Primate Placental MHC Immunogenetics

描述（由申请人提供）：绒毛外滋养层中MHC I类分子HLA-G，特别是HLA-C的独特表达被认为是人类妊娠的关键因素。虽然它们的MHC正在迅速进化，但很明显，其他灵长类动物积极保留了与HLA-G同源或直系同源的基因的胎盘表达，并且MHC I类分子的受体KIR和LILR基因家族成员正在经历平行进化，并反映了其同源MHC分子的多样性。然而，胎盘MHC I类分子和体内蜕膜白细胞上的特异性受体之间的对话，以及它们在不良妊娠结局情况下作为治疗靶点的潜力，需要更好地开发适当的动物模型。我们已经广泛地表征了Mamu-AG的表达，Mamu-AG是一种非经典的MHC I类分子，在恒河猴滋养层细胞中表达，具有明显的限制性多态性。我们提出了一个新的假设，即虽然恒河猴没有一个正向MHC-C位点，但胎盘Mamu-AG将履行人类HLA-C的胎盘作用。为了验证这一假设并推动这一重要的动物模型向前发展，我们提出了三个具体目标。具体目标1。采用高通量焦磷酸测序技术检测恒河猴胎盘滋养层细胞MHC I类分子mRNA的多态性。具体目标2。采用一种新的基于焦磷酸测序的表型分析方法，确定恒河猴蜕膜和外周血白细胞中KIR和LILR mRNA的表达。具体目标3。表达重组Fc标记的恒河猴蜕膜KIR/LILR受体，并将其作为探针鉴定胎盘Mamu-AG的候选受体。这些研究建议重新构建我们对恒河猴胎盘MHC表达的理解，并通过定义恒河猴外周血和蜕膜白细胞上的候选受体来推动该领域的发展。确定蜕膜白细胞上的Mamu-AG受体将加强对正在进行和未来的恒河猴体内实验的解释，这些实验研究母体免疫识别和着床反应、早期胎盘和蜕膜发育、胎儿健康和妊娠结局以及胎盘对子宫内膜粘膜免疫环境的影响。

DESCRIPTION (provided by applicant): The unique expression of MHC class I molecules HLA-G and particularly HLA-C in extravillous trophoblasts is thought to be a critical element of human pregnancy. Although their MHC is rapidly evolving, it is clear that other primates have actively retained placental expression of genes orthologous or homologous to HLA-G, and the receptors for MHC class I molecules, the KIR and LILR gene family members, are undergoing parallel evolution and reflect the diversity of their cognate MHC molecules. However, a full understanding of the dialog between placental MHC class I molecules and specific receptors on decidual leukocytes in vivo, and their potential as therapeutic targets in cases of adverse pregnancy outcomes will require better development of appropriate animal models. We have extensively characterized the expression of Mamu-AG, a nonclassical MHC class I molecule with apparently restricted polymorphism expressed in rhesus monkey trophoblasts. We have formulated a new hypothesis that although the rhesus does not have an orthologous MHC-C locus, placental Mamu-AG will fulfill the placental role of human HLA-C. To test this hypothesis and move this important animal model forward, we propose three Specific Aims. Specific Aim 1. To define the polymorphism of placental MHC class I mRNAs expressed in rhesus monkey trophoblasts by high throughput pyrosequencing. Specific Aim 2. To define the expression of KIR and LILR mRNAs in rhesus monkey decidual and peripheral blood leukocytes using a novel pyrosequencing-based phenotyping approach. Specific Aim 3. To express recombinant Fc-tagged rhesus decidual KIR/LILR receptors and use these as probes to identify candidate receptors for placental Mamu-AG. These studies propose to reframe our understanding of rhesus placental MHC expression, and move the field forward by defining the candidate receptors present on rhesus peripheral blood and decidual leukocytes. Defining the Mamu-AG receptor(s) on decidual leukocytes will strengthen interpretation of ongoing and future in vivo experiments with rhesus monkeys in the study of maternal immune recognition and response in implantation, early placental and decidual development, and fetal well-being and pregnancy outcome, as well as placental influences on the endometrial mucosal immunological environment.