Peripheral blood NK cells in patients with uterine scars and abnormally adherent and invasive placenta
Ponikarova N.Yu., Davydova A.A., Shelepova E.S., Osipova N.A., Sokolov D.I., Mikhailova V.A., Oganyan K. A., Selkov S.A., Zazerskaya I.E.
Objective: The aim of the study was to evaluate cytotoxic activity of peripheral blood NK cells against trophoblast cells in pregnant women with uterine scar and with or without abnormally adherent and invasive placenta (AAIP).
Materials and methods: The study included 18 pregnant women who were divided into 3 groups. The main group (n=6) included women with uterine scar after cesarean section and AAIP. The comparison group (n=6) included women with uterine scar and without AAIP. The control group (n=6) included pregnant women without uterine scar. The women were enrolled in the study at 28–32 weeks of pregnancy. Cytotoxic activity of peripheral blood NK cells against trophoblast cells of the JEG-3 line was evaluated in all patients.
Results: There were no differences in cytotoxic activity of NK cells between the group of women with AAIP and the comparison and control groups. However, the cytotoxic activity of pNK was lower in the group of pregnant women who underwent cesarean section in history versus women with normal pregnancy (p= p=0.022).
Conclusion: The data obtained in this study suggest that reduced cytotoxic activity of pNK cells in women with uterine scar and without AAIP is due to the mechanism that prevents adherence of placenta in a number of patients in risk group.
Authors’ contributions: Ponikarova N.Yu. – data collection and analysis, manuscript drafting; Davydova A.A. – cell culture work and and processing of biological material; Shelepova E.S., Osipova N.A. – data collection and analysis; Sokolov D.I., Mikhailova V.A., Selkov S.A. – manuscript editing; Oganyan K.A. – literature review, preparation of the manuscript for publication; Zazerskaya I.E. – the concept and design of the study, manuscript editing.
Conflicts of interest: The authors declare that they have no conflicts of interest.
Funding: The study was supported by Almazov National Medical Research Centre of the Ministry of Health of Russia; State Assignment 123 021 000 051-2 “Development of risk assessment scale for abnormally adherent and invasive placenta in pregnant women with uterine scars”.
Ethical Approval: The protocol of the study was approved by the local Ethics Committee at Almazov National Medical Research Centre of the Ministry of Health of Russia (minutes of the meeting No. 11-22 of November 2022, protocol No. 2211-22)
Patient Consent for Publication: The patients have signed informed consent for participation in the study and publication of their data.
Authors' Data Sharing Statement: The data supporting the findings of this study are available on request from the corresponding author after approval from the principal investigator.
For citation: Ponikarova N.Yu., Davydova A.A., Shelepova E.S., Osipova N.A.,
Sokolov D.I., Mikhailova V.A., Oganyan K.A., Selkov S.A., Zazerskaya I.E.
Peripheral blood NK cells in patients with uterine scars and abnormally adherent and invasive placenta.
Akusherstvo i Gynecologia/Obstetrics and Gynecology. 2025; (1): 66-72 (in Russian)
https://dx.doi.org/10.18565/aig.2024.303
Keywords
References
- Kobayashi H., Matsubara S., Yoshimoto C., Shigetomi H., Imanaka S. Current understanding of the pathogenesis of placenta accreta spectrum disorder with focus on mitochondrial function. J. Obstet. Gynaecol. Res. 2024; 50(6): 929-40. https://dx.doi.org/10.1111/jog.15936.
- Xu X., Zhou Y., Wei H. Roles of HLA-G in the maternal-fetal immune microenvironment. Front. Immunol. 2020; 11: 592010. https://dx.doi.org/10.3389/fimmu.2020.592010.
- Kanter J.R., Mani S., Gordon S.M., Mainigi M. Uterine natural killer cell biology and role in early pregnancy establishment and outcomes. F. S. Rev. 2021; 2(4): 265-86. https://dx.doi.org/10.1016/j.xfnr.2021.06.002.
- Gaynor L.M., Colucci F. Uterine natural killer cells: functional distinctions and influence on pregnancy in humans and mice. Front. Immunol. 2017; 8: 467. https://dx.doi.org/10.3389/fimmu.2017.00467.
- El-Badawy O., Helmy A.S., Abbas A.M., Zahran A.M., Afifi N.A., Abdel-Rahim M.H. Concordance between peripheral and decidual NK cell subsets and killer immunoglobulin-like receptors in women with recurrent spontaneous miscarriages. J. Reprod. Immunol. 2020; 140: 103130. https://dx.doi.org/10.1016/j.jri.2020.103130.
- Chen X., Zhang T., Liu Y., Cheung W.C., Zhao Y., Wang C.C. et al. Uterine CD56+ cell density and euploid miscarriage in women with a history of recurrent miscarriage: A clinical descriptive study. Eur. J. Immunol 2021; 51(2): 487-9. https://dx.doi.org/10.1002/eji.202048868.
- Cooper S., Laird S.M., Mariee N., Li T.C., Metwally M. The effect of prednisolone on endometrial uterine NK cell concentrations and pregnancy outcome in women with reproductive failure. A retrospective cohort study. J. Reprod. Immunol. 2019; 131: 1-6. https://dx.doi.org/10.1016/j.jri.2018.10.001.
- Xie M., Li Y., Meng Y.Z., Xu P., Yang Y.G., Dong S. et al. Uterine natural killer cells: a rising star in human pregnancy regulation. Front. Immunol. 2022; 13: 918550. https://dx.doi.org/10.3389/fimmu.2022.918550.
- Dons'koi B.V., Osypchuk D.V., Chernyshov V.P., Khazhylenko K.G. Expression of natural cytotoxicity receptor NKp46 on peripheral blood natural killer cells in women with a history of recurrent implantation failures. J. Obstet. Gynaecol. Res. 2021; 47(3): 1009-15. https://dx.doi.org/10.1111/jog.14631.
- Deer E., Herrock O., Campbell N., Cornelius D., Fitzgerald S., Amaral L.M. et al. The role of immune cells and mediators in preeclampsia. Nat. Rev. Nephrol. 2023; 19(4): 257-70. https://dx.doi.org/10.1038/s41581-022-00670-0.
- Hecht J.L., Karumanchi S.A., Shainker S.A. Immune cell infiltrate at the utero-placental interface is altered in placenta accreta spectrum disorders. Arch. Gynecol. Obstet. 2020; 301(2): 499-507. https://dx.doi.org/10.1007/s00404-020-05453-1.
- El-Badawy O., Abbas A.M., Radwan E., Makboul R., Khamis A.A., Ali M. et al. Cross-talk between mucosal-associated invariant T, natural killer, and natural killer T cell populations is implicated in the pathogenesis of placenta accreta spectrum. Inflammation. 2023; 46(4): 1192-208. https://dx.doi.org/10.1007/s10753-023-01799-1.
- AbdelFattah S., Morsy M., Ahmed A.M., Abdelsalam H., Hosny G. Microcellular approach for the pathogenesis of placenta accreta spectrum inflammatory versus apoptotic pathways; a thorough look on Treg, dNK and VEGF. Pathol. Res. Pract. 2024; 254: 155153. https://dx.doi.org/10.1016/j.prp.2024.155153.
- Marron K., Harrity C. Endometrial lymphocyte concentrations in adverse reproductive outcome populations. J. Assist. Reprod. Genet. 2019; 36(5): 837-46. https://dx.doi.org/10.1007/s10815-019-01427-8.
- Министерство здравоохранения Российской Федерации. Клинические рекомендации. Патологическое прикрепление плаценты (предлежание и врастание плаценты). 2023. [Ministry of Health of the Russian Federation. Clinical guidelines. Pathological attachment of the placenta (placenta previa and accreta). 2023. (in Russian)].
- ФГБУ «Северо-Западный федеральный медицинский исследовательский центр имени В.А. Алмазова» Министерства здравоохранения Российской Федерации. Клинические протоколы ведения пациентов по специальности «Акушерство и гинекология». Ч. I. 3‑е изд. СПб: Эко-Вектор; 2023. [V.A. Almazov North-Western Federal Medical Research Center of the Ministry of Health of the Russian Federation. Clinical protocols for patient management in the specialty "Obstetrics and Gynecology." Part I. 3rd ed. St. Petersburg: Eco-Vector; 2023. (in Russian)].
- Семенова Е.С., Мащенко И.А., Труфанов Г.Е., Фокин В.А., Ефимцев А.Ю., Лепёхина А.С., Горбунова Е.А., Сергиеня О.В., Шмедык Н.Ю., Тиллоев Т.А. Магнитно-резонансная томография при беременности: актуальные вопросы безопасности. REJR. 2020; 10(1): 216-30. [Semenova E.S., Mashchenko I.A., Trufanov G.E., Fokin V.A., Efimtsev A.Yu., Lepekhina A.S., Gorbunova E.A., Sergienya O.V., Shmedyk N.Yu., Tilloev T.A. Magnetic resonance imaging during pregnancy: current safety issues. REJR. 2020;10(1): 216-30. (in Russian)]. https://dx.doi.org/10.21569/2222-7415-2020-10-1-216-230.
- Загайнова В.А., Коган И.Ю., Беспалова О.Н., Сельков С.А., Соколов Д.И. Роль периферических и эндометриальных NK-клеток при повторных репродуктивных потерях. Акушерство и гинекология. 2021; 7: 19-27. [Zagainova V.A., Kogan I.Yu., Bespalova O.N., Selkov S.A., Sokolov D.I. The role of peripheral and endometrial natural killer cells in recurrent reproductive losses. Obstetrics and Gynecology. 2021; (7): 19-27 (in Russian)]. https://dx.doi.org/10.18565/aig.2021.7.19-27.
- Bulmer J.N., Lash G.E. Uterine natural killer cells: Time for a re-appraisal? F1000Res. 2019; 8: F1000 Faculty Rev-999. https://dx.doi.org/10.12688/f1000research.19132.1.
- Vacca P., Chiossone L., Mingari M.C., Moretta L. Heterogeneity of NK cells and other innate lymphoid cells in human and murine decidua. Front. Immunol. 2019; 10: 170. https://dx.doi.org/10.3389/fimmu.2019.00170.
- Fu B., Wei H. Natural killer cells in reproduction: Before, during and after pregnancy. In: Mor G., ed. Reproductive Immunology: Basic Concepts. 2021: 55-72. https://dx.doi.org/10.1016/B978-0-12-818508-7.00009-9.
- Strunz B., Bister J., Jönsson H., Filipovic I., Crona-Guterstam Y., Kvedaraite E. et al. Continuous human uterine NK cell differentiation in response to endometrial regeneration and pregnancy. Sci. Immunol. 2021; 6(56): eabb7800. https://dx.doi.org/10.1126/sciimmunol.abb7800.
- Михайлова В.А., Давыдова А.А., Загайнова В.А., Сельков С.А., Соколов Д.И. NK-клетки в диагностике репродуктивных нарушений: долгий путь от теории к практике. Тезисы III Общероссийской научно-практической конференции для акушеров-гинекологов «Оттовские чтения». М.: Издательство журнала StatusPraesens; 2021: 18-9. [Mikhailova V.A., Davydova A.A., Zagainova V.A., Selkov S.A., Sokolov D.I. NK cells in the diagnosis of reproductive disorders: a long way from theory to practice. Theses of the III All-Russian Scientific and Practical Conference for Obstetricians and Gynecologists "Ott's Readings". Moscow: StatusPraesens; 2021: 18-9. (in Russian)].
- Toth B., Zhu L., Karakizlis H., Weimer R., Morath C., Opelz G. et al. NK cell subsets in idiopathic recurrent miscarriage and renal transplant patients. J. Reprod. Immunol. 2020; 138: 103098. https://dx.doi.org/10.1016/j.jri.2020.103098.
- Баженов Д.О., Михайлова В.А. Влияние клеток трофобласта на цитотоксический потенциал NK-клеток. Актуальные проблемы биомедицины - 2021: материалы XXVII Всероссийской конференции молодых ученых с международным участием, Санкт-Петербург, 25-26 марта 2021 года. СПб: Первый Санкт-Петербургский государственный медицинский университет им. академика И.П. Павлова; 2021: 144-5. [Bazhenov D.O., Mikhailova V.A. Effect of trophoblast cells on the cytotoxic potential of NK cells. Topical problems of biomedicine - 2021: materials of the XXVII All-Russian Conference of Young Scientists with International Participation, St. Petersburg, March 25-26, 2021. St. Petersburg: Academician I.P. Pavlov First St. Petersburg State Medical University; 2021: 144-5. (in Russian)].
- Li C., Houser B.L., Nicotra M.L., Strominger J.L. HLA-G homodimer-induced cytokine secretion through HLA-G receptors on human decidual macrophages and natural killer cells. Proc. Natl. Acad. Sci. U. S. A. 2009; 106(14): 5767-72. https://dx.doi.org/10.1073/pnas.0901173106.
- Laban M., Ibrahim E.A., Elsafty M.S., Hassanin A.S. Placenta accreta is associated with decreased decidual natural killer (dNK) cells population: a comparative pilot study. Eur. J. Obstet. Gynecol. Reprod. Biol. 2014; 181: 284-8. https://dx.doi.org/10.1016/j.ejogrb.2014.08.015.
- Skret-Magierlo J., Wicherek L., Basta P., Galazka K., Sikora J., Wilk M. et al. RCAS1 decidual immunoreactivity during cesarean section in scar deciduosis: immune cell presence and activity. Gynecol. Obstet. Invest. 2008; 65(3): 187-94. https://dx.doi.org/10.1159/000111533.
- Smith A.L., Bole Aldo P., Racicot K.E. Placental regulation of immune functions. In: Mor G., ed. Reproductive Immunology: Basic Concepts. 2021: 335-48. https://dx.doi.org/10.1016/B978-0-12-818508-7.00004-X.
- Liu X., Wang Y., Wu Y., Zeng J., Yuan X., Tong C. et al. What we know about placenta accreta spectrum (PAS). Eur. J. Obstet. Gynecol. Reprod. Biol. 2021; 259: 81-9. https://dx.doi.org/10.1016/j.ejogrb.2021.02.001.
- Годзоева А.О., Зазерская И.Е., Васильева Е.Ю., Мащенко И.А., Яковлева Н.Ю., Ли О.А. Прогностическая значимость sFlt-1 и PlGF в диагностике глубокой инвазии плаценты. Журнал акушерства и женских болезней. 2022; 71(2): 39-48. [Godzoeva A.O., Zazerskaya I.E., Vasilyeva E.Y., Mashchenko I.A., Yakovleva N.Y., Li O.A. Prognostic value of sFlt-1 and PlGF in the diagnosis of abnormally deep placental invasion. Journal of obstetrics and women's diseases. 2022; 71(2): 39-48. (in Russian)]. https://dx.doi.org/10.17816/JOWD88697.
- Jauniaux E., Jurkovic D., Hussein A.M., Burton G.J. New insights into the etiopathology of placenta accreta spectrum. Am. J. Obstet. Gynecol. 2022; 227: 384-91. https://dx.doi.org/10.1016/j.ajog.2022.02.038.
- Zhou J., Chen H., Xu X., Liu Y., Chen S., Yang S. et al. Uterine damage induces placenta accreta and immune imbalance at the maternal-fetal interface in the mouse. Placenta. 2022; 119: 8-16. https://dx.doi.org/10.1016/j.placenta.2022.01.002.
- Harris L.K., Benagiano M., D'Elios M.M., Brosens I., Benagiano G. Placental bed research: II. Functional and immunological investigations of the placental bed. Am. J. Obstet. Gynecol. 2019; 221(5): 457-469. https://dx.doi.org/10.1016/j.ajog.2019.07.010.
Received 25.11.2024
Accepted 17.01.2025
About the Authors
Nataliya Yu. Ponikarova, PhD student, Department of Obstetrics and Gynecology, V.A. Almazov National Medical Research Center, Ministry of Health of Russia,197341, Russia, St. Petersburg, Akkuratova str., 2, +7(981)963-86-35, natalyponi@gmail.com, https://orcid.org/0000-0002-7230-3057
Alina A. Davydova, Junior Researcher at the Laboratory of Intercellular Interactions, Department of Immunology and Intercellular Interactions, D.O. Ott Research Institute
for Obstetrics, Gynecology and Reproductology, 199034, Russia, St. Petersburg, Mendeleevskaya line, 3, +7(812)328-98-50, alyadavydova@gmail.com,
https://orcid.org/0000-0001-5313-2910,
Ekatherina S. Shelepova, PhD, Teaching Assistant, Department of Obstetrics and Gynecology, V.A. Almazov National Medical Research Center, Ministry of Health of Russia, 197341, Russia, St. Petersburg, Akkuratova str., 2, shelepova_es@almazovcentre.ru, https://orcid.org/0000-0002-3233-8239
Nataliya A. Osipova, Dr. Med. Sci., Professor, Department of Obstetrics and Gynecology, Ministry of Health of Russia,
197341, Russia, St. Petersburg, Akkuratova str., 2, osipova_na@almazovcentre.ru
Dmitry I. Sokolov, Dr. Bio. Sci., Professor, Head of the Laboratory of Intercellular Interactions, Department of Immunology and Intercellular Interactions,
D.O. Ott Research Institute for Obstetrics, Gynecology and Reproductology, 199034, Russia, St. Petersburg, Mendeleevskaya line, 3, +7(812)328-98-50,
falcojugger@yandex.ru, https://orcid.org/0000-0002-5749-2531
Valentina A. Mikhailova, Dr. Bio. Sci., Senior Researcher at the Laboratory of Intercellular Interactions, Department of Immunology and Intercellular Interactions,
D.O. Ott Research Institute for Obstetrics, Gynecology and Reproductology, 199034, Russia, St. Petersburg, Mendeleevskaya line, 3, mva_spb@mail.ru,
https://orcid.org/0000-0003-1328-8157
Karina A. Oganyan, Resident Physician, Department of Obstetrics and Gynecology, V.A. Almazov National Medical Research Center, Ministry of Health of Russia,
197341, Russia, St. Petersburg, Akkuratova str., 2, oganyan_karina@bk.ru, https://orcid.org/0000-0002-2743-0882
Sergey A. Selkov, Merited Scolar of the Russian Federation, Dr. Med. Sci., Professor, Head of the Department of Immunology and Intercellular Interactions, D.O. Ott
Research Institute for Obstetrics, Gynecology and Reproductology, 199034, Russia, St. Petersburg, Mendeleevskaya line, 3, +7(812)328-98-50, selkovsa@mail.ru,
https://orcid.org/0000-0003-1560-7529
Irina E. Zazerskaya, Dr. Med. Sci., Professor, Head of the Department of Obstetrics and Gynecology, V.A. Almazov National Medical Research Center, Ministry of Health
of Russia, 197341, Russia, St. Petersburg, Akkuratova str., 2, zazera@mail.ru, https://orcid.org/0000-0003-4431-3917
Corresponding author: Nataliya Yu. Ponikarova, natalyponi@gmail.com