Th17/Treg失衡在原发性卵巢功能不全发生中的作用及其机制研究

Primary ovarian insufficiency (POI) is one of the most common endocrine disorders responsible for female infertility and sterility. Currently neither reliable indicator for prediction nor effective treatment for fertility exists. Therefore, it is of great importance for etiology research to identify POI patients at high risk. POI is highly heterogeneous in etiology and abnormal cellular immunity might contribute to its pathogenesis. However, the mechanism remains elusive. Our preliminary data revealed imbalance of Th17/Treg with increased pro-inflammatory Th17 cells and IL-17A, and decreased anti-inflammatory Tregs and TGF-β1 in POI patients. The increase of IL-17 induced by Th17/Treg imbalance might exert pro-inflammatory and ovarian destructive effect though NF-κB pathway. In current project, we aim to explore the phenotype of Th17/Treg imbalance and corresponding cytokine milieu in PBMC and ovarian microenvironment in POI patients, to elucidate the mechanism of IL-17/IL-17 receptors signaling pathway on ovarian function both in vivo and in vitro. The results will be helpful for POI clinical diagnosis and interference, and provide new clues to autoimmune etiology and pathogenesis of POI.

原发性卵巢功能不全（POI）是导致女性不孕不育的常见妇科内分泌疾病。目前尚无准确预测指标和有效的治疗手段，病因研究以识别高风险人群尤为必要。POI病因高度异质性，细胞免疫异常可能参与致病，但具体机制尚不明确。我们前期研究发现POI患者外周血Th17和促炎性细胞因子IL-17A升高，Treg和TGF-β1降低，提示POI患者存在Th17/Treg失衡；据此我们推测Th17/Treg失衡导致的IL-17/IL-17Rs信号通路异常可能参与POI的发生。本项目拟从全身性及卵巢局部微环境两方面明确POI患者Th17/Treg失衡的细胞表型、细胞因子异常及调节通路异常，通过卵巢炎动物模型和体外培养系统阐明Th17/Treg失衡、IL-17/IL-17Rs信号转导通路异常与POI致病的相关性及其作用机制，为自身免疫性POI的临床诊断和干预提供依据，为POI免疫学病因探讨及机制研究提供线索。

原发性卵巢功能不全（POI）是导致女性不孕不育的常见妇科内分泌疾病。目前尚无准确预测指标和有效的治疗手段，病因研究以识别高风险人群尤为必要。POI病因高度异质性，细胞免疫异常可能参与致病，但具体机制尚不明确。本项目对POI患者异常淋巴细胞亚群及炎性细胞因子的筛选和验证，从体外细胞实验和体内小鼠模型首次发现Th1/Treg失衡及高促炎性细胞因子通过影响颗粒细胞功能继而导致POI发生。对生化异常期POI患者进行卵泡液和血清多种细胞因子检测，发现卵泡液中存在异常升高的趋化因子及生长因子，且与卵巢储备降低明显相关，为探究免疫性POI疾病的发生和进展提供依据。在大样本POI病例中进行自身免疫抗体检测，发现抗肾上腺皮质抗体AAA的阳性率明显增高，提示自身免疫异常参与了POI发病，AAA可以作为预测和诊断卵巢自身免疫异常的标记物。完成大样本甲状腺自身免疫与卵巢储备的相关性分析，发现单纯甲状腺自身免疫异常、但甲功正常对女性卵巢储备并无明显影响，为甲状腺自身免疫异常女性的卵巢保护以及干预策略的制定提供了临床证据。首次对大规模POI病例进行病因分类及临床特征分析，对致病基因及其机制进行总结阐述，发现不同病因的POI患者临床表型有显著差异，为临床POI患者的病因诊断、生育指导和遗传咨询提供重要参考和依据。因此，本研究对POI免疫学病因进行了初步而系统地探讨，为自身免疫性POI的临床诊断和干预提供依据，为POI免疫学病因探讨及机制研究提供线索。