Farshchi Maral, Abdollahi Elham, Saghafi Nafiseh, Hosseini Ahmad, Fallahi Sara, Rostami Sirus, Rostami Parifar, Rafatpanah Houshang, Habibagahi Mojtaba
Immunology Research Center, Inflammation and Inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran.
Department of Gynecology and Obstricts, Mashhad University of Medical Sciences, Mashhad, Iran.
J Clin Transl Res. 2022 May 25;8(3):256-265. eCollection 2022 Jun 29.
The Th17/Treg balance in peripheral blood and reproductive tissues may have a role in the etiology of unexplained recurrent pregnancy loss (URPL). In this study, we evaluated the major cytokine of Treg cells transforming growth factor-beta (TGF-β), and their specific transcription factor Forkhead box P3 (FOXP3), as well as the most highlighted cytokine of Th17 cells (interleukin [IL]-17A) in both URPL patients and healthy women.
Samples were extracted from the peripheral blood, endocervix, endometrium, and vagina of 14 patients with URPL and 12 normal non-pregnant women as a control (normal) group. Quantitative reverse transcription polymerase chain reaction was used to determine gene expression. Enzyme-linked immunosorbent assay was used to determine the levels of cytokines in the serum and cervicovaginal fluid.
We found that in the URPL group, FOXP3 gene expression was considerably higher in peripheral blood than in the normal group (=0.043). TGF-β levels in the cervicovaginal fluid were different in the URPL and normal groups (=0.015). In comparison to the control group, women with URPL had significantly greater IL-17 gene expression in the peripheral blood (=0.01).
Lower TGF-β levels in the cervicovaginal fluid of patients compared to controls may be related with increased IL-17 and FOXP3 mRNA levels in patients with URPL. Dysregulation of local immune responses in reproductive tissues may represent dysregulation of systemic regulatory immunological responses in the pathogenesis of URPL.
Dysregulation of immune responses may play a role in the pathogenesis of URPL at least in some patients with URPL. We conclude that the breakdown of tolerance in the local immune responses is more critical than the breakdown of tolerance in systemic tolerance in the pathogenesis of URPL. Therefore, modulating immune responses in the endometrium and decidua may be the focus of future therapeutic approaches in URPL. The impact of seminal plasma on the expansion of Tregs may provide a novel therapeutic intervention that has already been used in assisted reproductive technologies. Therefore, we suggest that transvaginal TGF-β in women with URPL may induce maternal tolerance which leads to the successful pregnancy.
外周血及生殖组织中的Th17/Treg平衡可能在不明原因复发性流产（URPL）的病因中起作用。在本研究中，我们评估了URPL患者和健康女性中Treg细胞的主要细胞因子转化生长因子-β（TGF-β）及其特异性转录因子叉头框P3（FOXP3），以及Th17细胞最突出的细胞因子（白细胞介素[IL]-17A）。
从14例URPL患者以及作为对照组（正常组）的12名正常未孕女性的外周血、子宫颈、子宫内膜和阴道中提取样本。采用定量逆转录聚合酶链反应来测定基因表达。采用酶联免疫吸附测定法来测定血清和宫颈阴道液中的细胞因子水平。
我们发现，在URPL组中，外周血中FOXP3基因表达显著高于正常组（P = 0.043）。URPL组和正常组宫颈阴道液中的TGF-β水平存在差异（P = 0.015）。与对照组相比，URPL女性外周血中的IL-17基因表达显著更高（P = 0.01）。
与对照组相比，患者宫颈阴道液中较低的TGF-β水平可能与URPL患者中IL-17和FOXP3 mRNA水平升高有关。生殖组织中局部免疫反应的失调可能代表URPL发病机制中全身调节性免疫反应的失调。
免疫反应失调可能至少在部分URPL患者的发病机制中起作用。我们得出结论，在URPL的发病机制中，局部免疫反应中耐受性的破坏比全身耐受性的破坏更为关键。因此，调节子宫内膜和蜕膜中的免疫反应可能是未来URPL治疗方法的重点。精浆对Tregs扩增的影响可能提供一种已在辅助生殖技术中使用的新型治疗干预措施。因此，我们建议对URPL女性经阴道给予TGF-β可能诱导母体耐受性，从而实现成功妊娠。
