{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T12:40:31Z","timestamp":1781181631052,"version":"3.54.1"},"reference-count":28,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"vor","delay-in-days":15,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology CR"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Villitis of unknown etiology (VUE) is a chronic placental inflammatory lesion characterized by lymphohistiocytic infiltration and destruction of villous architecture in the absence of infection. Although VUE is well recognized for its association with fetal growth restriction and adverse pregnancy outcomes, its clinicopathologic correlates and molecular basis remain poorly understood. VUE cases were identified from the pathology database of Jinan Maternal and Child Health Hospital (2020\u20132023) and classified as high\u2010grade or low\u2010grade according to the Amsterdam criteria. Clinical data, maternal complications, and neonatal outcomes were collected from electronic medical records. Multivariable logistic regression was used to determine independent risk factors. RNA sequencing was performed on 28 placental samples (24 VUE and 4 controls) to identify differentially expressed genes and pathways. A total of 970 cases (381 high\u2010grade and 589 low\u2010grade) and 980 controls were included. VUE prevalence was 5.8%. Hypertensive disorders of pregnancy (HDP) were independently associated with VUE occurrence (odds ratio 1.67, 95% CI 1.28\u20132.19,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001). VUE placentas frequently exhibited chronic intervillositis, chronic deciduitis, and avascular villi, whereas maternal vascular malperfusion showed no significant difference from controls. High\u2010grade VUE was significantly associated with low\u2010birth\u2010weight, small\u2010for\u2010gestational\u2010age infants, and increased neonatal intensive care unit admissions, indicating a severity\u2010dependent impact on neonatal outcomes. Transcriptomic profiling revealed robust upregulation of interferon\u2010inducible, cytotoxic, and chemokine genes \u2013 most notably\n                    <jats:italic>GBP5<\/jats:italic>\n                    ,\n                    <jats:italic>CXCL9<\/jats:italic>\n                    , and\n                    <jats:italic>CXCL10<\/jats:italic>\n                    \u2013 with enrichment of interferon\u2010\u03b3, IL\u20106\/JAK\/STAT3, TNF\u2010\u03b1\/NF\u2010\u03baB, and antigen presentation pathways. VUE, particularly its high\u2010grade form, is a significant placental lesion associated with HDP, adverse neonatal outcomes, and avascular villi. Its distinct interferon\u2010rich molecular profile, consistent with a maternal anti\u2010fetal T\u2010cell\u2013mediated process, underscores its clinical and biological importance. GBP5 emerges as a potential biomarker of interferon\u2010driven inflammation, providing new mechanistic insight and diagnostic relevance for placental immune injury.\n                  <\/jats:p>","DOI":"10.1002\/2056-4538.70084","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T10:37:46Z","timestamp":1773657466000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinicopathologic and molecular landscape of villitis of unknown etiology: insights from a large\u2010scale case\u2013control study in PR China"],"prefix":"10.1002","volume":"12","author":[{"given":"Meiling","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pathology Jinan Maternity and Child Care Hospital  Jinan PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaorong","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pathology Jinan Maternity and Child Care Hospital  Jinan PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5194-7996","authenticated-orcid":false,"given":"Huayan","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Pathology The First Affiliated Hospital of Zhengzhou University  Zhengzhou PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengchun","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Obstetrics Jinan Maternity and Child Care Hospital  Jinan PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyu","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Information Jinan Maternal and Child Care Hospital  Jinan PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pathology Jinan Maternity and Child Care Hospital  Jinan PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanxue","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Pathology Jinan Maternity and Child Care Hospital  Jinan PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology Jinan Maternity and Child Care Hospital  Jinan PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengquan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pathology Magee\u2010Womens Hospital, University of Pittsburgh Medical Center  Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1016\/j.humpath.2007.05.025","article-title":"Villitis of unknown etiology: noninfectious chronic villitis in the placenta","volume":"38","author":"Redline RW","year":"2007","journal-title":"Hum Pathol"},{"key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"S53","DOI":"10.1016\/j.ajog.2015.08.041","article-title":"Chronic inflammation of the placenta: definition, classification, pathogenesis, and clinical significance","volume":"213","author":"Kim CJ","year":"2015","journal-title":"Am J Obstet Gynecol"},{"key":"e_1_2_9_4_1","doi-asserted-by":"crossref","first-page":"S21","DOI":"10.1016\/j.ajog.2015.05.056","article-title":"Classification of placental lesions","volume":"213","author":"Redline RW","year":"2015","journal-title":"Am J Obstet Gynecol"},{"key":"e_1_2_9_5_1","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s00428-025-04152-z","article-title":"Amsterdam placental workshop group consensus statement definitions revisited: basal chronic villitis","volume":"487","author":"Khong TY","year":"2025","journal-title":"Virchows Arch"},{"key":"e_1_2_9_6_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.jri.2021.103438","article-title":"Chronic villitis of unknown etiology (VUE): obstetrical features, outcome and treatment","volume":"148","author":"Mekinian A","year":"2021","journal-title":"J Reprod Immunol"},{"key":"e_1_2_9_7_1","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1080\/14767058.2020.1767577","article-title":"Villitis of unknown etiology (VUE): effect on placental size and association with clinical parameters","volume":"35","author":"Sebastian T","year":"2022","journal-title":"J Matern Fetal Neonatal Med"},{"key":"e_1_2_9_8_1","first-page":"473","article-title":"Villitis of unknown etiology is associated with major infiltration of fetal tissue by maternal inflammatory cells","volume":"143","author":"Redline RW","year":"1993","journal-title":"Am J Pathol"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2025.09.032"},{"key":"e_1_2_9_10_1","doi-asserted-by":"crossref","DOI":"10.1111\/aji.70077","article-title":"Understanding a potential role for the NLRP3 inflammasome in placenta\u2010mediated pregnancy complications","volume":"93","author":"Moss CG","year":"2025","journal-title":"Am J Reprod Immunol"},{"key":"e_1_2_9_11_1","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.placenta.2022.11.003","article-title":"Immunopathological insights into villitis of unknown etiology on the basis of transplant immunology","volume":"131","author":"Damas II","year":"2023","journal-title":"Placenta"},{"key":"e_1_2_9_12_1","doi-asserted-by":"crossref","first-page":"3919","DOI":"10.4049\/jimmunol.0803834","article-title":"Villitis of unknown etiology is associated with a distinct pattern of chemokine up\u2010regulation in the feto\u2010maternal and placental compartments: implications for conjoint maternal allograft rejection and maternal anti\u2010fetal graft\u2010versus\u2010host disease","volume":"182","author":"Kim MJ","year":"2009","journal-title":"J Immunol"},{"key":"e_1_2_9_13_1","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.placenta.2021.02.020","article-title":"Chronic villitis of unknown etiology: investigations into viral pathogenesis","volume":"107","author":"Ernst LM","year":"2021","journal-title":"Placenta"},{"key":"e_1_2_9_14_1","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.placenta.2022.02.006","article-title":"Recurrence risk of villitis of unknown etiology: analysis of a large retrospective cohort study, systematic review and meta\u2010analysis","volume":"120","author":"De Koning L","year":"2022","journal-title":"Placenta"},{"key":"e_1_2_9_15_1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.placenta.2023.11.001","article-title":"Impact of villitis of unknown etiology and adverse acute neonatal outcomes in Eastern Ontario","volume":"144","author":"Osborne B","year":"2023","journal-title":"Placenta"},{"key":"e_1_2_9_16_1","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.5858\/arpa.2017-0212-RA","article-title":"Fetal vascular malperfusion","volume":"141","author":"Heider A","year":"2017","journal-title":"Arch Pathol Lab Med"},{"key":"e_1_2_9_17_1","first-page":"449","article-title":"Practice guideline for examination of the placenta: developed by the Placental Pathology Practice Guideline Development Task Force of the College of American Pathologists","volume":"121","author":"Langston C","year":"1997","journal-title":"Arch Pathol Lab Med"},{"key":"e_1_2_9_18_1","doi-asserted-by":"crossref","first-page":"698","DOI":"10.5858\/arpa.2015-0225-CC","article-title":"Sampling and definitions of placental lesions: Amsterdam placental workshop group consensus statement","volume":"140","author":"Khong TY","year":"2016","journal-title":"Arch Pathol Lab Med"},{"key":"e_1_2_9_19_1","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1016\/j.placenta.2013.07.002","article-title":"The immunological basis of villitis of unknown etiology \u2013 review","volume":"34","author":"Tamblyn JA","year":"2013","journal-title":"Placenta"},{"key":"e_1_2_9_20_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.modpat.2022.100035","article-title":"Histopathologic and transcriptomic profiling identifies novel trophoblast defects in patients with preeclampsia and maternal vascular malperfusion","volume":"36","author":"Horii M","year":"2023","journal-title":"Mod Pathol"},{"key":"e_1_2_9_21_1","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/j.ajog.2022.05.043","article-title":"Diagnostic utility of serial circulating placental growth factor levels and uterine artery Doppler waveforms in diagnosing underlying placental diseases in pregnancies at high risk of placental dysfunction","volume":"227","author":"Agrawal S","year":"2022","journal-title":"Am J Obstet Gynecol"},{"key":"e_1_2_9_22_1","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1126\/science.1217141","article-title":"GBP5 promotes NLRP3 inflammasome assembly and immunity in mammals","volume":"336","author":"Shenoy AR","year":"2012","journal-title":"Science"},{"key":"e_1_2_9_23_1","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.placenta.2022.08.012","article-title":"Association of distinct features of villitis of unknown etiology histopathology and fetal growth restriction diagnosis in a retrospective cohort from Eastern Ontario","volume":"128","author":"Osborne B","year":"2022","journal-title":"Placenta"},{"key":"e_1_2_9_24_1","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1111\/apm.12849","article-title":"Fetal vascular malperfusion, an update","volume":"126","author":"Redline RW","year":"2018","journal-title":"APMIS"},{"key":"e_1_2_9_25_1","doi-asserted-by":"crossref","first-page":"79","DOI":"10.3390\/life14010079","article-title":"Prevalence of fetal inflammatory response syndrome and villitis of unknown etiology in the placenta of Saudi women and their association with baby sex","volume":"14","author":"Aldahmash W","year":"2024","journal-title":"Life"},{"key":"e_1_2_9_26_1","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.placenta.2023.02.002","article-title":"Villitis of unknown etiology, chronic deciduitis, chronic chorioamnionitis and chronic histiocytic intervillositis in monozygotic and dizygotic twin pregnancies. A retrospective analysis of 16 cases","volume":"133","author":"Feist H","year":"2023","journal-title":"Placenta"},{"key":"e_1_2_9_27_1","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/j.pathol.2022.03.015","article-title":"Chronic villitis of unknown aetiology: an Australian institution's 5\u2010year experience","volume":"54","author":"Ip S","year":"2022","journal-title":"Pathology"},{"key":"e_1_2_9_28_1","doi-asserted-by":"crossref","first-page":"e3351","DOI":"10.1055\/a-2223-3348","article-title":"Maternal factors and placental pathologies associated with a diagnosis of chronic villitis","volume":"41","author":"Rose SJ","year":"2024","journal-title":"Am J Perinatol"},{"key":"e_1_2_9_29_1","doi-asserted-by":"crossref","first-page":"123.e1","DOI":"10.1016\/j.ajog.2024.04.002","article-title":"Chronic villitis as a distinctive feature of placental injury in maternal SARS\u2010CoV\u20102 infection","volume":"232","author":"Gabby LC","year":"2025","journal-title":"Am J Obstet Gynecol"}],"container-title":["The Journal of Pathology: Clinical Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/2056-4538.70084","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/2056-4538.70084","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/2056-4538.70084","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T10:37:50Z","timestamp":1773657470000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/2056-4538.70084"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3]]},"references-count":28,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["10.1002\/2056-4538.70084"],"URL":"https:\/\/doi.org\/10.1002\/2056-4538.70084","archive":["Portico"],"relation":{},"ISSN":["2056-4538","2056-4538"],"issn-type":[{"value":"2056-4538","type":"print"},{"value":"2056-4538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3]]},"assertion":[{"value":"2025-11-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70084"}}