Investigation of sex variation in PD-1/pSTAT3/IL-17A signaling in sarcoidosis pathogenesis

项目摘要 结节病是一种病因不明的肉芽肿性疾病，在 临床结果。大约60%的结节病患者会自发地解决他们的 疾病，而其余的受试者经历肺功能的逐渐丧失，从~15- 20%的人最终会死亡。 我们之前曾报道，获得性免疫反应的强度是一个重要的 结节病临床转归的因素。先前的调查表明增加了程序化 结节病患者CD_4~+T细胞死亡-1的表达 进步。我们最近在《科学转化医学》上发表的文章证明了 PD-1+CD4+T细胞IL-6表达增强，可诱导pSTAT3转录， 导致致病细胞因子IL-17A和转化生长因子-β1的表达增加。这些细胞 与人肺成纤维细胞共培养时，可诱导胶原-1的产生。所占比例 女性结节病患者的PD-1+CD4+T细胞显著高于男性。 这些观察结果支持这一假设，即雌激素介导的改变在 PD-1途径/IL-6/pSTAT3信号通路驱动女性在结节病丢失中的优势 肺功能的变化。这项提案将描绘雌激素对Th17细胞的影响 发育是通过PD-1信号通路直接或间接调节的。我们还将 对目前FDA批准的治疗药物的疗效进行体内研究 PD-L1、PD-1、IL-6、pSTAT3和IL-17A在减少胶原生成中的作用。这些分析 将作为概念验证调查，从而为创新的设计奠定基础 肺结节病进展有效治疗方法的临床试验 性。

Project Summary Sarcoidosis is a granulomatous disease of unknown etiology with striking disparities in clinical outcome. Approximately 60% of sarcoidosis patients will spontaneously resolve their disease, while the remaining subjects experience a gradual loss of lung function, from with ~15- 20% ultimately die. We previously reported that the strength of the adaptive immune response is an important factor in sarcoidosis clinical outcome. Prior investigations demonstrate increased Programmed Death-1 (PD-1) expression on CD4+ T cells in sarcoidosis patients experiencing disease progression. Our recent publication in Science Translational Medicine demonstrates that PD-1+CD4+ T cells have augmented IL-6 expression that induces pSTAT3 transcription, leading to increased expression of the pathogenic cytokines, IL-17A and TGF-β1. These cells upon co-culture with human lung fibroblasts induce collagen-1 production. The percentage of PD-1+CD4+ T cells is significantly higher in female sarcoidosis subjects, compared to males. These observations support the hypothesis that estrogen-mediated alteration in PD-1 pathway/IL-6/pSTAT3 signaling drive the female predominance in sarcoidosis loss of lung function. This proposal will delineate if the effects of estrogen on Th17 cell development are directly or indirectly mediated through PD-1 pathway signaling. We will also conduct in vivo investigations of the efficacy of currently FDA-approved therapeutics against PD-L1, PD-1, IL-6, pSTAT3 and IL-17A on reduction of collagen production. These analyses will serve as proof-of-concept investigations, thus laying the foundation for design of innovative clinical trials of effective therapeutics against pulmonary sarcoidosis progression according to sex.