{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T20:02:52Z","timestamp":1792526572485,"version":"4.5.0"},"reference-count":115,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,10]],"date-time":"2021-02-10T00:00:00Z","timestamp":1612915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Multinucleate syncytialized trophoblast is found in three forms in the human placenta. In the earliest stages of pregnancy, it is seen at the invasive leading edge of the implanting embryo and has been called primitive trophoblast. In later pregnancy, it is represented by the immense, multinucleated layer covering the surface of placental villi and by the trophoblast giant cells found deep within the uterine decidua and myometrium. These syncytia interact with local and\/or systemic maternal immune effector cells in a fine balance that allows for invasion and persistence of allogeneic cells in a mother who must retain immunocompetence for 40 weeks of pregnancy. Maternal immune interactions with syncytialized trophoblast require tightly regulated mechanisms that may differ depending on the location of fetal cells and their invasiveness, the nature of the surrounding immune effector cells and the gestational age of the pregnancy. Some specifically reflect the unique mechanisms involved in trophoblast cell\u2013cell fusion (aka syncytialization). Here we will review and summarize several of the mechanisms that support healthy maternal\u2013fetal immune interactions specifically at syncytiotrophoblast interfaces.<\/jats:p>","DOI":"10.3390\/ijms22041767","type":"journal-article","created":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T00:49:26Z","timestamp":1613090966000},"page":"1767","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["The Immunology of Syncytialized Trophoblast"],"prefix":"10.3390","volume":"22","author":[{"given":"Danny J.","family":"Schust","sequence":"first","affiliation":[{"name":"Department of Obstetrics, Gynecology, University of Missouri School of Medicine, Columbia, MO 65202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Bonney","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Reproductive Sciences, University of Vermont College of Medicine, Burlington, VT 05405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Sugimoto","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Hiroshima University, Hiroshima 734-8551, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshi","family":"Ezashi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, University of Missouri School of Medicine, Columbia, MO 65202, USA"},{"name":"Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA"},{"name":"Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Michael","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, University of Missouri School of Medicine, Columbia, MO 65202, USA"},{"name":"Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA"},{"name":"Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5176-5113","authenticated-orcid":false,"given":"Sehee","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, University of Missouri School of Medicine, Columbia, MO 65202, USA"},{"name":"Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, University of Missouri School of Medicine, Columbia, MO 65202, USA"},{"name":"Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1093\/biolre\/ioy049","article-title":"Hemochorial placentation: Development, function, and adaptations","volume":"99","author":"Soares","year":"2018","journal-title":"Biol. Reprod."},{"key":"ref_2","first-page":"320","article-title":"Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates","volume":"7","author":"Medawar","year":"1953","journal-title":"Symp. Soc. Exp. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.fertnstert.2016.07.1073","article-title":"Immunologic challenges of human reproduction: An evolving story","volume":"106","author":"Hyde","year":"2016","journal-title":"Fertil. Steril."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.1093\/humrep\/dex301","article-title":"Early first trimester uteroplacental flow and the progressive disintegration of spiral artery plugs: New insights from contrast-enhanced ultrasound and tissue histopathology","volume":"32","author":"Roberts","year":"2017","journal-title":"Hum. Reprod."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Tersigni, C., Meli, F., Neri, C., Iacoangeli, A., Franco, R., Lanzone, A., Scambia, G., and Di Simone, N. (2020). Role of Human Leukocyte Antigens at the Feto-Maternal Interface in Normal and Pathological Pregnancy: An Update. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21134756"},{"key":"ref_6","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_7","doi-asserted-by":"crossref","unstructured":"Ander, S.E., Diamond, M.S., and Coyne, C.B. (2019). Immune responses at the maternal-fetal interface. Sci. Immunol., 4.","DOI":"10.1126\/sciimmunol.aat6114"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1016\/j.placenta.2015.05.002","article-title":"The role of chorionic cytotrophoblasts in the smooth chorion fusion with parietal decidua","volume":"36","author":"Larocque","year":"2015","journal-title":"Placenta"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9104","DOI":"10.1073\/pnas.97.16.9104","article-title":"Placental expression of the nonclassical MHC class I molecule Mamu-AG at implantation in the rhesus monkey","volume":"97","author":"Slukvin","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","first-page":"621","article-title":"Class I antigens of the major histocompatibility complex on cytotrophoblast of human chorion laeve","volume":"52","author":"Hsi","year":"1984","journal-title":"Immunology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/S0143-4004(05)80210-3","article-title":"Antigenic heterogeneity of human cytotrophoblast and evidence for the transient expression of MHC class I antigens distinct from HLA-G","volume":"14","author":"Shorter","year":"1993","journal-title":"Placenta"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Solders, M., Gorchs, L., Gidl\u00f6f, S., Tiblad, E., Lundell, A.-C., and Kaipe, H. (2017). Maternal adaptive immune cells in decidua parietalis display a more activated and coinhibitory phenotype compared to decidua basalis. Stem Cells Int., 2017.","DOI":"10.1155\/2017\/8010961"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1073\/pnas.93.2.705","article-title":"Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum","volume":"93","author":"Bianchi","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/nri.2017.38","article-title":"Immunological implications of pregnancy-induced microchimerism","volume":"17","author":"Kinder","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1191\/096120399678840783","article-title":"Autoimmune disease and the long-term persistence of fetal and maternal microchimerism","volume":"8","author":"Nelson","year":"1999","journal-title":"Lupus"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"45","DOI":"10.4161\/chim.20739","article-title":"Fetal microchimerism in skin wound healing","volume":"3","author":"Nassar","year":"2012","journal-title":"Chimerism"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1177\/1753495X19884484","article-title":"Fetal microchimerism and implications for maternal health","volume":"13","author":"Fjeldstad","year":"2020","journal-title":"Obstet. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.bbagrm.2016.10.013","article-title":"NF-Y and the immune response: Dissecting the complex regulation of MHC genes","volume":"1860","author":"Sachini","year":"2017","journal-title":"Biochim. Biophys. Acta Gene Regul. Mech."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/bs.apcsb.2016.08.002","article-title":"Histone acetylation and the regulation of major histocompatibility class II gene expression","volume":"106","author":"Suzuki","year":"2017","journal-title":"Adv. Protein Chem. Struct. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1097\/01.TP.0000073612.04525.46","article-title":"Class II transactivator promoter activity is suppressed through regulation by a trophoblast noncoding RNA1","volume":"76","author":"Geirsson","year":"2003","journal-title":"Transplantation"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1093\/biolre\/iox009","article-title":"NLRP2 is a suppressor of NF-\u0199B signaling and HLA-C expression in human trophoblasts","volume":"96","author":"Tilburgs","year":"2017","journal-title":"Biol. Reprod."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1053\/plac.1998.0380","article-title":"Downregulation of HLA class I gene transcription in choriocarcinoma cells is controlled by the proximal promoter element and can be reversed by CIITA","volume":"20","author":"Lefebvre","year":"1999","journal-title":"Placenta"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/0167-5699(90)90097-S","article-title":"In search of the \u2018missing self\u2019: MHC molecules and NK cell recognition","volume":"11","author":"Ljunggren","year":"1990","journal-title":"Immunol. Today"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1476-4598-9-118","article-title":"Identification of Siglec-9 as the receptor for MUC16 on human NK cells, B cells, and monocytes","volume":"9","author":"Belisle","year":"2010","journal-title":"Mol. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1074\/mcp.M115.055798","article-title":"Evidence for differential glycosylation of trophoblast cell types","volume":"15","author":"Chen","year":"2016","journal-title":"Mol. Cell. Proteom."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8504","DOI":"10.1021\/jp212550z","article-title":"Effect of bisecting GlcNAc and core fucosylation on conformational properties of biantennary complex-type N-glycans in solution","volume":"116","author":"Nishima","year":"2012","journal-title":"J. Phys. Chem. B"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"26970","DOI":"10.1074\/jbc.270.45.26970","article-title":"Glycophorin A Protects K562 Cells from Natural Killer Cell Attack ROLE OF OLIGOSACCHARIDES","volume":"270","author":"Benoist","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_28","first-page":"412","article-title":"Bisecting N-acetylglucosamine on K562 cells suppresses natural killer cytotoxicity and promotes spleen colonization","volume":"56","author":"Yoshimura","year":"1996","journal-title":"Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Borowski, S., Tirado-Gonzalez, I., Freitag, N., Garcia, M.G., Barrientos, G., and Blois, S.M. (2020). Altered glycosylation contributes to placental dysfunction upon early disruption of the NK cell-DC dynamics. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01316"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1093\/humrep\/dev153","article-title":"Altered \u03b21, 6-GlcNAc and bisecting GlcNAc-branched N-glycan on integrin \u03b21 are associated with early spontaneous miscarriage in humans","volume":"30","author":"Zhang","year":"2015","journal-title":"Hum. Reprod."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/j.acthis.2010.12.001","article-title":"Distribution of sugar residues in human placentas from pregnancies complicated by hypertensive disorders","volume":"113","author":"Marini","year":"2011","journal-title":"Acta Histochem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Bulmer, J.N., and Lash, G.E. (2019). Uterine natural killer cells: Time for a re-appraisal?. F1000research, 8.","DOI":"10.12688\/f1000research.19132.1"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1093\/humrep\/14.2.496","article-title":"Are human placental bed giant cells merely aggregates of small mononuclear trophoblast cells? An ultrastructural and immunocytochemical study","volume":"14","author":"Skepper","year":"1999","journal-title":"Hum. Reprod."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Ibeto, L., Antonopoulos, A., Grassi, P., Pang, P.-C., Panico, M., Bobdiwala, S., Al-Memar, M., Davis, P., Davis, M., and Norman Taylor, J. (2020). Insights into the hyperglycosylation of human chorionic gonadotropin revealed by glycomics analysis. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0228507"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/0165-0378(85)90064-6","article-title":"Hormonal modulation of human natural killer cell activity in vitro","volume":"7","author":"Sulke","year":"1985","journal-title":"J. Reprod. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1111\/j.1600-0897.2008.00682.x","article-title":"Activation of TLR3 in the trophoblast is associated with preterm delivery","volume":"61","author":"Koga","year":"2009","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/j.placenta.2009.07.001","article-title":"Toll-like receptor-3 stimulation upregulates sFLT-1 production by trophoblast cells","volume":"30","author":"Nakada","year":"2009","journal-title":"Placenta"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.ajog.2007.06.021","article-title":"Toll-like receptors in the uterus, cervix, and placenta: Is pregnancy an immunosuppressed state?","volume":"197","author":"Gonzalez","year":"2007","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1080\/08830185.2017.1380200","article-title":"Toll-like receptors: Significance, ligands, signaling pathways, and functions in mammals","volume":"37","author":"Vidya","year":"2018","journal-title":"Int. Rev. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Olmos-Ortiz, A., Flores-Espinosa, P., Mancilla-Herrera, I., Vega-S\u00e1nchez, R., D\u00edaz, L., and Zaga-Clavellina, V. (2019). Innate Immune Cells and Toll-like Receptor\u2013Dependent Responses at the Maternal\u2013Fetal Interface. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20153654"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.placenta.2016.07.005","article-title":"Differential expression of toll-like receptors in the human placenta across early gestation","volume":"46","author":"Pudney","year":"2016","journal-title":"Placenta"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4286","DOI":"10.4049\/jimmunol.173.7.4286","article-title":"Divergent trophoblast responses to bacterial products mediated by TLRs","volume":"173","author":"Abrahams","year":"2004","journal-title":"J. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1046\/j.1365-2567.2002.01491.x","article-title":"Expression and regulation of the pattern recognition receptors Toll-like receptor-2 and Toll-like receptor-4 in the human placenta","volume":"107","author":"Holmlund","year":"2002","journal-title":"Immunology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.humpath.2003.08.027","article-title":"Immunohistochemical distribution of Toll-like receptor 4 in term and preterm human placentas from normal and complicated pregnancy including chorioamnionitis","volume":"35","author":"Kumazaki","year":"2004","journal-title":"Hum. Pathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1016\/j.placenta.2007.05.003","article-title":"Cell type-specific expression and function of toll-like receptors 2 and 4 in human placenta: Implications in fetal infection","volume":"28","author":"Ma","year":"2007","journal-title":"Placenta"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.humpath.2006.09.009","article-title":"Toll-like receptor-2 expression in normal and pathologic human placenta","volume":"38","author":"Holmlund","year":"2007","journal-title":"Hum. Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1095\/biolreprod.108.069252","article-title":"Expression and activity of Toll-like receptors 1\u20139 in the human term placenta and changes associated with labor at term","volume":"80","author":"Patni","year":"2009","journal-title":"Biol. Reprod."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.jri.2006.02.003","article-title":"Macrophage-activating lipopeptide-2 induces cyclooxygenase-2 and prostaglandin E2 via toll-like receptor 2 in human placental trophoblast cells","volume":"72","author":"Mitsunari","year":"2006","journal-title":"J. Reprod. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1111\/cei.12960","article-title":"Human gestation-associated tissues express functional cytosolic nucleic acid sensing pattern recognition receptors","volume":"189","author":"Bryant","year":"2017","journal-title":"Clin. Exp. Immunol."},{"key":"ref_50","first-page":"53","article-title":"Placental inflammation by HMGB1 activation of TLR4 at the syncytium","volume":"72","author":"Silva","year":"2018","journal-title":"Placenta"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.1002\/jcp.27189","article-title":"Toll-like receptors signaling network in pre-eclampsia: An updated review","volume":"234","author":"Afkham","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.jri.2018.12.001","article-title":"Involvement of ILR4\u03b1 and TLR4 in miscarriages","volume":"131","author":"Kolben","year":"2019","journal-title":"J. Reprod. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.molmed.2016.11.001","article-title":"Co-Signaling Molecules in Maternal-Fetal Immunity","volume":"23","author":"Xu","year":"2017","journal-title":"Trends Mol. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1097\/PGP.0000000000000305","article-title":"PD-L1 Expression in Human Placentas and Gestational Trophoblastic Diseases","volume":"36","author":"Veras","year":"2017","journal-title":"Int. J. Gynecol. Pathol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Okuyama, M., Mezawa, H., Kawai, T., and Urashima, M. (2019). Elevated Soluble PD-L1 in Pregnant Women\u2019s Serum Suppresses the Immune Reaction. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.00086"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1095\/biolreprod.105.046581","article-title":"Trophoblast CD274 (B7-H1) is differentially expressed across gestation: Influence of oxygen concentration","volume":"74","author":"Holets","year":"2006","journal-title":"Biol. Reprod."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/S0002-9440(10)62990-2","article-title":"The immunomodulatory proteins B7-DC, B7-H2, and B7-H3 are differentially expressed across gestation in the human placenta","volume":"167","author":"Petroff","year":"2005","journal-title":"Am. J. Pathol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/s41586-018-0698-6","article-title":"Single-cell reconstruction of the early maternal-fetal interface in humans","volume":"563","author":"Efremova","year":"2018","journal-title":"Nature"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"E2598","DOI":"10.1073\/pnas.1601630113","article-title":"Comparison of syncytiotrophoblast generated from human embryonic stem cells and from term placentas","volume":"113","author":"Yabe","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","first-page":"E2337","article-title":"Heightened potency of human pluripotent stem cell lines created by transient BMP4 exposure","volume":"112","author":"Yang","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"E1212","DOI":"10.1073\/pnas.1303094110","article-title":"Complete and unidirectional conversion of human embryonic stem cells to trophoblast by BMP4","volume":"110","author":"Amita","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Roberts, R.M., Yabe, S., Yang, Y., and Ezashi, T. (2016). A human stem cell model for creating placental syncytiotrophoblast, the major cellular barrier that limits fetal exposure to xenobiotics. Stem Cells in Toxicology and Medicine, Wiley & Sons. [1st ed.].","DOI":"10.1002\/9781119135449.ch10"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1111\/aogs.12476","article-title":"Reduced CD200 and CD200R1 expression in human chorionic villi contributes to early spontaneous abortion","volume":"93","author":"Wang","year":"2014","journal-title":"Acta Obs. Gynecol. Scand."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Xu, J., Gu, Y., Sun, J., Zhu, H., Lewis, D.F., and Wang, Y. (2018). Reduced CD200 expression is associated with altered Th1\/Th2 cytokine production in placental trophoblasts from preeclampsia. Am. J. Reprod. Immunol., 79.","DOI":"10.1111\/aji.12763"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/nri.2017.112","article-title":"Immune checkpoint blockade in infectious diseases","volume":"18","author":"Wykes","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1158\/2159-8290.CD-18-0367","article-title":"Fundamental Mechanisms of Immune Checkpoint Blockade Therapy","volume":"8","author":"Wei","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1111\/aji.12311","article-title":"Placenta-derived exosomes and syncytiotrophoblast microparticles and their role in human reproduction: Immune modulation for pregnancy success","volume":"72","author":"Baranov","year":"2014","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.tem.2016.10.003","article-title":"Extracellular vesicles: Novel mediators of cell communication in metabolic disease","volume":"28","author":"Zhang","year":"2017","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1007\/s00401-016-1548-y","article-title":"Peripheral monocytes are functionally altered and invade the CNS in ALS patients","volume":"132","author":"Zondler","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_70","first-page":"3791","article-title":"Activated Platelets Release Two Types of Membrane Vesicles: Microvesicles by Surface Shedding and Exosomes Derived From Exocytosis of Multivesicular Bodies and alpha-Granules","volume":"94","author":"Heijnen","year":"1999","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Szajnik, M., Czystowska, M., Szczepanski, M.J., Mandapathil, M., and Whiteside, T.L. (2010). Tumor-derived microvesicles induce, expand and up-regulate biological activities of human regulatory T cells (Treg). PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0011469"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1161\/ATVBAHA.109.200956","article-title":"Cellular mechanisms underlying the formation of circulating microparticles","volume":"31","author":"Morel","year":"2011","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.placenta.2007.11.016","article-title":"Circulating microparticles in normal pregnancy and pre-eclampsia","volume":"29","author":"Redman","year":"2008","journal-title":"Placenta"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Bernischke, K., Kaufmann, P., and Baergen, R. (2000). Pathology of the Human Placenta, Springer. [4th ed.].","DOI":"10.1007\/978-1-4757-4199-5"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1007\/s004180050311","article-title":"Villous cytotrophoblast regulation of the syncytial apoptotic cascade in the human placenta","volume":"110","author":"Huppertz","year":"1998","journal-title":"Histochem. Cell Biol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.4049\/jimmunol.176.3.1534","article-title":"Pregnancy-associated exosomes and their modulation of T cell signaling","volume":"176","author":"Taylor","year":"2006","journal-title":"J. Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1038\/ncb1596","article-title":"Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells","volume":"9","author":"Valadi","year":"2007","journal-title":"Nat. Cell Biol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1007\/s13238-012-2003-z","article-title":"Horizontal transfer of microRNAs: Molecular mechanisms and clinical applications","volume":"3","author":"Chen","year":"2012","journal-title":"Protein Cell"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Bhatti, G., Romero, R., Rice, G.E., Fitzgerald, W., Pacora, P., Gomez-Lopez, N., Kavdia, M., Tarca, A.L., and Margolis, L. (2020). Compartmentalized profiling of amniotic fluid cytokines in women with preterm labor. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0227881"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1016\/j.placenta.2012.10.005","article-title":"Immunomodulatory molecules are released from the first trimester and term placenta via exosomes","volume":"33","author":"Kshirsagar","year":"2012","journal-title":"Placenta"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.biocel.2015.12.006","article-title":"Exosomes and nanotubes: Control of immune cell communication","volume":"71","author":"Hanna","year":"2016","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Aliotta, J.M., Pereira, M., Sears, E.H., Dooner, M.S., Wen, S., Goldberg, L.R., and Quesenberry, P.J. (2015). Lung-derived exosome uptake into and epigenetic modulation of marrow progenitor\/stem and differentiated cells. J. Extracell. Vesicles, 4.","DOI":"10.3402\/jev.v4.26166"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.jri.2007.03.008","article-title":"Microparticles and immunomodulation in pregnancy and pre-eclampsia","volume":"76","author":"Redman","year":"2007","journal-title":"J. Reprod. Immunol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"R189","DOI":"10.1530\/REP-19-0147","article-title":"Effects of extracellular vesicles on placentation and pregnancy disorders","volume":"158","author":"Yang","year":"2019","journal-title":"Reproduction"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s10815-018-1343-x","article-title":"Extracellular vesicle mediated embryo-endometrial cross talk during implantation and in pregnancy","volume":"36","author":"Kurian","year":"2019","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"14572","DOI":"10.1073\/pnas.0404838101","article-title":"Retroelements and the human genome: New perspectives on an old relation","volume":"101","author":"Bannert","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"4743","DOI":"10.1093\/nar\/gkm455","article-title":"Widely variable endogenous retroviral methylation levels in human placenta","volume":"35","author":"Reiss","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"13013","DOI":"10.1073\/pnas.2132646100","article-title":"Genomewide screening for fusogenic human endogenous retrovirus envelopes identifies syncytin 2, a gene conserved on primate evolution","volume":"100","author":"Blaise","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"17532","DOI":"10.1073\/pnas.0807413105","article-title":"A placenta-specific receptor for the fusogenic, endogenous retrovirus-derived, human syncytin-2","volume":"105","author":"Esnault","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-019-55933-x","article-title":"Suppressyn localization and dynamic expression patterns in primary human tissues support a physiologic role in human placentation","volume":"9","author":"Sugimoto","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1126\/science.2996136","article-title":"Inhibition of lymphocyte proliferation by a synthetic peptide homologous to retroviral envelope proteins","volume":"230","author":"Cianciolo","year":"1985","journal-title":"Science"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Gr\u00f6ger, V., and Cynis, H. (2018). Human endogenous retroviruses and their putative role in the development of autoimmune disorders such as multiple sclerosis. Front. Microbiol., 9.","DOI":"10.3389\/fmicb.2018.00265"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1099\/vir.0.000017","article-title":"Activation of the innate immune response by endogenous retroviruses","volume":"96","author":"Hurst","year":"2015","journal-title":"J. Gen. Virol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"20534","DOI":"10.1073\/pnas.0707873105","article-title":"Placental syncytins: Genetic disjunction between the fusogenic and immunosuppressive activity of retroviral envelope proteins","volume":"104","author":"Mangeney","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1111\/j.1365-2567.2012.03568.x","article-title":"Immune cell activation by trophoblast-derived microvesicles is mediated by syncytin 1","volume":"136","author":"Holder","year":"2012","journal-title":"Immunology"},{"key":"ref_96","first-page":"185","article-title":"Endogenous retrovirus-encoded Syncytin-2 contributes to exosome-mediated immunosuppression of T cells","volume":"102","author":"Lokossou","year":"2020","journal-title":"Biol. Reprod."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1073\/pnas.0406509102","article-title":"Syncytin-A and syncytin-B, two fusogenic placenta-specific murine envelope genes of retroviral origin conserved in Muridae","volume":"102","author":"Dupressoir","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Sugimoto, J., Sugimoto, M., Bernstein, H., Jinno, Y., and Schust, D. (2013). A novel human endogenous retroviral protein inhibits cell-cell fusion. Sci. Rep., 3.","DOI":"10.1038\/srep01462"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Nethe, M., Berkhout, B., and Van der Kuyl, A.C. (2005). Retroviral superinfection resistance. Retrovirology, 2.","DOI":"10.1186\/1742-4690-2-52"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"8085","DOI":"10.1128\/JVI.74.17.8085-8093.2000","article-title":"Sodium-dependent neutral amino acid transporter type 1 is an auxiliary receptor for baboon endogenous retrovirus","volume":"74","author":"Marin","year":"2000","journal-title":"J. Virol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"6808","DOI":"10.1128\/JVI.74.15.6808-6820.2000","article-title":"Human cytomegalovirus infection of placental cytotrophoblasts in vitro and in utero: Implications for transmission and pathogenesis","volume":"74","author":"Fisher","year":"2000","journal-title":"J. Virol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1095\/biolreprod64.3.1001","article-title":"Differential expression of the coxsackievirus and adenovirus receptor regulates adenovirus infection of the placenta","volume":"64","author":"Koi","year":"2001","journal-title":"Biol. Reprod."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.2353\/ajpath.2006.050482","article-title":"Maternal antibodies enhance or prevent cytomegalovirus infection in the placenta by neonatal Fc receptor-mediated transcytosis","volume":"168","author":"Maidji","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Robbins, J.R., Skrzypczynska, K.M., Zeldovich, V.B., Kapidzic, M., and Bakardjiev, A.I. (2010). Placental syncytiotrophoblast constitutes a major barrier to vertical transmission of Listeria monocytogenes. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1000732"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"12048","DOI":"10.1073\/pnas.1304718110","article-title":"Human placental trophoblasts confer viral resistance to recipient cells","volume":"110","author":"Donker","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.ajog.2014.07.060","article-title":"Human trophoblasts confer resistance to viruses implicated in perinatal infection","volume":"212","author":"Bayer","year":"2015","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1093\/cid\/ciy1128","article-title":"Sequelae of congenital cytomegalovirus following maternal primary infections are limited to those acquired in the first trimester of pregnancy","volume":"69","author":"Magny","year":"2019","journal-title":"Clin. Infect. Dis."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.jcv.2005.09.015","article-title":"Congenital cytomegalovirus infection following first trimester maternal infection: Symptoms at birth and outcome","volume":"35","author":"Pass","year":"2006","journal-title":"J. Clin. Virol."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Mendes, A.K.T., Ribeiro, M.R.C., Lamy-Filho, F., Amaral, G.A., Borges, M.C.R., Costa, L.C., Cavalcante, T.B., Batista, R.F.L., Sousa, P.d.S., and Silva, A.A.M.d. (2020). Congenital Zika syndrome: Association between the gestational trimester of maternal infection, severity of brain computed tomography findings and microcephaly at birth. Rev. Inst. Med. Trop. S\u00e3o Paulo, 62.","DOI":"10.1590\/s1678-9946202062056"},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Sheridan, M.A., Balaraman, V., Schust, D.J., Ezashi, T., Roberts, R.M., and Franz, A.W. (2018). African and Asian strains of Zika virus differ in their ability to infect and lyse primitive human placental trophoblast. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0200086"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/j.chom.2016.03.008","article-title":"Type III interferons produced by human placental trophoblasts confer protection against Zika virus infection","volume":"19","author":"Bayer","year":"2016","journal-title":"Cell Host Microbe"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"E1587","DOI":"10.1073\/pnas.1616097114","article-title":"Vulnerability of primitive human placental trophoblast to Zika virus","volume":"114","author":"Sheridan","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Pique-Regi, R., Romero, R., Tarca, A.L., Luca, F., Xu, Y., Alazizi, A., Leng, Y., Hsu, C.-D., and Gomez-Lopez, N. (2020). Does the human placenta express the canonical cell entry mediators for SARS-CoV-2?. Elife, 9.","DOI":"10.7554\/eLife.58716"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"R179","DOI":"10.1530\/REP-16-0325","article-title":"The evolution of the placenta","volume":"152","author":"Roberts","year":"2016","journal-title":"Reproduction"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"E10991","DOI":"10.1073\/pnas.1714590114","article-title":"An endogenous retroviral envelope syncytin and its cognate receptor identified in the viviparous placental Mabuya lizard","volume":"114","author":"Cornelis","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/1767\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:22:35Z","timestamp":1760160155000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/1767"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,10]]},"references-count":115,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["ijms22041767"],"URL":"https:\/\/doi.org\/10.3390\/ijms22041767","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,10]]}}}