{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T18:01:04Z","timestamp":1793556064160,"version":"4.5.0"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T00:00:00Z","timestamp":1724112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001245","name":"Jeffrey Modell Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001245","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"\n Background<\/jats:title>\n Patients with loss of function signal transducer and activator of transcription 3-related Hyper IgE Syndrome (LOF STAT3 HIES) present with recurrent staphylococcal skin and pulmonary infections along with the elevated serum IgE levels, eczematous rashes, and skeletal and facial abnormalities. Defective STAT3 signaling results in reduced Th17 cells and an impaired IL-17\/IL-22 response primarily due to a compromised canonical Janus kinase-signal transducer and activator of transcription (JAK\u2013STAT) pathway that involves STAT3 phosphorylation, dimerization, nuclear translocation, and gene transcription. The non-canonical pathway involving unphosphorylated STAT3 and its role in disease pathogenesis, however, is unexplored in HIES.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n This study aims to elucidate the role of unphosphorylated STAT3\u2013unphosphorylated NF-\u03baB (uSTAT3\u2013uNF-\u03baB) activation pathway in LOF STAT3 HIES patients.<\/jats:p>\n <\/jats:sec>\n \n Methodology<\/jats:title>\n The mRNA expression of downstream molecules of unphosphorylated STAT3\u2013unphosphorylated NF-\u03baB pathway was studied in five LOF STAT3 HIES patients and transfected STAT3 mutants post-IL-6 stimulation. Immunoprecipitation assays were performed to assess the binding of STAT3 and NF-\u03baB to RANTES promoter.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A reduced expression of the downstream signaling molecules of the uSTAT3\u2013uNF-\u03baB complex pathway, viz.,\n RANTES<\/jats:italic>\n ,\n STAT3<\/jats:italic>\n ,\n IL-6<\/jats:italic>\n ,\n IL-8<\/jats:italic>\n ,\n ICAM1<\/jats:italic>\n ,\n IL-8<\/jats:italic>\n ,\n ZFP36L2<\/jats:italic>\n ,\n CSF1<\/jats:italic>\n ,\n MRAS<\/jats:italic>\n , and\n SOCS3<\/jats:italic>\n , in LOF STAT3 HIES patients as well as the different STAT3 mutant plasmids was observed. Immunoprecipitation studies showed a reduced interaction of STAT3 and NF-\u03baB to RANTES in HIES patients.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n The reduced expression of downstream signaling molecules, specially\n RANTES<\/jats:italic>\n and\n STAT3<\/jats:italic>\n , confirmed the impaired uSTAT3\u2013uNF-\u03baB pathway in STAT3 LOF HIES. Decreased levels of RANTES and STAT3 could be a significant component in the disease pathogenesis of Hyper IgE Syndrome.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2024.1332817","type":"journal-article","created":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T07:38:36Z","timestamp":1724139516000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Unraveling the unphosphorylated STAT3\u2013unphosphorylated NF-\u03baB pathway in loss of function STAT3 Hyper IgE syndrome"],"prefix":"10.3389","volume":"15","author":[{"given":"Adil","family":"Karim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashi","family":"Garg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biman","family":"Saikia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abha","family":"Tiwari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smrity","family":"Sahu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehak","family":"Malhotra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranjana W.","family":"Minz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Rawat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surjit","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepti","family":"Suri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,8,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/j.iac.2008.01.005","article-title":"The hyper IgE syndromes","volume":"28","author":"Freeman","year":"2008","journal-title":"Immunol Allergy Clin North Am"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1601-0825.2008.01463.x","article-title":"Hyper IgE (Job\u2019s) syndrome: A primary immune deficiency with oral manifestations","author":"Freeman","year":"2009","journal-title":"Oral Dis"},{"key":"B3","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1038\/s41392-021-00791-1","article-title":"The JAK\/STAT signaling pathway: from bench to clinic","volume":"6","author":"Hu","year":"2021","journal-title":"Sig Transduct Target Ther"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2009.07.013","article-title":"Hyper-IgE syndrome","author":"Minegishi","year":"2009","journal-title":"Curr Opin Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s10238-023-01228-5","article-title":"A systematic review regarding the prevalence of Malignancy in patients with the hyper-IgE syndrome","volume":"23","author":"Mohammadi","year":"2023","journal-title":"Clin Exp Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-021-01051-1","article-title":"STAT3 hyper-IgE syndrome\u2014an update and unanswered questions","volume":"41","author":"Tsilifis","year":"2021","journal-title":"J Clin Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-023-01517-4","article-title":"New dominant-negative IL6ST variants expand the immunological and clinical spectrum of GP130-dependent hyper-IgE syndrome","volume":"43","author":"Arlabosse","year":"2023","journal-title":"J Clin Immunol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s11882-018-0806-6","article-title":"Clinical manifestation of hyper IgE syndrome including otitis media","volume":"18","author":"Wu","year":"2018","journal-title":"Curr Allergy Asthma Rep"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90333-6","article-title":"Cytokine signal transduction","author":"Kishimoto","year":"1994","journal-title":"Cell"},{"key":"B10","doi-asserted-by":"publisher","first-page":"jcs260182","DOI":"10.1242\/jcs.260182","article-title":"STAT3 signaling induced by the IL-6 family of cytokines modulates angiogenesis","volume":"136","author":"Rapp","year":"2023","journal-title":"J Cell Sci"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-021-01177-2","article-title":"The immune deficiency and dysregulation activity (IDDA2.1 \u2018Kaleidoscope\u2019) score and other clinical measures in inborn errors of immunity","volume":"42","author":"Seidel","year":"2021","journal-title":"J Clin Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"956","DOI":"10.3390\/biomedicines9080956","article-title":"The roles of post-translational modifications in STAT3 biological activities and functions","volume":"9","author":"Tesoriere","year":"2021","journal-title":"Biomed"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.2174\/1566524023362456","article-title":"The role of STATs in apoptosis","author":"Battle","year":"2005","journal-title":"Curr Mol Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2443.2005.00900.x","article-title":"Essential role of STAT3 in cytokine-driven NF-kappaB-mediated serum amyloid A gene expression","volume":"10","author":"Hagihara","year":"2005","journal-title":"Genes Cells"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M311498200","article-title":"Interleukin 1 activates STAT3\/nuclear factor-kappaB cross-talk via a unique TRAF6- and p65-dependent mechanism","volume":"279","author":"Yoshida","year":"2004","journal-title":"J Biol Chem"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1553707","article-title":"Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NF\u03baB","volume":"21","author":"Yang","year":"2007","journal-title":"Genes Dev"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s11658-018-0078-0","article-title":"STAT3, stem cells, cancer stem cells and p63","volume":"23","author":"Galoczova","year":"2018","journal-title":"Cell Mol Biol Lett"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1553707","article-title":"Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB","volume":"21","author":"Yang","year":"2007","journal-title":"Genes Dev"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/nature04444","article-title":"Restoring function in exhausted CD8 T cells during chronic viral infection","author":"Barber","year":"2006","journal-title":"Nature"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.63.6.2813-2819.1989","article-title":"Enhanced virus replication and inhibition of lymphocytic choriomeningitis virus disease in anti-gamma interferon-treated mice","volume":"63","author":"Leist","year":"1989","journal-title":"J Virol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20091706","article-title":"B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans","author":"Avery","year":"2010","journal-title":"J Exp Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20130323","article-title":"Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells","author":"Deenick","year":"2013","journal-title":"J Exp Med"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20151467","article-title":"Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets","author":"Ma","year":"2016","journal-title":"J Exp Med"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.09.016","article-title":"A critical role for STAT3 transcription factor signaling in the development and maintenance of human T cell memory","author":"Siegel","year":"2011","journal-title":"Immunity"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1111\/sji.12063","article-title":"Clinical features, STAT3 gene mutations and Th17 cell analysis in nine children with hyper-IgE syndrome in mainland China","author":"Zhang","year":"2013","journal-title":"Scand J Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2008.41","article-title":"Roles of unphosphorylated STATs in signaling","volume":"18","author":"Yang","year":"2008","journal-title":"Cell Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5332.1630","article-title":"STATs and gene regulation","volume":"277","author":"Darnell","year":"1997","journal-title":"Science"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/nrm909","article-title":"Stats: transcriptional control and biological impact","volume":"3","author":"Levy","year":"2002","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B30","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-540-38918-7_157","article-title":"JAK-STAT pathway","volume-title":"Encyclopedia of Molecular Pharmacology","author":"Meyer","year":"2008"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/nature06096","article-title":"Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome","volume":"448","author":"Minegishi","year":"2007","journal-title":"Nature"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa073687","article-title":"STAT3 mutations in the hyper-IgE syndrome","volume":"357","author":"Holland","year":"2007","journal-title":"N Engl J Med"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1901409116","article-title":"A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance","author":"Khourieh","year":"2019","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2008-2139EEEE","article-title":"STAT3 mutations in the hyper-IgE syndrome","volume":"122","author":"Bonilla","year":"2008","journal-title":"Pediatrics"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1543","DOI":"10.1084\/jem.20080321","article-title":"Mutations in STAT3 and IL12RB1 impair the development of human IL-17\u2013producing T cells","volume":"205","author":"De Beaucoudtey","year":"2008","journal-title":"J Exp Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2008.07.001","article-title":"Novel and recurrent STAT3 mutations in hyper-IgE syndrome patients from different ethnic groups","volume":"46","author":"Jiao","year":"2008","journal-title":"Mol Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nature06764","article-title":"Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome","volume":"452","author":"Milner","year":"2008","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2008.04.037","article-title":"Novel signal transducer and activator of transcription 3 (STAT3) mutations, reduced T(H)17 cell numbers, and variably defective STAT3 phosphorylation in hyper-IgE syndrome","volume":"122","author":"Renner","year":"2008","journal-title":"J Allergy Clin Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2011.39","article-title":"Mucosal antifungal defence: IL-17 signalling takes centre stage","volume":"89","author":"Glocker","year":"2011","journal-title":"Immunol Cell Biol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/j.immuni.2015.02.003","article-title":"Retinoic acid is essential for Th1 cell lineage stability and prevents transition to a Th17 cell program","volume":"42","author":"Brown","year":"2015","journal-title":"Immunity"},{"key":"B41","doi-asserted-by":"publisher","first-page":"2878","DOI":"10.3390\/ijms23052878","article-title":"STAT3 role in T-cell memory formation","volume":"23","author":"Kaminskiy","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2009.05133.x","article-title":"Th1 and Th17 cells","volume":"1183","author":"Damsker","year":"2009","journal-title":"Ann N Y Acad Sci"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.939.65.3","article-title":"Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation","author":"Yang","year":"2005","journal-title":"Cancer Res"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.897539","article-title":"Stat3 signaling pathway: A future therapeutic target for bone-related diseases","volume":"13","author":"Li","year":"2022","journal-title":"Front Pharmacol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.603894","article-title":"Critical role for lysine 685 in gene expression mediated by transcription factor unphosphorylated STAT3","volume":"289","author":"Dasgupta","year":"2014","journal-title":"J Biol Chem"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1503152112","article-title":"STAT3-driven transcription depends upon the dimethylation of K49 by EZH2","volume":"112","author":"Dasgupta","year":"2015","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M805941200","article-title":"The STAT3 NH2-terminal domain stabilizes enhanceosome assembly by interacting with the p300 bromodomain","author":"Hou","year":"2008","journal-title":"J Biol Chem"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1186\/1478-811X-11-83","article-title":"Dominant-negative activity of the STAT3-Y705F mutant depends on the N-terminal domain","author":"Mohr","year":"2013","journal-title":"Cell Commun Signal"},{"key":"B49","doi-asserted-by":"publisher","first-page":"e1002098","DOI":"10.1371\/journal.ppat.1002098","article-title":"A role for the chemokine RANTES in regulating CD8 T cell responses during chronic viral infection","volume":"7","author":"Crawford","year":"2011","journal-title":"PloS Pathog"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40463-016-0183-x","article-title":"Differences in RANTES and IL-6 levels among chronic rhinosinusitis patients with predominant gram-negative and gram-positive infection","volume":"46","author":"Rammal","year":"2017","journal-title":"J Otolaryngol Head Neck Surg"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra052723","article-title":"The many roles of chemokines and chemokine receptors in inflammation","volume":"354","author":"Charo","year":"2006","journal-title":"N Engl J Med"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1097\/00005537-200404000-00013","article-title":"Chemokine RANTES promoter polymorphisms in allergic rhinitis","volume":"114","author":"Kim","year":"2004","journal-title":"Laryngoscope"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.ehj.2004.05.005","article-title":"Association of RANTES G-403A gene polymorphism with increased risk of coronary arteriosclerosis","author":"Simeoni","year":"2004","journal-title":"Eur Heart J"},{"key":"B54","article-title":"RANTES promoter polymorphism as a genetic risk factor for rheumatoid arthritis in the Chinese","author":"Wang","year":"2005","journal-title":"Clin Exp Rheumatol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.8.4911-4927.2003","article-title":"Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment","author":"Wherry","year":"2003","journal-title":"J Virol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.1.31","article-title":"NKT cell-derived RANTES recruits APCs and CD8+ T cells to the spleen during the generation of regulatory T cells in tolerance","volume":"169","author":"Faunce","year":"2002","journal-title":"J Immunol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1038\/84205","article-title":"Chemokines as regulators of T cell differentiation","author":"Luther","year":"2001","journal-title":"Nat Immunol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1097\/00005537-200008000-00025","article-title":"Quantitative analysis of eotaxin and RANTES messenger RNA in nasal polyps: association of tissue and nasal eosinophils","volume":"110","author":"Shin","year":"2000","journal-title":"Laryngoscope"},{"key":"B59","article-title":"STAT3 Hyper IgE Syndrome. 2010 Feb 23 [updated 2020 Mar 26]","volume-title":"GeneReviews\u00ae [Internet]","author":"Hsu","year":""},{"key":"B60","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/nature15393","article-title":"A global reference for human genetic variation","volume":"526","author":"Auton","year":"2015","journal-title":"Nature"},{"key":"B61","doi-asserted-by":"publisher","first-page":"3812","DOI":"10.1093\/nar\/gkg509","article-title":"SIFT: predicting amino acid changes that affect protein function","volume":"31","author":"Ng","year":"2003","journal-title":"Nucleic Acids Res"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1332817\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T07:38:41Z","timestamp":1724139521000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1332817\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,20]]},"references-count":61,"alternative-id":["10.3389\/fimmu.2024.1332817"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1332817","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,20]]},"article-number":"1332817"}}