HLA_DR-TCR诱导NFκB信号通路介导CD4+T细胞活化在抗NMDAR脑炎中的机制研究

抗N-甲基-D-天冬氨酸受体(NMDAR)脑炎是一种罕见的神经免疫疾病。我们发现HLA_DRB1*16:02是该病的易感基因，且预测NMDAR亚基NR1抗原表位FRAITSTLA紧密结合HLA II类分子DRB1*16:02（J Neurol Neurosurg Psychiatry 2019）。提示CD4+T细胞参与抗NMDAR脑炎发病，但其致病机制不明。预实验中我们利用HLA_DRB1*16:02+患者PBMC可诱导人源化抗NMDAR脑炎小鼠模型，而敲除CD4+T细胞后却不能。基于本课题研究基础，我们提出假说：HLA_DR-TCR诱导NFκB信号通路活化CD4+T细胞，进而参与抗NMDAR脑炎发病。为论证该假说，我们拟进一步进行体内实验（基于人源化抗NMDAR脑炎小鼠模型）、体外实验（基于细胞共培养系统），以揭示CD4+T细胞在抗NMDAR脑炎的作用分子机制，为该病精准治疗提供新靶点。

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is rare neuroimmunological disease. In our recent paper, we found that HLA_DRB1*16:02 is associated with the susceptibility to anti-NMDAR encephalitis, and bioinformatic analysis suggested a close relationship between the epitope FRAITSTLA of NMDAR subunit NR1 and the HLA class II molecule DRB1*16:02. (J Neurol Neurosurg Psychiatry. 2019;90:652-8. PMID:30636700). The results henceforth showed that CD4+T cells are involved in anti-NMDAR encephalitis. However, the pathomechanism of CD4+T cells in anti-NMDAR encephalitis remains unclear. In our preliminary experiments, a novel humanized mouse model for anti-NMDAR encephalitis was established by the transfer of PBMC from HLA_DRB1*16:02+ anti-NMDAR encephalitis patients into the NOD/Prkdcem26IL2Rgem26/Gpt (NCG) immunodeficient mice, while the mouse model could be not successfully established by the transfer of CD4+T cell-depleted PBMC from the same patients with anti-NMDAR encephalitis. According to our previous research results, we hypothesize that CD4+T cell activation is mediated by HLA_DR-TCR-induced NFκB signaling pathway in anti-NMDAR encephalitis. To prove our hypothesis, we will further study the role of CD4+T cells in anti-NMDAR encephalitis by performing the experiment in vivo which was based on a humanized anti-NMDAR encephalitis mouse model, and the experiment in vitro which was based on CD4+T cells and DC cells co-incubation. This study will provide insights into the pathomechanism of CD4+T cells in anti-NMDAR encephalitis, and lay an important foundation for future treatment targets for anti-NMDAR encephalitis.