Mechanisms of mucosal autoinflammation elucidated by a novel monogenic transcription factor defect

项目摘要 发现人类先天免疫缺陷的遗传基础提供了有影响力的信息 关于对健康免疫功能至关重要的基因、蛋白质和途径。炎症 是免疫激活的关键成分，通常发出微生物存在的信号来启动分子 以及遏制和消除病原体所需的细胞反应。然而，异常高的炎症是 不利于宿主健康，并导致一系列人类疾病的病理。为了控制 炎症，有许多细胞内和分泌的抗炎蛋白在细胞内转录- 类型和上下文相关的方式。一个最好的例子是IL-10，当人类有缺陷时，它会导致 单基因极早发病的IBD。然而，关于转录因子的知识相对有限， 作为人类体内这些可诱导抗炎基因的主要调节者。我们现在发现了一种新的 ELF4转录因子基因新的功能缺失突变引起的人类先天免疫错误 我们假设在干扰素、炎症体和Th17的交叉点起主要的调节作用 生物学。通过我们的基因组学计划确认的三名患者患有黏膜自体炎症 IBD特征、发烧和口腔溃疡，我们现在已经产生了强大的Elf4基因敲除、点突变和 用小白鼠模型来增进我们的知识。我们在ELF4突变的人和小鼠细胞中的初步数据 强调该因子的细胞类型特异性功能，髓系和T细胞的炎症反应增加 与失败的抗炎基因表达计划相关的细胞。我们将追求两个目标来阐明 ELF4如何在干扰素、炎症体和Th17反应的交叉调节中发挥基石作用。 目的1)研究WT和突变型ELF4对髓系细胞和Th17细胞的分子和生化效应。目标2) 确定WT和突变体ELF4在髓系介导的细胞和组织炎症反应中的作用 和Th17细胞。这些调查的结果将提供宝贵的新见解，与 了解这种新的人类疾病的病因并设计有针对性的治疗方法，进而获得更多 广泛存在于流行的炎症性疾病中。

Project Summary Discovery of the genetic basis of inborn errors of immunity in humans provides impactful information about genes, proteins, and pathways that are fundamentally important for healthy immune function. Inflammation is a critical component of immune activation that normally signals the presence of microbes to initiate molecular and cellular responses required to contain and eliminate a pathogen. However, aberrantly high inflammation is detrimental to host fitness and contributes to pathology in an array of human diseases. In order to control inflammation, there are many intracellular and secreted anti-inflammatory proteins that are transcribed in a cell- type and context-dependent manner. A prime example is IL-10, which when defective in humans causes monogenic very early-onset IBD. However, there is relatively limited knowledge about transcription factors that act as master regulators of these inducible anti-inflammatory genes in humans. We have now discovered a new human inborn error of immunity caused by novel loss-of-function mutations in the ELF4 transcription factor gene that we hypothesize serves as a master regulator at the intersection of interferon, inflammasome, and Th17 biology. The three patients identified through our genomics program suffer from mucosal autoinflammation with IBD features, fever, and oral ulcers, and we have now generated powerful Elf4 knockout, point mutant, and floxed mouse models to advance our knowledge. Our preliminary data in ELF4-mutant human and mouse cells emphasize cell type-specific functions of this factor, with increased inflammatory responses in myeloid and T cells associated with failed anti-inflammatory gene expression programs. We will pursue two aims to illuminate how ELF4 functions as a cornerstone in the cross-regulation of interferon, inflammasome, and Th17 responses. Aim 1) Dissect molecular and biochemical effects of WT and mutant ELF4 in myeloid and Th17 cells. Aim 2) Define the roles of WT and mutant ELF4 in cellular and organismal inflammatory responses mediated by myeloid and Th17 cells. The results of these investigations will provide invaluable new insights with direct relevance for understanding the etiology and devising targeted therapy in this new human disorder and, by extension, more broadly in prevalent inflammatory diseases.