Departments of Microbiology, Infectiology and Immunology, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Université de Montréal, Montreal, Canada.
CHU Sainte-Justine Research Center, Montreal, Canada.
Am J Obstet Gynecol. 2023 Mar;228(3):332.e1-332.e17. doi: 10.1016/j.ajog.2022.08.035. Epub 2022 Aug 24.
Preterm birth remains a leading obstetrical complication because of the incomplete understanding of its multifaceted etiology. It is known that immune alterations toward a proinflammatory profile are observed in women with preterm birth, but therapeutic interventions are still lacking because of scarcity of evidence in the integration of maternal and placental interrelated compartments.
This study aimed to obtain an integrated view of the maternal and placental contribution to preterm birth compared with normal term pregnancies for an in-depth understanding of the immune/inflammatory involvement, intending to identify novel strategies to mitigate the negative impact of inflammation.
We prospectively recruited 79 women with preterm or term deliveries and collected placentas for RNA sequencing, histologic analyses, and to assess levels of inflammatory mediators. Blood samples were also collected to determine the circulating immune profiles by flow cytometry and to evaluate the circulating levels of inflammatory mediators.
Placental transcriptomic analyses revealed 102 differentially expressed genes upregulated in preterm birth, including known and novel targets, which were highly enriched for inflammatory biological processes according to gene ontology analyses. Analysis of maternal immune cells revealed distinct profiles in preterm births vs term births, including an increased percentage of CD3 cells and monocyte subsets and decreased CD3 cells along with Th17 subsets of CD4 lymphocytes. Supporting our bioinformatic findings, we found increases in proinflammatory mediators in the plasma, placenta, and fetal membranes (primarily the amnion) of women with preterm birth, such as interleukin-6 and tumor necrosis factor-α. These findings were not distinct between spontaneous and iatrogenic preterm births except at a molecular level where spontaneous preterm birth presented with an elevated inflammatory profile compared with iatrogenic preterm birth. Analysis of placental histology revealed increased structural and inflammatory lesions in preterm vs term births. We found that genes upregulated in placentas with inflammatory lesions have enrichment of proinflammatory pathways.
This work sheds light on changes within the immune system in preterm birth on multiple levels and compartments to help identify pregnancies at high risk of preterm birth and to discover novel therapeutic targets for preterm birth.
早产仍然是一种主要的产科并发症，因为人们对其多方面的病因尚未完全了解。已知患有早产的女性会出现向促炎表型的免疫改变，但由于缺乏将母体和胎盘相关隔室相关联的证据，治疗干预措施仍然缺乏。
本研究旨在获得与正常足月妊娠相比，早产时母体和胎盘对早产的综合贡献，以深入了解免疫/炎症的参与情况，旨在确定减轻炎症负面影响的新策略。
我们前瞻性地招募了 79 名早产或足月分娩的妇女，并采集胎盘进行 RNA 测序、组织学分析，并评估炎症介质水平。还采集了血液样本，通过流式细胞术确定循环免疫谱，并评估炎症介质的循环水平。
胎盘转录组分析显示，在早产中上调了 102 个差异表达基因，包括已知和新的靶标，这些靶标根据基因本体论分析高度富集于炎症的生物过程。对母体免疫细胞的分析显示，早产与足月分娩之间存在不同的特征，包括 CD3 细胞和单核细胞亚群的比例增加，以及 CD3 细胞和 Th17 亚群的 CD4 淋巴细胞比例降低。支持我们的生物信息学发现，我们发现患有早产的妇女的血浆、胎盘和胎膜（主要是羊膜）中的促炎介质增加，例如白细胞介素-6 和肿瘤坏死因子-α。除了在分子水平上自发性早产与医源性早产不同外，这些发现并没有在自发性早产和医源性早产之间有所区别，自发性早产的炎症特征明显高于医源性早产。胎盘组织学分析显示，早产与足月分娩相比，胎盘结构和炎症病变增加。我们发现，在有炎症病变的胎盘上调的基因有促炎途径的富集。
这项工作揭示了早产时免疫系统在多个层面和隔室的变化，有助于识别早产风险高的妊娠，并发现早产的新治疗靶点。
