长链非编码RNA NEAT1诱导Th1/Th2细胞免疫失衡在舍格伦综合征发病机制中的作用研究

Sjogren's syndrome (SS) is a typical autoimmune disease, often involving the salivary gland-based exocrine glands. Typical clinical manifestations are severe dry mouth, dry eye and repeated swelling of parotid gland. The pathogenesis is unclear. Patients with SS often suffered Th1 / Th2 cell imbalance which is manifested by increased expression of Th1-type cytokines. The immune system imbalance is closely related to the occurrence and development of the disease. Our previous study found that lncRNA NEAT1 was significantly increased in peripheral blood T lymphocytes of SS patients and positively correlated with the disease course. Further preliminary experiments showed that NEAT1 was significantly increased in the Th1 differentiation of naive T lymphocytes of SS patients, silencing its expression could affect Th1 differentiation function. Bioinformatics analysis showed that it may bind to small nuclear ribonucleoprotein A. The RNA-protein complex can promote the differentiation of Th1 cells by promoting the selective polynucleotide phenomenon in the 3'UTR region of STAT5 gene. Therefore, this project intends to identify the molecular mechanism of Th1 / Th2 cell immune imbalance induced by complex formation of NEAT1 and small nuclear ribonucleoprotein A, which are highly expressed in SS. Aiming to provide the theoretical basis for studying the pathogenesis of the disease and finding new targets for more specific drug therapy Point.

舍格伦综合征（SS）是一种典型的自身免疫性疾病，常累及以唾液腺为主的外分泌腺，临床表现为严重的口干、眼干以及腮腺区反复肿胀，病因尚不明确。SS患者常出现以Th1型细胞因子表达增高功能亢进为表现的Th1/Th2细胞失衡现象，与疾病的发生发展密切相关。课题组前期研究发现lncRNA NEAT1在SS患者外周血T淋巴细胞中显著升高并与疾病病程呈正相关。进一步预初实验发现NEAT1在SS幼稚T淋巴细胞Th1向分化时显著增高，沉默其表达后可影响Th1向分化功能。生物信息学分析结果显示其可能结合小核核糖核蛋白A，通过形成RNA蛋白质复合体促进STAT5基因3'UTR区的可选择性多聚核苷酸现象，进而促进Th1向分化功能。因此，本项目拟通过实验明确SS中高表达的NEAT1与小核核糖核蛋白A形成复合体诱导Th1/Th2细胞免疫失衡的分子机制，为疾病发病机制研究及寻找更具特异性的药物治疗新靶点提供理论基础。

原发性舍格伦综合征（primary Sjogren's syndrome, pSS）是由免疫系统异常攻击外分泌腺导致的自身免疫性疾病，已有研究认为固有免疫异常在疾病发生早期起重要作用，本项目探讨了固有免疫系统中长链非编码RNA（Long non-coding RNA, LncRNA）NEAT1的异常调控在pSS发病机制中所起的作用。研究首先明确了LncRNA NEAT1 在pSS患者的外周血CD4+ T淋巴细胞中表达异常，同时与疾病活动性指标呈相关性。进一步，利用T淋巴细胞系进行体外实验，证实在pSS患者的 CD4+ T 淋巴细胞中异常高表达的 NEAT1 可能通过调控MAPK 通路中的 p-p38 和 p-ERK1/2 来促进下游炎症因子 CXCL8 和TNF-α的表达，从而促进 T 淋巴细胞的异常免疫活化，进而在疾病的发生发展中起重要作用。同时，在pSS患者的临床样本中 ，我们也证实了NEAT1 的表达和 NEAT1 诱导因子（ CXCL8 和TNF-α等）的表达之间存在正相关，进一步验证了上述实验结果。基于以上实验研究结果，本项目初步证实了LncRNA的功能调控异常在舍格伦综合征的发生发展中起重要作用，为SS的发病机制研究提供了新方向，同时期望能够为探索新的靶向治疗提供理论依据和实践基础。