Human Miscarriage Is Associated With Dysregulations in Peripheral Blood-Derived Myeloid Dendritic Cell Subsets
Human Miscarriage Is Associated With Dysregulations in Peripheral Blood-Derived Myeloid Dendritic Cell Subsets
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DOI：
10.3389/fimmu.2019.02440
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发表时间：
2019-10-15
影响因子：
7.3
通讯作者：
Schumacher, Anne
中科院分区：
文献类型：
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作者：
Ehrentraut, Stefanie;Sauss, Karoline;Schumacher, Anne
树突状细胞(DC)在母体免疫系统接受或排斥外来胎儿抗原的决定中起着至关重要的作用。然而，尤其是对于人类外周血树突状细胞(PBDC)，现有的文献相当不一致，调节这些细胞的因素也定义不清。在这里，我们研究了正常和病理妊娠期间不同的人外周血树突状细胞亚群的表型和功能，并研究了人绒毛膜促性腺激素(HCG)在外周血树突状细胞调节中的作用。外周血样本取自所有三个月的正常孕妇、早孕流产患者和健康未孕妇女。样本分析了血浆hCG水平，调节性T(Treg)细胞数量，总的和成熟的浆细胞样细胞(PDC)和髓系(MDC1和MDC2)PBDC亚群的频率以及它们的细胞因子分泌。体外培养PDC、MDC1或MDC2，分别加入两种滋养层细胞系、胎盘外植体上清液或两种hCG制剂。检测hCG和非hCG刺激的MDC1诱导Treg的能力。在正常妊娠的早期和中期，MDC1和MDC2的总频率和成熟频率分别增加。流产与MDC1减少和MDC2激活谱增加相关。PDC在正常妊娠和流产过程中均未发生改变。在体外，分离的PBDC亚群在含有胎盘衍生因子的情况下培养会损害MDC1的成熟，并不同程度地影响PDC的成熟。尿源性人绒毛膜促性腺激素制剂对MDC1和PDC成熟也有抑制作用。最后，我们观察到在正常妊娠早期Treg细胞的升高，这在流产中不存在。刺激MDC1在体外诱导Treg细胞，但hCG不参与这一过程。我们的发现表明，在正常妊娠期间，PBDC亚群根据胎龄的不同而受到不同的调节。流产似乎与髓系外周血树突状细胞亚群的失调和Treg细胞频率的紊乱有关。此外，我们的结果表明，在怀孕早期，mdc1和Treg细胞之间存在相互依赖关系。人绒毛膜促性腺激素虽然被证明会损害MDC1的成熟，但似乎并不是妊娠期间PBDC改变的关键调节因素。
Dendritic cells (DC) are critically involved in decisions related to the acceptance or rejection of the foreign fetal antigens by the maternal immune system. However, particularly for human peripheral blood DCs (PBDC), available literature is rather inconsistent and the factors regulating these cells are ill-defined. Here, we investigated the phenotype and functionality of different human PBDC subsets during normal and pathologic pregnancies and studied an involvement of human chorionic gonadotropin (hCG) in PBDC regulation. Peripheral blood samples were obtained fromnormal pregnant women in all three trimesters, from first trimester miscarriage patients and from healthy non-pregnant women. Samples were analyzed for plasma hCG levels, for regulatory T (Treg) cell numbers, for frequencies of total and mature plasmacytoid (PDC) and myeloid (MDC1 and MDC2) PBDC subsets and for their cytokine secretion. In vitro assays, culturing PDC, MDC1 or MDC2 in the presence of two trophoblast cell lines, placenta explant supernatants or two hCG preparations were performed. The Treg-inducing capability of hCG- or non-hCG-treated stimulated MDC1 was assessed. Total andmature MDC1 and MDC2 frequencies increased during the first and second trimester of normal pregnancy, respectively. Miscarriage was associated with a reduced MDC1 and an increasedMDC2 activation profile. PDC were not altered neither during normal pregnancy progression nor during miscarriage. In vitro, the culture of isolated PBDC subsets in the presence of placenta-derived factors impaired the maturation of MDC1 and differentially affected PDC maturation. An inhibitory effect on MDC1 and PDC maturation was also proven for the urine-derived hCG preparation. Finally, we observed a Treg cell elevation during early normal pregnancy that was not present in miscarriages. Stimulated MDC1 induced Treg cells in vitro, however, hCG was not involved in this process. Our findings suggest that during normal pregnancy PBDC subsets are differentially regulated dependent on gestational age. Miscarriage seems to be associated with dysregulations in the myeloid PBDC subsets and with disturbances in Treg cell frequencies. Moreover, our results propose an interdependency between MDC1 and Treg cells during early pregnancy. hCG, although shown to impair MDC1 maturation, does not seem to be a key regulator of PBDC alterations during pregnancy.