Primate Placental MHC Immunogenetics

描述(申请人提供)：绒毛外滋养层细胞中MHC-I类分子人类白细胞抗原-G，特别是人类白细胞抗原-C的独特表达被认为是人类妊娠的关键因素。尽管它们的MHC正在快速进化，但很明显，其他灵长类动物积极地保留了与人类白细胞抗原-G同源或同源的基因在胎盘中的表达，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，反映了它们同源MHC分子的多样性。然而，要充分了解胎盘MHC I类分子和蜕膜白细胞上特定受体之间的对话，以及它们在不良妊娠结局情况下作为治疗靶点的潜力，将需要更好地开发合适的动物模型。MAMU-AG是一种非经典的MHC-I类分子，在恒河猴滋养层细胞中的表达具有明显的限制性多态。我们提出了一个新的假设，即虽然恒河猴没有同源的MHC-C基因座，但胎盘Mamu-AG将发挥人类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。具体目的1.应用高通量焦磷酸测序技术研究恒河猴滋养层细胞中胎盘MHC-I类mRNAs的多态性。具体目的2.用一种新的基于焦磷酸测序的表型方法确定KIR和LILR mRNAs在恒河猴蜕膜和外周血白细胞中的表达。具体目的3.表达Fc标记的重组恒河猴蜕膜KIR/LILR受体，并以其为探针鉴定胎盘Mamu-AG的候选受体。这些研究建议重塑我们对恒河猴胎盘MHC表达的理解，并通过定义恒河猴外周血和蜕膜白细胞上存在的候选受体来推动这一领域的发展。明确蜕膜白细胞上的MAMU-AG受体(S)将加强对正在进行的和未来的猕猴体内实验的解释，这些实验旨在研究着床、早期胎盘和蜕膜发育、胎儿福祉和妊娠结局中的母体免疫识别和反应，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.