Role of EBNA-1 in Eliciting Anti-dsDNA Antibodies

系统性红斑狼疮（SLE）是一种慢性自身免疫性疾病，其特征是产生 核糖核蛋白和双链DNA（dsDNA）的抗核抗体。约150万 美国人受这种疾病的影响，大多数是妇女。SLE的病因尚不清楚，但 几种病毒，特别是EB病毒（EBV）已经被牵涉。有所增加 SLE患者中观察到的EBV感染频率与正常个体相比。爱泼斯坦-巴尔核 抗原-1（EBNA-1）是参与病毒潜伏期的主要抗原，其含有病毒DNA的结合位点， 以及染色体。我们先前证明，表达EBNA-1的小鼠产生抗体， 双链DNA本提案的主要目的是确定EBNA-1暴露导致 抗dsDNA抗体的产生以及这些抗dsDNA抗体是否是致病的， 存款在肾脏。我们还将确定EBNA-1是否必须与真核DNA复合， 以引发抗DNA应答或抗EBNA-1抗体是否与dsDNA交叉反应。最后我们 将讨论是否存在对EBNA-1的反应性和抗dsDNA抗体的产生的菌株特异性差异 抗体，如果这是由TH 1或TH 2细胞介导的。

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by the production of antinuclear antibodies to ribonucleoproteins and double-stranded DNA (dsDNA). Approximately 1.5 million Americans are affected by this illness, the majority being women. The etiology of SLE is unknown, but several viruses in particular the Epstein-Barr virus (EBV) have been implicated. There is an increase in the frequency of EBV infection observed in SLE patients compared to normal individuals. Epstein-Barr Nuclear Antigen-1 (EBNA-1) is a major antigen involved in viral latency that contains binding sites for viral DNA as well as chromosomes. We previously demonstrated that mice expressing EBNA-1 develop antibodies to dsDNA. The major objective of this proposal is to define the mechanism by which EBNA-1 exposure leads to the production of anti-dsDNA antibodies and whether these anti-dsDNA antibodies are pathogenic and deposit in the kidney. We will also determine whether or not EBNA-1 must complex with eukaryotic DNA in order to elicit an anti-DNA response or whether anti-EBNA-1 antibodies cross-react with dsDNA. Finally, we will address if there are strain specific differences in responsiveness to EBNA-1 and the development of antidsDNA antibodies and if this is mediated by TH1 orTH2 cells.