Inborn Errors of Immunity Leading to Autoinflammatory Syndromes

项目摘要 虽然罕见，但复杂疾病的单基因病因为更深层次的 对常见病的了解。在这一应用中，我们试图研究新颖的、 罕见的单基因自体炎症性疾病。这些综合征患者的主要临床表现包括 严重的皮肤炎症，非特异性胃肠道炎症和异常的神经学特征。 利用整个外显子组测序(WES)，我们已经鉴定了14个天生的、极其罕见的新 先天免疫主要功能基因的遗传变异，特别是细胞因子的产生， 转导或调节。这些与生俱来的免疫缺陷可能是自体炎症的分子驱动因素， 我们建议详细探讨其作用机制。 I型干扰素(IFN)是通过JAK-STAT途径传递信号的细胞因子。的有益影响 IFN主要涉及抗病毒防御，但如果这样做，可能会对人类健康产生深远的有害影响 通路过度活跃。孟德尔I型干扰素病最好的例证是如何构成 干扰素-I活性上调可导致免疫和神经功能异常。 我们最近发现并报告了出现I型干扰素病特征的儿童，原因是 ISG15或USP18中的完全功能丧失突变，这是切断干扰素-I所必需的 干扰素-I受体的反应。这些缺陷是影响负调控的第一个基因缺陷 干扰素-I的反应。在这项建议中，我们试图描述患者的特征为新奇的、完全的或亚形性的， 这两个基因的突变，以及出现类似综合征的患者的基因突变 诱导干扰素-I或将信号传递到干扰素-I和其他JAK-STAT参与细胞因子的下游。 我们建议在体外、体外和体内对这些罕见的患者进行研究，以确定分子， 这些基因在JAK-STAT通路调节中的免疫学和临床意义，进而， 它们在严重的自体炎症免疫调节中的作用。 对这些疾病的分子病理生理学有更深入的了解将为 为更好地管理罕见或持续性炎症性疾病的药物开发奠定基础 很普通。

Project Summary Albeit rare, monogenic causes of complex disorders provide unique opportunities for a deeper understanding of common diseases. In this application, we seek to study the molecular pathogenesis of novel, rare, monogenic autoinflammatory disorders. Central clinical presentations of these syndromic patients include severe skin inflammation, non-specific gastrointestinal inflammation, and aberrant neurologic features. Using whole exome sequencing (WES) we have identified fourteen novel, exceedingly rare, inborn genetic variations in genes with primary functions in innate immunity, specifically cytokine production, transduction or regulation. These inborn errors of immunity are putative molecular drivers of autoinflammation, the mechanisms of which we propose to explore in detail. Type I Interferons (IFNs) are cytokines that signal through the JAK-STAT pathway. Beneficial effects of IFNs largely concern antiviral defense, but profound detrimental effects to human health can manifest if this pathway is overactive. Mendelian type I Interferonopathy disorders best exemplify how constitutive upregulation of IFN-I activity can lead to aberrant immune and neurologic features. We have recently identified and reported children presenting type I Interferonopathy features due to complete loss-of-function mutations in either ISG15 or USP18, which are essential for shutting off the IFN-I response at the IFN-I receptor. These deficiencies are the first genetic defects affecting the negative regulation of the IFN-I response. In this proposal we seek to characterize patients with novel, complete or hypomorphic, mutations in these two genes, but also patients who present with alike syndromes with mutations in genes that either induce IFN-I or convey the signal downstream of IFN-I and other JAK-STAT engaging cytokines. We propose to study these rare patients in vitro, ex vivo, and in vivo to determine the molecular, immunological, and clinical significance of these genes in JAK-STAT pathway regulation, and, by extension, their function in severe autoinflammatory immune regulation. A deeper understanding of the molecular pathophysiology governing these disorders will lay the groundwork for the development of medicines to better manage persistent inflammatory disorders, rare or common.