Genetic Versus Non-genetic Drivers of SLE: Implications of IRF5 Dysregulation in Both Roads Leading to SLE
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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.
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.
KeywordsInterferon regulatory factor Lupus Genotype Interferon
This work was supported in part by grants from the Lupus Research Alliance and DoD CDMRP Lupus Research Program to BJB.
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.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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