Resolving the mechanisms of IFIH1 risk variant in systemic lupus erythematosus

About This Grant

Modified Project Summary/Abstract Section Abstract Dysregulated type I interferon (IFN I) has been associated with systemic lupus erythematosus (SLE). Both viral infections and detrimental self-RNA sensing have been implicated in driving the dysregulated inflammation associated with SLE. However, we lack a comprehensive understanding of the mechanisms involved in distinguishing self- versus non-self RNA and how altered cellular responses to self-RNA might promote autoimmunity. Numerous single nucleotide polymorphisms (SNPs) within the innate immune signaling pathway have been associated with SLE pathogenesis. One SNP, rs1990760, is in interferon-induced helicase C domain-containing protein 1 (IFIH1), and results in an alanine to threonine substitution at amino acid 946 (A946T), which has been associated with SLE and identified as a critical allele to disease pathogenesis. Our previous work revealed that healthy individuals expressing this IFIH1 risk variant (IFIH1T946) exhibited a basal interferon-stimulated gene (ISG) signature, which was recapitulated in an IFIH1T946 (Ifih1R) knock-in mouse model. In an induced SLE murine model, Ifih1R mice displayed persistent elevated anti-nuclear autoantibodies linking this to the low grade interferonopathy. However, the cellular and molecular mechanisms by which IFIH1R promotes SLE remain undefined. Herein, we will focus on three aims: 1) examining how IFIH1R enhances inflammation, 2) determining if IFIH1R promotes SLE pathogenesis in Sle1b mice treated with R848, and 3) determining how human IFIH1R alters the IFN signature and immune cell effector functions in healthy individuals and in SLE patients without nephritis. Data generated from this application will give understanding into the mechanisms that drive inflammation that promotes SLE pathogenesis, which will help stratify patients and steer therapeutic strategies stemming from cellular pathways in SLE pathogenesis.