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- W4313383634 abstract "Abstract The transcription factor interferon regulatory factor 5 (IRF5) is a central mediator of innate and adaptive immunity. Genetic variations within IRF5 associate with risk for systemic lupus erythematosus (SLE) and mice lacking Irf5 are protected from lupus onset and severity. Here we show that IRF5 genetic variants confer risk by increasing basal IRF5 activation in plasmacytoid dendritic cells resulting in elevated IFNα production. IRF5 hyperactivation in SLE immune cells correlates with SLEDAI and dsDNA titers. Upon characterization of immune cells from NZB/W F1 lupus-prone mice, we found that Irf5 was hyperactivated at 19 weeks-old, which precedes clinical onset. To test whether IRF5 hyperactivation is a driver of SLE, we developed novel therapeutics targeting IRF5 activation. Inhibitors are cell permeable, non-toxic and selectively bind to full-length inactive IRF5 monomer. In vivo analysis revealed functional mimicry with Irf5 knockout mice and treatment of NZB/W F1 mice for a two-week period prior to clinical onset gave significantly reduced dsDNA titers, anti-nuclear antibody (ANA) staining, and improved survival. The IRF5 inhibitor also blocked ex vivo SLE serum-induced IRF5 activation and reversed IRF5 hyperactivation detected in SLE immune cells. Results implicate IRF5 hyperactivation as a risk factor that drives SLE and provide the first pre-clinical support for treating SLE patients or those at risk of SLE with IRF5 inhibitors." @default.
- W4313383634 created "2023-01-06" @default.
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- W4313383634 date "2018-05-01" @default.
- W4313383634 modified "2023-10-16" @default.
- W4313383634 title "IRF5 hyper-activation is a driver of systemic lupus erythematosus (SLE) onset and severity" @default.
- W4313383634 doi "https://doi.org/10.4049/jimmunol.200.supp.45.6" @default.
- W4313383634 hasPublicationYear "2018" @default.
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