Comprehensive analysis of associative relationships between indicators of cellular-humoral immunity, pro- and anti-inflammatory cytokines in women with first trimester pregnancy loss depending on РАІ-1 gene polymorphism
DOI:
https://doi.org/10.15574/HW.2025.4(179).2838Keywords:
pregnancy, miscarriage, genetic polymorphisms, thrombophilia, early terms of gestation, pro-inflammatory cytokines, anti-inflammatory cytokines, activity, hemostasisAbstract
Aim - to study the associations between cell-humoral immunity indicators, pro- and anti-inflammatory cytokines, serum PAI-1 levels, and the PAI-1 gene polymorphism variant in women with early reproductive losses.
Materials and methods. The selected patients (n=115) were divided into 3 groups according to the type of polymorphism: I - 20 patients with wild-type polymorphism of the РAI-1 gene (675 5G>5G), II - 53 women with heterozygous polymorphism of the РAI-1 gene (675 5G>4G), III - 42 women with homozygous pathological polymorphism of РAI-1 (675 4G>4G). The study was based on bibliosemantic analysis; anamnestic data were evaluated; polymerase chain reaction was used to determine thrombophilia gene polymorphisms; enzyme-linked immunosorbent assay to determine the level of РAI-1, tumour necrosis factor-α, interleukins (IL) 4, 6, 10 in the blood serum.
Results. The average age of women in the thematic groups was comparable and amounted to 32.5±0.9, 33.9±0.7 and 33.6±0.7 years, respectively. The analysis revealed certain associations between haemostasis parameters, pregnancy loss and gestational complications associated with PAI-1 gene polymorphisms. Close links were established between elevated levels of IL-4 and IL-10, their indicators with serum PAI-1 levels, and gene polymorphism. Elevated IL-4 levels were significantly associated with a history of early pregnancy loss and earlier gestation at the time of pregnancy termination. A tendency towards increased IL-6 production in the serum of women with PAI-1 gene polymorphism (675 5G>4G) and its association with a high frequency of spontaneous abortions in the history of these women was revealed.
Conclusions. Pregnancy loss in the first trimester should be considered as the result of a complex interaction of genetic, immune and haemostatic factors. PAI-1 is not only a key antifibrinolytic factor, but also an acute phase protein and mediator of immune-inflammatory reactions that affects cell migration, extracellular matrix remodelling and tissue invasion.
The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies.
No conflict of interests was declared by the authors.
References
Alecsandru D, Klimczak AM, Garcia Velasco JA, Pirtea P, Franasiak JM. (2021). Immunologic causes and thrombophilia in recurrent pregnancy loss. Fertil. Steril. 115(3): 561-566. https://doi.org/10.1016/j.fertnstert.2021.01.017; PMid:33610320
Ali S, Majid S, Ali MN, Taing S, Rehman MU, Arafah A. (2021). Cytokine imbalance at materno-embryonic interface as a potential immune mechanism for recurrent pregnancy loss. Int. Immunopharmacol. 90: 107-118. https://doi.org/10.1016/j.intimp.2020.107118; PMid:33191177
Bender AR, Christiansen OB, Elson J, Kolte AM, Lewis S, Middeldorp S et al. (2018). ESHRE guideline: recurrent pregnancy loss. Hum. Reprod. Open. 2018: y4. https://doi.org/10.1093/hropen/hoy004; PMid:31486805 PMCid:PMC6276652
Bender AR, Christiansen OB, Elson J, Kolte AM, Sheena L, Middeldorp S et al. (2023). ESHRE guideline: recurrent pregnancy loss: an update in 2022. Hum. Reprod. Open. 2023(1): hoad002. https://doi.org/10.1093/hropen/hoad002; PMid:36873081 PMCid:PMC9982362
Chambers M, Rees A, Cronin JG, Nair M, Jones N, Thornton CA. (2020). Macrophage plasticity in reproduction and environmental influences on their function. Front. Immunol. 11: 607328. https://doi.org/10.3389/fimmu.2020.607328; PMid:33519817 PMCid:PMC7840613
Cuadrado-Torroglosa I, Garcia-Velasco JA, Alecsandru D. (2024). The impacts of inflammatory and autoimmune conditions on the endometrium and reproductive outcomes. J. Clin. Med. 13(13): 3724. https://doi.org/10.3390/jcm13133724; PMid:38999290 PMCid:PMC11242609
De Ziegler D, Frydman RF. (2021). Recurrent pregnancy losses, a lasting cause of infertility. Fertil. Steril. 115: 531-532. https://doi.org/10.1016/j.fertnstert.2020.12.004; PMid:33581853
Ding J, Zhang Y, Cai X et al. (2022). Decidual immune cells and their roles at the maternal-fetal interface. Front. Immunol. 13: 901747. https://doi.org/10.3389/fimmu.2022.901747; PMid:35769482 PMCid:PMC9235356
Duka YuM, Panov VV. (2025). Kharakterystyka aktyvnosti pryrodnikh antykoahuliantiv u zhinok iz nevynoshuvanniam vahitnosti zalezhno vid vyiavlenoho polimorfizmu hena PAI-1 (675 5G/4G). Perspektyvy ta innovatsii nauky (Seriia "Psykholohiia", Seriia "Pedahohika", Seriia "Medytsyna"). (1): 2152-2165. https://doi.org/10.52058/2786-4952-2025-1(47)-2152-2165; PMid:40825184
Duka YuM. (2016). Patohenetychne obhruntuvannia diahnostyky, likuvalnoi taktyky ta profilaktyky vynyknennia systemnykh porushen u vahitnykh zhinok z nadmirnoiu masoiu tila. Dys. … d-ra med. nauk. Dnipro: 339.
Floridon C, Nielsen O, Holund B et al. (2000). Does plasminogen activator inhibitor-1 inhibit trophoblast invasion? Placenta. 21(7): 754-759. https://doi.org/10.1053/plac.2000.0573; PMid:11095924
Fu YY, Ren CE, Qiao PY, Meng YH. (2021). Uterine natural killer cells and recurrent spontaneous abortion. Am. J. Reprod. Immunol. 86: e13433. https://doi.org/10.1111/aji.13433; PMid:33896061
Gabay C. (2006). Interleukin-6 and chronic inflammation. Arthritis Res. Ther. 8(Suppl 2): S3. https://doi.org/10.1186/ar1917; PMid:16899107 PMCid:PMC3226076
Guan D, Sun W, Gao M, Chen Z, Ma X. (2024). Immunologic insights in recurrent spontaneous abortion: molecular mechanisms and therapeutic interventions. Biomed. Pharmacother. 177: 117082. https://doi.org/10.1016/j.biopha.2024.117082; PMid:38972152
Hohensinner PJ, Kaun C, Rychli K et al. (2017). STAT6-dependent regulation of PAI-1 expression in alternatively activated macrophages. Blood. 130(5): 507-518. https://doi.org/10.1182/blood-2017-02-768242; PMid:28705861
Hong LY, Marren A. (2018). Recurrent pregnancy loss: a summary of international evidence-based guidelines and practice. Aust. J. Gen. Pract. 47: 432-436. https://doi.org/10.31128/AJGP-01-18-4459; PMid:30114870
Huang HL, Yang HL, Lai ZZ, Yang SL, Li MQ, Li DJ. (2021). Decidual IDO(+) macrophage promotes the proliferation and restricts the apoptosis of trophoblasts. J. Reprod. Immunol. 148: 103364. https://doi.org/10.1016/j.jri.2021.103364; PMid:34482001
Italiani P, Boraschi D. (2014). From monocytes to M1/M2 macrophages: Phenotypical vs. functional differentiation. Front. Immunol. 5: 514. https://doi.org/10.3389/fimmu.2014.00514; PMid:25368618 PMCid:PMC4201108
Jardine L, Haniffa M. (2020). Reconstructing human DC, monocyte and macrophage development in utero using single cell technologies. Mol. Immunol. 123: 1-6. https://doi.org/10.1016/j.molimm.2020.04.023; PMid:32380279
Jena MK, Nayak N, Chen K, Nayak NR. (2019). Role of macrophages in pregnancy and related complications. Arch. Immunol. Ther. Exp. (Warsz). 67: 295-309. https://doi.org/10.1007/s00005-019-00552-7; PMid:31286151 PMCid:PMC7140981
Jiang X, Du MR, Li M, Wang H. (2018). Three macrophage subsets are identified in the uterus during early human pregnancy. Cell. Mol. Immunol. 15: 1027-1037. https://doi.org/10.1038/s41423-018-0008-0; PMid:29618777 PMCid:PMC6269440
Jiang X, Wang H. (2020). Macrophage subsets at the maternal-fetal interface. Cell. Mol. Immunol. 17: 889-891. https://doi.org/10.1038/s41423-020-0435-6; PMid:32382125 PMCid:PMC7203721
Kerr R, Stirling D, Ludlam CA. (2001). Interleukin-6 and haemostasis. Br. J. Haematol. 115(1): 3-12. https://doi.org/10.1046/j.1365-2141.2001.03061.x; PMid:11722403
Kishimoto T. (2006). Interleukin-6: from basic science to medicine - 40 years in immunology. Annu. Rev. Immunol. 24: 1-23. https://doi.org/10.1146/annurev.immunol.23.021704.115806; PMid:15771564
Li X, Liu Y, Zhang R et al. (2015). Association between plasminogen activator inhibitor-1 4G/5G polymorphism and recurrent pregnancy loss: a meta-analysis. Am. J. Reprod. Immunol. 73(4): 292-300. https://doi.org/10.1111/aji.12321; PMid:25250948
Maghsudlu M, Noroozi Z, Zokaei E, Motevaseli E. (2024). Systematic review and meta-analysis of association between plasminogen activator inhibitor-1 4G/5G polymorphism and recurrent pregnancy loss. Thrombosis J. 22: 44. https://doi.org/10.1186/s12959-024-00612-9; PMid:38807142 PMCid:PMC11134946
Medcalf RL. (2007). Fibrinolysis, inflammation and regulation of the plasminogen activating system. J. Thromb. Haemost. 5(Suppl 1): 132-142. https://doi.org/10.1111/j.1538-7836.2007.02464.x; PMid:17635719
Mor G, Aldo P, Alvero AB. (2022). The unique immunological and microbial aspects of pregnancy. Nat. Rev. Immunol. 22(8): 469-482. https://doi.org/10.1038/s41577-022-00679-3; PMid:35169260 PMCid:PMC9376198
Pajkrt D, Camoglio L, Tiel-van Buul MC et al. (1997). Attenuation of procoagulant response by recombinant human interleukin-10 in humans. Blood. 90(10): 4162-4167.
Panov VV, Duka YuM. (2025). Patohenetychno obgruntovani napriamky vtorynnoi profilaktyky rannikh reproduktyvnykh vtrat u zhinok iz nevynoshuvanniam vahitnosti ta nosiistvom polimorfizmu hena PAI-1 (675 5G/4G). Perspektyvy ta innovatsii nauky (Seriia "Psykholohiia", Seriia "Pedahohika", Seriia "Medytsyna"). 5(51): 3048-3066. https://doi.org/10.52058/2786-4952-2025-5(51)-3048-3066; PMid:40825184
Practice Committee of the American Society for Reproductive Medicine. (2020). Evaluation and treatment of recurrent pregnancy loss. Fertil. Steril. 113: 533-535. https://doi.org/10.1016/j.fertnstert.2019.11.025; PMid:32115183
Prins JR, Gomez-Lopez N, Robertson SA. (2012). Interleukin-6 in pregnancy and gestational disorders. J. Reprod. Immunol. 95(1-2): 1-14. https://doi.org/10.1016/j.jri.2012.05.004; PMid:22819759
Qiu Y, Li M, Wang S et al. (2025). Immune imbalance at the maternal-fetal interface contributes to first-trimester pregnancy loss. Reprod. Biol. Endocrinol. 23: 12.
Quenby S, Gallos ID, Dhillon-Smith RK, Podesek M, Stephenson MD, Fisher J et al. (2021). Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet. 397(10285): 1658-1667. https://doi.org/10.1016/S0140-6736(21)00682-6; PMid:33915094
Raghupathy R. (2013). Cytokines as key players in the pathophysiology of pregnancy complications. Am. J. Reprod. Immunol. 69(1): 8-17. https://doi.org/10.1111/aji.12015; PMid:23006048 PMCid:PMC3493688
Rasmark RE, Christiansen OB, Kallen K, Hansson SR. (2021). Women with a history of recurrent pregnancy loss are a high-risk population for adverse obstetrical outcome: a retrospective cohort study. J. Clin. Med. 10: 179. https://doi.org/10.3390/jcm10020179; PMid:33419111 PMCid:PMC7825424
Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F et al. (2018). Macrophage plasticity, polarization, and function in health and disease. J. Cell. Physiol. 233: 6425-6440. https://doi.org/10.1002/jcp.26429; PMid:29319160
Sillen M, Declerck PJ. (2021). Targeting PAI-1 in pathological thrombosis and fibrosis. Int. J. Mol. Sci. 22(8): 4085. https://doi.org/10.3390/ijms22084085; PMid:33920936 PMCid:PMC8071291
Stephanie EA, Michael SD, Carolyn BC. (2019). Immune responses at the maternal-fetal interface. Sci. Immunol. 4: eaat6114. https://doi.org/10.1126/sciimmunol.aat6114; PMid:30635356 PMCid:PMC6744611
Thaxton JE, Sharma S. (2010). Interleukin-6: a mediator of inflammation and immune tolerance in pregnancy. Am. J. Reprod. Immunol. 63(6): 539-548. https://doi.org/10.1111/j.1600-0897.2010.00810.x; PMid:20163400 PMCid:PMC3628686
Ticconi C, Pietropolli A, Specchia M, Nicastri E, Chiaramonte C, Piccione E et al. (2020). Pregnancy-related complications in women with recurrent pregnancy loss: a prospective cohort study. J. Clin. Med. 9: 2833. https://doi.org/10.3390/jcm9092833; PMid:32882985 PMCid:PMC7564138
Tsao FY, Wu MY, Chang YL, Wu CT, Ho HN. (2018). M1 macrophages decrease in the deciduae from normal pregnancies but not from spontaneous abortions or unexplained recurrent spontaneous abortions. J. Formos. Med. Assoc. 117: 204-211. https://doi.org/10.1016/j.jfma.2017.03.011; PMid:28465068
Van Dijk MM, Kolte AM, Limpens J, Kirk E, Quenby S, van Wely M et al. (2020). Recurrent pregnancy loss: diagnostic workup after two or three pregnancy losses? A systematic review of the literature and meta-analysis. Hum. Reprod. Update. 26: 356-367. https://doi.org/10.1093/humupd/dmz048; PMid:32103270 PMCid:PMC7161667
Vomstein K, Feil K, Strobel L, Aulitzky A, Hofer-Tollinger S, Kuon RJ, Toth B. (2021). Immunological risk factors in recurrent pregnancy loss: guidelines versus current state of the art. J. Clin. Med. 10(4): 869. https://doi.org/10.3390/jcm10040869; PMid:33672505 PMCid:PMC7923780
Wheeler KC, Jena MK, Pradhan BS, Nayak N, Das S, Hsu CD et al. (2018). VEGF may contribute to macrophage recruitment and M2 polarization in the decidua. PLoS One. 13: e0191040. https://doi.org/10.1371/journal.pone.0191040; PMid:29324807 PMCid:PMC5764356
Whyte CS, Mutch NJ. (2023). Plasminogen activator inhibitor-1 and regulation of fibrinolysis in inflammatory disease. J. Thromb. Haemost. 21(2): 234-247. doi: 10.1111/jth.16089.
Yi X, Zhang J, Liu H, Yi T, Ou Y, Liu M et al. (2019). Suppressed immune-related profile rescues abortion-prone fetuses: a novel insight into the CBA/J × DBA/2J mouse model. Reprod. Sci. 26: 1485-1492. https://doi.org/10.1177/1933719119828042; PMid:30791861
Zhao QY, Li QH, Fu YY, Ren CE, Jiang AF, Meng YH. (2022). Decidual macrophages in recurrent spontaneous abortion. Front. Immunol. 13: 994888. https://doi.org/10.3389/fimmu.2022.994888; PMid:36569856 PMCid:PMC9781943
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Ukrainian Journal Health of Woman
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
The policy of the Journal UKRAINIAN JOURNAL «HEALTH OF WOMAN» is compatible with the vast majority of funders' of open access and self-archiving policies. The journal provides immediate open access route being convinced that everyone – not only scientists - can benefit from research results, and publishes articles exclusively under open access distribution, with a Creative Commons Attribution-Noncommercial 4.0 international license (СС BY-NC).
Authors transfer the copyright to the Journal UKRAINIAN JOURNAL «HEALTH OF WOMAN» when the manuscript is accepted for publication. Authors declare that this manuscript has not been published nor is under simultaneous consideration for publication elsewhere. After publication, the articles become freely available on-line to the public.
Readers have the right to use, distribute, and reproduce articles in any medium, provided the articles and the journal are properly cited.
The use of published materials for commercial purposes is strongly prohibited.
