{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T12:25:30Z","timestamp":1771331130050,"version":"3.50.1"},"reference-count":24,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100014834","name":"McCusker Charitable Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014834","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100025520","name":"Medical Research Future Fund","doi-asserted-by":"publisher","award":["MRF20223294"],"award-info":[{"award-number":["MRF20223294"]}],"id":[{"id":"10.13039\/501100025520","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100025520","name":"Medical Research Future Fund","doi-asserted-by":"publisher","award":["MRF2025693"],"award-info":[{"award-number":["MRF2025693"]}],"id":[{"id":"10.13039\/501100025520","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis & Rheumatology"],"abstract":"\n Objective<\/jats:title>\n \n Phenotypic diversity of autoimmune diseases presents an ongoing diagnostic and therapeutic challenge. The discovery of mutations in\n RELA<\/jats:italic>\n (encoding RELA\/p65) in patients with diverse disease phenotypes suggests heterogeneous pathophysiologic mechanisms are at play, which may explain the observed phenotypic diversity. We identified seven novel\/rare\n RELA<\/jats:italic>\n variants in patients with autoimmune diseases and examined the functional consequences on immune signaling.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Whole\u2010exome sequencing analysis revealed seven novel\/rare\n RELA<\/jats:italic>\n variants. Following ectopic expression of wild type (WT) and mutant RELA proteins in HEK293 cells,\n NF\u2010<\/jats:italic>\n \n \u03ba<\/jats:italic>\n <\/jats:sc>\n B\/interferon\u2010<\/jats:italic>\n \u03b2 (IFN\u03b2)<\/jats:italic>\n luciferase reporter assays were used to determine transcriptional activity. RELA expression was also assessed in transfected HEK293 cells and in patient peripheral blood mononuclear cells (PBMCs) via Western blot. NF\u2010\n \u03ba<\/jats:sc>\n B and interferon\u2010stimulated genes in patient PBMCs were assessed via quantitative polymerase chain reaction following toll\u2010like receptor (TLR) activation.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n RELA\n I250V<\/jats:sup>\n , RELA\n R295H<\/jats:sup>\n and RELA\n E3*<\/jats:sup>\n displayed a loss in NF\u2010\u03baB transcriptional activity. RELA\n I250V<\/jats:sup>\n and RELA\n R295H<\/jats:sup>\n induced hyperactivation of the\n IFN\u03b2<\/jats:italic>\n promoter. Comparative to RELA\n WT<\/jats:sup>\n , ectopically expressed RELA\n I250V<\/jats:sup>\n protein levels were reduced. Collectively, an elevated IFN gene signature was not detected in patient PBMCs following TLR activation, however the patient heterozygous for\n I250V<\/jats:italic>\n had elevated\n IFN\u03b2<\/jats:italic>\n transcripts after TLR7\/8 activation.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n We expand upon the clinical syndromes linked to RELA dysfunction and uncover rare\/novel variants that have distinct functional effects on gene transcription downstream of\n NF\u2010\u03baB<\/jats:italic>\n and\n IFN\u03b2<\/jats:italic>\n promoter elements. These findings reinforce an important role for RELA in a range of autoimmune and autoinflammatory diseases.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/art.70046","type":"journal-article","created":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T12:26:32Z","timestamp":1766751992000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rare and Novel\n \n RELA<\/i>\n <\/scp>\n Variants Contribute to Systemic Autoimmunity"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3784-6814","authenticated-orcid":false,"given":"Morgan B.","family":"Downes","sequence":"first","affiliation":[{"name":"Division of Immunology and Infectious Diseases, John Curtin School of Medical Research The Australian National University Canberra Australian Capital Territory Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonia B.","family":"Nambadan","sequence":"additional","affiliation":[{"name":"Division of Immunology and Infectious Diseases, John Curtin School of Medical Research The Australian National University Canberra Australian Capital Territory Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanne","family":"Chow","sequence":"additional","affiliation":[{"name":"Division of Immunology and Infectious Diseases, John Curtin School of Medical Research The Australian National University Canberra Australian Capital Territory Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3352-5578","authenticated-orcid":false,"given":"Ainsley R.","family":"Davies","sequence":"additional","affiliation":[{"name":"Canberra Clinical Phenomics Service, Australian Phenomics Facility and John Curtin School of Medical Research The Australian National University Canberra Australian Capital Territory Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gemma","family":"Hart","sequence":"additional","affiliation":[{"name":"Division of Immunology and Infectious Diseases, John Curtin School of Medical Research The Australian National University Canberra Australian Capital Territory Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas D.","family":"Andrews","sequence":"additional","affiliation":[{"name":"Division of Immunology and Infectious Diseases, John Curtin School of Medical Research The Australian National University Canberra Australian Capital Territory Australia"},{"name":"School of Computing The Australian National University Canberra Australian Capital Territory Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"Lehmann","sequence":"additional","affiliation":[{"name":"Division of Immunology and Infectious Diseases, John Curtin School of Medical Research The Australian National University Canberra Australian Capital Territory Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabella","family":"Bales","sequence":"additional","affiliation":[{"name":"Division of Immunology and Infectious Diseases, John Curtin School of Medical Research The Australian National University Canberra Australian Capital Territory Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alamelu","family":"Vengatasalam","sequence":"additional","affiliation":[{"name":"Division of Immunology and Infectious Diseases, John Curtin School of Medical Research The Australian National University Canberra Australian Capital Territory Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arthur Richard","family":"Kitching","sequence":"additional","affiliation":[{"name":"Centre for Inflammatory Diseases, Department of Medicine Monash University Melbourne Victoria 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