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

• 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
• 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

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.

系统性红斑狼疮(SLE)是一种自身免疫性疾病，由遗传和 环境因素。系统性红斑狼疮与I型干扰素水平升高和病毒感染有关。 先天免疫信号通路中的单核苷酸多态(SNPs)与一种 全基因组关联研究增加系统性红斑狼疮的风险。一个常见的SNP与 SLE位于病毒dsRNA传感器IFIH1(Rs1990760)上，导致氨基酸变化(A946T)。 IFIHI T946变异在SLE发病机制中的确切作用尚不清楚。最近，我们展示了敲门声- 在表达IFIH1变异体(IFIH1T946；IFIH1R)的小鼠模型中，基础干扰素I表达增加， 免疫细胞中干扰素刺激基因(ISGs)的特征。这种低度干扰素病与 在诱导的系统性红斑狼疮模型中，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变异如何启动免疫细胞以产生更高的反应 来促进自身免疫力。在这里，我们将集中于两个目标：1)阐明pDC在高危人群中的作用 IFIH1R小鼠中的干扰素信号，以及2)确定IFIH1R如何改变CD4+T细胞效应器的功能和相关 导致SLE发病机制的细胞代谢重塑。这些目标的成功完成将阐明 IFIH1R启动pDC和CD4+T细胞促进SLE的转录和代谢机制 发病机制。获得的信息将有助于指导基于代谢变化的治疗方法 系统性红斑狼疮和其他自身免疫性疾病的通路。