HLA-G at the Maternal Fetal Interface

来源于主要组织相容性复合体(MHC)Ib类基因的糖蛋白，人类白细胞抗原-G，首次在 人类胎盘，位于母体蜕膜内和邻近的细胞滋养层(CTB)细胞中。 尽管进行了近20年的密集研究，但这种新基因的产物(S)的作用仍不清楚，尽管 大多数研究指出，人类白细胞抗原-G在调节半异基因妊娠的免疫方面发挥了作用。人类白细胞抗原G基因 具有许多新的特征：该基因在编码区几乎没有多态，但在编码区有多个多态 调节区；至少7种异构体由来自单个基因的mRNA的选择性剪接产生；HLAG 有有限的组织分布，包括在胎盘中的高表达，也显示出不同的异构体 CTB细胞亚群的表达。在这个项目申请中，来自两个机构的三名调查人员提议 探讨胎盘组织中人类白细胞抗原-G在妊娠中的作用。这三位都是琼·亨特博士(堪萨斯大学医学中心， 堪萨斯城，肯塔基州)，同一机构的玛格丽特·彼得罗夫博士和卡罗尔·奥贝尔博士(芝加哥大学， 芝加哥，伊利诺伊州)在生殖免疫学方面拥有丰富的经验，并将大部分研究集中在MHC上 妊娠中的抗原。在项目I中，亨特将研究异构体特异性表达和 利用新产生的重组可溶性人类白细胞抗原-G糖蛋白和重组人白细胞抗原 抗这些蛋白质的单抗。在项目II中，彼得罗夫将检查人类白细胞抗原-G亚型和 B7家族的成员，并将研究对免疫细胞功能调节的影响 转染细胞表达不同组合的人类白细胞抗原G/B7蛋白。在HI项目中，Ober将追求功能性 使用新开发的等位基因特异性探针研究人类白细胞抗原-G基因分型，并将探索与减少的关系 生育能力。该程序由两个内核支持。核心A.由亨特领导的行政部门将负责 确保实验结果的整合和发布。核心B组织收集和基因分型， 由Ober指导，将收集并提供所有研究人员的早期妊娠组织和问题组织 怀孕。该核心还将确定与每个项目相关的基因的多态。这起案件的调查人员 计划完全期待他们密切和系统的合作将包括一种强有力的方法来阐明 人类白细胞抗原-G的表达、调节和功能的关键方面，并最终将导致新的和改进的治疗方法 对于生育能力受损的人。

Glycoproteins derived from the major histocompatibility complex (MHC) class Ib gene, HLA-G, were first described in human placentas, where they were located in cytotrophoblast (CTB) cells within and adjacent to the maternal decidua. Despite nearly two decades of intensive research, the role(s) of the products of this novel gene remain unclear, although most studies point to a role for HLA-G in regulating immune aspects of semiallogeneic pregnancy. The HLA-G gene has many novel features: the gene contains few polymorphisms in the coding region but multiple polymorphisms in the regulatory regions; at least 7 isoforms are generated by alternative splicing of mRNA derived from a single gene; HLAG has limited tissue distribution that includes high expression in placentas and also demonstrates differential isoform expression in CTB cell subpopulations. In this program application, three investigators from two institutions propose to study the role of placental HLA-G in pregnancy. All three, Dr. Joan Hunt (University of Kansas Medical Center, Kansas City, KS), Dr. Margaret Petroff from the same institution, and Dr. Carole Ober (University of Chicago, Chicago, IL) have extensive experience in reproductive immunology and have focused much of their research on MHC antigens in pregnancy. In Project I, Hunt will investigate mechanisms underlying isoform-specific expression and isoform-specific functions of HLA-G using newly generated recombinant soluble HLA-G glycoproteins and monoclonal antibodies to these proteins. In Project II, Petroff will examine co-expression of HLA-G isoforms and members of the B7 family, and will investigate implications for regulation of immune cell function using stably transfected cells expressing various combinations of HLA-G/B7 proteins. In Project HI, Ober will pursue functional aspects of HLA-G genotypes using newly developed allele-specific probes, and will explore relationships to diminished fertility. The program is supported by two Cores. Core A. Administration, directed by Hunt, will be responsible for assuring integration and publication of the outcomes of the experiments. Core B Tissue Collection and Genotyping, directed by Ober, will collect and supply all investigators with early gestation tissues and tissues from problem pregnancies. This core will also identify polymorphisms in genes relevant to each project. The investigators in this program fully expect that their close and systematic collaboration will comprise a powerful approach to elucidating critical aspects of HLA-G expression, regulation and function, and will ultimately lead to new and improved therapies for impaired fertility.