糖酵解异常促进B细胞活化及分化参与IgG4相关性疾病发病的机制研究

IgG4相关性疾病（IgG4-RD）是以受累器官肿瘤样肿大、血清IgG4升高、组织中大量IgG4阳性浆细胞浸润为特征的慢性炎症伴纤维化的疾病。B细胞异常参与IgG4-RD发病，但其活化、分化机制尚不清楚。我们前期进行血浆代谢组学及颌下腺蛋白组学研究提示IgG4-RD糖酵解通路异常活跃，进一步B细胞糖酵解检测，也证实IgG4-RD患者B细胞糖酵解明显升高。因此我们提出研究假设：糖酵解异常促进B细胞活化及分化参与IgG4-RD发病。本课题拟探究糖酵解异常参与B细胞活化及分化机制。我们将通过体外实验阐明IgG4-RD患者B细胞糖酵解异常以及与疾病的相关性，探讨糖酵解参与B细胞活化及分化的机制，并进一步通过动物模型揭示糖酵解异常对B细胞影响具体机制，最后探究干预糖酵解是否有效减轻模型鼠的器官损伤。该研究首次从代谢层面探究IgG4-RD发病机制，并为后续治疗提供可靠的理论依据。

IgG4 related disease (IgG4-RD) is a chronic inflammatory and fibrous disease characterized by tumefactive swelling of involved organs, elevation of serum IgG4, dense infiltration of lymph cells and IgG4 positive plasma cells. B cells participated in pathogenesis of IgG4-RD, but the mechanism of B cell activation and differentiation was not well delineated. Our previous studies of plasma metabolomics and submandibular gland proteomics indicated that glycolytic pathway is abnormally activated in IgG4-RD. In addition, glycolysis in B cells of IgG4-RD was also elevated in IgG4-RD. Therefore, we put forward the research hypothesis: abnormal glycolysis promotes B cell activation and differentiation in the pathogenesis of IgG4-RD. This study aims to investigate the role of abnormal glycolysis in B cell activation and differentiation of IgG4-RD. In vitro and in vivo experiments will be conducted to clarify mechanism of abnormal glycolysis on B cell activation, differentiation and correlation with clinical parameters in IgG4-RD and mouse models. Finally, to explore whether intervention of glycolysis can effectively reduce organ damage in mouse models. This study is first to demonstrate the pathogenesis of IgG4-RD in metabolic level and will provide therapeutic strategy in subsequent treatment.