Posted August 3, 2022

Betsy Barnes, Ph.D., Feinstein Institute for Medical Research

Betsy Barnes, Ph.D., Feinstein Institute for Medical Research Betsy Barnes, Ph.D.,
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The Feinstein Institute for Medical Research received fiscal year 2017 funding from the Congressionally Directed Medical Research Programs’ (CDMRP’s) Lupus Research Program (LRP) to support work in the laboratory of Dr. Betsy Barnes. The proposal, titled “Targeting IRF5 Hyperactivation in SLE as a Driver of Disease Risk and Pathogenesis,” addresses the important question of whether elevated activation of Interferon regulatory factor 5 (IRF5) in Systemic Lupus Erythematosus (SLE) immune cells can be therapeutically targeted to alleviate disease onset and severity.

SLE is a progressive, multisystem autoimmune disease that is severely debilitating and is the result of dysfunctional immune regulation. The condition has both genetic and environmental risk factors. Among the identified risk factors is elevation of interferon alpha (IFN-α), an important cytokine modulator of both the innate and adaptive immune system. IRF5 is one of the key transcription factors (i.e., a protein that helps turn specific genes “on” or “off”) that regulates IFN-α activity, amongst other SLE-associated inflammatory cytokines. In addition, mutations in the IRF5 gene, termed IRF5 genetic variants, associate with risk of SLE.

Dr. Barnes and her colleagues made several important discoveries using both human specimens and mouse models of Lupus. They found that healthy individuals who carry IRF5 genetic risk variants have elevated IRF5 hyper-activation in their circulating blood cells (i.e., immune cells) that drives or initiates pre-symptomatic SLE.1 These data support a genetic contribution from IRF5 that contributes to the heterogeneous nature of SLE by heightening an individual’s risk to additional environmental factors that may trigger SLE. Thus, the Principal Investigator (PI), Dr. Barnes, and her colleagues suggest that a patient’s condition is likely driven by a “multi-hit” scenario where dysfunction or dysregulation of a single (or multiple) master regulatory factor, like IRF5, will predispose individuals to developing a specific brand of immune dysregulation with similar pathological and clinical symptoms that lead to SLE.

To further test the theory that IRF5 hyper-activation is a driver of lupus disease onset and severity, the PI developed therapeutic inhibitors that directly bind to IRF5 to inhibit its activation.2 These inhibitors were evaluated in human SLE immune cells, as well as mouse models of lupus, to determine the mechanisms by which IRF5 contributes to SLE pathogenesis. In three distinct models of murine lupus (NZB/W F1, MRL/lpr, and pristane-induced), the PI and her colleagues showed therapeutic efficacy of the inhibitors, resulting in decreased IRF5 hyper-activation and anti-dsDNA autoantibody titers, and improved overall survival of the mice. Findings from this CDMRP-funded work support the feasibility of therapeutically targeting transcription factors such as IRF5 that are dysregulated in SLE immune cells and contribute to disease pathogenesis, in part through the dysregulated release of pro-inflammatory cytokines and generation of autoantibodies.

The impact of the work being performed by Dr. Barnes and her colleagues strongly suggests that: (1) individuals carrying the IRF5-SLE haplotype are more susceptible to environmental and random influences that trigger chronic immune activation and predispose to development of SLE, but more importantly, (2) inhibitors of IRF5, and other transcription factors, can be developed and effectively deployed.

1Li D, Matta B, Song S, Nelson V, Diggins K, Simpfendorfer KR, Gregersen PK, Linsley P, and Barnes BJ. 2020. IRF5 genetic risk variants drive myeloid-specific IRF5 hyperactivation and presymptomatic SLE. JCI Insight 30;5(2):e124020. doi: 10.1172/jci.insight.124020. PMID: 31877114; PMCID: PMC7098722.

2Song S, De S, Nelson V, Chopra S, LaPan M, Kampta K, Sun S, He M, Thompson CD, Li D, Shih T, Tan N, Al-Abed Y, Capitle E, Aranow C, Mackay M, Clapp WL, and Barnes BJ. 2020. Inhibition of IRF5 hyperactivation protects from lupus onset and severity. Journal of Clinical Investigation 130(12):6700-6717. doi: 10.1172/JCI120288. PMID: 32897883; PMCID: PMC7685739.

Public and Technical Abstracts: Targeting IRF5 Hyperactivation in SLE as a Driver of Disease Risk and Pathogenesis

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Last updated Wednesday, August 3, 2022