Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University, 39108 Magdeburg, Germany.
Institute for Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, Germany.
Cells. 2021 Oct 8;10(10):2693. doi: 10.3390/cells10102693.
Immunological networks balance tolerance towards paternal alloantigens during pregnancy with normal immune response to pathogens. Subclinical infections can impact this balance and lead to preterm birth or even intrauterine fetal death (IUFD). We recently showed that loss of maternal B cells renders murine fetuses susceptible to IUFD after LPS exposure. Since the signaling pathway involved in this B-cell mediated response remains unclear, we aimed to understand the participation of MyD88 in this response using B-cell-specific MyD88-deficient (BMyD88) mice. B cells isolated from wild-type (WT), BMyD88, CD19 and MyD88 dams on gestational day (gd) 10 responded differently to LPS concerning cytokine secretion. In vivo LPS challenge on gd 10 provoked IUFD in CD19 mothers with functional MyD88, while fetuses from BMyD88 and MyD88 mice were protected. These outcomes were associated with altered cytokine levels in the maternal serum and changes in CD4 T-cell responses. Overall, the loss of MyD88 signaling in maternal B cells prevents the activation of cytokine release that leads to IUFD. Thus, while MyD88 signaling in maternal B cells protects the mother from infection, it ultimately kills the fetus. Understanding the cellular mechanisms underlying infection-driven pregnancy complications is the first step to designing powerful therapeutic strategies in the future.
免疫网络在妊娠期间平衡母体对父系同种异体抗原的耐受性与对病原体的正常免疫反应。亚临床感染会影响这种平衡，导致早产甚至宫内胎儿死亡 (IUFD)。我们最近表明，在 LPS 暴露后，母体 B 细胞的缺失会使小鼠胎儿易患 IUFD。由于涉及这种 B 细胞介导反应的信号通路尚不清楚，我们旨在使用 B 细胞特异性 MyD88 缺陷型 (BMyD88) 小鼠来了解 MyD88 在这种反应中的参与。从野生型 (WT)、BMyD88、CD19 和 MyD88 母鼠的妊娠第 10 天 (gd) 分离的 B 细胞对 LPS 的细胞因子分泌反应不同。在 gd 10 天体内 LPS 挑战会导致具有功能性 MyD88 的 CD19 母体发生 IUFD，而 BMyD88 和 MyD88 小鼠的胎儿则受到保护。这些结果与母血清中细胞因子水平的改变和 CD4 T 细胞反应的变化有关。总的来说，母体 B 细胞中 MyD88 信号的缺失阻止了导致 IUFD 的细胞因子释放的激活。因此，虽然母体 B 细胞中的 MyD88 信号可以保护母亲免受感染，但它最终会杀死胎儿。了解感染驱动的妊娠并发症的细胞机制是未来设计强大治疗策略的第一步。
