{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:50:21Z","timestamp":1787028621513,"version":"build-2736575974"},"reference-count":53,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T00:00:00Z","timestamp":1638835200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Successful pregnancy requires an immunological shift with T helper CD4+ bias based on disbalance Th1\/Th17 versus Th2\/T regulatory (Tregs) required to induce tolerance against the semi-allogeneic fetus and placenta and to support fetal growth. Considered a pregnancy-specific hypertensive disorder, pre-eclampsia is characterized by multifaceted organ involvement related to impaired maternal immune tolerance to paternal antigens triggered by hypoxic placental injury as well as excessive local and systemic anti-angiogenic and inflammatory factor synthesis. Both systemic and local Th1\/Th2 shift further expands to Th17 cells and their cytokines (IL-17) complemented by suppressive Treg and Th2 cytokines (IL-10, IL-4); alterations in Th17 and Tregs cause hypertension during pregnancy throughout vasoactive factors and endothelial dysfunction, providing an explanatory link between immunological and vascular events in the pathobiology of pre-eclamptic pregnancy. Apart from immunological changes representative of normotensive pregnancy, lupus pregnancy is generally defined by higher serum pro-inflammatory cytokines, lower Th2 polarization, defective and lower number of Tregs, potential blockade of complement inhibitors by anti-phospholipid antibodies, and similar immune alterations to those seen in pre-eclampsia. The current review underpins the immune mechanisms of pre-eclampsia focusing on local (placental) and systemic (maternal) aberrant adaptive and innate immune response versus normotensive pregnancy and pregnancy in systemic autoimmune conditions, particularly lupus.<\/jats:p>","DOI":"10.3390\/jcm10245722","type":"journal-article","created":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T11:00:23Z","timestamp":1638874823000},"page":"5722","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["The Complement System, T Cell Response, and Cytokine Shift in Normotensive versus Pre-Eclamptic and Lupus Pregnancy"],"prefix":"10.3390","volume":"10","author":[{"given":"Eugen","family":"Ancu\u021ba","sequence":"first","affiliation":[{"name":"Research Department, \u201cElena Doamna\u201d Obstetrics and Gynecology Clinical Hospital, 700398 Ia\u0219i, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radu","family":"Zamfir","sequence":"additional","affiliation":[{"name":"Fundeni Clinical Institute, 022328 Bucure\u0219ti, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Martinescu","sequence":"additional","affiliation":[{"name":"Research Department, \u201cElena Doamna\u201d Obstetrics and Gynecology Clinical Hospital, 700398 Ia\u0219i, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Drago\u0219 Valentin","family":"Crauciuc","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Ia\u0219i, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1777-8121","authenticated-orcid":false,"given":"Codrina","family":"Ancu\u021ba","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Ia\u0219i, Romania"},{"name":"2nd Rheumatology Department, Clinical Rehabilitation Hospital, 700661 Ia\u0219i, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.humimm.2021.01.004","article-title":"Review of the immune mechanisms of pre-eclampsia and the potential of immune modulating therapy","volume":"82","author":"Collier","year":"2021","journal-title":"Hum. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1161\/CIRCRESAHA.118.313276","article-title":"Pre-eclampsia Pathophysiology, Challenges, and Perspectives. Compendium on the Pathophysiology and Treatment of Hypertension","volume":"124","author":"Rana","year":"2019","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15761\/JPR.1000124","article-title":"Defining pregnancy phases with cytokine shift","volume":"1","author":"Dutta","year":"2017","journal-title":"J. Pregnancy Reprod."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.immuni.2018.07.017","article-title":"Immunity Review Interferons and Proinflammatory Cytokines in Pregnancy and Fetal Development","volume":"49","author":"Yockey","year":"2018","journal-title":"Immunity"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/ni.3131","article-title":"Immune mechanisms at the maternal-fetal interface: Perspectives and challenges","volume":"16","author":"Prabhudas","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1152\/ajpregu.00052.2016","article-title":"Identifying immune mechanisms mediating the hypertension during pre-eclampsia","volume":"311","author":"LaMarca","year":"2016","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_7","first-page":"225","article-title":"Elucidating immune mechanisms causing hypertension during pregnancy","volume":"28","author":"LaMarca","year":"2013","journal-title":"Phisiology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4224","DOI":"10.1172\/JCI122182","article-title":"Regulatory T cells in embryo implantation and the immune response to pregnancy","volume":"128","author":"Robertson","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.3389\/fimmu.2019.01305","article-title":"Differential dynamics of the maternal immune system in healthy pregnancy and pre-eclampsia","volume":"10","author":"Han","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Todros, T., Paulesu, L., Cardaropoli, S., Rolfo, A., Masturzo, B., Ermini, L., Romagnoli, R., and Ietta, F. (2021). Role of the Macrophage Migration Inhibitory Factor in the Pathophysiology of Pre-Eclampsia. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041823"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/s41581-019-0119-6","article-title":"Pre-eclampsia: Pathogenesis, novel diagnostics and therapies","volume":"15","author":"Phipps","year":"2019","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1016\/j.molmed.2021.05.003","article-title":"Pre-eclampsia: Challenges for nanomedicine development in pregnancy","volume":"27","author":"Binder","year":"2021","journal-title":"Trends Mol. Med."},{"key":"ref_13","unstructured":"American College of Obstetricians and Gynecologists, and Task Force on Hypertension in Pregnancy (2013). Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists\u2019 Task Force on Hypertension in Pregnancy. Obs. Gynecol., 122, 1122\u20131131."},{"key":"ref_14","unstructured":"ACOG (2019). Practice bulletin no. 202 Summary: Gestational hypertension and pre-eclampsia. Obs. Gynecol., 133, 211\u2013214."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2775","DOI":"10.1172\/JCI70431","article-title":"Pre-eclampsia: A link between trophoblast dysregulation and an antiangiogenic state","volume":"123","author":"Romero","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1136\/annrheumdis-2020-218272","article-title":"Update \u03bfn the diagnosis and management of systemic lupus erythematosus","volume":"80","author":"Fanouriakis","year":"2021","journal-title":"Ann. Rheum. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"61","DOI":"10.37897\/RJR.2021.2.3","article-title":"Pregnancy, systemic lupus erythematosus and a short communication on labor complications as new onset of the disease","volume":"30","author":"Simionescu","year":"2021","journal-title":"Rom. J. Rheumatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1136\/annrheumdis-2016-209770","article-title":"EULAR recommendations for women\u2019s health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and\/or antiphospholipid syndrome","volume":"76","author":"Andreoli","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Fernandes, M., Bernardino, V., Taulaigo, A., Fernandes, J., Llad\u00f3, A., and Serrano, F. (2021). Systemic Lupus Erythematosus Pregnancy, InTech Open.","DOI":"10.5772\/intechopen.99008"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.3389\/fimmu.2020.02084","article-title":"The Complement System in the Pathophysiology of Pregnancy and in Systemic Autoimmune Rheumatic Diseases during Pregnancy","volume":"11","author":"Chighizola","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1136\/annrheumdis-2017-212224","article-title":"Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and\/or antiphospholipid antibodies","volume":"77","author":"Kim","year":"2018","journal-title":"Ann. Rheum. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s42358-019-0082-8","article-title":"Altered Tregs and oxidative stress in pregnancy associated lupus","volume":"59","author":"Pannu","year":"2019","journal-title":"Adv. Rheumatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"101337","DOI":"10.1016\/j.smim.2019.101337","article-title":"Regulation of the complement system and immunological tolerance in pregnancy","volume":"45","author":"Kotimaa","year":"2019","journal-title":"Semin. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.3389\/fimmu.2020.01681","article-title":"Essential Role of Complement in Pregnancy: From Implantation to Parturition and Beyond","volume":"11","author":"Girardi","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.1084\/jem.20061022","article-title":"Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction","volume":"203","author":"Girardi","year":"2006","journal-title":"J. Exp. Med."},{"key":"ref_26","doi-asserted-by":"crossref","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":"ref_27","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/aji.12000","article-title":"Complement in Pregnancy: A Delicate Balance","volume":"69","author":"Denny","year":"2013","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/j.celrep.2019.04.109","article-title":"Three Types of Functional Regulatory T Cells Control T Cell Responses at the Human Maternal-Fetal Interface","volume":"27","author":"Benner","year":"2019","journal-title":"Cell Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1111\/j.1365-2249.2011.04493.x","article-title":"Pregnancy-associated diseases are characterized by the composition of the systemic regulatory T cell (T reg) pool with distinct subsets of T regs","volume":"167","author":"Steinborn","year":"2012","journal-title":"Clin. Exp. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1111\/j.1365-2567.2004.01869.x","article-title":"Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset","volume":"112","author":"Somerset","year":"2004","journal-title":"Immunology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.3389\/fimmu.2018.01934","article-title":"Clonally Expanded Decidual Effector Regulatory T Cells Increase in Late Gestation of Normal Pregnancy, but Not in Preeclampsia, in Humans","volume":"9","author":"Tsuda","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1126\/science.1111726","article-title":"Latest advances in understanding pre-eclampsia","volume":"308","author":"Redman","year":"2005","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.3389\/fimmu.2020.01864","article-title":"Mechanisms of key innate immune cells in early-and late-onset pre-eclampsia","volume":"11","author":"Aneman","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1111\/apha.12106","article-title":"Pathophysiology of hypertension in pre-eclampsia: A lesson in integrative physiology","volume":"208","author":"Palei","year":"2013","journal-title":"Acta Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1067\/mob.2001.112905","article-title":"Mild gestational hypertension remote from term: Progression and outcome","volume":"184","author":"Barton","year":"2001","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1161\/HYPERTENSIONAHA.118.11644","article-title":"Research Recommendations from the National Institutes of Health Workshop on Predicting, Preventing, and Treating Preeclampsia","volume":"73","author":"Abrahams","year":"2019","journal-title":"Hypertension"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"i1753","DOI":"10.1136\/bmj.i1753","article-title":"High Risk of Pre-eclampsia Identification Group. Clinical risk factors for pre-eclampsia determined in early pregnancy: Systematic review and meta-analysis of large cohort studies","volume":"353","author":"Bartsch","year":"2016","journal-title":"BMJ"},{"key":"ref_38","first-page":"193","article-title":"Placental sFLT1 is associated with complement activation and syncytiotrophoblast damage in pre-eclampsia, Hypertens","volume":"38","author":"Zsengeller","year":"2019","journal-title":"Pregnancy"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fimmu.2019.03098","article-title":"Dysregulation of Complement Activation and Placental Dysfunction: A Potential Target to Treat Pre-eclampsia?","volume":"10","author":"Pierik","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"312","DOI":"10.3389\/fimmu.2014.00312","article-title":"Complement Activation and Regulation in Pre-eclamptic Placenta","volume":"5","author":"Lokki","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1161\/HYPERTENSIONAHA.112.194324","article-title":"Pre-eclampsia is characterized by placental complement dysregulation","volume":"60","author":"Buurma","year":"2012","journal-title":"Hypertension"},{"key":"ref_42","unstructured":"Burwick, R.M., and Feinberg, B.B. (2020). Complement activation and regulation in pre-eclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome. Am. J. Obstet. Gynecol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1097\/AOG.0000000000002980","article-title":"Terminal Complement Activation in Pre-eclampsia","volume":"132","author":"Burwick","year":"2018","journal-title":"Obstet. Gynecol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1111\/aji.12439","article-title":"The Relationship of Longitudinal Levels of Complement Bb during Pregnancy with Pre-eclampsia","volume":"75","author":"Lynch","year":"2016","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e13033","DOI":"10.1111\/aji.13033","article-title":"Upregulation and release of soluble fms-like tyrosine kinase receptor 1 mediated by complement activation in human syncytiotrophoblast cells","volume":"80","author":"Banadakoppa","year":"2018","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1161\/HYPERTENSIONAHA.120.15870","article-title":"Pre-eclamptic Women Have Decreased Circulating IL-10 (Interleukin-10) Values at the Time of Pre-eclampsia Diagnosis\u2014Systematic Review and Meta-Analysis","volume":"76","author":"Nath","year":"2020","journal-title":"Hypertension"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"102613","DOI":"10.1016\/j.jri.2019.102613","article-title":"Lower activation of CD4+ memory T cells in pre-eclampsia compared to healthy pregnancies persists postpartum","volume":"136","author":"Kieffer","year":"2019","journal-title":"J. Reprod. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3031","DOI":"10.1038\/s41467-019-10703-1","article-title":"Decreased maternal serum acetate and impaired fetal thymic and regulatory T cell development in pre-eclampsia","volume":"10","author":"Hu","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"291","DOI":"10.3109\/10641955.2015.1032054","article-title":"IL-10 supplementation increases Tregs and decreases hypertension in the RUPP rat model of pre-eclampsia","volume":"34","author":"Harmon","year":"2015","journal-title":"Hypertens. Pregnancy"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.3389\/fimmu.2020.02025","article-title":"T Helper (Th) Cell Profiles in Pregnancy and Recurrent Pregnancy Losses: Th1\/Th2\/Th9\/Th17\/Th22\/Tfh Cells","volume":"11","author":"Wang","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.jri.2012.01.006","article-title":"The predominance of Th17 lymphocytes and decreased number and function of Treg cells in pre-eclampsia","volume":"93","author":"Tabarkiewicz","year":"2012","journal-title":"J. Reprod. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1111\/j.1600-0897.2011.00987.x","article-title":"Increased Prevalence of IL-17-Producing Peripheral Blood Lymphocytes in Pre-eclampsia","volume":"66","author":"Toldi","year":"2011","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Salmon, J.E., Heuser, C., Triebwasser, M., Liszewski, M.K., Kavanagh, D., Roumenina, L., Branch, D.W., Goodship, T., Fremeaux-Bacchi, V., and Atkinson, J.P. (2011). Mutations in complement regulatory proteins predispose to pre-eclampsia: A genetic analysis of the PROMISSE cohort. 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