高迁移率族蛋白1氧化还原失衡在系统性红斑狼疮发生发展中的作用机制研究

抗原抗体复合物结合补体C1q启动补体经典激活途径清除外来抗原和自身衰老细胞是保持机体免疫平衡的重要机制。文献和前期研究结果表明系统性红斑狼疮（SLE）患者体内循环复合物中HMGB1蛋白是引起异常自身免疫反应，妨碍衰老细胞正常清除的关键。而HMGB1蛋白细胞定位和免疫功能和其半胱氨酸残基氧化状态有关，据此提出HMGB1蛋白被轻度氧化（23，45位半胱氨酸残基被氧化形成二硫键，106位半胱氨酸残基仍为还原态）从而进入胞浆和胞外，进一步结合到免疫复合物上阻止了免疫复合物的清除，造成免疫复合物沉积和机体自身免疫反应，导致SLE的发生发展的假说。本项目拟通过构建HMGB1基因第四外显子21位碱基G→C点突变小鼠（C106S）建立SLE动物模型，并采用激光共聚焦、流式技术来探讨HMGB1蛋白氧化修饰状态和其免疫功能的关系，以及在抗核抗体和SLE发生发展中的作用，评估HMGB1作为SLE治疗靶点的潜力。

Antigen-antibody complex binds to C1q complement and starts the classical activation pathway to clear foreign antigens and/or senescent cells is an important mechanism to maintain immune balance. Literature and preliminary results indicate that HMGB1 is contained in systemic lupus erythematosus (SLE) patients' circulating immune complexes and cause abnormal autoimmune response, impede the normal clearance of senescent cells. Because HMGB1 protein cellular localization and immune function are determined by the redox station of its cysteine residues , we hypothesize that the HMGB1 protein is mildly oxidized ( 23,45 cysteine residues were oxidized to form a disulfide bond, while the 106 cysteine residue remain reduced) and then enter the cytoplasm and extracellular further bound to immune complexes, thus prevents the clearance of immune complexes, resulting in the deposition of immune complexes and autoimmune response , causing in the occurrence and development of SLE. This project intends to induce G →C mutation on exon 4 21st bp of HMGB1 in mice to construct a HMGB1C106S gene mutation mice to establish the SLE animal model, and further using confocal microscope, flow cytometry technologies to explore the relationship between HMGB1 protein oxidative modification status and its immune functions, as well as the role of HMGB1 in the development of anti-nuclear antibodies and the pathogenesis of SLE, and assess the potentiality of HMGB1 as a therapeutic target of SLE.