Viral sensor IFIH1 promotes SLE through an altered interferon program

病毒传感器 IFIH1 通过改变干扰素程序促进 SLE

基本信息

批准号：
10339354
负责人：
Jacquelyn Gorman
金额：
$ 34.96万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-05 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10339354
关键词：
Affect Alanine American Amino Acids Autoantibodies Autoantigens Autoimmune Diseases Autoimmunity C-terminal CD4 Positive T Lymphocytes Cells Codon Nucleotides Coupled Dendritic Cells Disease Double-Stranded RNA Environmental Risk Factor Etiology Exhibits Exposure to Gene Expression Genes Genetic Genetic Transcription Glycolysis IRF3 gene Immune Immune Tolerance Immune signaling In Vitro Inflammation Inflammatory Inflammatory Response Interferon Type I Interferons Internet Knock-in Mouse Lead Link Lupus Lymphocyte Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Mus Nutrient Oklahoma Oxidative Phosphorylation Pathogenesis Pathogenicity Pathway interactions Phenotype Predisposition Production Proteins Research Risk Risk Factors Role Signal Pathway Signal Transduction Signaling Protein Single Nucleotide Polymorphism Source Systemic Lupus Erythematosus T cell differentiation T cell response T-Cell Activation T-Lymphocyte Subsets Testing Therapeutic Threonine Variant Viral Virus Diseases base cell type effector T cell genetic variant genome wide association study helicase in vitro Assay in vivo lupus-like mouse model programs response sensor

项目摘要

Systemic lupus erythematosus (SLE) is an autoimmune disease resulting from an interactive web of genetic and environmental factors. SLE is associated with elevated levels of type I interferons (IFN I) and viral infections. Single nucleotide polymorphisms (SNPs) in the innate immune signaling pathway have been linked to an increased risk for SLE by genome wide association studies. One common SNP that is strongly associated with SLE is located in the viral dsRNA sensor, IFIH1 (rs1990760), which results in an amino acid change (A946T). The precise roles of the IFIHI T946 variant in SLE pathogenesis remain unclear. Recently, we showed that a knock- in mouse model expressing the IFIH1 variant (IFIH1T946; Ifih1R) displays heightened basal IFN I expression and a signature of interferon-stimulated genes (ISGs) in immune cells. This low grade interferonopathy correlates with increased persistence of anti-nuclear autoantibodies in an induced SLE model. Therefore, the Ifih1R model provides a unique opportunity to determine how the IFIH1T946 variant primes immune cells for elevated responses that promote autoimmunity. Herein, we will focus on two aims: 1) elucidating the role of pDCs in the elevated IFN signature in Ifih1R mice, and 2) determining how IFIH1R alters CD4+ T cell effector function and associated cellular metabolic remodeling that lead to SLE pathogenesis. Successful completion of these aims will elucidate transcriptional and metabolic mechanisms by which IFIH1R primes pDCs and CD4+ T cells to promote SLE pathogenesis. The information gained will help guide therapeutic approaches based on alterations in metabolic pathways in SLE and other autoimmune diseases.

全身性红斑狼疮（SLE）是一种自身免疫性疾病，由遗传和环境因素。 SLE与I型干扰素（IFN I）和病毒感染的水平升高有关。先天免疫信号通路中的单核苷酸多态性（SNP）已与一个通过基因组广泛的关联研究增加了SLE的风险。一个与之密切相关的常见SNP SLE位于病毒DSRNA传感器中，IFIH1（RS1990760），导致氨基酸变化（A946T）。 IFIHI T946变体在SLE发病机理中的确切作用尚不清楚。最近，我们表明了一个敲门在表达IFIH1变体（IFIH1T946; IFIH1R）的鼠标模型中显示出增强的基础IFN I表达和免疫细胞中干扰素刺激的基因（ISG）的特征。这种低级干涉疗法相关随着诱导SLE模型中抗核自身抗体的持久性增加。因此，IFIH1R模型提供了一个独特的机会来确定IFIH1T946变体素质免疫细胞如何用于升高的响应促进自身免疫性。在此，我们将重点介绍两个目标：1）阐明PDC在升高中的作用 IFN签名在IFIH1R小鼠中，以及2）确定IFIH1R如何改变CD4+ T细胞效应子函数和相关细胞代谢重塑导致SLE发病机理。这些目标的成功完成将阐明转录和代谢机制，通过IFIH1R Primes PDC和CD4+ T细胞促进SLE的机制发病。获得的信息将根据代谢的改变有助于指导治疗方法 SLE和其他自身免疫性疾病的途径。