induction of IFN-Is. We have recently described more than 20 children presenting Mendelian type I interferonopathy. Genetically, we have shown these conditions to be due to complete or partial deficiencies of ISG15 or USP18. These deficiencies affect downregulation of the IFN-I response. Individuals with deficiencies of ISG15 or USP18 have high levels of IFN-I-stimulated gene products in their blood cells, high levels of resistance to viral infections, but also neurologic, autoinflammatory and autoimmune manifestations, akin to those of AGS and SPENCD. This proposal is built around the hypothesis that the pathogenesis of these deficiencies is driven by IFN-I responses in specific tissues, and that these responses could be harnessed in the development of new treatments. We plan to test this hypothesis by studying these deficiencies in vitro, ex vivo, and in vivo at the molecular, immunological, and tissue-specific levels, to determine their functional significance in IFN-I pathway regulation and resistance to viral infections in humans. Improvements in our understanding of the molecular regulation of IFN-I should shed light on the pathophysiology of these deficiencies, paving the way for the development of new treatments for managing persistent inflammatory disorders and enhancing antiviral responses.