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：
10090982
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/10090982
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.

系统性红斑狼疮 (SLE) 是一种自身免疫性疾病，由遗传和遗传相互作用网络引起。环境因素。 SLE 与 I 型干扰素 (IFN I) 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性 (SNP) 与全基因组关联研究增加了 SLE 的风险。一种与以下因素密切相关的常见 SNP： SLE 位于病毒 dsRNA 传感器 IFIH1 (rs1990760) 中，导致氨基酸变化 (A946T)。 IFIHI T946 变异在 SLE 发病机制中的确切作用仍不清楚。最近，我们展示了一种敲击在表达 IFIH1 变体（IFIH1T946；Ifih1R）的小鼠模型中，基础 IFN I 表达升高，并且免疫细胞中干扰素刺激基因（ISG）的特征。这种低级别干扰素病与在诱导的 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 变体如何启动免疫细胞以提高反应促进自身免疫。在这里，我们将重点关注两个目标：1）阐明 pDC 在升高中的作用 IFIH1R 小鼠中的 IFN 特征，以及 2) 确定 IFIH1R 如何改变 CD4+ T 细胞效应功能和相关导致 SLE 发病机制的细胞代谢重塑。成功完成这些目标将阐明 IFIH1R 启动 pDC 和 CD4+ T 细胞促进 SLE 的转录和代谢机制发病。获得的信息将有助于指导基于代谢改变的治疗方法 SLE 和其他自身免疫性疾病的途径。