{
    "abstract": "Recurrent pregnancy loss (RPL) is a complex early pregnancy complication affecting 1-2% of couples and is often linked to immune dysfunction. Aberrations in T and B cell subpopulations, as well as natural killer (NK) cell activity, are particularly influential, with studies showing that abnormal NK cell activation and imbalances in T and B cell subtypes contribute to immune-mediated miscarriage risk. Successful pregnancy requires a tightly regulated balance between pro-inflammatory and anti-inflammatory immune responses. In the early stages, inflammation supports processes such as trophoblast invasion and spiral artery remodeling, but this must be tempered to prevent immune rejection of the fetus. In this review, we explore the underlying immune mechanisms of RPL, focusing on how dysregulated T, B, and NK cell function disrupts maternal tolerance. Specifically, we discuss the essential role of uterine NK cells in the early stages of vascular remodeling in the decidua and regulate the depth of invasion by extravillous trophoblasts. Furthermore, we focus on the delicate Treg dynamics that enable the maintenance of optimal immune homeostasis, where the balance, and not only the quantity of Tregs, is crucial for fostering maternal-fetal tolerance. Other T cell subpopulations, such as Th1, Th2, and Th17 cells, also contribute to immune imbalance, with Th1 and Th17 cells promoting inflammation and potentially harming fetal tolerance, while Th2 cells support immune tolerance. Finally, we show how changes in B cell subpopulations and their functions have been associated with adverse pregnancy outcomes. We further discuss current therapeutic strategies aimed at correcting these immune imbalances, including intravenous immunoglobulin (IVIg), glucocorticoids, and TNF-\u03b1 inhibitors, examining their efficacy, challenges, and potential side effects. By highlighting both the therapeutic benefits and limitations of these interventions, we aim to offer a balanced perspective on clinical applications for women facing immune-related causes of RPL.",
    "authors": [
        {
            "affiliation": "Center of Immuno-Physiology and Biotechnologies, Department of Functional Sciences, \"Victor Babe\u0219\" University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania.\nTimis County Emergency Clinical Hospital \"Pius Brinzeu\", 156 Liviu Rebreanu Bd., 300723 Timisoara, Romania.",
            "firstname": "Cristina",
            "initials": "C",
            "lastname": "U\u021ba"
        },
        {
            "affiliation": "Center of Immuno-Physiology and Biotechnologies, Department of Functional Sciences, \"Victor Babe\u0219\" University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania.\nDepartment of Functional Sciences, Physiology Discipline, Faculty of Medicine, \"Victor Babe\u0219\" University of Medicine and Pharmacy Timi\u0219oara, 2 Eftimie Murgu Square, 300041 Timi\u015foara, Romania.\nInstitute of Cardiovascular Diseases Timisoara, 13A Gheorghe Adam Street, 300310 Timisoara, Romania.",
            "firstname": "Alexandru",
            "initials": "A",
            "lastname": "T\u00eerziu"
        },
        {
            "affiliation": "Center of Immuno-Physiology and Biotechnologies, Department of Functional Sciences, \"Victor Babe\u0219\" University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania.\nDepartment of Functional Sciences, Physiology Discipline, Faculty of Medicine, \"Victor Babe\u0219\" University of Medicine and Pharmacy Timi\u0219oara, 2 Eftimie Murgu Square, 300041 Timi\u015foara, Romania.\nResearch Center for Gene and Cellular Therapies in the Treatment of Cancer-OncoGen, Timis County Emergency Clinical Hospital \"Pius Brinzeu\", 156 Liviu Rebreanu Bd., 300723 Timisoara, Romania.",
            "firstname": "Elena-Larisa",
            "initials": "EL",
            "lastname": "Zimbru"
        },
        {
            "affiliation": "Center of Immuno-Physiology and Biotechnologies, Department of Functional Sciences, \"Victor Babe\u0219\" University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania.\nDepartment of Functional Sciences, Physiology Discipline, Faculty of Medicine, \"Victor Babe\u0219\" University of Medicine and Pharmacy Timi\u0219oara, 2 Eftimie Murgu Square, 300041 Timi\u015foara, Romania.\nResearch Center for Gene and Cellular Therapies in the Treatment of Cancer-OncoGen, Timis County Emergency Clinical Hospital \"Pius Brinzeu\", 156 Liviu Rebreanu Bd., 300723 Timisoara, Romania.",
            "firstname": "R\u0103zvan-Ionu\u021b",
            "initials": "RI",
            "lastname": "Zimbru"
        },
        {
            "affiliation": "Center of Immuno-Physiology and Biotechnologies, Department of Functional Sciences, \"Victor Babe\u0219\" University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania.\nDepartment of Functional Sciences, Physiology Discipline, Faculty of Medicine, \"Victor Babe\u0219\" University of Medicine and Pharmacy Timi\u0219oara, 2 Eftimie Murgu Square, 300041 Timi\u015foara, Romania.",
            "firstname": "Marius",
            "initials": "M",
            "lastname": "Georgescu"
        },
        {
            "affiliation": "Center of Immuno-Physiology and Biotechnologies, Department of Functional Sciences, \"Victor Babe\u0219\" University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania.\nDepartment of Functional Sciences, Physiology Discipline, Faculty of Medicine, \"Victor Babe\u0219\" University of Medicine and Pharmacy Timi\u0219oara, 2 Eftimie Murgu Square, 300041 Timi\u015foara, Romania.",
            "firstname": "Laura",
            "initials": "L",
            "lastname": "Haidar"
        },
        {
            "affiliation": "Center of Immuno-Physiology and Biotechnologies, Department of Functional Sciences, \"Victor Babe\u0219\" University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania.\nDepartment of Functional Sciences, Physiology Discipline, Faculty of Medicine, \"Victor Babe\u0219\" University of Medicine and Pharmacy Timi\u0219oara, 2 Eftimie Murgu Square, 300041 Timi\u015foara, Romania.",
            "firstname": "Carmen",
            "initials": "C",
            "lastname": "Panaitescu"
        }
    ],
    "conclusions": null,
    "copyrights": null,
    "doi": "10.3390/medicina60111896\n10.1016/j.fertnstert.2012.06.048\n10.1093/hropen/hoad002\n10.1093/hropen/hoy004\n10.1186/s12884-023-05479-8\n10.1007/s10815-022-02644-4\n10.1093/humupd/dmt045\n10.3390/healthcare9040466\n10.1055/a-1916-9180\n10.1016/j.fertnstert.2020.08.1421\n10.1016/j.midw.2023.103827\n10.1186/s12884-019-2677-9\n10.1186/s12884-020-03514-6\n10.1371/journal.pone.0217395\n10.7759/cureus.30320\n10.1080/07481187.2024.2385386\n10.1016/S0140-6736(21)00682-6\n10.1016/j.lfs.2022.120503\n10.1136/postgradmedj-2014-132672\n10.1620/tjem.250.49\n10.3390/biomedicines9101350\n10.1155/2022/7567708\n10.3390/biology12030402\n10.1016/j.xfnr.2021.11.002\n10.1016/j.reprotox.2020.02.004\n10.1038/nri.2017.64\n10.1016/j.semcdb.2022.01.007\n10.3390/ijms21061973\n10.3389/fimmu.2019.00573\n10.1016/j.fertnstert.2019.05.003\n10.1038/s41598-023-32156-9\n10.1016/j.ecoenv.2023.115851\n10.1038/s41420-024-01867-x\n10.3389/fimmu.2023.1198430\n10.3389/fimmu.2021.642392\n10.3390/biom13081213\n10.1016/j.healun.2022.03.004\n10.3389/fimmu.2020.00167\n10.1038/s41392-021-00629-w\n10.3389/fgene.2024.1442938\n10.3389/fimmu.2022.988370\n10.3390/cells10071777\n10.3389/fimmu.2017.00467\n10.3389/fimmu.2022.918550\n10.1016/j.xfnr.2021.06.002\n10.1016/j.ajog.2017.09.010\n10.3390/biomedicines9101425\n10.4049/jimmunol.1501229\n10.3389/fimmu.2023.1009867\n10.3390/jcm13082379\n10.3390/cells13010059\n10.3389/fimmu.2022.1108163\n10.3389/fimmu.2023.1166451\n10.1038/s41577-022-00777-2\n10.1111/aji.12797\n10.1016/j.tpr.2020.100040\n10.1155/2020/4808072\n10.3390/ijms24021527\n10.3389/fimmu.2024.1328193\n10.1172/JCI122182\n10.3389/fimmu.2019.00478\n10.37349/ei.2022.00056\n10.1055/s-0044-101609\n10.1093/cei/uxac123\n10.1182/blood-2017-06-741033\n10.1186/s12884-019-2218-6\n10.3389/fimmu.2022.900537\n10.3389/fimmu.2020.01023\n10.3390/ijms25094884\n10.3389/fmed.2023.1244424\n10.1016/j.chom.2011.06.005\n10.5468/ogs.2014.57.3.208\n10.1038/s41423-023-01036-7\n10.1007/s12016-018-8721-0\n10.14814/phy2.14038\n10.1186/s13104-023-06579-6\n10.3389/fimmu.2020.575197\n10.3389/fimmu.2020.02025\n10.1016/j.bpobgyn.2019.09.005\n10.2147/IJWH.S282604\n10.7150/ijms.48128\n10.1016/S2665-9913(24)00160-7\n10.1186/s13075-022-02783-0\n10.1007/s10067-016-3323-9\n10.1016/j.clinsp.2022.100140\n10.1038/s41581-022-00670-0\n10.1093/humrep/17.9.2439\n10.3390/ijms232315200\n10.3390/jcm11113006\n10.1016/j.intimp.2020.106806\n10.1016/B978-0-323-90805-4.00016-X\n10.3389/fimmu.2019.02899\n10.3389/fimmu.2018.01045\n10.1111/aji.13195\n10.3390/jcm12010018\n10.3390/ijerph192416500\n10.1146/annurev-pathmechdis-012418-012743\n10.1038/s41467-024-49993-5\n10.3390/jcm12124074\n10.3389/fimmu.2022.826198\n10.1016/j.bbih.2024.100868\n10.3389/fendo.2023.1219205\n10.1038/s41371-021-00637-x\n10.1111/1471-0528.13192\n10.1016/j.rbmo.2016.08.025\n10.1111/aji.13395\n10.1016/j.jri.2024.104322\n10.1016/j.jri.2019.06.001\n10.1016/j.eclinm.2022.101527\n10.1016/j.genrep.2021.101490\n10.1186/s13223-022-00660-8\n10.3390/jcm11071894\n10.3389/fmed.2022.819406\n10.1111/jcpt.13629\n10.1007/s00404-014-3262-0\n10.1111/j.1600-0897.2012.01178.x\n10.3389/fimmu.2024.1445852\n10.4103/jrms.jrms_81_21\n10.1038/s41598-024-62949-5\n10.1017/erm.2022.18\n10.3233/THC-240757\n10.1016/j.ejogrb.2019.02.036\n10.3390/ijms22062922\n10.1016/j.tjog.2019.07.007\n10.1177/1753495X19841799\n10.1016/j.jaut.2021.102676\n10.1016/j.intimp.2023.110326\n10.1111/aji.12853\n10.1155/2021/7878752\n10.18103/mra.v11i7.1.4061\n10.1111/aji.13605\n10.1016/j.jri.2023.103986\n10.1111/jog.15348\n10.1016/B978-0-12-818731-9.00068-9\n10.1002/ctd2.135\n10.1002/jcp.28543\n10.1186/s12958-021-00728-x\n10.3390/jcm7120552\n10.1093/humrep/dep470\n10.1007/s00228-023-03473-9\n10.1016/j.ajog.2023.04.022\n10.1080/14647273.2021.1955415\n10.1111/aji.13142\n10.1038/s41392-023-01608-z\n10.1016/j.transproceed.2019.04.067\n10.1016/j.intimp.2019.105730\n10.1530/RAF-20-0052\n10.4103/jhrs.JHRS_28_18\n10.1111/aji.13506\n10.1016/j.ejogrb.2020.06.017\n10.1080/14737159.2024.2375235\n10.3892/mmr.2021.12021\n10.1016/j.fertnstert.2022.04.017\n10.1038/s41423-021-00707-7\n10.1093/biolre/ioae074\n10.1111/aji.13737\n10.1016/j.jri.2023.103977\n10.1016/j.jri.2021.103369\n10.1016/j.intimp.2016.09.018",
    "journal": "Medicina (Kaunas, Lithuania)",
    "keywords": [
        "NK cells",
        "T cells",
        "alloimmune",
        "immunotherapy",
        "killer cell immunoglobulin-like receptors",
        "recurrent pregnancy loss"
    ],
    "methods": null,
    "publication_date": "2024-11-27",
    "pubmed_id": "39597081\n22835448\n36873081\n31486805\n36890460\n36305976\n24082042\n33920767\n36643876\n33039130\n37741180\n31918681\n33413199\n31136597\n36407201\n39096315\n33915094\n35381221\n25681385\n31996497\n34680467\n35785037\n36979094\n32061676\n28627518\n35094946\n32183093\n30972068\n31280950\n36997584\n38157800\n38409106\n37350956\n33717198\n37627278\n35382979\n32117298\n34158475\n39144721\n36532068\n34359951\n28484462\n35720413\n35756138\n28935491\n34680540\n26320253\n36865565\n38673652\n38201263\n36713400\n37051244\n36192648\n29205643\n32309433\n36675037\n38380317\n30272581\n30984163\n29576631\n36571811\n29118008\n30782114\n35693803\n32676072\n38732104\n38239620\n21767812\n24883292\n37217798\n30449014\n30963715\n37907956\n33133091\n32973809\n31672290\n35210867\n33029083\n39153486\n35477585\n27271701\n36403428\n36635411\n12202438\n36499520\n35683395\n32693358\n31921160\n29868008\n31585488\n36614819\n36554381\n30183507\n39019884\n37373766\n35572542\n39391794\n37842294\n34837033\n25412569\n27720163\n33511656\n39216166\n31238263\n35795714\n35277202\n35407500\n35646975\n35249235\n24818590\n22835220\n39391301\n36438075\n38898143\n35687009\n39058470\n30872045\n33805757\n31542082\n32284726\n34126302\n37290322\n29603821\n34692842\n35894648\n37413775\n35775609\n30924169\n33726772\n30558290\n20085916\n36912957\n37088276\n34304683\n31081959\n37779156\n31399190\n31299610\n35118388\n30568356\n34935238\n32592916\n37564251\n38973412\n33760145\n35637024\n34172931\n38718142\n37491929\n37354783\n34492567\n27673476",
    "results": null,
    "title": "Alloimmune Causes of Recurrent Pregnancy Loss: Cellular Mechanisms and Overview of Therapeutic Approaches.",
    "xml": "<Element 'PubmedArticle' at 0x78850318ff60>"
}