Peters Anna L, Stunz Laura L, Meyerholz David K, Mohan Chandra, Bishop Gail A
Immunology Graduate Program, University of Iowa, Iowa City, IA 52242, USA.
J Immunol. 2010 Oct 1;185(7):4053-62. doi: 10.4049/jimmunol.0904065. Epub 2010 Sep 1.
EBV infection is associated with development of the autoimmune disease systemic lupus erythematosus (SLE), and EBV can reactivate during SLE flares. Latent membrane protein 1 (LMP1) is an EBV-encoded oncogenic mimic of CD40 that can be re-expressed in PBMCs during SLE flares, as >90% of humans are latently EBV-infected. Whether LMP1 signaling exacerbates SLE is unknown. The phenotype of mice expressing a chimeric molecule with the mouse CD40 extracellular domain and the LMP1 intracellular signaling regions (mCD40-LMP1 transgenic [tg]) includes enhanced autoreactivity, yet these mice do not develop fatal autoimmune disease. We hypothesized that LMP1-mediated activation signals cooperate with and/or amplify events that predispose individuals to development of autoimmunity. To determine which aspects of autoimmunity may be exacerbated by LMP1, we bred mCD40-LMP1tg mice to two lupus-prone strains, B6.Sle1 and B6.Sle3, and analyzed autoimmunity parameters. LMP1(+)Sle1(+/+) mice developed enlarged lymphoid organs containing increased frequencies of germinal center, B cells, CD86(+) B cells, and activated and memory T cells compared with non-tg littermates. Anti-histone Abs were elevated in serum of LMP1(+)Sle1(+/+) mice, and they had signs of kidney pathology. LMP1(+)Sle1(+/+) B cells produced increased IL-6 and upregulated CD86 to a higher degree following CD40 stimulation in vitro, suggesting that the in vivo autoimmune exacerbation is B cell intrinsic. In contrast, the LMP1 transgene has no additional effects on autoimmunity on the B6.Sle3 background. These data indicate that LMP1-induced effects can cooperate with distinct subsets of host genes that predispose to autoimmunity and can thus be an exacerbating factor in autoimmune disease via multiple mechanisms.
EB病毒（EBV）感染与自身免疫性疾病系统性红斑狼疮（SLE）的发生有关，并且EBV可在SLE病情活动时重新激活。潜伏膜蛋白1（LMP1）是EBV编码的一种CD40致癌模拟物，在SLE病情活动期间可在外周血单个核细胞（PBMC）中重新表达，因为超过90%的人潜伏感染EBV。LMP1信号传导是否会加重SLE尚不清楚。表达具有小鼠CD40细胞外结构域和LMP1细胞内信号区域的嵌合分子（mCD40-LMP1转基因 [tg]）的小鼠的表型包括自身反应性增强，但这些小鼠不会发展为致命的自身免疫性疾病。我们推测LMP1介导的激活信号与使个体易患自身免疫性疾病的事件协同作用和/或放大这些事件。为了确定LMP1可能会加重自身免疫的哪些方面，我们将mCD40-LMP1tg小鼠与两种狼疮易感品系B6.Sle1和B6.Sle3进行杂交，并分析自身免疫参数。与非转基因同窝小鼠相比，LMP1(+)Sle1(+/+)小鼠的淋巴器官肿大，生发中心、B细胞、CD86(+) B细胞以及活化和记忆T细胞的频率增加。LMP1(+)Sle1(+/+)小鼠血清中的抗组蛋白抗体升高，并且有肾脏病变的迹象。体外CD40刺激后，LMP1(+)Sle1(+/+) B细胞产生的白细胞介素-6增加，CD86上调程度更高，这表明体内自身免疫的加重是B细胞内在性的。相比之下，LMP1转基因在B6.Sle3背景下对自身免疫没有额外影响。这些数据表明，LMP1诱导的效应可与易患自身免疫性疾病的不同宿主基因亚群协同作用，因此可通过多种机制成为自身免疫性疾病的加重因素。
