EB病毒BZLF1和EBNA1蛋白调控宿主TCR基因重排在机体丧失自身免疫耐受的机制

EB病毒（EBV）参与多种自身免疫性疾病的发生发展，但其确切机制尚未阐明。我们前期发现自身免疫性疾病患者（包括SLE，RA，T1D，PBC）和EBV感染所致的传单（IM）患者的T细胞受体（TCR）CDR3区段异常短。短CDR3与MHC-抗原肽结合的亲和力更高。且文献报道EBV的BZLF1和EBNA1基因与宿主的Ku80和RAG基因（TCR重排相关）相互作用。我们推测：EBV通过BZLF1和EBNA1基因调控宿主的TCR基因重排，产生异常短的CDR3，以致机体免疫功能紊乱，丧失自身免疫耐受。本研究拟在iPS细胞和小鼠中论证BZLF1和EBNA1基因与短CDR3分子的相关性，采用IR-seq和RNA-seq技术研究EBV调控TCR重排的机制，分析BZLF1/EBNA1双转基因小鼠的免疫功能及SLE易感性，从短CDR3分子这个新视角揭示EBV参与自身免疫性疾病的机制，为其预防和治疗提供新思路。

Epstein-Barr virus (EBV) is involved in the occurrence and development of many autoimmune diseases, but its exact mechanism has not been clarified. We previously found that the CDR3 region of T cell receptor (TCR) was abnormally short in patients with autoimmune diseases (including SLE, RA, T1D, PBC) and patients with EBV induced infecfious mononucleosis (IM). The shorter CDR3 molecule has higher affinity for MHC antigen peptide. It has been reported that EBV' BZLF1 and EBNA1 genes can interact with the Ku80 and RAG genes (TCR rearrangement related) of the host. We speculate that EBV regulates host' TCR gene rearrangement through BZLF1 and EBNA1 genes, and produces abnormally short CDR3 molecules, resulting in immune dysfunction and loss of autoimmune tolerance. In this study, we will demonstrate the correlation between BZLF1/EBNA1 genes and short CDR3 molecules in iPS cells and mouse, study the mechanism of EBV regulating TCR gene rearrangement by using Immune Repertoire sequencing (IR-seq) and RNA sequencing (RNA-seq), and analyze the immune function and SLE susceptibility of BZLF1/EBNA1 double transgenic mice, to study the mechanism of EBV in autoimmune diseases from the perspective of short CDR3 molecules, and to provide new ideas for its prevention and treatment.