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.

项目摘要尽管很少见，但复杂疾病的单基因原因为更深层次提供了独特的机会了解常见疾病。在此应用中，我们试图研究新颖的分子发病机理罕见的，单基因自发性疾病。这些综合症患者的中心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。使用整个外显子组测序（WES），我们已经确定了十四种新颖，极为罕见的天生具有先天免疫的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。这些先生的免疫力是自身炎症的推定分子驱动因素，我们建议详细探索的机制。 I型干扰素（IFN）是通过JAK-STAT途径发出信号的细胞因子。有益的效果 IFN在很大程度上关注抗病毒防御，但如果这是对人类健康的严重有害影响途径过度活跃。 Mendelian I型干预疾病疾病最好的体现 IFN-I活性的上调可能导致异常的免疫和神经系统特征。我们最近已经确定并报告了由于 ISG15或USP18中的完全丧失功能突变，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节的第一个遗传缺陷 IFN-I响应。在此提案中，我们试图表征具有新颖，完整或肌莫尔的患者这两个基因中的突变，也存在患有综合症的患者，具有突变的基因突变诱导IFN-I或传达IFN-I和其他JAK-STAT参与细胞因子的信号。我们建议在体外和体内研究这些稀有患者，以确定分子，这些基因在JAK-STAT途径调节中的免疫学和临床意义，并扩大它们在严重自发性免疫调节中的功能。对管理这些疾病的分子病理生理学的更深入了解将是开发药物以更好地管理持续性炎症性疾病的基础工作，罕见或常见的。