{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T19:09:17Z","timestamp":1785179357207,"version":"3.55.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T00:00:00Z","timestamp":1610323200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006306","name":"Sigrid Jus\u00e9liuksen S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006306","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008376","name":"Helsingin ja Uudenmaan Sairaanhoitopiiri","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008376","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Human pregnancy alters profoundly the immune system. The local involvement and mechanisms of activation of the complement system in the cervicovaginal milieu during pregnancy and delivery remain unexplored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>To determine whether normal pregnancy and delivery are associated with local activation of complement or changes in the immunoglobulin profile in the cervix.<\/jats:p><\/jats:sec><jats:sec><jats:title>Study Design<\/jats:title><jats:p>This study was designed to assess IgA, IgG, and complement activation in the cervicovaginal area in three groups of patients: i) 49 pregnant women (week 41+3\u201342+0) not in active labor, ii) 24 women in active labor (38+4\u201342+2), and iii) a control group of nonpregnant women (n=23) at child-bearing age. We collected mucosal samples from the lateral fornix of the vagina and external cervix during routine visits and delivery. The Western blot technique was used to detect complement C3 and its activation products. For semiquantitative analysis, the bands of the electrophoresed proteins in gels were digitized on a flatbed photo scanner and analyzed. IgA and IgG were analyzed by Western blotting and quantified by ELISA. One-way ANOVA and Tukey\u2019s Multiple Comparison tests were used for statistical comparisons.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A higher abundance but lower activation level of C3 in both the external cervix (P&amp;lt;0.001) and lateral fornix of the vagina (P&amp;lt;0.001) was observed during delivery (58 \u00b1 22, n= 24) in comparison to the groups of nonpregnant (72 \u00b1 13%; mean \u00b1 SD, n=23) and pregnant women (78 \u00b1 22%, n=49). Complement activating IgG was detected in higher abundance than IgA in the cervicovaginal secretions of pregnant women. In a small proportion samples also C3-IgG complexes were detected.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results reveal an unexpectedly strong activation of the complement system and the presence IgG immunoglobulins in the cervicovaginal area during pregnancy, active labor, and among nonpregnant women. In contrast to the higher amounts of C3 in the cervicovaginal secretions during labor, its activation level was lower. Complement activating IgG was detected in higher concentrations than IgA in the mucosal secretions during pregnancy and labor. Taken together our results imply the presence a locally operating humoral immune system in the cervicovaginal mucosa.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2020.563073","type":"journal-article","created":{"date-parts":[[2021,1,12]],"date-time":"2021-01-12T20:12:05Z","timestamp":1610482325000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Activation of the Complement System in the Lower Genital Tract During Pregnancy and Delivery"],"prefix":"10.3389","volume":"11","author":[{"given":"Sivan","family":"Livson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Jarva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilkka","family":"Kalliala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Inkeri","family":"Lokki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenni","family":"Heikkinen-Eloranta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pekka","family":"Nieminen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seppo","family":"Meri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,1,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1111\/j.1600-065X.2006.00436.x","article-title":"Stranger in a strange land","volume":"213","author":"Hunt","year":"2006","journal-title":"Immunol Rev"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jri.2010.01.008","article-title":"Immune regulation of conception and embryo implantation-all about quality control","volume":"85","author":"Robertson","year":"2010","journal-title":"J Reprod Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2012-303305","article-title":"Effects of coronary sinus occlusion on myocardial ischaemia in humans: role of coronary collateral function","volume":"99","author":"Stoller","year":"2013","journal-title":"Heart"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2013.120","article-title":"IgG in cervicovaginal mucus traps HSV and prevents vaginal herpes infections","volume":"7","author":"Wang","year":"2014","journal-title":"Mucosal Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1081\/IAS-120003658","article-title":"Validation of a high sensitive immunoenzymatic assay to establish the origin of immunoglobulins in female genital secretions","volume":"23","author":"Bard","year":"2002","journal-title":"J Immunoassay Immunochem"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2014.10.1098","article-title":"Activation of vestibule-associated lymphoid tissue in localized provoked vulvodynia","volume":"212","author":"Tommola","year":"2015","journal-title":"Am J Obstet Gynecol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/14.1.229","article-title":"Leukocytes infiltrate the myometrium during human parturition: further evidence that labour is an inflammatory process","volume":"14","author":"Thomson","year":"1999","journal-title":"Hum Reprod (Oxford England)"},{"key":"B8","doi-asserted-by":"publisher","first-page":"S8","DOI":"10.1186\/1471-2393-13-S1-S8","article-title":"Maternal circulating leukocytes display early chemotactic responsiveness during late gestation","author":"Gomez-Lopez","year":"2013","journal-title":"BMC Pregnancy Childbirth"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod66.2.445","article-title":"Immunolocalization of proinflammatory cytokines in myometrium, cervix, and fetal membranes during human parturition at term","volume":"66","author":"Young","year":"2002","journal-title":"Biol Reproduction"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-017-0645-x","article-title":"Complement activation, a threat to pregnancy","volume":"40","author":"Girardi","year":"2018","journal-title":"Semin Immunopathol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1530\/REP-16-0453","article-title":"Sterile inflammation and pregnancy complications: a review","volume":"152","author":"Nadeau-Vallee","year":"2016","journal-title":"Reproduction"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12440","article-title":"A Role for the Inflammasome in Spontaneous Labor at Term","volume":"79","author":"Romero","year":"2018","journal-title":"Am J Reprod Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.semnephrol.2013.08.001","article-title":"Overview of complement activation and regulation","volume":"33","author":"Noris","year":"2013","journal-title":"Semin Nephrol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.3.1305","article-title":"The central role of the alternative complement pathway in human disease","volume":"176","author":"Thurman","year":"2006","journal-title":"J Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2009.04.029","article-title":"Complement in human diseases: Lessons from complement deficiencies","volume":"46","author":"Botto","year":"2009","journal-title":"Mol Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200104123441506","article-title":"Complement. Second of two parts","volume":"344","author":"Walport","year":"2001","journal-title":"N Engl J Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1923","article-title":"Complement: a key system for immune surveillance and homeostasis","volume":"11","author":"Ricklin","year":"2010","journal-title":"Nat Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/0009-8981(74)90272-1","article-title":"Adaption of SMA 12-60 methodology to the analysis of urine","volume":"53","author":"Baines","year":"1974","journal-title":"Clinica chimica acta; Int J Clin Chem"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1080\/14767050500072722","article-title":"Normal pregnancy is characterized by systemic activation of the complement system","volume":"17","author":"Richani","year":"2005","journal-title":"J Maternal Fetal Neonatal Med Off J Eur Assoc Perinatal Medicine Fed Asia Oceania Perinatal Societies Int Soc Perinatal Obstet"},{"key":"B20","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.jri.2015.02.008","article-title":"Blood SC5b-9 complement levels increase at parturition during term and preterm labor","volume":"109","author":"Segura-Cervantes","year":"2015","journal-title":"J Reprod Immunol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.molimm.2005.06.017","article-title":"The complement system in the pathophysiology of pregnancy","volume":"43","author":"Girardi","year":"2006","journal-title":"Mol Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.41.6.650","article-title":"C3 and C4 complement components and acute phase proteins in late pregnancy and parturition","volume":"41","author":"Kovar","year":"1988","journal-title":"J Clin Pathol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1080\/0891693031000067322","article-title":"The role of complement in pregnancy and fetal loss","volume":"36","author":"Girardi","year":"2003","journal-title":"Autoimmunity"},{"key":"B24","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.molimm.2015.02.030","article-title":"The complement system and adverse pregnancy outcomes","volume":"67","author":"Regal","year":"2015","journal-title":"Mol Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0897.1982.tb00198.x","article-title":"Circulating C3, C4, and C3 split products (C3c and C3d) during normal pregnancy","volume":"2","author":"Teisner","year":"1982","journal-title":"Am J Reprod Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1111\/aji.13202","article-title":"Normal range of complement components during pregnancy: A prospective study","volume":"83","author":"He","year":"2020","journal-title":"Am J Reprod Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00312","article-title":"Complement activation and regulation in preeclamptic placenta","volume":"5","author":"Lokki","year":"2014","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00589","article-title":"Analysis of Complement C3 Gene Reveals Susceptibility to Severe Preeclampsia","volume":"8","author":"Lokki","year":"2017","journal-title":"Front Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1160\/TH11-08-0554","article-title":"Complement activation in patients with isolated antiphospholipid antibodies or primary antiphospholipid syndrome","volume":"107","author":"Breen","year":"2012","journal-title":"Thromb Haemostasis"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2012.02.035","article-title":"Prepregnancy obesity and complement system activation in early pregnancy and the subsequent development of preeclampsia","volume":"206","author":"Lynch","year":"2012","journal-title":"Am J Obstet Gynecol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1097\/AOG.0b013e3181fc3afa","article-title":"Early elevations of the complement activation fragment C3a and adverse pregnancy outcomes","volume":"117","author":"Lynch","year":"2011","journal-title":"Obstet Gynecol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2015.11.001","article-title":"The relationship of circulating proteins in early pregnancy with preterm birth","volume":"214","author":"Lynch","year":"2016","journal-title":"Am J Obstet Gynecol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jri.2012.07.008","article-title":"Comparison of the mechanisms responsible for cervical remodeling in preterm and term labor","volume":"97","author":"Gonzalez","year":"2013","journal-title":"J Reprod Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1097\/00005537-200010000-00035","article-title":"Complement C3 cleavage and cytokines interleukin-1beta and tumor necrosis factor-alpha in otitis media with effusion","volume":"110","author":"N\u00e4rki\u00f6-M\u00e4kel\u00e4","year":"2000","journal-title":"Laryngoscope"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2013.00200","article-title":"Antibodies and their receptors: different potential roles in mucosal defense","volume":"4","author":"Horton","year":"2013","journal-title":"Front Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00262","article-title":"Complement System Part I - Molecular Mechanisms of Activation and Regulation","volume":"6","author":"Merle","year":"2015","journal-title":"Front Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.12412","article-title":"Low pH impairs complement-dependent cytotoxicity against IgG-coated target cells","volume":"7","author":"Dantas","year":"2016","journal-title":"Oncotarget"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00257","article-title":"Complement System Part II: Role in Immunity","volume":"6","author":"Merle","year":"2015","journal-title":"Front Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2019.101337","article-title":"Regulation of the complement system and immunological tolerance in pregnancy","volume":"45","author":"Teiril\u00e4","year":"2019","journal-title":"Semin Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2007.06.150","article-title":"Complement analysis in the 21st century","volume":"44","author":"Mollnes","year":"2007","journal-title":"Mol Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.105.043133","article-title":"Immunological microenvironments in the human vagina and cervix: mediators of cellular immunity are concentrated in the cervical transformation zone","volume":"73","author":"Pudney","year":"2005","journal-title":"Biol Reproduction"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1084\/jem.175.4.939","article-title":"Activation of the alternative pathway of complement by monoclonal lambda light chains in membranoproliferative glomerulonephritis","volume":"175","author":"Meri","year":"1992","journal-title":"J Exp Medicine"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2013.10.010","article-title":"Microbiome, sex hormones, and immune responses in the reproductive tract: challenges for vaccine development against sexually transmitted infections","volume":"32","author":"Brotman","year":"2014","journal-title":"Vaccine"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2014.10.1098","article-title":"Activation of vestibule-associated lymphoid tissue in localized provoked vulvodynia","volume":"212","author":"Tommola","year":"2015","journal-title":"Am J Obstet Gynecol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.563073\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,14]],"date-time":"2021-01-14T00:46:48Z","timestamp":1610585208000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.563073\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,11]]},"references-count":44,"alternative-id":["10.3389\/fimmu.2020.563073"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2020.563073","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,11]]},"article-number":"563073"}}