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Aberrant inflammatory responses to type I interferon in STAT2 or IRF9 deficiency

Lookup NU author(s): Dr Florian Gothe, Catherine Hatton, Dr Helen GriffinORCiD, Dr Christopher DuncanORCiD, Professor Sophie HambletonORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2022 The Authors. 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.

Publication metadata

Author(s): Gothe F, Stremenova Spegarova J, Hatton CF, Griffin H, Sargent T, Cowley SA, James W, Roppelt A, Shcherbina A, Hauck F, Reyburn HT, Duncan CJA, Hambleton S

Publication type: Article

Publication status: Published

Journal: Journal of Allergy and Clinical Immunology

Year: 2022

Pages: Epub ahead of print

Online publication date: 17/02/2022

Acceptance date: 14/01/2022

Date deposited: 29/03/2022

ISSN (print): 0091-6749

ISSN (electronic): 1097-6825

Publisher: Elsevier Inc.


DOI: 10.1016/j.jaci.2022.01.026

PubMed id: 35182547


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Funder referenceFunder name
207556/Z/17/ZWellcome Trust
211153/Z/18/ZWellcome Trust