蜕膜自然杀伤细胞在反复妊娠丢失中的作用及相关治疗

doi:10.12280/gjszjk.20210615

摘要/Abstract

摘要：

反复妊娠丢失（recurrent pregnancy loss,RPL）的发生率约为1%~5%。近年研究发现,母胎界面免疫微环境对妊娠结局有重要影响。蜕膜自然杀伤（decidual natural killer,dNK）细胞作为母胎界面重要的免疫细胞,可产生多种细胞因子,调节滋养细胞侵袭,促进子宫螺旋动脉重塑,参与妊娠早期母胎界面免疫耐受的建立,从而维持妊娠。而RPL患者的dNK细胞呈高活跃状态,其活性及功能发生改变,可能影响妊娠的免疫环境,进而导致妊娠失败。目前,通过改善dNK细胞活性及功能进而影响母胎界面微环境的治疗包括静脉滴注丙种球蛋白或脂肪乳、粒细胞集落刺激因子、糖皮质激素、间充质干细胞、枸橼酸西地那非和西罗莫司等,已成为RPL治疗中的新研究方向。

关键词: 胚胎丢失, 自身免疫, 蜕膜, 杀伤细胞,天然, 免疫耐受, 免疫疗法

Abstract:

The incidence of recurrent pregnancy loss (RPL) is about 1%-5%. The immune microenvironment at the maternal-fetal interface has a vital impact on the pregnancy outcomes. Decidual natural killer (dNK) cells, as important immune cells at the maternal-fetal interface, can produce a variety of cytokines, regulate trophoblast cells invasion, promote uterine spiral arteries remodeling, and participate in the establishment of immune tolerance at the maternal-fetal interface in early pregnancy, so as to maintain pregnancy. However, the dNK cells are highly activated in RPL patients. The increased activity and changed function of dNK cells may affect the immune environment of pregnancy, thereby leading to pregnancy failure. At present, the therapeutic regimens that affects the microenvironment of the maternal-fetal interface by improving the activity and function of dNK cells, including intravenous immunoglobulin G and lipid emulsion, granulocyte colony-stimulating factor, glucocorticoid, mesenchymal stem cells, sildenafil citrate and Sirolimus have become new research directions in the treatment of RPL.

Key words: Embryo Loss, Autoimmunity, Decidua, Killer cells,natural, Immune tolerance, Immunotherapy

王璐, 李洋, 杜伯涛. 蜕膜自然杀伤细胞在反复妊娠丢失中的作用及相关治疗[J]. 国际生殖健康/计划生育, 2022, 41(3): 219-224.

WANG Lu, LI Yang, DU Bo-tao. The Role of Decidual Natural Killer Cells in Recurrent Pregnancy Loss and Related Treatment[J]. Journal of International Reproductive Health/Family Planning, 2022, 41(3): 219-224.

参考文献 32

[1]	Bender Atik R, Christiansen OB, Elson J, et al. ESHRE guideline: recurrent pregnancy loss[J]. Hum Reprod Open, 2018, 2018(2): hoy004. doi: 10.1093/hropen/hoy004. doi: 10.1093/hropen/hoy004
[2]	Huhn O, Zhao XH, Esposito L, et al. How do uterine natural killer and innate lymphoid cells contribute to successful pregnancy?[J]. Front Immunol, 2021, 12:607669. doi: 10.3389/fimmu.2021.607669. doi: 10.3389/fimmu.2021.607669 URL
[3]	Parker EL, Silverstein RB, Verma S, et al. Viral-Immune Cell Interactions at the Maternal-Fetal Interface in Human Pregnancy[J]. Front Immunol, 2020, 11:522047. doi: 10.3389 /fimmu. 2020. 522047. doi: 10.3389 /fimmu. 2020. 522047 URL
[4]	Carlino C, Stabile H, Morrone S, et al. Recruitment of circulating NK cells through decidual tissues: a possible mechanism controlling NK cell accumulation in the uterus during early pregnancy[J]. Blood, 2008, 111(6):3108-3115. doi: 10.1182/blood-2007-08-105965. doi: 10 URL
[5]	Vento-Tormo R, Efremova M, Botting RA, et al. Single-cell reconstruction of the early maternal-fetal interface in humans[J]. Nature, 2018, 563(7731):347-353. doi: 10.1038/s41586-018-0698-6. doi: 10.1038/s41586-018-0698-6 URL
[6]	Keskin DB, Allan DS, Rybalov B, et al. TGFbeta promotes conversion of CD16⁺ peripheral blood NK cells into CD16^- NK cells with similarities to decidual NK cells[J]. Proc Natl Acad Sci U S A, 2007, 104(9):3378-3383. doi: 10.1073/pnas.0611098104. doi: 10.1073/pnas.0611098104 pmid: 17360654
[7]	刘伊宁, 孟金来, 王谢桐, 等. 蜕膜自然杀伤细胞在子宫螺旋动脉重塑中的作用[J]. 中华生殖与避孕杂志, 2020, 40(1):83-87. doi: 10.3760/cma.j.issn.2096-2916.2020.0008. doi: 10.3760/cma.j.issn.2096-2916.2020.0008
[8]	Liu Y, Gao S, Zhao Y, et al. Decidual Natural Killer Cells: A Good Nanny at the Maternal-Fetal Interface During Early Pregnancy[J]. Front Immunol, 2021, 12:663660. doi: 10.3389/fimmu. 2021.663660. doi: 10.3389/fimmu. 2021.663660 URL
[9]	Ban Y, Zhao Y, Liu F, et al. Effect of Indoleamine 2,3-Dioxygenase Expressed in HTR-8/SVneo Cells on Decidual NK Cell Cytotoxicity[J]. Am J Reprod Immunol, 2016, 75(5):519-528. doi: 10.1111/aji.12481. doi: 10.1111/aji.12481 URL
[10]	Wang XQ, Zhou WJ, Hou XX, et al. Correction: Trophoblast-derived CXCL16 induces M2 macrophage polarization that in turn inactivates NK cells at the maternal-fetal interface[J]. Cell Mol Immunol, 2019, 16(3):313. doi: 10.1038/s41423-018-0194-9. doi: 10.1038/s41423-018-0194-9
[11]	Zhang J, Lye SJ. The immune potential of decidua-resident CD16(+)CD56(+) NK cells in human pregnancy[J]. Hum Immunol, 2021, 82(5):332-339. doi: 10.1016/j.humimm.2021.01.014. doi: 10.1016/j.humimm.2021.01.014 URL
[12]	Chang RQ, Zhou WJ, Li DJ, et al. Innate Lymphoid Cells at the Maternal-Fetal Interface in Human Pregnancy[J]. Int J Biol Sci, 2020, 16(6):957-969. doi: 10.7150/ijbs.38264. doi: 10.7150/ijbs.38264 URL
[13]	Gamliel M, Goldman-Wohl D, Isaacson B, et al. Trained Memory of Human Uterine NK Cells Enhances Their Function in Subsequent Pregnancies[J]. Immunity, 2018, 48(5):951-962.e5. doi: 10.1016/j.immuni.2018.03.030. doi: S1074-7613(18)30128-6 pmid: 29768178
[14]	Jabrane-Ferrat N. Features of Human Decidual NK Cells in Healthy Pregnancy and During Viral Infection[J]. Front Immunol, 2019, 10:1397. doi: 10.3389/fimmu.2019.01397. doi: 10.3389/fimmu.2019.01397 pmid: 31379803
[15]	El-Badawy O, Helmy AS, Abbas AM, et al. Concordance between peripheral and decidual NK cell subsets and killer immunoglobulin-like receptors in women with recurrent spontaneous miscarriages[J]. J Reprod Immunol, 2020, 140:103130. doi: 10.1016/j.jri.2020.103130. doi: 10.1016/j.jri.2020.103130 URL
[16]	Kurioka A, Cosgrove C, Simoni Y, et al. CD161 Defines a Functionally Distinct Subset of Pro-Inflammatory Natural Killer Cells[J]. Front Immunol, 2018, 9:486. doi: 10.3389/fimmu. 2018. 00486. doi: 10.3389/fimmu.2018.00486 pmid: 29686665
[17]	谈程, 范蒙洁, 贾文通, 等. CLEC2D/CD161分子相互作用调节蜕膜自然杀伤细胞的免疫杀伤功能[J]. 中华围产医学杂志, 2019, 22(10): 704-711. doi: 10.3760/cma.j.issn.1007-9408.2019.10.005. doi: 10.3760/cma.j.issn.1007-9408.2019.10.005
[18]	Ay ME, Ay Öİ, Çayan FE, et al. Genetic Predisposition to Unexplained Recurrent Pregnancy Loss: Killer Cell Immunoglobulin-Like Receptor Gene Polymorphisms as Potential Biomarkers[J]. Genet Test Mol Biomarkers, 2019, 23(1):57-65. doi: 10.1089/gtmb.2018.0082. doi: 10.1089/gtmb.2018.0082 URL
[19]	孙梦晨, 张宁, 苗秀明. 自然杀伤细胞活性及其受体和配体的调节在复发性流产中的作用研究进展[J]. 新乡医学院学报, 2021, 38(4):382-385. doi: 10.7683/xxyxyxb.2021.04.019. doi: 10.7683/xxyxyxb.2021.04.019
[20]	陈静, 杨润雨, 陈璐, 等. 自然杀伤细胞与不明原因复发性流产关系的研究进展[J]. 国际免疫学杂志, 2018, 41(3):322-326. doi: 10.3760/cma.j.issn.1673-4394.2018.03.016. doi: 10.3760/cma.j.issn.1673-4394.2018.03.016
[21]	Li H, Hou Y, Zhang S, et al. CD49a regulates the function of human decidual natural killer cells[J]. Am J Reprod Immunol, 2019, 81(4):e13101. doi: 10.1111/aji.13101. doi: 10.1111/aji.13101 URL
[22]	Guo W, Fang L, Li B, et al. Decreased Human Leukocyte Antigen-G Expression by miR-133a Contributes to Impairment of Proinvasion and Proangiogenesis Functions of Decidual NK Cells[J]. Front Immunol, 2017, 8:741. doi: 10.3389/fimmu.2017.00741. doi: 10.3389/fimmu.2017.00741 URL
[23]	Parhizkar F, Motavalli-Khiavi R, Aghebati-Maleki L, et al. The Impact of New Immunological Therapeutic Strategies on Recurrent Miscarriage and Recurrent Implantation Failure[J]. Immunol Lett, 2021, 236:20-30. doi: 10.1016/j.imlet.2021.05.008. doi: 10.1016/j.imlet.2021.05.008 pmid: 34090942
[24]	Lédée N, Vasseur C, Petitbarat M, et al. Intralipid may represent a new hope for patients with reproductive failures and simultaneously an over-immune endometrial activation[J]. J Reprod Immunol, 2018, 130:18-22. doi: 10.1016/j.jri.2018.09.050. doi: 10.1016/j.jri.2018.09.050 URL
[25]	韩昕宇, 赵小萱, 冯晓玲. 粒细胞集落刺激因子在妊娠中的调节机制及其在不明原因复发性流产治疗中的研究进展[J]. 中华生殖与避孕杂志, 2021, 41(3):276-281. doi: 10.3760/cma.j.cn101441-20200309-00112. doi: 10.3760/cma.j.cn101441-20200309-00112
[26]	Kamath MS, Kirubakaran R, Sunkara SK. Granulocyte-colony stimulating factor administration for subfertile women undergoing assisted reproduction[J]. Cochrane Database Syst Rev, 2020, 1(1):CD013226. doi: 10.1002/14651858.CD013226.pub2. doi: 10.1002/14651858.CD013226.pub2
[27]	Dan S, Wei W, Yichao S, et al. Effect of Prednisolone Administration on Patients with Unexplained Recurrent Miscarriage and in Routine Intracytoplasmic Sperm Injection: A Meta-Analysis[J]. Am J Reprod Immunol, 2015, 74(1):89-97. doi: 10.1111/aji.12373. doi: 10.1111/aji.12373 URL
[28]	Rezaei Kahmini F, Shahgaldi S, Moazzeni SM. Mesenchymal stem cells alter the frequency and cytokine profile of natural killer cells in abortion-prone mice[J]. J Cell Physiol, 2020, 235(10):7214-7223. doi: 10.1002/jcp.29620. doi: 10.1002/jcp.29620 URL
[29]	Kniotek M, Zych M, Roszczyk A, et al. Decreased Production of TNF-α and IL-6 Inflammatory Cytokines in Non-Pregnant Idiopathic RPL Women Immunomodulatory Effect of Sildenafil Citrate on the Cellular Response of Idiopathic RPL Women[J]. J Clin Med, 2021, 10(14):3115. doi: 10.3390/jcm10143115. doi: 10.3390/jcm10143115 URL
[30]	Kniotek M, Roszczyk A, Zych M, et al. Differences in the Expression of KIR, ILT Inhibitory Receptors, and VEGF Production in the Induced Decidual NK Cell Cultures of Fertile and RPL Women[J]. Biomed Res Int, 2021, 2021:6673427. doi: 10.1155/2021/6673427. doi: 10.1155/2021/6673427
[31]	Ahmadi M, Abdolmohamadi-Vahid S, Ghaebi M, et al. Sirolimus as a new drug to treat RIF patients with elevated Th17/Treg ratio: A double-blind, phase II randomized clinical trial[J]. Int Immunopharmacol, 2019, 74:105730. doi: 10.1016/j.intimp.2019. 105730. doi: 10.1016/j.intimp.2019. 105730 URL
[32]	Tan HX, Yang SL, Li MQ, et al. Autophagy suppression of trophoblast cells induces pregnancy loss by activating decidual NK cytotoxicity and inhibiting trophoblast invasion[J]. Cell Commun Signal, 2020, 18(1):73. doi: 10.1186/s12964-020-00579-w. doi: 10.1186/s12964-020-00579-w URL