{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:31:54Z","timestamp":1786977114400,"version":"build-2736575974"},"reference-count":55,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T00:00:00Z","timestamp":1679443200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003141","name":"National Council of Science and Technology, Mexico","doi-asserted-by":"publisher","award":["FOSISS\u2010261539 and A3\u2010S\u201039996"],"award-info":[{"award-number":["FOSISS\u2010261539 and A3\u2010S\u201039996"]}],"id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010292","name":"Fundaci\u00f3n Miguel Alem\u00e1n, A.C.","doi-asserted-by":"publisher","award":["Est\u00edmulo a la Investigaci\u00f3n, 2018"],"award-info":[{"award-number":["Est\u00edmulo a la Investigaci\u00f3n, 2018"]}],"id":[{"id":"10.13039\/501100010292","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis & Rheumatology"],"published-print":{"date-parts":[[2023,6]]},"abstract":"\n Objective<\/jats:title>\n \n Variants in\n STAT4<\/jats:italic>\n are associated with systemic lupus erythematosus (SLE) and other autoimmune diseases. We undertook this study to investigate how disease\u2010associated variants affect STAT4 expression, in particular in CD4+ T cells where STAT4 plays an essential role.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We compared Th1 differentiation between naive CD4+ T cells from healthy donors homozygous for the risk (R\/R) or nonrisk (NR\/NR) alleles. We analyzed epigenetic marks in\n STAT4<\/jats:italic>\n and evaluated the relevance of its third intron, assessed the consequences of Stat4 overexpression in vivo in mice, and analyzed the effects of the\n STAT4<\/jats:italic>\n genotype in patients with lupus nephritis.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Naive CD4+ T cells from NR\/NR healthy donors down\u2010regulated\n STAT4<\/jats:italic>\n in response to interleukin\u201012 (IL\u201012). In contrast, cells from R\/R healthy donors maintained high levels. R\/R cells exhibited a higher abundance of transcriptionally active STAT4 and increased interferon\u2010\u03b3 production. Accordingly, R\/R healthy donors exhibited a stronger induction of local active enhancer marks. Genetic editing confirmed the presence of a negative regulatory region in the\n STAT4<\/jats:italic>\n third intron, where most of the SLE\u2010associated\n STAT4<\/jats:italic>\n single\u2010nucleotide polymorphisms (SNPs) are located. In vivo forced expression demonstrated that increases in Stat4 levels in T cells enhanced glomerulonephritis in mice. Accordingly, the R\/R genotype was associated with suboptimal response to treatment and with worse clinical outcomes in patients with proliferative lupus nephritis.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n The SLE\u2010associated\n STAT4<\/jats:italic>\n haplotype correlates with an abnormal IL\u201012\u2013mediated\n STAT4<\/jats:italic>\n transcriptional regulation. Carriers of the risk variant exhibit exaggerated CD4+\u2009proinflammatory capacities that, in the context of SLE, contribute to more severe disease. R\/R patients may benefit from blockade of the IL\u201012\/STAT4 pathway.\n <\/jats:p>\n \n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/art.42435","type":"journal-article","created":{"date-parts":[[2022,12,28]],"date-time":"2022-12-28T01:39:42Z","timestamp":1672191582000},"page":"961-972","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Down\u2010Regulation\u2013Resistant\n STAT4<\/i>\n Risk Haplotype Contributes to Lupus Nephritis Through CD4+ T Cell Interferon\u2010\u03b3 Production"],"prefix":"10.1002","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0741-9248","authenticated-orcid":false,"given":"Iris K.","family":"Madera\u2010Salcedo","sequence":"first","affiliation":[{"name":"Department of Immunology and Rheumatology Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n Mexico City 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