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原因为更深入的研究提供了独特的机会。 了解常见疾病。在本申请中，我们寻求研究新的， 罕见的单基因自身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神经学特征。 使用全外显子组测序（WES），我们已经确定了14个新的，非常罕见的，先天性 在先天免疫中具有主要功能的基因的遗传变异，特别是细胞因子的产生， 转导或调节。这些先天性免疫缺陷是自身炎症的假定分子驱动因素， 我们建议详细探讨其机制。 I型干扰素（IFN）是通过JAK-STAT途径发出信号的细胞因子。有益效果 干扰素在很大程度上涉及抗病毒防御，但如果这种情况发生， 路径过于活跃。孟德尔I型干扰素病最佳遗传组成 IFN-1活性的上调可导致异常的免疫和神经学特征。 我们最近发现并报告了由于以下原因而表现出I型干扰素病特征的儿童： ISG 15或USP 18中的功能完全丧失突变，这对于关闭IFN-I至关重要。 IFN-I受体的反应。这些缺陷是影响负调控的第一遗传缺陷 IFN-I的反应。在这个建议中，我们试图描述患者的新的，完整的或亚形态， 这两个基因的突变，而且患者也表现出类似的基因突变综合征， 诱导IFN-1或传递IFN-1和其它JAK-STAT结合细胞因子下游的信号。 我们建议在体外、离体和体内研究这些罕见患者，以确定其分子， 这些基因在JAK-STAT途径调节中的免疫学和临床意义，并且，通过扩展， 它们在严重的自身炎症免疫调节中的功能。 更深入地了解这些疾病的分子病理生理学将奠定 为开发药物以更好地管理持续性炎症性疾病，罕见或 共同

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.