γδT细胞及TLR通路在SLE易发感染中的作用研究

Systemic lupus erythematosus(SLE) patients are susceptible to infections, and infections represent a chief cause of mortality in these patients. γδT cells have a profound role in human immunity against infections. Reduced peripheral γδ T cell quantity，impaired proliferation and increased apoptosis were found in SLE patients. Our previous studies revealed the abnormal activation of TLR and p-p65 in γδ T cells of SLE patients. High infection vulnerability and poor prognosis were related to the reduced γδT cell quantity. Upon this, we proposed the hypothesis that the overactive TLR/NF-κB pathway of peripheral γδT cells in SLE patients could lead to impaired proliferation, elevated apoptosis and reduced γδT cell quantity which contribute to raised infection risk in SLE patients. To test our hypothesis, we conducted following experiments: 1) We analyzed the relationship between the abormal expression of TLR/ NF-κB pathway in γδT cells and the unusual proliferation as well as apoptosis of the cells in SLE patients. 2)On this basis, we imitate infections in lupus model mice，then evaluate incidence and severity of infections as well as the local and circulating γδT cells and their TLR pathway in both groups，further verify the role of γδT cells in susceptibility to infections via TLR in SLE patients. This project will further clarify the internal mechanism of high infection vulnerability in SLE patients and will also provide a theoretical basis and data support for the infection control in SLE patients.

SLE患者是感染易发人群，且感染是SLE重要死因。γδT细胞在抗感染中发挥重要作用。SLE患者外周血γδT细胞数量下降、增殖受限、凋亡增加。预实验提示，SLE患者γδT细胞TLR及p-p65表达增高，其数目下降与SLE患者易发感染及预后不佳相关。我们提出假说：SLE患者外周血中γδT细胞TLR/NF-κB信号通路活化，导致该细胞增殖凋亡异常、数量减少及相关功能异常，与SLE患者易发感染相关。课题组将首先分析SLE患者外周血γδT细胞TLR/ NF-κB通路在γδT细胞数目降低及其增殖凋亡异常中的作用；接着模拟动物感染，观察狼疮鼠及B6鼠感染发生率及感染严重程度，同时评估局部及循环中γδT细胞数量、功能及其TLR通路状态，进一步验证γδT细胞在SLE易发感染中的作用机制。本研究将进一步阐明SLE患者易发感染的内在机制，为SLE患者感染控制提供理论依据和数据支持。

系统性红斑狼疮（SLE）是一种淋巴细胞失衡、多系统受累的自身免疫性疾病。SLE患者是感染易发人群，且感染是SLE重要死因。γδT细胞在抗感染中发挥重要作用。我们先前的研究证实SLE患者外周血γδT细胞数量下降、增殖受限、凋亡增加。本研究首先通过临床观察随访证实淋巴细胞失衡（包括γδT细胞）在合并各型感染（包括细菌、病毒等）的SLE患者中的重要作用，并探讨其对合并感染的SLE患者短期预后的预测作用。接着证实合并感染（主要为细菌感染）SLE患者外周血中γδT细胞数量及比例显著减少。进一步研究证实SLE患者外周血γδT细胞线粒体活性氧（ROS）表达增高，TLR9/NF-κB 信号通路异常活化，凋亡相关蛋白表达异常，体外增殖受限。TLR9激动剂（CpG ODN）体外刺激增加γδT细胞ROS表达，激活NF-κB 信号通路，参与其凋亡增加、增殖受限。Meta分析证实规律服用羟氯喹（hydroxychloroquine，HCQ）（可抑制TLR9）是SLE患者并发感染的保护因素。我们长期随访研究中发现，规律服用HCQ的SLE患者体内γδT细胞比例增加，TLR9表达减少。在本项目执行过程中，已发表相关的SCI文章6篇；国内核心期刊文章1篇。通过上述研究，阐明SLE患者易发感染的内在机制，为SLE患者感染控制提供理论依据和数据支持。