孕妇外周血中妊娠早期免疫生物标志物对子痫前期的预测价值研究

Study on the predictive value of immune biomarkers of early pregnancy in maternal peripheral blood for preeclampsia

目的分析孕妇外周血中妊娠早期免疫生物标志物对子痫前期的预测价值。方法选取2018年2月至2019年2月于三亚市中医院接受产前检查及分娩的1072例孕妇作为研究对象。根据随访结果是否发生子痫前期分为正常组(974例)和病例组(98例);在妊娠5周~16周时收集孕妇外周血5mL,采用流式细胞术检测淋巴细胞亚群并进行细胞内细胞因子分析,Luminex方法检测血清细胞因子和趋化因子;比较两组妊娠结局、外周血淋巴细胞亚群、细胞内细胞因子及血清细胞因子、趋化因子表达水平,分析妊娠早期免疫生物标志物与妊娠结局的相关性,使用受试者工作特征曲线(ROC)分析相关妊娠早期免疫生物标志物对子痫前期的预测效能。结果两组孕妇在分娩孕周、新生儿出生体重及早产率上差异均具有统计学意义(P<0.05);病例组外周血Treg细胞表达水平明显低于正常组;病例组CD4^+TNFα^+(Th1)、CD4^+IL-17^+(Th17)细胞表达水平,TNFα/IL-10、Th17/Treg细胞比,血清IL-8、MCP-1、MIP-1α水平均明显高于正常组,差异均具有统计学意义(P<0.05);经Pearson相关性分析,妊娠早期孕妇外周血Treg细胞和MCP-1均与分娩孕周、新生儿出生体重呈正相关(P<0.05),TNFα/IL-10、Th17/Treg和IL-8均与分娩孕周、新生儿出生体重呈负相关(P<0.05);妊娠早期孕妇TNFα/IL-10、IL-8联合MCP-1预测子痫前期ROC曲线下面积(AUC)为0.937,经Delong检验,显著大于单独指标的AUC(Z值分别为2.011、2.066、2.131,P值分别为0.044、0.039、0.033)。结论妊娠早期孕妇Th1和Th17细胞表达水平升高,TNFα/IL-10、Th17/Treg细胞比升高和Treg细胞表达水平下降均与子痫前期有关,其中以TNFα/IL-10、IL-8和MCP-1联合预测子痫前期的效能最佳,值得临床进一步研究应用。

Objective To analyze the predictive value of immune biomarkers of early pregnancy in maternal peripheral blood for preeclampsia.Methods 1072 pregnant women who received prenatal examination and delivered in our hospital from February 2018 to February 2019 were selected and divided into normal group(974 cases)and case group(98 cases)according to the occurrence of preeclampsia in the follow-up.5 mL of peripheral blood was collected at 5~16 weeks of gestation;lymphocyte subsets were detected by flow cytometry and intracellular cytokine analysis was performed;Luminex method was used to detect serum cytokines and chemokines.The expression levels of lymphocyte subsets,intracellular cytokines,serum cytokines and chemokines in the two groups were compared;the correlation between immune biomarkers in early pregnancy and pregnancy outcome was analyzed;the predictive efficacy of immune biomarkers in early pregnancy on preeclampsia was analyzed using the receiver operating characteristic curve(ROC).Results There were significant differences in the gestational weeks,birth weight and preterm birth between the two groups(P<0.05);the expression level of Treg cells in peripheral blood of the case group was significantly lower than that of the normal group;the expression levels of CD4^+TNFα^+(Th1),CD4^+IL-17^+(Th17)cells,TNFα/IL-10,Th17/Treg cells and serum IL-8,MCP-1 and MIP-1αlevels in the case group were significantly higher than those in the normal group,with statistically significant differences(P<0.05).Based on Pearson correlation analysis,the peripheral blood Treg cells and MCP-1 in pregnant women were positively correlated with gestational age and birth weight(P<0.05),and TNFα/IL-10,Th17/Treg and IL-8 were negatively correlated with gestational age and birth weight(P<0.05).The areas under curve(AUC)of TNFα/IL-10,IL-8 combined with MCP-1 in early pregnancy in predicting pre-eclampsia was 0.937,which was significantly greater than the AUC of individual indicator(Z values=2.011,2.066,2.131,respectively,P values=0.044,0.039,0.033,respectively)according to Delong test.Conclusions The increased expression levels of Th1 and Th17 cells,increased ratios of TNFα/IL-10,Th17/Treg and decreased expression levels of Treg cells in early pregnancy are associated with preeclampsia,among which joint detection of TNFα/IL-10,IL-8 and MCP-1 is of the best efficacy to predict pre-eclampsia,worthy of further clinical research and application.