{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T01:03:35Z","timestamp":1791594215240,"version":"4.3.4"},"reference-count":76,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"703","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2023,7,5]]},"abstract":"<jats:p>\n                    Heterozygous signal transducer and activator of transcription 1 (\n                    <jats:italic>STAT1<\/jats:italic>\n                    ) gain-of-function (GOF) mutations promote a clinical syndrome of immune dysregulation characterized by recurrent infections and predisposition to humoral autoimmunity. To gain insights into immune characteristics of STAT1-driven inflammation, we performed deep immunophenotyping of pediatric patients with STAT1 GOF syndrome and age-matched controls. Affected individuals exhibited dysregulated CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell and B cell activation, including expansion of T\n                    <jats:sub>H<\/jats:sub>\n                    1-skewed CXCR3\n                    <jats:sup>+<\/jats:sup>\n                    populations that correlated with serum autoantibody titers. To dissect underlying immune mechanisms, we generated\n                    <jats:italic>Stat1<\/jats:italic>\n                    GOF transgenic mice (\n                    <jats:italic>\n                      Stat1\n                      <jats:sup>GOF<\/jats:sup>\n                    <\/jats:italic>\n                    mice) and confirmed the development of spontaneous humoral autoimmunity that recapitulated the human phenotype. Despite clinical resemblance to human regulatory T cell (T\n                    <jats:sub>reg<\/jats:sub>\n                    ) deficiency,\n                    <jats:italic>\n                      Stat1\n                      <jats:sup>GOF<\/jats:sup>\n                    <\/jats:italic>\n                    mice and humans with STAT1 GOF syndrome exhibited normal T\n                    <jats:sub>reg<\/jats:sub>\n                    development and function. In contrast, STAT1 GOF autoimmunity was characterized by adaptive immune activation driven by dysregulated STAT1-dependent signals downstream of the type 1 and type 2 interferon (IFN) receptors. However, in contrast to the prevailing type 1 IFN-centric model for STAT1 GOF autoimmunity,\n                    <jats:italic>\n                      Stat1\n                      <jats:sup>GOF<\/jats:sup>\n                    <\/jats:italic>\n                    mice lacking the type 1 IFN receptor were only partially protected from STAT1-driven systemic inflammation, whereas loss of type 2 IFN (IFN-\u03b3) signals abrogated autoimmunity. Last, germline\n                    <jats:italic>STAT1<\/jats:italic>\n                    GOF alleles are thought to enhance transcriptional activity by increasing total STAT1 protein, but the underlying biochemical mechanisms have not been defined. We showed that IFN-\u03b3 receptor deletion normalized total STAT1 expression across immune lineages, highlighting IFN-\u03b3 as the critical driver of feedforward STAT1 elevation in STAT1 GOF syndrome.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.ade7028","type":"journal-article","created":{"date-parts":[[2023,7,5]],"date-time":"2023-07-05T13:58:13Z","timestamp":1688565493000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":40,"title":["Dysregulated IFN-\u03b3 signals promote autoimmunity in STAT1 gain-of-function syndrome"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2518-0469","authenticated-orcid":true,"given":"Andrea D.","family":"Largent","sequence":"first","affiliation":[{"name":"Seattle Children\u2019s Research Institute, Seattle, WA 98101, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1998-0024","authenticated-orcid":true,"given":"Katharina","family":"Lambert","sequence":"additional","affiliation":[{"name":"Benaroya Research Institute, Seattle, WA 98101, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7322-0811","authenticated-orcid":true,"given":"Kristy","family":"Chiang","sequence":"additional","affiliation":[{"name":"Seattle Children\u2019s Research Institute, Seattle, WA 98101, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2692-2308","authenticated-orcid":true,"given":"Natali","family":"Shumlak","sequence":"additional","affiliation":[{"name":"Seattle Children\u2019s Research Institute, Seattle, WA 98101, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denny","family":"Liggitt","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Oukka","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA."},{"name":"Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3489-5036","authenticated-orcid":true,"given":"Troy R.","family":"Torgerson","sequence":"additional","affiliation":[{"name":"Allen Institute for Immunology, Seattle, WA 98109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9005-1885","authenticated-orcid":true,"given":"Jane H.","family":"Buckner","sequence":"additional","affiliation":[{"name":"Benaroya Research Institute, Seattle, WA 98101, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7346-5835","authenticated-orcid":true,"given":"Eric J.","family":"Allenspach","sequence":"additional","affiliation":[{"name":"Seattle Children\u2019s Research Institute, Seattle, WA 98101, USA."},{"name":"Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4370-4772","authenticated-orcid":true,"given":"David J.","family":"Rawlings","sequence":"additional","affiliation":[{"name":"Seattle Children\u2019s Research Institute, Seattle, WA 98101, USA."},{"name":"Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA."},{"name":"Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7024-5252","authenticated-orcid":true,"given":"Shaun W.","family":"Jackson","sequence":"additional","affiliation":[{"name":"Seattle Children\u2019s Research Institute, Seattle, WA 98101, USA."},{"name":"Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA."},{"name":"Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98195, 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