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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-α2b mimicked the effect of IFN-γ. 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-α receptor signaling in STAT2- and IRF9-deficient cells switches the transcriptional output to a prolonged, IFN-γ-like response and likely contributes to clinically overt inflammation in these individuals.

Original publication

DOI

10.1016/j.jaci.2022.01.026

Type

Journal article

Journal

J Allergy Clin Immunol

Publication Date

10/2022

Volume

150

Pages

955 - 964.e16

Keywords

GAF, HLH, IRF9, ISGF3, STAT2, Type I interferon, antiviral immunity, type II interferon, Factor IX, Humans, Interferon Type I, Interferon-Stimulated Gene Factor 3, gamma Subunit, Interferon-alpha, STAT1 Transcription Factor, STAT2 Transcription Factor, Ubiquitin Thiolesterase, Ubiquitin-Specific Proteases