Department of Obstetrics, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, China.
Xiamen Key Laboratory of Basic and Clinical Research on Major Obstetrical Diseases Xiamen, Xiamen, China.
J Gene Med. 2024 Feb;26(2):e3676. doi: 10.1002/jgm.3676.
Preeclampsia, a severe pregnancy syndrome, is widely accepted divided into early- and late-onset preeclampsia (EOPE and LOPE) based on the onset time of preeclampsia, with distinct pathophysiological origins. However, the molecular mechanism especially immune-related mechanisms for EOPE and LOPE is currently obscure. In the present study, we focused on placental immune alterations between EOPE and LOPE and search for immune-related biomarkers that could potentially serve as potential therapeutic targets through bioinformatic analysis.
The gene expression profiling data was obtained from the Gene Expression Omnibus database. ESTIMATE algorithm and Gene Set Enrichment Analysis were employed to evaluate the immune status. The intersection of differentially expressed genes in GSE74341 series and immune-related genes set screened differentially expressed immune-related genes. Protein-protein interaction network and random forest were used to identify hub genes with a validation by a quantitative real-time PCR. Kyoto Encyclopedia of Genes and Genomes pathways, Gene Ontology and gene set variation analysis were utilized to conduct biological function and pathway enrichment analyses. Single-sample gene set enrichment analysis and CIBERSORTx tools were employed to calculate the immune cell infiltration score. Correlation analyses were evaluated by Pearson correlation analysis. Hub genes-miRNA network was performed by the NetworkAnalyst online tool.
Immune score and stromal score were all lower in EOPE samples. The immune system-related gene set was significantly downregulated in EOPE compared to LOPE samples. Four hub differentially expressed immune-related genes (IL15, GZMB, IL1B and CXCL12) were identified based on a protein-protein interaction network and random forest. Quantitative real-time polymerase chain reaction validated the lower expression levels of four hub genes in EOPE compared to LOPE samples. Immune cell infiltration analysis found that innate and adaptive immune cells were apparent lacking in EOPE samples compared to LOPE samples. Cytokine-cytokine receptor, para-inflammation, major histocompatibility complex class I and T cell co-stimulation pathways were significantly deficient and highly correlated with hub genes. We constructed a hub genes-miRNA regulatory network, revealing the correlation between hub genes and hsa-miR-374a-5p, hsa-miR-203a-3p, hsa-miR-128-3p, hsa-miR-155-3p, hsa-miR-129-2-3p and hsa-miR-7-5p.
The innate and adaptive immune systems were severely impaired in placentas of EOPE. Four immune-related genes (IL15, GZMB, IL1B and CXCL12) were closely correlated with immune-related pathogenesis of EOPE. The result of our study may provide a new basis for discriminating between EOPE and LOPE and acknowledging the role of the immune landscape in the eventual interference and tailored treatment of EOPE.
子痫前期是一种严重的妊娠综合征，根据子痫前期的发病时间，广泛分为早发型和晚发型子痫前期（EOPE 和 LOPE），具有明显不同的病理生理起源。然而，EOPE 和 LOPE 的分子机制，尤其是免疫相关机制目前尚不清楚。本研究通过生物信息学分析，聚焦于 EOPE 和 LOPE 胎盘免疫改变，并寻找潜在的免疫相关生物标志物，这些标志物可能成为潜在的治疗靶点。
从基因表达综合数据库中获取基因表达谱数据。采用 ESTIMATE 算法和基因集富集分析评估免疫状态。在 GSE74341 系列中差异表达基因与免疫相关基因集的交集，筛选差异表达的免疫相关基因。通过蛋白质-蛋白质相互作用网络和随机森林识别与免疫相关发病机制密切相关的枢纽基因，并通过定量实时 PCR 进行验证。京都基因与基因组百科全书通路、基因本体论和基因集变异分析用于进行生物功能和通路富集分析。通过单样本基因集富集分析和 CIBERSORTx 工具计算免疫细胞浸润评分。通过 Pearson 相关性分析评估相关性。通过 NetworkAnalyst 在线工具进行枢纽基因-miRNA 网络分析。
EOPE 样本的免疫评分和基质评分均较低。与 LOPE 样本相比，与免疫系统相关的基因集在 EOPE 中显著下调。基于蛋白质-蛋白质相互作用网络和随机森林，确定了 4 个枢纽差异表达的免疫相关基因（IL15、GZMB、IL1B 和 CXCL12）。定量实时聚合酶链反应验证了 EOPE 样本中这 4 个枢纽基因的表达水平低于 LOPE 样本。免疫细胞浸润分析发现，与 LOPE 样本相比，EOPE 样本中固有和适应性免疫细胞明显缺乏。细胞因子-细胞因子受体、副炎症、主要组织相容性复合体 I 类和 T 细胞共刺激途径明显缺乏，并与枢纽基因高度相关。我们构建了一个枢纽基因-miRNA 调控网络，揭示了枢纽基因与 hsa-miR-374a-5p、hsa-miR-203a-3p、hsa-miR-128-3p、hsa-miR-155-3p、hsa-miR-129-2-3p 和 hsa-miR-7-5p 之间的相关性。
EOPE 胎盘的固有和适应性免疫系统严重受损。4 个与免疫相关的基因（IL15、GZMB、IL1B 和 CXCL12）与 EOPE 的免疫相关发病机制密切相关。本研究结果可能为区分 EOPE 和 LOPE 提供新的依据，并认识到免疫景观在最终干预和个体化治疗 EOPE 中的作用。
