IL-23在系统性红斑狼疮发病中作用的研究

发布时间：2018-06-29 12:45

本文选题：系统性红斑狼疮 + 白介素-23　；参考：《吉林大学》2015年博士论文

【摘要】：系统性红斑狼疮（Systemic Lupus Erythematosus，SLE）是自身免疫介导的、以免疫性炎症为突出表现的弥漫性结缔组织病。狼疮肾炎（Lupus Nephritis，LN）是SLE最严重的并发症之一，也是SLE患者最主要的死因之一，早期诊断和规范的治疗是提高LN预后的关键所在，但由于缺少对SLE及LN的发病机制的深入了解，所以目前对SLE以及LN的治疗仍为控制病情进展，因此对SLE以及LN具体的致病机制的探讨迫在眉睫。已有研究证实辅助性T细胞17（Th17cell）通过分泌白介素-17（IL-17）等细胞因子在SLE及LN的发生发展中发挥非常重要的作用，而Th17细胞的增殖与分化受到白介素-23（IL-23）的严格调控。IL-23是一种异二聚体组成的细胞因子，多种组织和细胞均可分泌IL-23, SLE患者体内的单核巨噬细胞可分泌大量的IL-23，IL-23通过与Th17细胞表面的受体结合促进IL-17的大量分泌，从而使SLE进行性加重。本研究应用RT-PCR等技术检测了158例SLE患者和60例健康对照组外周血IL-23和IL-17mRNA的水平，并分析了外周血IL-23mRNA和IL-17mRNA/IL-23mRNA比值的变化与SLE发生发展的关系；进一步明确SLE患者外周血IL-23mRNA和IL-23与LN的发病及严重程度有关系。结果显示，与健康对照组相比，SLE患者的外周血IL-23mRNA表达水平以及IL-17mRNA/IL-23mRNA的比值均明显上升，差异有统计学意义（P＜0.001）；而且SLE患者的外周血IL-23mRNA表达水平上升与性别、SLE疾病活动度无关；与健康对照组相比，LN患者的外周血IL-23mRNA和蛋白表达水平上调更加明显，并且差异有统计学意义，（P＜0.001）。对LN患者IL-23mRNA的表达水平与RenalSLEDAI评分做了相关性分析，二者呈明显正相关（r=0.9210，P0.0001）。与健康对照组及非LN组比较，LN组外周血IL-23的表达水平明显升高，差异有统计学意义（P＜0.001）。本研究的创新之处在于：第一，本研究首次从分子水平阐明IL-23mRNA表达水平以及IL-17mRNA/IL-23mRNA的比值与SLE的发病密切相关，为SLE发病机理的研究提供新的证据；第二，本研究从分子水平阐明IL-23mRNA水平与SLE的发病有关，与SLE的疾病活动性没有直接关系；第三，本研究首次证实，外周血IL-23mRNA水平与LN的关系更为密切，为LN治疗提供新的靶点。总之，，本研究为SLE发病机制的研究提供新的证据，为LN的治疗提供新的靶点。
[Abstract]:Systemic lupus erythematosus (SLE) is an autoimmune mediated diffuse connective tissue disease characterized by immune inflammation. Lupus nephritis (LN) is one of the most serious complications of SLE and one of the most important cause of death in SLE patients. Early diagnosis and standardized treatment are the key to improve the prognosis of LN. However, there is a lack of in-depth understanding of the pathogenesis of SLE and LN. So at present, the treatment of SLE and LN is still to control the progress of the disease, so it is urgent to explore the specific pathogenesis of SLE and LN. It has been proved that T helper cell 17 (Th17cell) plays a very important role in the pathogenesis and development of SLE and LN by secreting cytokines such as interleukin-17 (IL-17). The proliferation and differentiation of Th17 cells are strictly regulated by interleukin-23 (IL-23). IL-23 is a cytokine composed of heterodimer. A variety of tissues and cells can secrete IL-23. Mononuclear macrophages in SLE patients can secrete a large amount of IL-23 and IL-23 can promote the secretion of IL-17 by binding to the receptors on the surface of Th17 cells. In this study, the levels of IL-23 and IL-17 mRNA in peripheral blood of 158 SLE patients and 60 healthy controls were detected by RT-PCR, and the relationship between the ratio of IL-23 mRNA and IL-17mRNA-IL-23 mRNA in peripheral blood and the occurrence and development of SLE was analyzed. To further clarify the relationship between IL-23 mRNA and IL-23 in peripheral blood of SLE patients and the pathogenesis and severity of LN. The results showed that the expression level of IL-23 mRNA and the ratio of IL-17 mRNA-IL-23 mRNA in peripheral blood of SLE patients were significantly higher than those in healthy controls (P < 0.001), and the increase of IL-23 mRNA expression in peripheral blood was not related to the disease activity of SLE patients. The expression of IL-23 mRNA and protein in peripheral blood of LN patients was significantly higher than that of healthy controls (P < 0.001). The expression of IL-23 mRNA was positively correlated with the Renal SLEDAI score in LN patients (r = 0.9210, P 0.0001). The expression of IL-23 in peripheral blood of LN group was significantly higher than that of healthy control group and non-LN group (P < 0.001). The innovations of this study are as follows: firstly, the expression level of IL-23 mRNA and the ratio of IL-17mRNA-IL-23 mRNA to the pathogenesis of SLE were elucidated for the first time in this study, which provided new evidence for the study of pathogenesis of SLE; second, the expression level of IL-23 mRNA and the ratio of IL-17mRNA-IL-23 mRNA were closely related to the pathogenesis of SLE. In this study, the molecular level of IL-23 mRNA was demonstrated to be related to the pathogenesis of SLE, but not to the disease activity of SLE. Third, it was first confirmed that the level of IL-23 mRNA in peripheral blood was more closely related to LN, which provided a new target for the treatment of LN. In conclusion, this study provides new evidence for the pathogenesis of SLE and a new target for the treatment of LN.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R593.241

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