免疫检查点分子在复发性流产中的研究进展
Research Progress of Immune Checkpoint Molecules in Recurrent Spontaneous Abortion
摘要: 复发性流产近年来发病率呈升高趋势,其病因复杂,约40%~50%的患者流产没有明确病因,尚无令人满意的治疗方案,严重影响育龄期患者的身心健康,如何改善这部分患者的妊娠结局是目前生殖医学领域急需解决的一大问题。免疫检查点分子是抑制免疫效应细胞的调节分子,已在肿瘤学、免疫学等领域得到了广泛的研究。近期研究表明免疫检查点分子在母胎界面免疫耐受中起重要作用,其异常表达可能通过调节母胎界面免疫细胞功能,进而参与复发性流产的发病。本文就目前研究较深入的免疫检查点分子对复发性流产的影响及干预免疫检查点分子对复发性流产妊娠结局的影响进行综述,已期为下一步病因相关的基础研究和治疗相关的临床应用提供新的思路。
Abstract: The incidence of recurrent spontaneous abortion has been increasing in recent years, and its etiol-ogy is complex, about 40%~50% of patients have no clear cause of abortion, there is no satisfactory treatment plan, which seriously affects the physical and mental health of patients of childbearing age, how to improve the pregnancy outcome of these patients is a major problem that needs to be solved urgently in the field of reproductive medicine. Immune checkpoint molecules are regulatory molecules that inhibit immune effector cells and have been widely studied in oncology, immunology and other fields. Recent studies have shown that immune checkpoint molecules play an important role in maternal-fetal interface immune tolerance, and their abnormal expression may be involved in the onset of recurrent miscarriage by regulating the function of maternal-fetal interface immune cells. This article reviews the effect of immune checkpoint molecules on recurrent spontaneous abortion and the effect of intervening immune checkpoint molecules on the pregnancy outcome of recurrent spontaneous abortion, which is expected to provide new ideas for the next basic research related to etiology and clinical application related to treatment.
文章引用:杨慧, 王珊. 免疫检查点分子在复发性流产中的研究进展[J]. 临床医学进展, 2023, 13(8): 12952-12958. https://doi.org/10.12677/ACM.2023.1381814

参考文献

[1] 中华医学会妇产科学分会产科学组, 复发性流产诊治专家共识编写组. 复发性流产诊治专家共识(2022) [J]. 中华妇产科杂志 2022, 57(9):653-667.
[2] Dimitriadis, E., Menkhorst, E., Saito, S., Kutteh, W.H. and Brosens, J.J. (2020) Recurrent Pregnancy Loss. Nature Reviews Disease Primers, 6, Article No. 98. [Google Scholar] [CrossRef] [PubMed]
[3] Rowshanravan, B., Halliday, N. and Sansom, D.M. (2018) CTLA-4: A Moving Target in Immunotherapy. Blood, 131, 58-67. [Google Scholar] [CrossRef] [PubMed]
[4] Hosseini, A., Gharibi, T., Marofi, F., Babaloo, Z. and Bara-daran, B. (2020) CTLA-4: From Mechanism to Autoimmune Therapy. International Immunopharmacology, 80, Article No. 106221. [Google Scholar] [CrossRef] [PubMed]
[5] Zhang, H., Dai, Z., Wu, W., Wang, Z., Zhang, N., Zhang, L., Zeng, W.J., Liu, Z. and Cheng, Q. (2021) Regulatory Mechanisms of Immune Checkpoints PD-L1 and CTLA-4 in Can-cer. Journal of Experimental & Clinical Cancer Research, 40, Article No. 184. [Google Scholar] [CrossRef] [PubMed]
[6] Yu, X., Gao, R., Li, Y. and Zeng, C. (2020) Regulation of PD-1 in T Cells for Cancer Immunotherapy. Journal of Experimental & Clinical Cancer Research, 881, Article ID: 173240. [Google Scholar] [CrossRef] [PubMed]
[7] Zhao, L., Cheng, S., Fan, L., Zhang, B. and Xu, S. (2021) TIM-3: An Update on Immunotherapy. International Immunopharmacology, 99, Article ID: 107933. [Google Scholar] [CrossRef] [PubMed]
[8] Zolfaghari, M.A., Arefnezhad, R., Parhizkar, F., Hejazi, M.S., Motavalli Khiavi, F., Mahmoodpoor, A. and Yousefi, M. (2021) T Lymphocytes and Preeclampsia: The Potential Role of T-Cell Subsets and Related MicroRNAs in the Pathogenesis of Preeclampsia. American Journal of Reproductive Immu-nology, 86, e13475. [Google Scholar] [CrossRef] [PubMed]
[9] Saito, S., Nakashima, A., Shima, T. and Ito, M. (2010) Th1/Th2/Th17 and Regulatory T-Cell Paradigm in Pregnancy. American Journal of Reproductive Immunology, 63, 601-610. [Google Scholar] [CrossRef] [PubMed]
[10] Jutel, M., Akdis, M., Budak, F., Aebischer-Casaulta, C., Wrzyszcz, M., Blaser, K. and Akdis, C.A. (2003) IL-10 and TGF-β Cooperate in the Regulatory T Cell Response to Mucosal Allergens in Normal Immunity and Specific Immunotherapy. European Journal of Immu-nology, 33, 1205-1214. [Google Scholar] [CrossRef] [PubMed]
[11] Lee, G.R. (2018) The Balance of Th17 versus Treg Cells in Autoimmunity. International Journal of Molecular Sciences, 19, Article 730. [Google Scholar] [CrossRef] [PubMed]
[12] Jin, L.P., Chen, Q.Y., Zhang, T., Guo, P.F. and Li, D.J. (2009) The CD4+CD25bright Regulatory T Cells and CTLA-4 Expression in Peripheral and Decidual Lymphocytes Are Down-Regulated in Human Miscarriage. Clinical Immunology, 133, 402-410. [Google Scholar] [CrossRef] [PubMed]
[13] Jin, L.P., Fan, D.X., Zhang, T., Guo, P.F. and Li, D.J. (2011) The Costimulatory Signal Upregulation Is Associated with Th1 Bias at the Maternal-Fetal Interface in Human Miscarriage. American Journal of Reproductive Immunology, 66, 270-278. [Google Scholar] [CrossRef] [PubMed]
[14] Guo, R., Jiang, S., Zhang, J., Yang, Q., Gao, L., Xia, W., Tong, L., Feng, P., Xu, Y., Zhang, T., et al. (2022) PD-1 Mediates Decidual γδ T Cells Cytotoxicity during Recurrent Pregnancy Loss. American Journal of Reproductive Immunology, 88, e13562. [Google Scholar] [CrossRef] [PubMed]
[15] Wang, W.J., Salazar Garcia, M.D., Deutsch, G., Sung, N., Yang, X., He, Q., Jubiz, G., Bilal, M., Dambaeva, S., Gilman-Sachs, A., et al. (2020) PD-1 and PD-L1 Expression on T-Cell Subsets in Women with Unexplained Recurrent Pregnancy Losses. American Journal of Reproductive Immunology, 83, e13230. [Google Scholar] [CrossRef] [PubMed]
[16] Li, Y.H., Zhou, W.H., Tao, Y., Wang, S.C., Jiang, Y.L., Zhang, D., Piao, H.L., Fu, Q., Li, D.J. and Du, M.R. (2016) The Galectin-9/Tim-3 Pathway Is Involved in the Regulation of NK Cell Function at the Maternal-Fetal Interface in Early Pregnancy. Cellular & Molecular Immunology, 13, 73-81. [Google Scholar] [CrossRef] [PubMed]
[17] Sun, J., Yang, M., Ban, Y., Gao, W., Song, B., Wang, Y., Zhang, Y., Shao, Q., Kong, B. and Qu, X. (2016) Tim-3 Is Upregulated in NK Cells during Early Pregnancy and Inhibits NK Cyto-toxicity toward Trophoblast in Galectin-9 Dependent Pathway. PLOS ONE, 11, e0147186. [Google Scholar] [CrossRef] [PubMed]
[18] Zhang, Y., Ma, L., Hu, X., Ji, J., Mor, G. and Liao, A. (2019) The Role of the PD-1/PD-L1 Axis in Macrophage Differentiation and Function during Pregnancy. Human Reproduction, 34, 25-36. [Google Scholar] [CrossRef] [PubMed]
[19] Li, M., Sun, F., Xu, Y., Chen, L., Chen, C., Cui, L., Qian, J., Li, D., Wang, S. and Du, M. (2022) Tim-3+ Decidual Mφs Induced Th2 and Treg Bias in Decidual CD4+T Cells and Promoted Pregnancy Maintenance via CD132. Cell Death & Disease, 13, Article No. 454. [Google Scholar] [CrossRef] [PubMed]
[20] Cui, L., Sun, F., Xu, Y., Li, M., Chen, L., Chen, C., Qian, J., Li, D., Du, M. and Wang, S. (2023) Tim-3 Coordinates Macrophage-Trophoblast Crosstalk via Angiogenic Growth Factors to Promote Pregnancy Maintenance. International Journal of Molecular Sciences, 24, Article 1538. [Google Scholar] [CrossRef] [PubMed]
[21] Wang, S., Zhu, X., Xu, Y., Zhang, D., Li, Y., Tao, Y., Piao, H., Li, D. and Du, M. (2016) 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. Human Reproduction, 31, 700-711. [Google Scholar] [CrossRef] [PubMed]
[22] Xu, Y.Y., Wang, S.C., Lin, Y.K., Li, D.J. and Du, M.R. (2017) Tim-3 and PD-1 Regulate CD8+ T Cell Function to Maintain Early Pregnancy in Mice. Journal of Reproduction and De-velopment, 63, 289-294. [Google Scholar] [CrossRef] [PubMed]
[23] Wang, S., Sun, F., Li, M., Qian, J., Chen, C., Wang, M., Zang, X., Li, D., Yu, M. and Du, M. (2019) The Appropriate Frequency and Function of Decidual Tim-3+CTLA-4+CD8+ T Cells Are Important in Maintaining Normal Pregnancy. Cell Death & Disease, 10, Article No. 407. [Google Scholar] [CrossRef] [PubMed]
[24] Wang, S., Chen, C., Li, M., Qian, J., Sun, F., Li, Y., Yu, M., Wang, M., Zang, X., Zhu, R., et al. (2019) Blockade of CTLA-4 and Tim-3 Pathways Induces Fetal Loss with Altered Cytokine Profiles by Decidual CD4+T Cells. Cell Death & Disease, 10, Article No. 15. [Google Scholar] [CrossRef] [PubMed]
[25] Wang, X., Lin, Q., Ma, Z., Hong, Y., Zhao, A., Di, W. and Lu, P. (2005) Association of the A/G Polymorphism at Position 49 in Exon 1 of CTLA-4 with the Susceptibility to Unexplained Recurrent Spontaneous Abortion in the Chinese Population. American Journal of Reproductive Immunology, 53, 100-105. [Google Scholar] [CrossRef] [PubMed]
[26] Gupta, R., Prakash, S., Parveen, F. and Agrawal, S. (2012) Association of CTLA-4 and TNF-α Polymorphism with Recurrent Miscarriage among North Indian Women. Cytokine, 60, 456-462. [Google Scholar] [CrossRef] [PubMed]
[27] Nasiri, M. and Rasti, Z. (2016) CTLA-4 and IL-6 Gene Polymorphisms: Risk Factors for Recurrent Pregnancy Loss. Human Immunology, 77, 1271-1274. [Google Scholar] [CrossRef] [PubMed]
[28] Hayashi, Y., Nishiyama, T., Nakatochi, M., Suzuki, S., Takahashi, S. and Sugiura-Ogasawara, M. (2018) Association of Genetic Variants of PD1 with Recurrent Pregnancy Loss. Reproductive Medicine and Biology, 17, 195-202. [Google Scholar] [CrossRef] [PubMed]
[29] Jin, L.P., Zhou, Y.H., Wang, M.Y., Zhu, X.Y. and Li, D.J. (2005) Blockade of CD80 and CD86 at the Time of Implantation Inhibits Maternal Rejection to the Allogeneic Fetus in Abor-tion-Prone Matings. Journal of Reproductive Immunology, 65, 133-146. [Google Scholar] [CrossRef] [PubMed]
[30] 周晓燕. CTLA-4Ig对小鼠流产模型外周Th17/Treg细胞及妊娠结局的影响[D]: [硕士学位论文]. 合肥: 安徽医科大学, 2012.
[31] Ling, Y., Huang, Y., Chen, C., Mao, J. and Zhang, H. (2017) Low Dose Cyclosporin A Treatment Increases Live Birth Rate of Unexplained Recurrent Abortion—Initial Cohort Study. Clinical and Experimental Obstetrics & Gynecology, 44, 230-235. [Google Scholar] [CrossRef
[32] Zhou, W.H., Dong, L., Du, M.R., Zhu, X.Y. and Li, D.J. (2008) Cy-closporin A Improves Murine Pregnancy Outcome in Abortion-Prone Matings: Involvement of CD80/86 and CD28/CTLA-4. Reproduction, 135, 385-395. [Google Scholar] [CrossRef
[33] Wang, S., Li, M., Sun, F., Chen, C., Ye, J., Li, D., Qian, J. and Du, M. (2021) Th17/Treg-Cell Balance in the Peripheral Blood of Pregnant Females with a History of Recurrent Spontaneous Abortion Receiving Progesterone or Cyclosporine A. Experimental and Therapeutic Medicine, 21, Article No. 37. [Google Scholar] [CrossRef] [PubMed]
[34] 伍金华, 谢志威, 车小群, 李秀娟, 黎淑贞. 原因不明复发性流产患者外周血PD-1、Th1/Th2型细胞因子水平测定及其相关性研究[J]. 中华临床医师杂志(电子版), 2014(9): 1592-1596.
[35] Wang, J., Zhao, S.J., Wang, L.L., Lin, X.X., Mor, G. and Liao, A.H. (2023) Leukocyte Immunoglobu-lin-Like Receptor Subfamily B: A Novel Immune Checkpoint Molecule at the Maternal-Fetal Interface. Journal of Re-productive Immunology, 155, Article ID: 103764. [Google Scholar] [CrossRef] [PubMed]
[36] Chen, Z., Huang, J., Kwak-Kim, J. and Wang, W. (2023) Immune Checkpoint Inhibitors and Reproductive Failures. Journal of Reproduc-tive Immunology, 156, Article ID: 103799. [Google Scholar] [CrossRef] [PubMed]