Inborn Errors of Immunity Leading to Autoinflammatory Syndromes

先天性免疫缺陷导致自身炎症综合征

基本信息

批准号：
10206016
负责人：
Dusan Bogunovic
金额：
$ 49.31万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10206016
关键词：
Address Alleles Anti-Inflammatory Agents Antiviral Agents Apoptosis Arthritis Atopic Dermatitis Autophagocytosis Biochemical Biological Assay Biological Process Cell Line Child Clinical Complex Cytokine Signaling Data Dermatitis Development Disease Ectopic Expression Evaluation Family Functional disorder Gastrointestinal tract structure Genes Genetic Predisposition to Disease Genetic Variation Goals Health Hereditary Disease Human Human Pathology IL6ST gene IRF3 gene ISG15 gene Immune Immune System Diseases Immune system Immunity Immunologic Receptors Immunologics Impairment In Vitro Individual Inflammation Inflammatory Interferon Type I Interferons Interleukin-10 Interleukin-6 JAK1 gene Knowledge Laboratories Lead Lesion Mediating Medicine Membranous Glomerulonephritis Methods Molecular Mutation Natural Immunity Neurologic Outcome Pathogenesis Pathway interactions Patients Phenotype Play Point Mutation Predisposition Production RIPK1 gene Regulation Reporting Role STAT2 gene Series Signal Pathway Signal Transduction Skin Syndrome TBK1 gene TLR3 gene TNF gene Technology Therapeutic Transactivation Up-Regulation Virus Diseases autoinflammation autoinflammatory body system cell type clinically significant cytokine design early onset enteritis exome sequencing gain of function mutation gastrointestinal gene function gene product human disease immunoregulation improved in vivo innate immune function insight loss of function mutation member negative affect novel pathogen protein function receptor recruit response transmission process white matter

项目摘要

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.

项目概要尽管罕见，但复杂疾病的单基因原因为深入研究提供了独特的机会。了解常见疾病。在此应用中，我们寻求研究新的分子发病机制，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的神经系统特征。使用全外显子组测序 (WES)，我们鉴定了 14 种新颖的、极为罕见的先天基因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。这些先天性免疫错误被认为是自身炎症的分子驱动因素，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。的有益效果干扰素主要涉及抗病毒防御，但如果这种情况发生，就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 型干扰素病疾病最好地说明了如何构成 IFN-I 活性的上调可导致异常的免疫和神经系统特征。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： ISG15 或 USP18 完全丧失功能突变，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首要遗传缺陷 IFN-I 反应。在这个提案中，我们试图描述患者具有新颖的、完整的或亚形态的特征，这两个基因发生突变，而且患有类似综合征的患者基因突变诱导 IFN-I 或向 IFN-I 和其他 JAK-STAT 参与细胞因子的下游传递信号。我们建议对这些罕见患者进行体外、离体和体内研究，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，并且推而广之，它们在严重的自身炎症免疫调节中的作用。对控制这些疾病的分子病理生理学的更深入的了解将为为开发药物以更好地管理持续性炎症性疾病（罕见或罕见）奠定基础常见的。