Th17细胞诱导血管平滑肌细胞活化和表型转化在系统性硬皮病血管病发病中的作用和机制研究

Systemic scleroderma（SSc）is an autoimmune disease. Vasculopathy is its main pathologic manifestation, characterized by vascular intima and media thickening, eventually leading to vascular stenosis. Vasculopathy occurs in earliest stage and exists throughout the course of the disease. It is the pathologic basis of main clinical manifestation in SSc patients. However, the pathogenesis of SSc-related vasculopathy is still unknown. In recent years, our studies have shown an increase of Th17 cells around the vessels and in peripheral blood of SSc patients. Th17 cell is closely related to vascular endothelial cells-mediated vasculitis. The expression of IL-17A receptor is increased on the vascular smooth muscle cells in SSc patients. Based on the pathologic characterization of vasculopathy and our previous studies, we supposed that the proliferation and vascular smooth muscle cells migration from media to intima induced by Th17 cells as well as its phenotype transformation from contraction type to synthetic type, which results in over-production of collagen, may play key roles in the pathogenesis of SSc-related vasculopathy. First, we plan to study the role and mechanism of Th17 cells in the activation and phenotype transformation of vascular smooth muscle cells, and then the role and mechanism of Th17 cells-mediated vascular endothelial cells transformation to vascular smooth muscle cells. Finally, animal model of SSc will be used to demonstrate the above hypothesis. Anti-IL-17A neutralized antibody will be used to treat SSc murine model. This study can further assist us to understand the pathogenesis of SSc-related vasculopathy, and help to find therapeutic targets for the treatment of SSc.

系统性硬皮病（SSc）是一种自身免疫病，血管病是其主要组织病理表现，特点是血管内膜、中膜增厚并管腔狭窄，早期出现并贯穿疾病始终，是该病主要病变的病理基础，迄今病因不明。我们前期观察到SSc患者血管壁和外周血有异常活化的Th17细胞，该细胞与血管内皮细胞介导的血管炎有关，还观察到SSc患者皮肤血管平滑肌细胞IL-17A受体表达增强。基于SSc血管病病理特点和前期工作基础，我们推测Th17细胞介导的血管平滑肌细胞增殖、从中膜向内膜迁移、由收缩型向合成型表型转化使胶原合成增加，可能在该病血管病发病中起重要作用。本课题拟主要研究Th17细胞对SSc患者血管平滑肌细胞功能活化和表型转化的作用和机制；其次研究Th17细胞诱导血管内皮细胞向血管平滑肌细胞表型转化的作用和机制；并通过SSc动物模型在体验证上述作用，注射抗IL-17A中和抗体干预治疗。该研究可深入了解SSc血管病发病机制，为治疗提供新靶点。

系统性硬皮病（SSc）是一种自身免疫病，血管病是其主要组织病理表现，早期出现，并贯穿疾病始终,但其发生机制尚不清楚。本研究以SSc患者血管病为切入点，以SSc患者皮肤血管平滑肌细胞为靶细胞，研究了SSc患者外周血中Th17细胞分泌的主要细胞因子IL-17A对皮肤血管平滑肌细胞功能活化的影响，阐述了经由IL-17A刺激后SSc患者皮肤血管平滑肌细胞增殖、胶原合成和分泌、迁移能力的变化情况；利用慢病毒载体、重组质粒和shRNA技术成功构建IL-17RA表达缺陷的SSc患者皮肤血管平滑肌细胞模型，进一步验证了IL-17A对平滑肌细胞功能活化的影响；通过体外实验初步探讨了丹参的主要活性成分丹参酮IIA对于IL-17A介导的SSc患者皮肤血管平滑肌细胞功能活化的影响。通过SSc动物模型在体验证上述作用，注射抗IL-17A中和抗体干预治疗。同时在SSc患者皮肤组织血管中验证了内皮间质化的存在，证实了缺氧诱导因子HIF1α在皮肤血管组织的阳性表达，并在SSc患者皮肤血管中进一步验证了两者之间的相关性。通过两种不同类型的博来霉素-硬皮病小鼠模型，在体进一步验证了该结果。本研究提示Th17细胞参与诱导了血管平滑肌细胞的活化和表型转化，并在SSc患者血管病发病的机制中起重要作用，低氧参与了SSc患者血管病的发病，且在血管内皮间质转化中起重要作用。该研究对SSc血管病发病机制进行了深入研究，对SSc的临床治疗有重要参考价值。