{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T11:47:26Z","timestamp":1788954446509,"version":"build-2803163510"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Syndrome of Undifferentiated Recurrent Fever (SURF) is an autoinflammatory disorder with onset in childhood, marked by recurrent episodes of fever without an established molecular diagnosis. Although NOD2 gene variants that are generally considered non-pathogenic are often identified in these patients, their contribution to disease development is still not well understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study aimed to assess the clinical characteristics, long-term progression, and functional implications of NOD2 variants in a group of twelve children diagnosed with SURF, along with two Blau syndrome cases and two healthy controls. Clinical information was gathered at presentation and during follow-up. Peripheral blood mononuclear cells were examined for cytokine secretion and NF-kB pathway activation, both at baseline and following muramyl dipeptide stimulation, using multiplex cytokine analysis, Western blot, and ELISA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The median follow-up period was 3.75 years, with most children developing symptoms before 10 years of age. Abdominal pain and limb pain were the most frequent complaints. All patients were treated with colchicine, and selected cases required corticosteroids or disease-modifying antirheumatic drugs. Elevated levels of proinflammatory cytokines, including IL-2, TNF-a, IL- 6, and IL-8, were observed in SURF patients. Our functional studies suggested that variants like R702W, G908R, P268S\/V955I, and R702W\/P268S might have triggered stronger inflammatory responses, whereas L682F, L1007fs, and R587C might have been linked to diminished cytokine production and lower NF-kB activity. Certain variants, such as A1000T and P268S, appeared to show baseline NF-kB activation with moderate inflammatory activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our findings emphasize the clinical and functional diversity of NOD2\u00a0variants in SURF and may point to a possible genotype\u2013phenotype relationship that could aid in understanding disease pathways and refining diagnostic approaches.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1657782","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T06:29:09Z","timestamp":1763706549000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Exploring the role of NOD2 variants in pediatric undifferentiated recurrent fever: a clinical and functional perspective"],"prefix":"10.3389","volume":"16","author":[{"given":"Raziye Burcu","family":"Ta\u015fk\u0131n","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arzum Hande","family":"Kamilo\u011flu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bu\u015fra","family":"Bara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gizem","family":"Akyol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0130lyas","family":"Ayd\u0131n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gulcin","family":"Aytac","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neslihan Edeer","family":"Karaca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fczide","family":"Aksu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afig","family":"Berdeli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vildan","family":"Bozok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Necil","family":"K\u00fct\u00fck\u00e7\u00fcler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.berh.2020.101529","article-title":"Systemic autoinflammatory diseases: Clinical state of the art","volume":"34","author":"Georgin-Lavialle","year":"2020","journal-title":"Best Pract Res Clin Rheumatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2019-215048","article-title":"Classification criteria for autoinflammatory recurrent fevers","volume":"78","author":"Gattorno","year":"2019","journal-title":"Ann Rheum Dis"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10091963","article-title":"Syndrome of undifferentiated recurrent fever (SURF): an emerging group of autoinflammatory recurrent fevers","volume":"10","author":"Papa","year":"2021","journal-title":"J Clin Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/cells10082031","article-title":"Inborn errors in the LRR domain of nod2 and their potential consequences on the function of the receptor","volume":"10","author":"Alipoor","year":"2021","journal-title":"Cells"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e000097","DOI":"10.1136\/rmdopen-2015-000097","article-title":"Autoinflammatory granulomatous diseases: from Blau syndrome and early-onset sarcoidosis to NOD2-mediated disease and Crohn's disease","volume":"1","author":"Caso","year":"2015","journal-title":"RMD Open"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kez376","article-title":"Next generation sequencing panel in undifferentiated autoinflammatory diseases identifies patients with colchicine-responder recurrent fevers","volume":"59","author":"Papa","year":"2020","journal-title":"Rheumatol (Oxford)"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2018-214472","article-title":"Clinical characteristics and genetic analyses of 187 patients with Undefined autoinflammatory diseases","volume":"78","author":"Ter Haar","year":"2019","journal-title":"Ann Rheum Dis"},{"key":"B8","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1002\/art.43065","article-title":"Clinical, immunologic, and genetic characteristics in patients with syndrome of undifferentiated recurrent fevers","volume":"77","author":"Macaraeg","year":"2025","journal-title":"Arthritis Rheumatol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1342668","article-title":"The expanding clinical spectrum of autoinflammatory diseases with NOD2 variants: a case series and literature review","volume":"15","author":"Karamanakos","year":"2024","journal-title":"Front Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.4274\/balkanmedj.galenos.2020.2020.4.82","article-title":"Autoinflammatory diseases in childhood","volume":"37","author":"Y\u0131ld\u0131z","year":"2020","journal-title":"Balkan Med J"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-023-01649-7","article-title":"Pyrin inflammasome activation defines colchicine-responsive SURF patients from FMF and other recurrent fevers","volume":"44","author":"Palmeri","year":"2024","journal-title":"J Clin Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1007\/s12031-019-01466-x","article-title":"Phenotypic differences in primary murine microglia treated with NOD1, NOD2, and NOD1\/2 agonists","volume":"70","author":"Wasmuth","year":"2020","journal-title":"J Mol Neurosci"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13215351","article-title":"Monitoring the levels of cellular NF-\u03baB activation states","volume":"13","author":"Meier-Soelch","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22031003","article-title":"p38 signalling pathway","volume":"22","author":"Sanz-Ezquerro","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B16","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.tig.2022.11.002","article-title":"Genetically transitional disease: a new concept in genomic medicine","volume":"39","author":"Yao","year":"2023","journal-title":"Trends Genet"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3390\/genes15060799","article-title":"Blau syndrome: challenging molecular genetic diagnostics of autoinflammatory disease","volume":"15","author":"Brichova","year":"2024","journal-title":"Genes (Basel)"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-019-04280-1","article-title":"Diagnostic utility of a targeted next-generation sequencing gene panel in the clinical suspicion of systemic autoinflammatory diseases: a multi-center study","volume":"39","author":"Karacan","year":"2019","journal-title":"Rheumatol Int"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2021.108697","article-title":"Undifferentiated recurrent fevers in pediatrics are clinically distinct from PFAPA syndrome but retain an IL-1 signature","volume":"226","author":"Luu","year":"2021","journal-title":"Clin Immunol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"152024","DOI":"10.1016\/j.semarthrit.2023.152195","article-title":"Clinical characterization, long-term follow-up, and response to treatment of patients with syndrome of undifferentiated recurrent fever (SURF)","volume":"55","author":"Sutera","year":"2022","journal-title":"Semin Arthritis Rheumatol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"e70246","DOI":"10.1111\/1756-185X.70246","article-title":"Clinical manifestations and treatment response of patients with syndrome of undifferentiated recurrent fever (SURF)","volume":"28","author":"Longoni","year":"2025","journal-title":"Int J Rheum Dis"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1816","DOI":"10.55563\/clinexprheumatol\/jmtag4","article-title":"On demand corticosteroid use in the syndrome of undifferentiated recurrent fever: a literature review and results from JIR-CLiPS survey study","volume":"7","author":"Batu","year":"2025","journal-title":"Clin Exp Rheumatol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.cytogfr.2016.11.001","article-title":"Cytokine signatures in hereditary fever syndromes (HFS)","volume":"33","author":"Ibrahim","year":"2017","journal-title":"Cytokine Growth Factor Rev"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.5MIR0420-055R","article-title":"Roles of IL-2 in bridging adaptive and innate immunity, and as a tool for cellular immunotherapy","volume":"108","author":"Bendickova","year":"2020","journal-title":"J Leukoc Biol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-011-1935-7","article-title":"The role of regulatory T cells in familial Mediterranean fever (FMF)","volume":"31","author":"Rimar","year":"2012","journal-title":"Clin Rheumatol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2008.03.017","article-title":"Cytokine profile of Armenian patients with Familial Mediterranean fever","volume":"41","author":"Manukyan","year":"2008","journal-title":"Clin Biochem"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-023-01576-7","article-title":"Peripheral T cell populations are differentially affected in familial mediterranean fever, chronic granulomatous disease, and gout","volume":"43","author":"Al","year":"2023","journal-title":"J Clin Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2004.02632.x","article-title":"Does immune activation continue during an attack-free period in familial Mediterranean fever","volume":"138","author":"Musabak","year":"2004","journal-title":"Clin Exp Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C200673200","article-title":"Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease","volume":"278","author":"Inohara","year":"2003","journal-title":"J Biol Chem"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2003.50019","article-title":"Crohn's disease-associated NOD2 variants share a signaling defect in response to lipopolysaccharide and peptidoglycan","volume":"124","author":"Bonen","year":"2003","journal-title":"Gastroenterology"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1458118","article-title":"Comprehensive clinical phenotype, genotype and therapy in Yao syndrome","volume":"15","author":"Nomani","year":"2024","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.4161\/gmic.28404","article-title":"Functional defects in NOD2 signaling in experimental and human Crohn disease","volume":"5","author":"Corridoni","year":"2014","journal-title":"Gut Microbes"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20091233","article-title":"Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease","volume":"206","author":"Smith","year":"2009","journal-title":"J Exp Med"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1097\/MPG.0000000000002719","article-title":"Immunological profiling of paediatric inflammatory bowel disease using unsupervised machine learning","volume":"70","author":"Coelho","year":"2020","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"B35","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/s12931-018-0748-5","article-title":"G908R NOD2 variant in a family with sarcoidosis","volume":"19","author":"Besnard","year":"2018","journal-title":"Respir Res"},{"key":"B36","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1186\/s13075-024-03286-w","article-title":"Identifying functional dysregulation of NOD2 variant Q902K in patients with Yao syndrome","volume":"26","author":"Zhang","year":"2024","journal-title":"Arthritis Res Ther"},{"key":"B37","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1080\/08916934.2018.1442442","article-title":"Alterations in nucleotide-binding oligomerization domain-2 expression, pathway activation, and cytokine production in Yao syndrome","volume":"51","author":"McDonald","year":"2018","journal-title":"Autoimmunity"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1433620","article-title":"NOD2-mediated dual negative regulation of inflammatory responses triggered by TLRs in the gastrointestinal tract","volume":"15","author":"Masaki","year":"2024","journal-title":"Front Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2022.03.014","article-title":"Genetic and clinical features of blau syndrome among chinese patients with uveitis","volume":"129","author":"Zhong","year":"2022","journal-title":"Ophthalmology"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2020-217320","article-title":"Clinical characteristics and treatment of 50 cases of Blau syndrome in Japan confirmed by genetic analysis of the NOD2 mutation","volume":"79","author":"Matsuda","year":"2020","journal-title":"Ann Rheum Dis"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2014.07.029","article-title":"Blau syndrome polymorphisms in NOD2 identify nucleotide hydrolysis and helical domain 1 as signalling regulators","volume":"588","author":"Parkhouse","year":"2014","journal-title":"FEBS Lett"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.988862","article-title":"Blau syndrome NOD2 mutations result in loss of NOD2 cross-regulatory function","volume":"13","author":"Mao","year":"2022","journal-title":"Front Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-00322-w","article-title":"Diversity and versatility of p38 kinase signalling in health and disease","volume":"22","author":"Canovas","year":"2021","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2023.1065907","article-title":"Systematic genetic analysis of pediatric patients with autoinflammatory diseases","volume":"14","author":"Poker","year":"2023","journal-title":"Front Genet"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1657782\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T06:29:10Z","timestamp":1763706550000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1657782\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,21]]},"references-count":44,"alternative-id":["10.3389\/fimmu.2025.1657782"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1657782","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,21]]},"article-number":"1657782"}}