GITRL/GITR分子通过调控MDSCs参与小鼠实验性干燥综合征的机制研究

As a systemic autoimmune disease, primary Sjögren’s syndrome (pSS) is characterised by progressive inflammation and tissue damage of salivary glands and lacrimal glands. Myeloid-derived suppressor cells (MDSCs) is a population of immature myeloid cells with suppressive capability, and its role in autoimmune disease is still controversial. In mouse experimental Sjögren’s syndrome (ESS), we found that the suppressive capacity of these accumulated MDSCs gradually reduced with the progression of the disease, whereas the GITRL expression enhanced in vivo. The in vitro data showed that MDSCs expressed GITR, and the suppressive capacity of MDSCs was down-regulated after GITRL stimulation. Thereafter, we propose the hypothesis: in ESS, the increased GITRL could directly interact with MDSCs and down-regulate the suppressive capacity of the cells, thus aggravating the disease. This project mainly focuses on:(1) the changes of suppressive capacity of different subsets of MDSCs during the development of ESS; (2) the regulation of GITRL on the function of different subsets of MDSCs in vitro and its molecular mechanism; (3) the regulation of GITRL on MDSCs and their subsets in ESS model. This project will further elucidate the role of MDSCs and their subsets in SS, and providing new ideas for the treatment of SS.

原发性干燥综合征（pSS）是一种以进行性炎症和唾液腺、泪腺损伤为特征的自身免疫性疾病。髓源性抑制细胞（MDSCs）是一群具有免疫抑制能力的未成熟髓系细胞，但在自身免疫性疾病中的作用存在争议。我们在小鼠实验性干燥综合征（ESS）模型中发现，随着疾病的进展，聚积的MDSCs免疫抑制能力逐渐降低，而小鼠体内GITRL的表达则逐渐增多；体外研究显示MDSCs表达GITR，GITRL蛋白能够下调MDSCs的免疫抑制能力。因此，我们提出假设：ESS中逐渐升高的GITRL可直接作用于MDSCs，下调体内MDSCs的免疫抑制能力，促使疾病持续加重。本项目主要研究：（1）ESS中MDSCs不同亚群的功能变化；（2）体外GITRL对MDSCs不同亚群的功能调控及分子机制；（3）ESS小鼠体内GITRL对MDSCs及其亚群的功能调控。本项目将进一步阐明MDSCs及其亚群在SS中的作用，为SS的治疗提供新的思路。

原发性干燥综合征（primary Sjögren’s syndrome, pSS）是一种以进行性炎症和唾液腺、泪腺损伤为特征的自身免疫性疾病。髓源性抑制细胞（myeloid derived suppressor cells, MDSCs）是一群具有免疫抑制能力的、未成熟的异质性髓系细胞，包括多核细胞样MDSCs（polymorphonuclear MDSCs, PMN-MDSCs）和单核细胞样MDSCs（monocytic MDSCs, M-MDSCs）。本研究的主要目的是探讨MDSCs在原发性干燥综合征发展过程中的作用。我们首先发现实验性干燥综合征小鼠（experimental Sjögren’s syndrome, ESS）体内MDSCs及其亚群明显升高，且这些升高的MDSCs细胞随着疾病的进程逐渐失去其免疫抑制功能。进一步研究发现，随着疾病的进展，ESS小鼠体内GITRL （The ligand for glucocorticoid-induced TNFR family-related protein, GITRL）显著升高，且体内和体外实验均证实GITRL能够下调MDSCs及其亚群的免疫抑制能力，且阻断GITR/GITRL通路后，MDSCs恢复了其免疫抑制能力并有效延缓疾病的进程。除此之外，我们发现pSS患者体内也出现大量MDSCs，且表达GITR分子。且MDSCs中精氨酸酶的表达水平与患者的疾病活动指数呈负相关。此外，pSS患者血清中GITRL明显上调，且与MDSCs的免疫抑制功能呈负相关。人GITRL蛋白同样能够下调人MDSCs的免疫抑制能力。综上，我们的研究证实了在原发性干燥综合征中上调的GITRL能够抑制MDSCs的免疫抑制能力，进而促进疾病的发生发展。这些数据提示GITRL能够作为pSS治疗的潜在靶点。