{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T03:33:04Z","timestamp":1781148784689,"version":"3.54.1"},"reference-count":42,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T00:00:00Z","timestamp":1737676800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Rep Immunol"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Problem<\/jats:title><jats:p>Natural killer (NK) cells undergo education for full functionality via interactions between killer immunoglobulin\u2010like receptors (KIRs) or NKG2A and human leukocyte antigen (HLA) ligands. Presumably, education is important during early pregnancy as insufficient education has been associated with impaired vascular remodeling and restricted fetal growth in mice. NK cell education is influenced by receptor co\u2010expression patterns, human cytomegalovirus (CMV), the HLA\u2010E<jats:sup>R<\/jats:sup>107<jats:sup>G<\/jats:sup> dimorphism, and HLA\u2010B leader peptide variants. We hypothesized altered NK cell education status and differences in frequencies of HLA\u2010E genotypes and HLA\u2010B leader peptide variants in women with recurrent pregnancy loss (RPL) compared to women with previously uncomplicated pregnancies, and between CMV seropositive and seronegative RPL women.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods of Study<\/jats:title><jats:p>Peripheral blood mononuclear cells were analyzed by flow cytometry. HLA\u2010ABC was typed by sequence\u2010specific oligonucleotide PCR, and HLA\u2010E by Sanger sequencing. CMV status was determined by anti\u2010CMV IgG immunoassay. NK cells were considered \u201ceducated\u201d if the HLA ligand to a KIR or NKG2A was present.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>KIR\/NKG2A co\u2010expression patterns and percentages of educated NK cells were similar between RPL and controls, and between seropositive and seronegative RPL women. Frequencies of HLA\u2010E genotypes and HLA\u2010B leader peptide variants were comparable. RPL women with the HLA\u2010B T\/T variant had a lower percentage of NKG2A\u2010educated NK cells (47.8%) compared to controls (66.4%) (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.025).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>HLA\u2010B leader peptide variants might impact NKG2A\u2010specific NK cell education in RPL, warranting validation in larger studies. Follow\u2010up studies are needed to investigate the education status of uterine NK cells and their role in pregnancy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/aji.70045","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T13:55:06Z","timestamp":1737726906000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Natural Killer Cell Education in Women With Recurrent Pregnancy Loss"],"prefix":"10.1111","volume":"93","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3093-5647","authenticated-orcid":false,"given":"Amber E. M.","family":"Lombardi","sequence":"first","affiliation":[{"name":"GROW Research Institute for Oncology and Reproduction Maastricht University  Maastricht The Netherlands"},{"name":"Department of Transplantation Immunology Maastricht University Medical Centre+  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise H. J.","family":"Habets","sequence":"additional","affiliation":[{"name":"GROW Research Institute for Oncology and Reproduction Maastricht University  Maastricht The Netherlands"},{"name":"Department of Transplantation Immunology Maastricht University Medical Centre+  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salwan","family":"Al\u2010Nasiry","sequence":"additional","affiliation":[{"name":"GROW Research Institute for Oncology and Reproduction Maastricht University  Maastricht The Netherlands"},{"name":"Department of Obstetrics and Gynecology Maastricht University Medical Centre+  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc E. A.","family":"Spaanderman","sequence":"additional","affiliation":[{"name":"GROW Research Institute for Oncology and Reproduction Maastricht University  Maastricht The Netherlands"},{"name":"Department of Obstetrics and Gynecology Maastricht University Medical Centre+  Maastricht The Netherlands"},{"name":"Department of Obstetrics and Gynecology Radboud University Medical Centre  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lotte","family":"Wieten","sequence":"additional","affiliation":[{"name":"GROW Research Institute for Oncology and Reproduction Maastricht University  Maastricht The Netherlands"},{"name":"Department of Transplantation Immunology Maastricht University Medical Centre+  Maastricht The 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