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Gothe, Florian; Stremenova Spegarova, Jarmila; Hatton, Catherine F.; Griffin, Helen; Sargent, Thomas; Cowley, Sally A.; James, William; Roppelt, Anna; Shcherbina, Anna; Hauck, Fabian; Reyburn, Hugh T.; Duncan, Christopher J. A. and Hambleton, Sophie (2022): Aberrant inflammatory responses to type I interferon in STAT2 or IRF9 deficiency. In: Journal of Allergy and Clinical Immunology, Vol. 150, No. 4: pp. 955-964

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Background: Inflammatory phenomena such as hyperinflammation or hemophagocytic lymphohistiocytosis are a frequent yet paradoxical accompaniment to virus susceptibility in patients with impairment of type I interferon (IFN-I) signaling caused by deficiency of signal transducer and activator of transcription 2 (STAT2) or IFN regulatory factor 9 (IRF9). Objective: We hypothesized that altered and/or prolonged IFN-I signaling contributes to inflammatory complications in these patients. Methods: We explored the signaling kinetics and residual transcriptional responses of IFN-stimulated primary cells from individuals with complete loss of one of STAT1, STAT2, or IRF9 as well as gene-edited induced pluripotent stem cell-derived macrophages. Results: Deficiency of any IFN-stimulated gene factor 3 component suppressed but did not abrogate IFN-I receptor signaling, which was abnormally prolonged, in keeping with insufficient induction of negative regulators such as ubiquitin-specific peptidase 18 (USP18). In cells lacking either STAT2 or IRF9, this late transcriptional response to IFN-alpha 2b mimicked the effect of IFN-gamma. Conclusion: Our data suggest a model wherein the failure of negative feedback of IFN-I signaling in STAT2 and IRF9 deficiency leads to immune dysregulation. Aberrant IFN-alpha receptor signaling in STAT2- and IRF9-deficient cells switches the transcriptional output to a prolonged, IFN-gamma-like response and likely contributes to clinically overt inflammation in these individuals.

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