Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN 55905;
Adaptive Biotechnologies, Seattle, WA 98102.
J Immunol. 2020 Jun 1;204(11):2931-2939. doi: 10.4049/jimmunol.1901297. Epub 2020 Apr 22.
During human pregnancy, proinflammatory responses in the placenta can cause severe fetal complications, including growth restriction, preterm birth, and stillbirth. Villitis of unknown etiology (VUE), an inflammatory condition characterized by the infiltration of maternal CD8 T cells into the placenta, is hypothesized to be secondary to either a tissue rejection response to the haploidentical fetus or from an undiagnosed infection. In this study, we characterized the global TCR β-chain profile in human T cells isolated from placentae diagnosed with VUE compared with control and infectious villitis-placentae by immunoSEQ. Immunosequencing demonstrated that VUE is driven predominantly by maternal T cell infiltration, which is significantly different from controls and infectious cases; however, these T cell clones show very little overlap between subjects. Mapping TCR clones to common viral epitopes (CMV, EBV, and influenza A) demonstrated that Ag specificity in VUE was equal to controls and significantly lower than CMV-specific clones in infectious villitis. Our data indicate VUE represents an allograft response, not an undetected infection. These observations support the development of screening methods to predict those at risk for VUE and the use of specific immunomodulatory therapies during gestation to improve outcomes in affected fetuses.
在人类妊娠期间，胎盘的促炎反应可导致严重的胎儿并发症，包括生长受限、早产和死产。原因不明的绒毛膜炎（VUE）是一种以母体 CD8 T 细胞浸润胎盘为特征的炎症状态，据推测是同种异体胎儿组织排斥反应或未确诊感染的结果。在这项研究中，我们通过 immunoSEQ 对诊断为 VUE 的胎盘与对照和感染性绒毛膜炎胎盘分离的人 T 细胞进行了 TCRβ 链谱的全面分析。免疫测序表明，VUE 主要由母体 T 细胞浸润驱动，与对照和感染病例明显不同；然而，这些 T 细胞克隆在个体之间几乎没有重叠。将 TCR 克隆映射到常见病毒表位（CMV、EBV 和流感 A）上表明，VUE 中的 Ag 特异性与对照相当，明显低于感染性绒毛膜炎中的 CMV 特异性克隆。我们的数据表明，VUE 代表同种异体反应，而不是未被发现的感染。这些观察结果支持开发筛查方法来预测那些有患 VUE 风险的人，并在妊娠期间使用特定的免疫调节疗法来改善受影响胎儿的结局。
