KDM4B-CD226轴调节Th17.1细胞分化在重症肌无力发病机制中的作用

Th17细胞在重症肌无力(MG)发病中有重要作用，Th17.1细胞（IFN-γ+IL-17+）是Th17中主要的致病亚群且与自身抗体产生有关，但其分化机制仍不清楚。我们前期研究发现：MG患者及动物模型中均存在Th17.1细胞比例异常上调；转录组测序提示Th17.1细胞分化可能受组蛋白去甲基化酶KDM4B及共刺激分子CD226调节；体外实验证实抑制KDM4B、CD226可使Th17.1细胞分化减少，且KDM4B可调节CD226的表达，由此提出假说：KDM4B-CD226轴可促进Th17.1细胞分化，介导致病性自身抗体产生而参与MG发病。本项目拟进一步分析Th17.1比例、KDM4B及CD226表达水平与MG的临床相关性，阐明KDM4B与CD226的分子互作模式及其调节Th17.1细胞分化、诱导致病抗体产生的作用机制，评估体内干预KDM4B-CD226轴对MG动物的治疗作用，探索新的治疗靶点。

Th17 cells play an important role in the pathogenesis of myasthenia gravis (MG), of which the Th17.1 cells (IFN-γ+IL-17+) are the major pathogenic subgroup. However, the differentiation mechanism of Th17.1 is still unclear. Our previous studies found that the proportion of Th17.1 cells was abnormally upregulated in both MG patients and experimental autoimmune myasthenia gravis (EAMG) rats. After analysis of transcriptional profiling data, we demonstrated that differentiation of Th17.1 cells might be induced by histone demethylase KDM4B and costimulatory molecule CD226. Inhibiting the function of KDM4B or CD226 could reduce the differentiation of Th17.1 cells, and KDM4B could regulate the expression of CD226 in vitro. Based on our prior studies, we hypothesized that the KDM4B-CD226 axis was involved in the pathogenesis of MG via promoting differentiation of Th17.1 and subsequent expression of autoimmune antibody. We aim to analyze the clinical relevance of Th17.1 cells and expression levels of KDM4B and CD226 with MG, to investigate the underlying mechanisms of molecular interaction between KDM4B and CD226, to clarify its mechanism of inducing Th17.1 cell differentiation and role in producing pathogenic antibodies. Furthermore, we will evaluate the therapeutic effect of targeting KDM4B-CD226 signal axis in MG animals in vivo, in order to provide evidence for exploring new therapeutic targets of MG.