# The Role of Interferon Regulatory Factor 5 in the Pathogenesis of SLE

> **NIH NIH R01** · BOSTON MEDICAL CENTER · 2021 · $519,976

## Abstract

ABSTRACT
Systemic lupus erythematosus (SLE) is an autoimmune disease that affects approximately 0.1% of the
population and causes substantial morbidity and reduced lifespan. Current treatment is largely based on non-
specific immunosuppression which is often only partially effective and may have serious side-effects. The
development of more specific, effective and safer therapies is urgently needed. Polymorphisms in the
transcription factor interferon regulatory factor 5 (IRF5) are strongly associated in human genetic studies with
an increased risk of developing SLE and other autoimmune diseases. IRF5 plays an important role in Toll-like
receptor signaling. Deficiency of IRF5 markedly reduces disease severity in a number of mouse models of
SLE. Taken together, this suggests that IRF5 inhibition may be an effective therapeutic approach in SLE. The
goal of this project is to obtain detailed information about IRF5 function and activation that will lead to a better
understanding of the basic mechanisms underlying SLE pathogenesis and potentially to new approaches to
inhibit IRF5 and the identification of novel therapeutic targets. This will be done by: (1) determining the IRF5-
expressing cell type(s) responsible for mediating disease in a mouse model of SLE by deleting IRF5 in specific
immune cell types and evaluating the effect of the deletion on disease development; (2) determining whether
deletion of IRF5 after disease is established can reverse disease or prevent disease progression in a mouse
model of SLE; (3) using the complementary approaches of retrogenic technology and CRISPR gene editing to
create novel mouse models to determine the specific phosphorylation site(s) in IRF5 required for lupus
pathogenesis in vivo and for IRF5 function and activation in primary immune cells ex vivo; (4) determining how
the IRF5 polymorphisms associated with lupus risk modulate IRF5 expression and function in human myeloid
dendritic cells. This will be done by making induced pluripotent stem (iPS) cells from peripheral blood
mononuclear cells of healthy volunteers with and without the IRF5 risk polymorphisms and then differentiating
the iPS cells into myeloid dendritic cells using a novel in vitro technique. In addition, in order to definitively
determine the effect of the IRF5 risk polymorphisms, the polymorphisms will be introduced into non-
polymorphic iPS cells using gene editing and functional IRF5 responses will be compared in isogenic myeloid
dendritic cells that are genetically identical, except for the risk polymorphism of interest.

## Key facts

- **NIH application ID:** 10234090
- **Project number:** 5R01AI130199-05
- **Recipient organization:** BOSTON MEDICAL CENTER
- **Principal Investigator:** IAN R RIFKIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $519,976
- **Award type:** 5
- **Project period:** 2017-09-22 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10234090

## Citation

> US National Institutes of Health, RePORTER application 10234090, The Role of Interferon Regulatory Factor 5 in the Pathogenesis of SLE (5R01AI130199-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10234090. Licensed CC0.

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