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

在与母体循环直接接触的胎盘滋养层细胞上缺乏“自身”分子表达，以及在该界面处对母体免疫反应的局部抑制，可能是胚胎成功植入的重要因素。这种免疫学上的“沉默”使胚胎能够逃避通常与异体移植相关的排斥反应，而胚胎的父系遗传贡献使其在免疫学上对母体是外来的。黄病毒感染增加了脊椎动物细胞（包括胎盘的滋养层细胞）中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，并将胚胎作为破坏目标。我们假设，这些分子的诱导，这种病毒和其他病毒可能会打破免疫沉默的早期胚胎和扭转局部抑制母体免疫反应。这将导致母体对胚胎的免疫排斥和流产。母亲对病毒的这种最初的敏感性可能是一些妇女遭受复发性流产的原因之一。我们将使用一种新型病毒小鼠模型，将病毒感染的胚胎植入受体动物体内，使我们能够剖析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开发的，以直接测试我们的假设。它不会引起母亲的全身性疾病，而全身性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消除病毒和维持妊娠之间的微妙平衡相关的特定机制。该项目的结果将为社区复发性流产治疗的合理设计提供信息。

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.