uNK细胞杀伤受体及其配体与URSA母胎免疫紊乱分子机制研究

Unexplained recurrent spontaneous abortion is a common complication of obstetrics and gynecology, the reasons of which are complex. To investigate the interaction mechanism between the embryo and the matrix after pregnancy, and clarify the pathogenesis of some unexplained recurrent miscarriage, this research project is to first study the subtype proportion and change rule of toxicity of the uNK cell of URSA patients and normal controls pregnant, exploring the role that uNK cells play during the occurring of URSA at a cellular level; and through the detection of the two groups of the KIRs in suterine decidua, HLA-C, -G and HLA-E in villi tissue, it is to explore their distribution and KIR/HLA matching rule at gene, protein and mRNA level, and further explore the role that uNK cells play during the occurring of URSA. On this basis, this research is to predict the miRNA which may be target of KIR and HLA genes, to detect the target miRNA of the two groups of uterine decidua and villi tissue, screening differentially expressed miRNA, and to make mRNA - miRNA integration analysis. Through the above research, it aims to make clear the molecular mechanism of uNK during the occurring of URSA. This topic makes more comprehensive and in-depth studies to the roles that uNK cells play during the occurring of URSA, which lays a foundation for further studying URSA occurrence mechanism and individualized treatment.

原因不明复发性流产 (URSA) 是妇产科常见的并发症，病因复杂。为了探讨妊娠后胚胎和母体相互作用机制，阐明部分URSA发病机理，本课题拟先研究URSA患者和正常孕妇子宫蜕膜NK (uNK) 细胞亚型比例和毒性变化规律，在细胞水平探讨uNK细胞在URSA发生中的作用；在基因、蛋白和mRNA水平上，通过检测两组子宫蜕膜KIRs、绒毛HLA-C、-G和HLA-E，探索其分布规律及KIR/HLA配对规律，进一步探讨uNK细胞在URSA发生中的作用；在此基础上，对目标KIR和HLA基因可能结合的miRNA进行预测，对两组子宫蜕膜和绒毛组织目标miRNA进行检测，筛选出差异表达miRNA，进行mRNA-miRNA整合分析；通过以上研究明确uNK在URSA发生中的分子作用机制。本课题更全面更深入的对uNK细胞在URSA发生中作用进行了研究，为以后进一步的研究URSA发生机制及进行个体化治疗奠定基础。

不明原因复发性流产病因复杂，患者往往经历多次妊娠和多次流产，给患者身心带来极大痛苦，而且可能由此导致家庭不和与婚姻破裂。本课题通过研究子宫NK细胞分类及毒性、子宫蜕膜KIR及绒毛组织HLA基因、分布、表达及调控机制，试图构建uNK细胞杀伤受体及其配体导致不明原因复发性流产母胎免疫紊乱的作用通路。流产≥3次的患者KIR3DL1基因相比对照组明显降低；在KIRAB及BB患者中HLA-C2C2的频率显著高于对照；RSA组纯合HLAC2C2的患者中携带2DS1基因的频率明显高于对照；研究表明免疫治疗对于对汉族RSA患者有效，MLR-Bf是一个可以衡量反复自然流产孕妇体内免疫状态的一种免疫物质，说明免疫因素是导致流产的其中之一原因。本课题共发表SCI收录论文5篇，获得成果奖一项，培养硕士研究生一名。本研究结果有望应用于临床提高对反复自然流产的治疗疗效。