# Viral sensor IFIH1 promotes SLE through an altered interferon program

> **NIH NIH P20** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2021 · $349,600

## Abstract

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.

## Key facts

- **NIH application ID:** 10090982
- **Project number:** 1P20GM139763-01
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Jacquelyn Gorman
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $349,600
- **Award type:** 1
- **Project period:** 2021-02-05 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10090982

## Citation

> US National Institutes of Health, RePORTER application 10090982, Viral sensor IFIH1 promotes SLE through an altered interferon program (1P20GM139763-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10090982. Licensed CC0.

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