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Review
. 2019 Jan 15;21(1):2.
doi: 10.1007/s11926-019-0803-3.

Genetic Versus Non-genetic Drivers of SLE: Implications of IRF5 Dysregulation in Both Roads Leading to SLE

Betsy J Barnes  1
Affiliations
Review

Genetic Versus Non-genetic Drivers of SLE: Implications of IRF5 Dysregulation in Both Roads Leading to SLE

Betsy J Barnes. Curr Rheumatol Rep. .

Abstract

Purpose of review: Systemic lupus erythematosus (SLE) is characterized by a breakdown of immune tolerance, resulting in inflammation and tissue destruction. While the primary causes of SLE are still obscure, the disorder is highly heritable. Genetic risk variants, on their own, are rarely causal or fully explain disease pathogenesis. We discuss the possibility that IRF5, a SLE susceptibility gene, has both genetic and non-genetic contributions to disease pathogenesis.

Recent findings: Genetic variants within and around IRF5 robustly associate with SLE risk. In SLE blood cells, IRF5 risk variants associate with elevated IRF5 expression and IFN production. Whether the observed increase in expression is due to risk variants or other disease-associated factors is not clear. Data from Irf5-/- mice backcrossed to multiple models of murine lupus support that IRF5's role in disease pathogenesis is non-genetic. Studies of IRF5 expression and function in genotyped healthy donors will address the question of whether IRF5 dysregulation in SLE is driven by genetic or non-genetic factors.

Keywords: Genotype; Interferon; Interferon regulatory factor; Lupus.

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Conflict of interest statement

Compliance with Ethical Standards

Conflict of Interest Dr. Barnes reports grants from Lupus Research Alliance and grants from DoD CDMRP Lupus Research Program, during the conduct of the study. In addition, Dr. Barnes has a patent WO2017/044855A2 issued.

Figures

Fig. 1
Fig. 1
Candidate causal SNPs associated with SLE are shown relative to the human IRF5 gene. The four genetic variants that make up the homozygous IRF5-SLE risk haplotype in European Caucasians are shown with stated functionalities. Variants listed underneath the listed functionalities are those that are candidate causal or associated with SLE in GWAS, and thus proxies for the candidate causal variants
Fig. 2
Fig. 2
IRF5 expression and activation are significantly elevated in SLE patients independent of genotype. a q-PCR analysis of IRF5 expression in purified PBMC from healthy donors and SLE patients. Symbols represent independent donors. Relative expression was calculated by the ΔCt method. Lines show mean ± SD [9]. b, c IRF5 activation is significantly elevated in SLE monocytes (b) and B cells (c). IRF5 activation was determined with nuclear DRAQ5 staining by imaging flow cytometry [16]. *p < 0.05; ***p < 0.001
See this image and copyright information in PMC

References

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