2658-6533Research Results in Biomedicine2658-653310.18413/2658-6533-2019-5-3-0-81755Medicine (miscellaneous)IL-2, IL-10, IL-12 and IL-23 mRNA expression in the decidual tissue in patients with missed and spontaneous abortions in early pregnancyIL-2, IL-10, IL-12 and IL-23 mRNA expression in the decidual tissue in patients with missed and spontaneous abortions in early pregnancyLebedevaOlga P.LebedevaOlga P.safonova2@yandex.ruIvascheviciAliona N.IvascheviciAliona N.alionka_iv@yahoo.com20195300

Background: Miscarriages are one of the most common complications of the first term of pregnancy. The rate of early miscarriages is about 15% of all diagnosed cases. Meanwhile, immune causes of miscarriages are not well understood. The aim of the study: To study the expression of IL-2, IL-10, IL-12 and IL-23 mRNAs, participating in differentiation of Th1, Treg and Th17, in the decidua of patients with sporadic missed and spontaneous abortions at 6-10 weeks of gestation. Materials and methods: 34 patients with missed abortions, 34 patients with spontaneous abortions and 57 patents with progressive pregnancy (control group), admitted for medical abortion, were examined at 6-10 weeks of gestation. Patients with severe extragenital diseases, antiphospholipid syndrome, endocrine disorders, anatomic abnormalities of the uterus, сhromosomal abnormalities of embryo and fetus were excluded from the research. The decidual tissue was obtained by uterine abrasion. IL-2, IL-10, IL-12 and IL-23 mRNA expression was detected by reverse-transcription qPCR. Statistical analysis was performed by Mann-Whitney test using Statistica 13.2 (Statsoft, USA). Results: The expression of IL-12 mRNA was significantly higher in the decidua of patients with spontaneous abortions compared with the control group. The expression of IL-12 in patients with missed abortions didn’t have significant differences with the control group. IL-12 provides differentiation of Th1-lymphocytes and stimulates NK-cells. The levels of IL-2, IL-10 and IL-23 in the decidua of patients with missed and spontaneous abortions had no significant differences compared with the control group. IL-2 provides differentiation of Treg. IL-10 is anti-inflammatory cytokine, secreted predominantly by Th2 and Treg, and inhibiting Th17 differentiation. IL-23 provides differentiation of Th17. Conclusion: Thus, patients with spontaneous abortions have higher expression of IL-12 mRNA, providing differentiation of Th1 lymphocytes, in the decidual tissue compared with the control group. As patients with missed and spontaneous abortions don’t have significant differences with the control group in mRNA expression of IL-2, IL-10 and IL-23, regulating Treg/Th17 balance, further investigations should be performed for estimating the role of these cytokines in pathogenesis of miscarriages. 

Background: Miscarriages are one of the most common complications of the first term of pregnancy. The rate of early miscarriages is about 15% of all diagnosed cases. Meanwhile, immune causes of miscarriages are not well understood. The aim of the study: To study the expression of IL-2, IL-10, IL-12 and IL-23 mRNAs, participating in differentiation of Th1, Treg and Th17, in the decidua of patients with sporadic missed and spontaneous abortions at 6-10 weeks of gestation. Materials and methods: 34 patients with missed abortions, 34 patients with spontaneous abortions and 57 patents with progressive pregnancy (control group), admitted for medical abortion, were examined at 6-10 weeks of gestation. Patients with severe extragenital diseases, antiphospholipid syndrome, endocrine disorders, anatomic abnormalities of the uterus, сhromosomal abnormalities of embryo and fetus were excluded from the research. The decidual tissue was obtained by uterine abrasion. IL-2, IL-10, IL-12 and IL-23 mRNA expression was detected by reverse-transcription qPCR. Statistical analysis was performed by Mann-Whitney test using Statistica 13.2 (Statsoft, USA). Results: The expression of IL-12 mRNA was significantly higher in the decidua of patients with spontaneous abortions compared with the control group. The expression of IL-12 in patients with missed abortions didn’t have significant differences with the control group. IL-12 provides differentiation of Th1-lymphocytes and stimulates NK-cells. The levels of IL-2, IL-10 and IL-23 in the decidua of patients with missed and spontaneous abortions had no significant differences compared with the control group. IL-2 provides differentiation of Treg. IL-10 is anti-inflammatory cytokine, secreted predominantly by Th2 and Treg, and inhibiting Th17 differentiation. IL-23 provides differentiation of Th17. Conclusion: Thus, patients with spontaneous abortions have higher expression of IL-12 mRNA, providing differentiation of Th1 lymphocytes, in the decidual tissue compared with the control group. As patients with missed and spontaneous abortions don’t have significant differences with the control group in mRNA expression of IL-2, IL-10 and IL-23, regulating Treg/Th17 balance, further investigations should be performed for estimating the role of these cytokines in pathogenesis of miscarriages. 

miscarriagemissed abortionspontaneous abortiondecidual tissueendometriummRNAIL-2IL-10IL-12IL-23miscarriagemissed abortionspontaneous abortiondecidual tissueendometriummRNAIL-2IL-10IL-12IL-23

This work was supported by the grant of the President of the Russian Federation MD-2326.2017.7 «Development of molecular methods for individual prediction of miscarriages in early pregnancy».

Список литературыD'Ippolito S, Tersigni C, Marana R, et al. Inflammosome in the human endometrium: further step in the evaluation of the “maternal side”. Fertility and sterility. 2016;105(1):111-118. DOI: https://doi.org/10.1016/j.fertnstert.2015.09.027Saito S, Nakashima A, Shima T, et al. Th1/Th2/Th17 and regulatory T‐cell paradigm in pregnancy. American journal of reproductive immunology. 2010;63(6):601-610. DOI: https://doi.org/10.1111/j.1600-0897.2010.00852.xSharma S. Natural killer cells and regulatory T cells in early pregnancy loss. The International journal of developmental biology. 2014;58:219. DOI: 10.1387/ijdb.140109ssLebedeva OP, Zhukova IO, Ivashova ON, et al. [Subpopulations of T-lymphocytes of the endometrium in pathogenesis of early miscarriages]. Russian Journal of Human Reproduction (Problemy reproduktsii). 2018;24(1):82-86. DOI: 10.17116/repro201824182-86Kalinski P. Regulation of immune responses by prostaglandin E2. The Journal of Immunology. 2012;188(1):21-28. DOI: 10.4049/jimmunol.1101029Bustin SA, Benes V, Garson JA, et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clinical chemistry. 2009;55(4):611-622. DOI: 10.1373/clinchem.2008.112797Pfaffl MV. Quantification strategies in real-time PCR. In: S.A. Bustin, ed. A-Z of quantitative PCR. La Jolla: Int. University Line; 2004:87-112.Khaitov RM, Yarilin AA, Pinegin BV. [Immunology: an atlas]. Moscow: GEOTAR-Media; 2011. Russian.Madar T, Shahaf  G, Sheiner E, et al. Low levels of circulating alpha-1 antitrypsin are associated with spontaneous abortions. The Journal of Maternal-Fetal and Neonatal Medicine. 2013;26(18):1782-1787. DOI: https://doi.org/10.3109/14767058.2013.801955Paradisi R, Porcu E, Venturoli S, et al. Maternal serum levels of pro-inflammatory cytokines in missed and threatened abortion. American Journal of Reproductive Immunology. 2003;50(4):302-308. DOI: https://doi.org/10.1034/j.1600-0897.2003.00065.xTian C-F, Kang M-H. Common stress and serum cortisol and IL-12 levels in missed abortion. Journal of Obstetrics and Gynaecology. 2013;34(1):33-35. DOI: https://doi.org/10.3109/01443615.2013.830089Wilson R, Moor J, Jenkins C, et al. Abnormal first trimester serum interleukin 18 levels are associated with a poor outcome in women with a history of recurrent miscarriage. American Journal of Reproductive Immunology. 2004;51(2):156-159. DOI: https://doi.org/10.1046/j.8755-8920.2003.00126.xZenclussen AC, Fest S, Busse P, et al. Questioning the Th1/Th2 paradigm in reproduction: peripheral levels of IL-12 are down-regulated in miscarriage patients. American Journal of Reproductive Immunology. 2002;48(4):245-251. DOI: https://doi.org/10.1034/j.1600-0897.2002.01136.xRad HA, Basirat Z, Mostafazadeh A, et al. Evaluation of peripheral blood NK cell subsets and cytokines in unexplained recurrent miscarriage. Journal of the Chinese Medical Association. 2018;81(12):1065-1070. DOI: https://doi.org/10.1016/j.jcma.2018.05.005Comba C, Bastu E, Dural O, et al. Role of inflammatory mediators in patients with recurrent pregnancy loss. Fertility and sterility. 2015;104(6):1467-1474. DOI: https://doi.org/10.1016/j.fertnstert.2015.08.011Lim KJ, Odukoya OA, Ajjan RA, et al. The role of T-helper cytokines in human reproduction. Fertility and sterility. 2000;73(1):136-142. DOI: https://doi.org/10.1016/S0015-0282(99)00457-4Calleja-Agius J, Jauniaux E, Pizzey AR, et al. Investigation of systemic inflammatory response in first trimester pregnancy failure. Human reproduction. 2011;27(2):349-357. DOI: https://doi.org/10.1093/humrep/der402Raghupathy R, Makhseed M, Azizieh F, et al. Cytokine production by maternal lymphocytes during normal human pregnancy and in unexplained recurrent spontaneous abortion. Human Reproduction. 2002;15(3):713-718. DOI: https://doi.org/10.1093/humrep/15.3.713Hadinedoushan H, Mirahmadian M, Aflatounian A. Increased Natural Killer Cell Cytotoxicity and IL-2 Production in Recurrent Spontaneous Abortion. American Journal of Reproductive Immunology. 2007;58(5):409-414. DOI: https://doi.org/10.1111/j.1600-0897.2007.00524.xRezaei A, Dabbagh A. T-helper (1) cytokines increase during early pregnancy in women with a history of recurrent spontaneous abortion. Medical Science Monitor. 2002;8(8):CR607-CR610.Plevyak M, Hanna N, Mayer S, et al. Deficiency of decidual IL-10 in first trimester missed abortion: a lack of correlation with the decidual immune cell profile. American Journal of Reproductive Immunology. 2002;47(4):242-250. DOI: https://doi.org/10.1034/j.1600-0897.2002.01060.xYuan J, Li J, Huang S-Y, et al. Characterization of the subsets of human NKT-like cells and the expression of Th1/Th2 cytokines in patients with unexplained recurrent spontaneous abortion. Journal of Reproductive Immunology. 2015;110:81-88. DOI: https://doi.org/10.1016/j.jri.2015.05.001Cai J, Li M, Huang Q, et al. Differences in cytokine expression and STAT3 activation between healthy controls and patients of unexplained recurrent spontaneous abortion (URSA) during early pregnancy. PloS one. 2016;11(9):e0163252. DOI: https://doi.org/10.1371/journal.pone.0163252Sereshki N, Gharagozloo M, Ostadi V, et al. Variations in T-helper 17 and regulatory T cells during the menstrual cycle in peripheral blood of women with recurrent spontaneous abortion. International journal of fertility and sterility. 2014;8(1):59.Jasper MJ, Tremellen KP, Robertson SA. Reduced expression of IL-6 and IL-1α mRNAs in secretory phase endometrium of women with recurrent miscarriage. Journal of Reproductive Immunology. 2007;73(1):74-84. DOI: https://doi.org/10.1016/j.jri.2006.06.003Wang W-J, Hao C-F, Yi-Lin Yin G-J, et al. Increased prevalence of T helper 17 (Th17) cells in peripheral blood and decidua in unexplained recurrent spontaneous abortion patients. Journal of Reproductive Immunology. 2010;84(2):164-170. DOI: https://doi.org/10.1016/j.jri.2009.12.003Saifi B, Rezaee SA, Tajik N, et al. Th17 cells and related cytokines in unexplained recurrent spontaneous miscarriage at the implantation window. Reproductive BioMedicine Online. 2014;29(4):481-489. DOI: https://doi.org/10.1016/j.rbmo.2014.06.008