系统性硬化症中IL-35诱导iTr35细胞分化导致Treg/ Th17细胞失衡及纤维化病变的分子机制

Systemic sclerosis (SSc) is a type of autoimmune disease, characterized by immune system abnormalities as well as fibrosis of the skin and internal organs. However, its etiology is not completely understood. T lymphocytes are known to play an important role in the process of the disease. Interleukin(IL)-35 is a novel immune-suppressive cytokine, which can induce naive T cell to differentiate into a regulatory T-cell(Treg) population, called iTr35 that produces mature IL-35 and strongly suppresses inflammation，which positive feedback regulation was formed. Recent studies showing IL-35 was involved in the immunopathogenesis of CTD. Our previous research demonstrated that the increased level of IL-35 in SSc patient’s peripheral blood, the elevated expansion of the Th17 cell population, the changed number and/or defective suppressive function of Treg cells in SSc patients and animal models, which were correlated with the fibrotic lesions. However, whether IL-35 can induce CD4+ T lymphocytes differentiate to iTr35 cell and affect the balance Teff/Treg cell, to suppress immune in SSc patients, are still need to further study. The primary aim of this project is to explore the molecular mechanism how IL-35 induce CD4+ T lymphocytes differentiate to iTr35 cell, and find out the regulatory role of iTr35 on Teff/Treg cell balance and the effect on fibroblast function in patients with SSc. This study would further elucidate the role of IL-35 and iTr35 cells in the pathogenesis of SSc, and provide a valuable information of biological target therapy.

系统性硬化病(SSc)是一种以炎症和纤维化为主的结缔组织病（CTD），T淋巴细胞发挥重要的作用。IL-35是一种免疫抑制因子，能诱导初始T细胞转变成一种强抑制性的调节性T细胞(iTr35)，分泌成熟IL-35发挥强大免疫抑制作用，形成正反馈调节。研究认为IL-35在CTD中发挥了重要作用。我们前期研究显示，SSc患者及小鼠模型外周血和肺、皮肤组织中IL-35表达增高，Treg细胞功能异常，Th17细胞数量增加，与纤维化病变程度相关。SSc患者体内，IL-35是否可诱导CD4+T细胞分化成iTr35细胞，调节Treg/Th17细胞的平衡，发挥免疫抑制功能有待于进一步研究。本项目采用体外细胞培养、分子生物学和小鼠模型等方法，研究SSc中IL-35诱导CD4+T淋巴细胞分化为iTr35的分子机制，及其对Treg/Th17细胞失衡和成纤维细胞功能的影响，阐明IL-35和iTr35在SSc中的作用。

系统性硬化症(SSc)是一种以皮肤和内脏器官纤维化、免疫异常和血管病变为特征的结缔组织病(CTD)。IL-35是一种免疫抑制因子，能诱导初始T细胞转变成调节性T细胞(iTr35)，分泌成熟IL-35，调节Th17/Treg细胞的平衡，发挥强大免疫抑制作用，前期研究显示IL-35参与SSc的发病机制。本研究主要探讨IL-35及相关受体、iTr35和Treg/Th17细胞在SSc患者体内的表达，IL-35诱导CD4+T细胞分化为iTr35细胞，导致Treg/Th17细胞失衡的机制以及对FB细胞的作用。研究结果发现SSc患者外周血IL-35、iTr35细胞及其受体表达增高，iTr35在SSc患者皮肤中表达减少，IL-35抑制CD4+T细胞的增殖，呈剂量依赖性，诱导CD4+T细胞分化为Treg细胞，可能通过STAT1信号通道发挥作用，IL-35抑制HSF细胞增殖、α-SMA和COL-1蛋白表达发挥抑制炎症和纤维化的作用，但阻断IL-35后胶原表达无明显下降，IL-35中的P35亚基可能通过调节Th17细胞，上调Th17/Treg细胞比例在SSc小鼠模型早期发挥促炎作用。拮抗P35亚基后，SSc小鼠模型纤维化加重，提示IL-35可能可以通过P35亚基起抑制纤维化作用。本项目锻炼了风湿免疫科科研队伍，培养研究生3名，共发表论文6篇，其中SCI论文5篇，国内核心期刊1篇。研究结果得到国内外同行的认可，引用次数10余次，获得国内和国际会议上壁报和发言的机会。我们提出IL-35可抑制SSc炎症和纤维化纤维化病变，为有望在不久的将来IL-35成为SSc免疫治疗的新靶点提供坚实的理论基础，具有不可估量的潜在应用价值。