病毒蛋白EBNA2激活Th17细胞并诱发多发性硬化复发进展的机制和治疗策略

多发性硬化（MS）是全世界中青年人群致残率最高的疾病，目前没有治愈药物。频繁复发是疾病的关键特征，但目前没有针对复发诱因的治疗策略。.既往JAMA等临床研究提示EB病毒蛋白EBNA2水平与MS频繁复发显著相关，但BNA2是否能直接促进MS复发进展尚缺乏报道，其研究瓶颈在于：MS的经典疾病小鼠模型对EB病毒抵抗，难以在模型中表达EBNA2。为突破此限制，申请人构建了EBNA2过表达工具小鼠。.申请人近期对这种新型EBNA2小鼠进行研究，兴奋的发现EBNA2过表达确实能够引起Th17升高和疾病发生发展，这与MS复发时的临床表型是非常相符的。申请人通过质谱筛选和体外研究，进一步发现EBNA2能够通过与ASK1结合，促进Th17炎性因子分泌。基于此，本研究将探索：EBNA2促进MS疾病复发进展的作用、免疫机制和新型干预策略，为开发针对MS复发诱因的新疗法提供线索。

Multiple Sclerosis (MS) is the most common cause of disability in young adults and has no cure. One of the hallmark of MS is the presence of frequent relapse. For now, none of any strategies have been established to target the factor that potentially triggers the relapse of the MS..Previous publications in JAMA et al have suggested that the loading level of EB virus derived toxic factor EBNA2 was tightly associated with the annual disease relapse. However, whether EBNA2 is capable of promoting the development still lacks direct evidence and has yet to be determined. One of the greatest limitation for studying EBNA2 in MS is that the normally used MS model resisted to EB infection, which leads to the tremendous difficulty in inducing the EBNA2 expression in EAE model. To overcome this issue, we generated a transgenic mice strain with EBNA2 flapped with flox allowing it for conditional overexpression in target cell. .Based on this novel EBNA2 transgenic mouse, we found that specific overexpression of EBNA2 in T cell is sufficient to trigger Th17 up-regulation and EAE disease progression, which is very consistent with the phenomena of MS relapse. Moreover, we applied the MS/MS screening and cell-based in vitro experiments and determined the direct a previous undefined events that EBNA2 directly bond with ASK1. In addition, EBNA2 overexpression evoked the Th17 activation and elevation of associated pro-inflammatory cytokines. Therefore, we aimed to explore the function of EBNA1 on disease progression and relapse, and reveal the key mechanism as well as determine the therapeutic strategy. The results will provide potential key evidences for development of novel strategy for management of MS relapse.