{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T04:50:07Z","timestamp":1782190207079,"version":"3.54.5"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"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>Background<\/jats:title>\n                    <jats:p>Cervical insufficiency (CI), characterized by painless cervical dilation during the second trimester, is a major cause of preterm birth. However, the local microenvironment associated with CI, particularly the roles of immune-checkpoint regulators (ICRs) and inflammatory cytokines and chemokines (ICKs), remains poorly understood. This study aimed to investigate the changes in ICRs and ICKs before and after cervical cerclage, as well as to identify predictors of preterm birth in patients with CI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A total of 64 women with CI comprised the study group, and 128 endocervical swab samples were collected before and after cervical cerclage. Participants were categorized according to disease severity, specifically, membrane bulging vs. non-bulging, and delivery outcomes, namely preterm vs. full-term delivery. Seventeen soluble ICRs and 17 ICKs were quantified using a Luminex multiplex assay.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our results indicated significant differences in immunologic microenvironments before and after cerclage. Among ICRs, BTLA, CD28, GITR, and CD80 (B7-1) levels were significantly decreased after cerclage compared with pre-cerclage levels. In contrast, TIM-3 and PD-L2 were significantly increased, along with twelve other ICKs. Pre-cerclage ICRs and ICKs were generally higher in patients who received emergent cerclage with bulging membranes compared to those without bulging membranes. In particular, pre-cerclage levels of CCL2 (MCP-1), CXCL10 (IP-10), GM-CSF, IL-1\u03b1, IL-6, IL-10, and IL-17A were significantly elevated in patients who subsequently experienced preterm birth compared with those who delivered at term. Post-cerclage levels of LAG-3, CTLA-4, CD86 (B7-2), and PD-L2 were significantly lower in the preterm birth group. Among these, pre-cerclage IL-17A was the most significant predictor (odds ratio = 2.3) in the final multivariate model. The combination of pre-cerclage IL-17A and post-cerclage PD-L1 demonstrated excellent predictive performance, with an area under the receiver operating characteristic curve (AUC) of 0.901.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our study revealed the dynamic changes of ICKs and ICRs following cervical cerclage and identified key markers for preterm birth, including pre-cerclage IL-17A and post-cerclage PD-L1, in patients with CI. By focusing on these components, our work enhances the understanding of the local immune landscape and supports the development of targeted strategies to improve pregnancy outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1731111","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T04:29:54Z","timestamp":1782188994000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Dynamics of immune-checkpoint regulators and inflammatory cytokines and chemokines associated with preterm birth before and after cervical cerclage"],"prefix":"10.3389","volume":"17","author":[{"given":"Seri","family":"Jeong","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine","place":["Seoul, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keun-Young","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine","place":["Seoul, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ga-Hyun","family":"Son","sequence":"additional","affiliation":[{"name":"Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine","place":["Seoul, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyong-No","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Chungnam National University College of Medicine, Chungnam National University Hospital","place":["Daejeon, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Won Kyong","family":"Cho","sequence":"additional","affiliation":[{"name":"Agriculture and Life Sciences Research Institute, Kangwon National University","place":["Chuncheon, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoseong","family":"Choi","sequence":"additional","affiliation":[{"name":"Biocube System, Inc.","place":["Suwon, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonghyun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Kwak-Kim","sequence":"additional","affiliation":[{"name":"Reproductive Medicine and Immunology, Obstetrics and Gynecology, Clinical Sciences Department, Chicago Medical School, Rosalind Franklin University of Medicine and Science","place":["North Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)00878-4","article-title":"National, regional, and global estimates of preterm birth in 2020, with trends from 2010: A systematic analysis","volume":"402","author":"Ohuma","year":"2023","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1111\/1471-0528.14273","article-title":"Variations in very preterm birth rates in 30 high-income countries: Are valid international comparisons possible using routine data","volume":"124","author":"Delnord","year":"2017","journal-title":"BJOG"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/1471-0528.15600","article-title":"Prospective observational study of vaginal microbiota pre- and post-rescue cervical cerclage","volume":"126","author":"Brown","year":"2019","journal-title":"BJOG"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199602293340904","article-title":"The length of the cervix and the risk of spontaneous premature delivery","volume":"334","author":"Iams","year":"1996","journal-title":"N Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1016\/j.ajog.2007.05.041","article-title":"Expectant management compared with physical examination-indicated cerclage (Em-Pec) in selected women with a dilated cervix at 14(0\/7)-25(6\/7) weeks: Results from the Em-Pec international cohort study","volume":"197","author":"Pereira","year":"2007","journal-title":"Am J Obstet Gynecol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/j.ajog.2009.08.015","article-title":"Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened midtrimester cervical length","volume":"201","author":"Owen","year":"2009","journal-title":"Am J Obstet Gynecol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1186\/s40168-016-0223-9","article-title":"The interaction between vaginal microbiota, cervical length, and vaginal progesterone treatment for preterm birth risk","volume":"5","author":"Kindinger","year":"2017","journal-title":"Microbiome"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1067\/mob.2001.116685","article-title":"An in vitro study of antibacterial properties of the cervical mucus plug in pregnancy","volume":"185","author":"Hein","year":"2001","journal-title":"Am J Obstet Gynecol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ajog.2025.04.009","article-title":"Experimental evidence that cervical cerclage prevents ascending intra-amniotic infection","volume":"233","author":"Parry","year":"2025","journal-title":"Am J Obstet Gynecol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD008991.pub3","article-title":"Cervical stitch (cerclage) for preventing preterm birth in singleton pregnancy","volume":"6","author":"Alfirevic","year":"2017","journal-title":"Cochrane Database Syst Rev"},{"key":"B11","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1016\/j.ajog.2017.06.024","article-title":"Cervical cerclage placement decreases local levels of proinflammatory cytokines in patients with cervical insufficiency","volume":"217","author":"Monsanto","year":"2017","journal-title":"Am J Obstet Gynecol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1080\/00016340902852898","article-title":"The cervical mucus plug: Structured review of the literature","volume":"88","author":"Becher","year":"2009","journal-title":"Acta Obstet Gynecol Scand"},{"key":"B13","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1016\/j.ajog.2023.10.004","article-title":"Cerclage prevents ascending intrauterine infection in pregnant mice","volume":"230","author":"Zhang","year":"2024","journal-title":"Am J Obstet Gynecol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1080\/1047322x.1990.10389587","article-title":"Estimation of average concentration in the presence of nondetectable values","volume":"5","author":"Hornung","year":"1990","journal-title":"Appl Occup Environ Hygiene"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2172-9-59","article-title":"Evaluation of regression methods when immunological measurements are constrained by detection limits","volume":"9","author":"Uh","year":"2008","journal-title":"BMC Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btm069","article-title":"Pcamethods--a Bioconductor package providing Pca methods for incomplete data","volume":"23","author":"Stacklies","year":"2007","journal-title":"Bioinformatics"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv468","article-title":"Clustvis: A web tool for visualizing clustering of multivariate data using principal component analysis and heatmap","volume":"43","author":"Metsalu","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpobgyn.2007.03.009","article-title":"Cervical cerclage in the prevention of preterm birth","volume":"21","author":"Simcox","year":"2007","journal-title":"Best Pract Res Clin Obstet Gynaecol"},{"key":"B19","volume-title":"Cervical Cerclage","author":"Bieber","year":"2023"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1515\/jpm-2018-0388","article-title":"Patients with acute cervical insufficiency without intra-amniotic infection\/inflammation treated with cerclage have a good prognosis","volume":"47","author":"Monckeberg","year":"2019","journal-title":"J Perinat Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.837645","article-title":"The role of immune checkpoint molecules on macrophages in cancer, infection, and autoimmune pathologies","volume":"13","author":"Brom","year":"2022","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.3390\/v12091051","article-title":"Immune checkpoints in viral infections","volume":"12","author":"Cai","year":"2020","journal-title":"Viruses"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/s0002-9378(99)70542-9","article-title":"Cervical incompetence: Elective, emergent, or urgent cerclage","volume":"181","author":"Kurup","year":"1999","journal-title":"Am J Obstet Gynecol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"3515","DOI":"10.3390\/jcm14103515","article-title":"Comparison of perinatal outcomes following elective and emergency cerclage insertion: A ten-year retrospective cohort study","volume":"14","author":"Lugowski","year":"2025","journal-title":"J Clin Med"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.6994","article-title":"Rescue cervical cerclage : Prevention of a previable birth","volume":"12","author":"Pandey","year":"2020","journal-title":"Cureus"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1080\/01443615.2023.2280840","article-title":"Role of the Cd40-Cd40l expression level pathway in the diagnosis of unexplained recurrent pregnancy loss","volume":"43","author":"Ding","year":"2023","journal-title":"J Obstet Gynaecol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1007\/s00404-024-07887-3","article-title":"Emergency cerclage outcomes for bulging fetal membranes: A single-center retrospective study","volume":"311","author":"Masui","year":"2025","journal-title":"Arch Gynecol Obstet"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1097\/OGX.0b013e31828737c7","article-title":"Emergency cerclage: Literature review","volume":"68","author":"Namouz","year":"2013","journal-title":"Obstet Gynecol Surv"},{"key":"B29","doi-asserted-by":"publisher","first-page":"101782","DOI":"10.1016\/j.ajogmf.2025.101782","article-title":"Cervical dilation staging and early preterm birth risk after exam-indicated cerclage: A retrospective cohort study with the International Collaborative for Cerclage Longitudinal Evaluation and Research (Ic-Clear)","volume":"8","author":"Robinson","year":"2025","journal-title":"Am J Obstet Gynecol MFM"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1080\/14767050500141329","article-title":"Monocyte chemotactic protein-1 is increased in the amniotic fluid of women who deliver preterm in the presence or absence of intra-amniotic infection","volume":"17","author":"Esplin","year":"2005","journal-title":"J Matern Fetal Neonatal Med"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1053457","article-title":"Ccl2: An important cytokine in normal and pathological pregnancies: A review","volume":"13","author":"Lin","year":"2022","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/aji.13424","article-title":"Granulocyte-macrophage colony-stimulating factor initiates amniotic membrane rupture and preterm birth in a mouse model","volume":"86","author":"Nold","year":"2021","journal-title":"Am J Reprod Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1177\/1933719118804420","article-title":"Block of granulocyte-macrophage colony-stimulating factor prevents inflammation-induced preterm birth in a mouse model for parturition","volume":"26","author":"Nold","year":"2019","journal-title":"Reprod Sci"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12800","article-title":"Il-17 in neonatal health and disease","volume":"79","author":"Lawrence","year":"2018","journal-title":"Am J Reprod Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12803","article-title":"Chorioamnionitis, Il-17a, and fetal origins of neurologic disease","volume":"79","author":"Lawrence","year":"2018","journal-title":"Am J Reprod Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2021.40584","article-title":"Association of maternal inflammation during pregnancy with birth outcomes and infant growth among women with or without Hiv in India","volume":"4","author":"Shafiq","year":"2021","journal-title":"JAMA Netw Open"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1186\/s12958-018-0444-9","article-title":"Endometrial Tgf-Beta, Il-10, Il-17 and autophagy are dysregulated in women with recurrent implantation failure with chronic endometritis","volume":"17","author":"Wang","year":"2019","journal-title":"Reprod Biol Endocrinol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"7903","DOI":"10.1038\/s41598-023-35051-5","article-title":"Single cell profiling at the maternal-fetal interface reveals a deficiency of Pd-L1(+) non-immune cells in human spontaneous preterm labor","volume":"13","author":"Liu","year":"2023","journal-title":"Sci Rep"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0000000000000418","article-title":"Immune checkpoint inhibitor exposure in pregnancy: A scoping review","volume":"45","author":"Salehi","year":"2022","journal-title":"J Immunother"},{"key":"B40","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1093\/humrep\/deu260","article-title":"Cervical conization doubles the risk of preterm and very preterm birth in assisted reproductive technology twin pregnancies","volume":"30","author":"Pinborg","year":"2015","journal-title":"Hum Reprod"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3802\/jgo.2010.21.4.207","article-title":"Prediction and prevention of preterm birth after cervical conization","volume":"21","author":"Lee","year":"2010","journal-title":"J Gynecol Oncol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00846","article-title":"Immune checkpoint molecules in reproductive immunology","volume":"10","author":"Miko","year":"2019","journal-title":"Front Immunol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"499","DOI":"10.3390\/ijms25010499","article-title":"Soluble forms of immune checkpoints and their ligands as potential biomarkers in the diagnosis of recurrent pregnancy loss-a preliminary study","volume":"25","author":"Zych","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2010.01.011","article-title":"Cervical remodeling during pregnancy and parturition","volume":"21","author":"Timmons","year":"2010","journal-title":"Trends Endocrinol Metab"},{"key":"B45","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1095\/biolreprod.116.142844","article-title":"Contributions to the dynamics of cervix remodeling prior to term and preterm birth","volume":"96","author":"Yellon","year":"2017","journal-title":"Biol Reprod"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1731111\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T04:29:55Z","timestamp":1782188995000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1731111\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,23]]},"references-count":45,"alternative-id":["10.3389\/fimmu.2026.1731111"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1731111","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,23]]},"article-number":"1731111"}}