Immunobiology of Early Pregnancy - A Model of Virus-induced Abortion

胎盘滋养细胞直接与母体循环界面缺乏“自我”分子表达，以及母体在该界面的免疫反应受到局部抑制，可能是胚胎成功着床的重要因素。这种免疫“沉默”允许胚胎，其父亲的遗传贡献使其免疫外来的母亲，逃避排斥反应通常与外来移植物移植相关。黄病毒感染可增加脊椎动物细胞（包括胎盘滋养层细胞）细胞表面自身和粘附分子的浓度。因此，这些分子可以被母体免疫系统识别，并成为胚胎的破坏目标。我们推测，这种病毒和其他病毒诱导这些分子可能会打破早期胚胎的免疫沉默，逆转母体免疫反应的局部抑制。这将导致母体对胚胎的免疫排斥和流产。母亲对病毒的这种初始敏感可能是一些妇女反复流产的原因之一。我们将使用一种新的病毒小鼠模型，我们将病毒感染的胚胎植入接受期动物，使我们能够解剖出在怀孕期间诱导母体抗病毒免疫的不寻常要求。这个模型是在我们的实验室里开发出来的，用来直接检验我们的假设。它不会引起母亲的全身性疾病，而这种疾病本身可能导致非特异性流产。因此，该模型可以首次阐明与根除病毒和维持妊娠之间的微妙平衡有关的具体机制。本项目的研究结果将为社区复发性流产治疗的合理设计提供参考。

The lack of 'self' molecule expression on the trophoblast cells of the placenta which interface directly with the mother's circulation, as well as the local suppression of the mother's immune response at this interface, may be important factors in the successful implantation of the embryo. This immunological 'silence' allows the embryo, whose paternal genetic contribution makes it immunologically foreign to the mother, to escape the rejection reaction normally associated with foreign graft transplantation. Infection with flaviviruses increases the concentrations of cell surface self and adhesion molecules in vertebrate cells, including the trophoblast cells of the placenta. As a result, these molecules can then be recognised by the maternal immune system and the embryo targeted for destruction. We hypothesise that the induction of these molecules by this and other viruses may break the immunological silence of the early embryo and reverse the local suppression of the maternal immune response. This would result in maternal immune rejection of the embryo and abortion. This initial sensitisation of the mother by the virus might be one of the reasons that some women suffer recurrent abortions. We will use a novel viral mouse model where we implant virus-infected embryos into receptive animals to enable us to dissect out the unusual requirements for induction of maternal anti-viral immunity during pregnancy. This model was developed in our laboratory to directly test our hypotheses. It does not cause systemic illness in the mother which itself can lead to non-specific abortion. This model therefore can for the first time elucidate the specific mechanisms associated with the delicate balance between eradicating virus and maintaining pregnancy. Results from this project will inform rational design of treatment of recurrent abortions in the community.