Research Progress of Recurrent Spontaneous Abortion Caused by Abnormal Immune Microenvironment at the Maternal-Fetal Interface

doi:10.12280/gjszjk.20220509

Abstract

Abstract:

Maternal recognition of embryos and the establishment of immune tolerance are necessary conditions for pregnancy. The essence of immune tolerance at the maternal-fetal interface is that embryonic trophoblast cells, decidual stromal cells and decidual immune cells jointly participate in the process of maternal-fetal dialogue, promoting the transformation of the immune microenvironment and the establishment of adaptive immunity at the maternal-fetal interface, such as trophoblast cell infiltration, spiral artery remodeling, maternal-fetal immune tolerance establishment and so on. The imbalanced immune homeostasis caused by abnormal maternal-fetal immune microenvironment is an important cause of recurrent spontaneous abortion (RSA). Abnormal maternal-fetal immune microenvironment includes excessive immune inflammatory response, the impaired immune tolerance, and the oscillation of maternal-fetal immune microenvironment. Therefore, immunomodulation should be one of the core strategies for the treatment of RSA, including the application of immunosuppressants, immunomodulatory drugs, and active lymphocyte immunotherapy. However, the efficacy of immunomodulation needs to be verified by more high-quality evidence from evidence-based medicine.

Key words: Maternal-fetal interface, Immune tolerance, Immune microenviroment, Abortion, habitual, Immunomodulation

SU Dan-na, DIAO Rui-ying, SHE Jia-jie, SHUAI Ling, GUO Yan, LI Dong-dong, YE Xiao-feng, WANG Li-ping. Research Progress of Recurrent Spontaneous Abortion Caused by Abnormal Immune Microenvironment at the Maternal-Fetal Interface[J]. Journal of International Reproductive Health/Family Planning, 2023, 42(3): 254-260.

Figures/Tables 1

References 48

[1]	Mori M, Bogdan A, Balassa T, et al. The decidua-the maternal bed embracing the embryo-maintains the pregnancy[J]. Semin Immunopathol, 2016, 38(6):635-649. doi: 10.1007/s00281-016-0574-0. doi: 10.1007/s00281-016-0574-0 pmid: 27287066
[2]	Xu L, Li Y, Sang Y, et al. Crosstalk Between Trophoblasts and Decidual Immune Cells: The Cornerstone of Maternal-Fetal Immunotolerance[J]. Front Immunol, 2021, 12:642392. doi: 10.3389/fimmu.2021.642392. doi: 10.3389/fimmu.2021.642392
[3]	Fu B, Wei H. Decidual natural killer cells and the immune microenvironment at the maternal-fetal interface[J]. Sci China Life Sci, 2016, 59(12):1224-1231. doi: 10.1007/s11427-016-0337-1. doi: 10.1007/s11427-016-0337-1 pmid: 27905000
[4]	Li YH, Zhou WH, Tao Y, et al. The Galectin-9/Tim-3 pathway is involved in the regulation of NK cell function at the maternal-fetal interface in early pregnancy[J]. Cell Mol Immunol, 2016, 13(1):73-81. doi: 10.1038/cmi.2014.126. doi: 10.1038/cmi.2014.126
[5]	Abumaree MH, Chamley LW, Badri M, et al. Trophoblast debris modulates the expression of immune proteins in macrophages: a key to maternal tolerance of the fetal allograft?[J]. J Reprod Immunol, 2012, 94(2):131-141. doi: 10.1016/j.jri.2012.03.488. doi: 10.1016/j.jri.2012.03.488 pmid: 22542910
[6]	Svensson-Arvelund J, Mehta RB, Lindau R, et al. The human fetal placenta promotes tolerance against the semiallogeneic fetus by inducing regulatory T cells and homeostatic M2 macrophages[J]. J Immunol, 2015, 194(4):1534-1544. doi: 10.4049/jimmunol.1401536. doi: 10.4049/jimmunol.1401536 pmid: 25560409
[7]	Wang XQ, Zhou WJ, Hou XX, et al. Trophoblast-derived CXCL16 induces M2 macrophage polarization that in turn inactivates NK cells at the maternal-fetal interface[J]. Cell Mol Immunol, 2018, 15(12):1038-1046. doi: 10.1038/s41423-018-0019-x. doi: 10.1038/s41423-018-0019-x
[8]	Wang S, Sun F, Han M, et al. Trophoblast-derived hyaluronan promotes the regulatory phenotype of decidual macrophages[J]. Reproduction, 2019, 157(2):189-198. doi: 10.1530/REP-18-0450. doi: 10.1530/REP-18-0450 pmid: 30605433
[9]	Gao L, Xu QH, Ma LN, et al. Trophoblast-derived Lactic Acid Orchestrates Decidual Macrophage Differentiation via SRC/LDHA Signaling in Early Pregnancy[J]. Int J Biol Sci, 2022, 18(2):599-616. doi: 10.7150/ijbs.67816. doi: 10.7150/ijbs.67816 pmid: 35002512
[10]	Wang SC, Li YH, Piao HL, et al. PD-1 and Tim-3 pathways are associated with regulatory CD8⁺ T-cell function in decidua and maintenance of normal pregnancy[J]. Cell Death Dis, 2015, 6(5):e1738. doi: 10.1038/cddis.2015.112. doi: 10.1038/cddis.2015.112
[11]	Du MR, Guo PF, Piao HL, et al. Embryonic trophoblasts induce decidual regulatory T cell differentiation and maternal-fetal tolerance through thymic stromal lymphopoietin instructing dendritic cells[J]. J Immunol, 2014, 192(4):1502-1511. doi: 10.4049/jimmunol.1203425. doi: 10.4049/jimmunol.1203425 URL
[12]	Lombardelli L, Logiodice F, Kullolli O, et al. At Embryo Implantation Site IL-35 Secreted by Trophoblast, Polarizing T Cells towards IL-35⁺ IL-10⁺ IL-4⁺ Th2-Type Cells, Could Favour Fetal Allograft Tolerance and Pregnancy Success[J]. Int J Mol Sci, 2022, 23(9):4926. doi: 10.3390/ijms23094926. doi: 10.3390/ijms23094926 URL
[13]	Hu X, Zhu Q, Wang Y, et al. Newly characterized decidual Tim-3+ Treg cells are abundant during early pregnancy and driven by IL-27 coordinately with Gal-9 from trophoblasts[J]. Hum Reprod, 2020, 35(11):2454-2466. doi: 10.1093/humrep/deaa223. doi: 10.1093/humrep/deaa223 URL
[14]	Fan DX, Zhou WJ, Jin LP, et al. Trophoblast-Derived CXCL16 Decreased Granzyme B Production of Decidual γδ T Cells and Promoted Bcl-xL Expression of Trophoblasts[J]. Reprod Sci, 2019, 26(4):532-542. doi: 10.1177/1933719118777638. doi: 10.1177/1933719118777638 URL
[15]	He YY, He XJ, Guo PF, et al. The decidual stromal cells-secreted CCL2 induces and maintains decidual leukocytes into Th2 bias in human early pregnancy[J]. Clin Immunol, 2012, 145(2):161-173. doi: 10.1016/j.clim.2012.07.017. doi: 10.1016/j.clim.2012.07.017 URL
[16]	Hassan E, Kojima R, Ozawa F, et al. Abnormal ciliogenesis in decidual stromal cells in recurrent miscarriage[J]. J Reprod Immunol, 2022, 150:103486. doi: 10.1016/j.jri.2022.103486. doi: 10.1016/j.jri.2022.103486
[17]	You Y, Stelzl P, Joseph DN, et al. TNF-α Regulated Endometrial Stroma Secretome Promotes Trophoblast Invasion[J]. Front Immunol, 2021, 12:737401. doi: 10.3389/fimmu.2021.737401. doi: 10.3389/fimmu.2021.737401
[18]	Wang F, Jia W, Fan M, et al. Single-cell Immune Landscape of Human Recurrent Miscarriage[J]. Genomics Proteomics Bioinformatics, 2021, 19(2):208-222. doi: 10.1016/j.gpb.2020.11.002. doi: 10.1016/j.gpb.2020.11.002 URL
[19]	Zhu J, Song G, Zhou X, et al. CD39/CD73 Dysregulation of Adenosine Metabolism Increases Decidual Natural Killer Cell Cytotoxicity: Implications in Unexplained Recurrent Spontaneous Abortion[J]. Front Immunol, 2022, 13:813218. doi: 10.3389/fimmu.2022.813218. doi: 10.3389/fimmu.2022.813218
[20]	Yang SL, Tan HX, Niu TT, et al. Kynurenine promotes the cytotoxicity of NK cells through aryl hydrocarbon receptor in early pregnancy[J]. J Reprod Immunol, 2021, 143:103270. doi: 10.1016/j.jri.2020.103270. doi: 10.1016/j.jri.2020.103270
[21]	He M, Zhou Y, Jiang M, et al. Increased Toll-Like Receptor-Myeloid Differentiation Factor 88 Expression at the Maternal-Fetal Interface Is Associated with Spontaneous Abortion[J]. Gynecol Obstet Invest, 2017, 82(6):553-562. doi: 10.1159/000468931. doi: 10.1159/000468931 URL
[22]	Ding J, Yin T, Yan N, et al. FasL on decidual macrophages mediates trophoblast apoptosis: A potential cause of recurrent miscarriage[J]. Int J Mol Med, 2019, 43(6):2376-2386. doi: 10.3892/ijmm.2019.4146. doi: 10.3892/ijmm.2019.4146 pmid: 30942389
[23]	Ye Y, Peng L, Chelariu-Raicu A, et al. Prostaglandin E2 receptor 3 promotes M1 macrophages polarization in unexplained recurrent pregnancy loss[J]. Biol Reprod, 2022, 106(5):910-918. doi: 10.1093/biolre/ioac030. doi: 10.1093/biolre/ioac030 URL
[24]	Zhen XX, Yang L, Gu Y, et al. MNSFβ Regulates TNFα Production by Interacting with RC3H1 in Human Macrophages, and Dysfunction of MNSFβ in Decidual Macrophages Is Associated With Recurrent Pregnancy Loss[J]. Front Immunol, 2021, 12:691908. doi: 10.3389/fimmu.2021.691908. doi: 10.3389/fimmu.2021.691908
[25]	Guo C, Cai P, Jin L, et al. Single-cell profiling of the human decidual immune microenvironment in patients with recurrent pregnancy loss[J]. Cell Discov, 2021, 7(1):1. doi: 10.1038/s41421-020-00236-z. doi: 10.1038/s41421-020-00236-z pmid: 33390590
[26]	Wu L, Li J, Xu HL, et al. IL-7/IL-7R signaling pathway might play a role in recurrent pregnancy losses by increasing inflammatory Th17 cells and decreasing Treg cells[J]. Am J Reprod Immunol, 2016, 76(6):454-464. doi: 10.1111/aji.12588. doi: 10.1111/aji.12588 URL
[27]	Chang S, Yin T, He F, et al. CaMK4 promotes abortion-related Th17 cell imbalance by activating AKT/mTOR signaling pathway[J]. Am J Reprod Immunol, 2020, 84(6):e13315. doi: 10.1111/aji.13315. doi: 10.1111/aji.13315
[28]	Yao Y, Hao F, Tang LC, et al. Downregulation of HDAC8 expression decreases CD163 levels and promotes the apoptosis of macrophages by activating the ERK signaling pathway in recurrent spontaneous miscarriage[J]. Mol Hum Reprod, 2020, 26(7):521-531. doi: 10.1093/molehr/gaaa035. doi: 10.1093/molehr/gaaa035 pmid: 32433749
[29]	Wang S, Zhu X, Xu Y, et al. Programmed cell death-1 (PD-1) and T-cell immunoglobulin mucin-3 (Tim-3) regulate CD4⁺ T cells to induce Type 2 helper T cell (Th2) bias at the maternal-fetal interface[J]. Hum Reprod, 2016, 31(4):700-711. doi: 10.1093/humrep/dew019. doi: 10.1093/humrep/dew019 URL
[30]	Wang S, Li M, Sun F, et al. Altered frequency and function of spleen CTLA-4+Tim-3+ T cells are associated with miscarriage?[J]. Biol Reprod, 2021, 104(2):410-417. doi: 10.1093/biolre/ioz076. doi: 10.1093/biolre/ioz076 URL
[31]	Li F, Dang J, Jiang M, et al. Upregulation of Tim-3 expression at feto-maternal interface may explain embryo survival in the CBAxDBA/2 model of abortion[J]. Am J Reprod Immunol,2018 Jan; 79(1). doi: 10.1111/aji.12775. doi: 10.1111/aji.12775
[32]	Lin Y, Zhang D, Li Y, et al. Decidual NR2F2-Expressing CD4⁺ T Cells Promote TH2 Transcriptional Program During Early Pregnancy[J]. Front Immunol, 2021, 12:670777. doi: 10.3389/fimmu.2021.670777. doi: 10.3389/fimmu.2021.670777
[33]	Qian J, Zhang N, Lin J, et al. Distinct pattern of Th17/Treg cells in pregnant women with a history of unexplained recurrent spontaneous abortion[J]. Biosci Trends, 2018, 12(2):157-167. doi: 10.5582/bst.2018.01012. doi: 10.5582/bst.2018.01012 pmid: 29657243
[34]	Du L, Deng W, Zeng S, et al. Single-cell transcriptome analysis reveals defective decidua stromal niche attributes to recurrent spontaneous abortion[J]. Cell Prolif, 2021, 54(11):e13125. doi: 10.1111/cpr.13125. doi: 10.1111/cpr.13125
[35]	Zhu D, Zou H, Liu J, et al. Inhibition of HMGB1 Ameliorates the Maternal-Fetal Interface Destruction in Unexplained Recurrent Spontaneous Abortion by Suppressing Pyroptosis Activation[J]. Front Immunol, 2021, 12:782792. doi: 10.3389/fimmu.2021.782792. doi: 10.3389/fimmu.2021.782792
[36]	Ying X, Jin X, Zhu Y, et al. Exosomes released from decidual macrophages deliver miR-153-3p, which inhibits trophoblastic biological behavior in unexplained recurrent spontaneous abortion[J]. Int Immunopharmacol, 2020, 88:106981. doi: 10.1016/j.intimp.2020.106981. doi: 10.1016/j.intimp.2020.106981
[37]	Chang RQ, Shao J, Meng YH, et al. Decidual RANKL/RANK interaction promotes the residence and polarization of TGF-β1-producing regulatory γδ T cells[J]. Cell Death Dis, 2019, 10(2):113. doi: 10.1038/s41419-019-1380-0. doi: 10.1038/s41419-019-1380-0
[38]	Yu L, Zhang Y, Xiong J, et al. Activated γδ T Cells With Higher CD107a Expression and Inflammatory Potential During Early Pregnancy in Patients With Recurrent Spontaneous Abortion[J]. Front Immunol, 2021, 12:724662. doi: 10.3389/fimmu.2021.724662. doi: 10.3389/fimmu.2021.724662
[39]	Yan X, Wang D, Yan P, et al. Low molecular weight heparin or LMWH plus aspirin in the treatment of unexplained recurrent miscarriage with negative antiphospholipid antibodies: A meta-analysis of randomized controlled trial[J]. Eur J Obstet Gynecol Reprod Biol, 2022, 268:22-30. doi: 10.1016/j.ejogrb.2021.10.036. doi: 10.1016/j.ejogrb.2021.10.036 URL
[40]	Cooper S, Laird SM, Mariee N, et al. The effect of prednisolone on endometrial uterine NK cell concentrations and pregnancy outcome in women with reproductive failure. A retrospective cohort study[J]. J Reprod Immunol, 2019, 131:1-6. doi: 10.1016/j.jri.2018.10.001. doi: S0165-0378(18)30160-8 pmid: 30390547
[41]	de Moreuil C, Alavi Z, Pasquier E. Hydroxychloroquine may be beneficial in preeclampsia and recurrent miscarriage[J]. Br J Clin Pharmacol, 2020, 86(1):39-49. doi: 10.1111/bcp.14131. doi: 10.1111/bcp.14131 pmid: 31633823
[42]	Chen X, Diao L, Lian R, et al. Potential impact of maternal vitamin D status on peripheral blood and endometrium cellular immunity in women with recurrent implantation failure[J]. Am J Reprod Immunol, 2020, 84(1):e13243. doi: 10.1111/aji.13243. doi: 10.1111/aji.13243
[43]	Kumar P, Marron K, Harrity C. Intralipid therapy and adverse reproductive outcome: is there any evidence?[J]. Reprod Fertil, 2021, 2(3):173-186. doi: 10.1530/RAF-20-0052. doi: 10.1530/RAF-20-0052 pmid: 35118388
[44]	Rimmer MP, Black N, Keay S, et al. Intralipid infusion at time of embryo transfer in women with history of recurrent implantation failure: A systematic review and meta-analysis[J]. J Obstet Gynaecol Res, 2021, 47(6):2149-2156. doi: 10.1111/jog.14763. doi: 10.1111/jog.14763 URL
[45]	李文娜, 李娜, 冯晓玲. 补肾活血中药治疗免疫型复发性流产的研究进展[J]. 中华中医药学刊, 2019, 37(4):849-854. doi: 10.13193/j.issn.1673-7717.2019.04.018. doi: 10.13193/j.issn.1673-7717.2019.04.018
[46]	Kolte AM, Olsen LR, Mikkelsen EM, et al. Depression and emotional stress is highly prevalent among women with recurrent pregnancy loss[J]. Hum Reprod, 2015, 30(4):777-782. doi: 10.1093/humrep/dev014. doi: 10.1093/humrep/dev014 URL
[47]	Bai CF, Cui NX, Xu X, et al. Effectiveness of two guided self-administered interventions for psychological distress among women with infertility: a three-armed, randomized controlled trial[J]. Hum Reprod, 2019, 34(7):1235-1248. doi: 10.1093/humrep/dez066. doi: 10.1093/humrep/dez066 URL
[48]	Wang DN, Weng XL, Gao LL. Mindfulness-based intervention in Chinese pregnant women with recurrent miscarriage: A non-randomized controlled study[J]. Midwifery, 2021, 103:103152. doi: 10.1016/j.midw.2021.103152. doi: 10.1016/j.midw.2021.103152