Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Pediatric Department of the 3rd Xiangya Hospital, Central South University, Changsha, 410078, China.
Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410078, China.
Reprod Sci. 2024 Sep;31(9):2783-2793. doi: 10.1007/s43032-024-01555-2. Epub 2024 Apr 24.
Recurrent pregnancy loss (RPL) is thought to be related to maternal-fetal immune tolerance disorders. Immune monitoring of RPL patients mainly involves two aspects: inflammatory factors and immune cells. However, most observational studies have reported controversial findings. This study aimed to confirm whether abnormal inflammatory factors and immune cells in peripheral blood may lead to RPL, and guide clinical immune monitoring. We demonstrated causality using two-sample Mendelian randomization. Sensitivity analysis, reverse Mendelian randomization and meta-analysis were used to enhance the effectiveness of the results. There was a causal relationship between the level of IL-12 (OR = 1.78, 95% CI = 1.25-2.55; P = 0.00149) and RPL for 41 inflammatory factors. We screened 5 groups of immune cell subtypes that were causally associated with RPL: switched memory B-cell absolute count (OR = 0.66, 95% CI = 0.49-0.87, P = 0.00406), IgD + CD24 + B-cell absolute count (OR = 0.69, 95% CI = 0.53-0.88, P = 0.00319), CD39 + resting CD4 regulatory T-cell %CD4 regulatory T-cell (OR = 0.86, 95% CI = 0.78-0.95, P = 0.00252), activated & resting CD4 regulatory T-cell %CD4 regulatory T-cell (OR = 0.89, 95% CI = 0.82-0.97, P = 0.00938) and CD45 RA + CD28-CD8 + T-cell %CD8 + T-cell (OR = 0.99, 95% CI = 0.98-1.00, P = 0.01231). In terms of inflammatory factors, a causal relationship between IL-12 and RPL in peripheral blood was confirmed. We also identified five immune cell phenotypes that play a protective role. This suggests that there may be protective B cells and CD8 + T-cell subsets in peripheral blood, and the protective effect of Tregs was proved again. Immune monitoring of peripheral blood in patients with RPL seems to be necessary and the foundation for precision medicine.
复发性流产（RPL）被认为与母胎免疫耐受紊乱有关。RPL 患者的免疫监测主要涉及两个方面：炎症因子和免疫细胞。然而，大多数观察性研究的结果存在争议。本研究旨在证实外周血中异常的炎症因子和免疫细胞是否会导致 RPL，并指导临床免疫监测。我们使用两样本孟德尔随机化来证明因果关系。敏感性分析、反向孟德尔随机化和荟萃分析用于增强结果的有效性。有 41 种炎症因子的白细胞介素 12（IL-12）水平与 RPL 之间存在因果关系（OR=1.78，95%CI=1.25-2.55；P=0.00149）。我们筛选了与 RPL 因果相关的 5 组免疫细胞亚型：转换记忆 B 细胞绝对计数（OR=0.66，95%CI=0.49-0.87，P=0.00406）、IgD+CD24+B 细胞绝对计数（OR=0.69，95%CI=0.53-0.88，P=0.00319）、CD39+静息 CD4 调节性 T 细胞%调节性 T 细胞（OR=0.86，95%CI=0.78-0.95，P=0.00252）、激活和静息 CD4 调节性 T 细胞%调节性 T 细胞（OR=0.89，95%CI=0.82-0.97，P=0.00938）和 CD45RA+CD28-CD8+T 细胞%CD8+T 细胞（OR=0.99，95%CI=0.98-1.00，P=0.01231）。在炎症因子方面，证实了外周血中白细胞介素 12（IL-12）与 RPL 之间存在因果关系。我们还发现了五种具有保护作用的免疫细胞表型。这表明外周血中可能存在保护性 B 细胞和 CD8+T 细胞亚群，再次证明了 Tregs 的保护作用。对 RPL 患者外周血进行免疫监测似乎是必要的，也是精准医学的基础。
