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- W4313430198 abstract "Abstract Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by chronic immune activation, loss of self-tolerance and organ destruction. More than 90 genetic risk loci are implicated in the etiology of SLE, yet the mechanisms connecting these loci to disease risk are not well understood. We focus on a SLE-associated coding variant (rs1131665) at the IRF7 risk locus that results in an arginine (R, non-risk) to glutamine (Q, risk) amino acid change in the auto inhibitory domain of interferon regulatory factor-7 (IRF7), a key transcriptional regulator of the expression of and response to type I interferon (IFN). The majority of SLE patients exhibit elevated levels of circulating IFN, a feature that correlates with disease activity. We generated cell lines expressing the risk and non-risk variants of IRF7 and isolated plasmacytoid dendritic cells from mice with CRISPR-mediated introduction of a mouse homologue of the risk variant of IRF7. In both experimental systems, the rs1131665 lupus risk variant drives increased toll like receptor-7 (TLR-7) ligand-induced IFN-α expression at both the mRNA and protein levels compared to the non-risk variant of IRF7. Additionally, we performed a covariance analysis that predicts that amino acid residues at the 84, 140, 142 positions interact with the variant position in the three-dimensional structure of IRF7. Mutation of the amino acid at the 84 position from a glutamic acid (E) residue to a threonine (T) residue results in amplified IFN production in response to TLR-7 stimulation. Our findings suggest a genotype-dependent mechanism for lupus risk variants in IRF7 in promoting exaggerated IFN production in SLE. These experiments would not have been possible with out NIH NIAMS R01 AR073228." @default.
- W4313430198 created "2023-01-06" @default.
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- W4313430198 date "2022-05-01" @default.
- W4313430198 modified "2023-09-27" @default.
- W4313430198 title "A Lupus-Associated Variant in IRF7 amplifies IFN-α Production in response to TLR stimulation" @default.
- W4313430198 doi "https://doi.org/10.4049/jimmunol.208.supp.158.02" @default.
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