{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T21:59:22Z","timestamp":1788991162363,"version":"build-2803163510"},"reference-count":163,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T00:00:00Z","timestamp":1756339200000},"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><jats:title>Introduction<\/jats:title><jats:p>Miscarriages affect 50-70% of all gestations and 15-20% of clinically recognized pregnancies. Recurrent pregnancy loss (RPL) occurs in 1-5% of clinical pregnancies and has an enormous demographic impact. However, the etiologies and molecular pathways of RPL are scarcely understood, and therefore, reliable diagnostic and preventive methods are not yet available. Here, we aimed to discover novel biomarkers for RPL using next-generation proteomics technology to help develop early and effective diagnostic tools.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>First-trimester blood samples were collected from women with RPL (<jats:italic>n<\/jats:italic>=11) and controls with elective termination of pregnancy (<jats:italic>n<\/jats:italic>=11) between 6\u201313 weeks of gestation. After immunodepleting 14 highly abundant proteins, plasma samples were reduced, alkylated, and trypsin digested. For the separation of peptides, nano-flow reversed-phase chromatography was applied, and then mass spectrometric analysis was performed. Differentially abundant (DA) proteins were identified using strict criteria and analyzed by protein network and Gene Ontology (GO) enrichment analyses, and two biomarker candidates (CGB and PAPPA) were validated by immunoassay. Biomarker predictive properties were demonstrated using Receiver Operating Characteristic (ROC) curves. Assessments were performed for all cases and then for two gestational age groups, before and after the start of placental circulation [\u201cearly RPL\u201d: gestational weeks (GW) 6\u20139, \u201clate RPL\u201d: GW 9<jats:bold>\u2013<\/jats:bold>13].<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Altogether, 651 proteins were identified and quantified across all samples. When comparing \u201cearly control\u201d and \u201clate control\u201d samples, 60 proteins [11 predominantly placenta-expressed (PPE)] were DA. When analyzing all cases, 50 DA proteins were found in RPL (top 3 down: PZP, PSG9, CGB; top 3 up: C4BPA, HBA, HBB), among which 11 PPE proteins were found, all downregulated. Enriched GO terms included \u2018placental function\u2019, \u2018oxidative processes\u2019, \u2018immune function\u2019, and \u2018blood coagulation\u2019 related biological processes. When cases were split into early and late RPL groups, 40 DA proteins were identified in early RPL (top 3 down: SHBG, CGB, CGA; top 3 up: C4BPA, SAMP, C4BPB) and 90 in late RPL (top 3 down: PZP, PAPPA, PSG9; top 3 up: THBS1, ECM1, HBB), among which only 15 were shared by both RPL groups. In early RPL, only \u2018placental function\u2019 and \u2018immune function\u2019 related biological processes were enriched, while in late RPL the top enriched GO terms included \u2018placental function\u2019, \u2018oxidative processes\u2019, \u2018immune function\u2019, \u2018blood coagulation\u2019, \u2018angiogenesis\u2019, \u2018cell migration\u2019, and \u2018blood circulation\u2019 related biological processes. Among GO terms, only \u2018placental function\u2019 related biological processes were enriched when early- and late RPL DA proteins were analyzed together. Furthermore, the areas under the ROC curves were &amp;gt;0.9 for two protein candidates in all RPL, for five proteins in early RPL, and for ten proteins in late RPL. Among these candidates, CGB and PAPPA were validated by immunoassay which showed a good correlation with MS data (R<jats:sub>CGB<\/jats:sub>=0.795 and R<jats:sub>PAPPA<\/jats:sub>=0.965).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We discovered distinct as well as shared molecular pathways associated with RPL pathogenesis before and after the start of placental circulation and identified novel biomarkers for these pathways which have outstanding discriminative properties. Our results may facilitate a better understanding of the molecular pathways of RPL. However, larger clinical studies are needed to investigate whether the identified biomarkers also have predictive power for RPL before pregnancies fail and to test drugs for the modulation of the identified disease pathways and the prevention of RPL. Our findings highlight the importance of the maternal immune system in maintaining successful pregnancy and suggest that targeting immune pathways may offer novel therapeutic approaches for RPL.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1621168","type":"journal-article","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T04:10:40Z","timestamp":1756354240000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Novel proteomics biomarkers of recurrent pregnancy loss reflect the dysregulation of immune interactions at the maternal-fetal interface"],"prefix":"10.3389","volume":"16","author":[{"given":"Eszter","family":"T\u00f3th","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1t\u00e9","family":"Posta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00e1niel","family":"Gy\u00f6rffy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orsolya","family":"Oravecz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emese","family":"Farkas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Balogh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Escher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Bober","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e1s","family":"Szil\u00e1gyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petronella","family":"Hupuczi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lajos","family":"Veress","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"T\u00f6r\u00f6k","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e1ndor","family":"Nagy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Rinner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Offer","family":"Erez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zolt\u00e1n","family":"Papp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N\u00e1ndor","family":"\u00c1cs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N\u00e1ndor G\u00e1bor","family":"Than","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,28]]},"reference":[{"key":"B1","article-title":"Miscarriage","volume-title":"StatPearls","author":"Dugas","year":"2020"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3109\/00016347709162009","article-title":"WHO: recommended definitions, terminology and format for statistical tables related to the perinatal period and use of a new certificate for cause of perinatal deaths. 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