Study on the mechanism by which EB virus LMP genes modify B cell development in host

EB病毒（Epstein-Barr virus，EBV）是一种嗜人B淋巴细胞和上皮细胞的病毒，在世界范围内感染率高达95%。还已知EBV是与伯基特淋巴瘤、霍奇金淋巴瘤、AIDS相关淋巴瘤相关的致病试剂。EB病毒感染并诱导B淋巴细胞致瘤时可逃避免疫监视，但其在人体内的侵袭分子机制尚不清楚。首先，我们建立了B细胞特异性表达EBV核抗原（EBNA 1）的转基因小鼠（tg），EBNA 1通过稳定p53抑癌蛋白参与EBV基因组在细胞中的维持和生长转化。它们携带在IG增强子/多瘤立即早期基因启动子控制下的EBV EBNA 1基因，使EBNA 1在B细胞中表达。 ...更多信息 特别的EBNA 1 tg显示脾和淋巴结增生，其中B细胞表达大量EBNA 1蛋白。EBNA 1 tg的致瘤性与对照组无显著差异，提示EBV的致瘤性可能依赖于其它EBV潜伏基因，如LMP 1和EBNA 1，也可能依赖于人类易感性遗传背景的多样性。二是如何建立潜伏膜蛋白（LMP）诱导B细胞生长转化的体内研究体系。研究表明，LMP 1和LMP 2a的表达抑制和改变了晚期B细胞的发育，特别是次级淋巴器官中滤泡B细胞向生殖中心B细胞的转变。在这种情况下，很难确定LMP参与淋巴瘤发生以发展伯基特淋巴瘤，霍奇金淋巴瘤，其被认为是来源于生殖中心B细胞。为了克服这些困难，我们在小鼠中开发了更复杂的药物诱导的LMP表达系统，其中早期B细胞发育在诱导LMP 1表达方面有缺陷，这表明LMP 1负责在EBV感染中逃避宿主免疫监视。少

Epstein-Barr virus (EBV) has tropism for the human B lymphocytes and epithelial cells and widely infects into 95% of human being in the world-wide. It is also known that EBV is a causative reagent to be associated with Burkitt's lymphomas, Hodgkin's lymphomas, AIDS-associated lymphomas. EBV escapes immunosurveillance when it infects and induces its tumorigenicity in B lymphocytes but little is known about the molecular mechanisms by which EBV invades well in human. lb clarify the mechanism, here we tried to show how EBV latent gene products contribute to EBV-induce B cell growth transformation and activation in viva First of all, we generated transgenic mice (tg) with B cell-specific expression of EBV nuclear antigen (EBNA1) which is involved in the EBV genome maintenance in cells and the growth transformation by stabilizing p53 tumor suppressor protein. They carry EBV EBNA1 gene under the control of Ig enhancer/polyoma immediate early gene promoter to give EBNA1 expressed in B cells s … More pecifically. EBNA1tg showed hyperplasia in the spleen and lymph nodes where B cells express large amount of EBNA1 protein. There is no difference in the incidence of tumorigenicity between EBNA1tg and the control suggesting that tumorigenicity of EBV would be dependent on the other EBV latent gene such as LMP1 and EBNA1 and that it could be on the diversity of genetic background in human which is susceptibility for EBV. The second aspect was that how in vivo system could be established for searching the pathogenesis of EBV on B cell growth transformation induced by latent membrane proteins (LMP). The data have been shown that the expression of LMP including LMP1 and LMP2a inhibit and modify B cell development at the late stage, especially, the transition of follicular B cells to germinal center B cells in secondary lymphoid organs. In this context, it is difficult to determine the involvement of LMP in lymphomagenesis to develop Burkitt's lymphomas, Hodgkin's lymphomas which are thought to be derived from germinal center B cells. lb overcome the difficulties, we developed more sophisticated drug-inducible LMP expression system in mouse where early B cell development was defective in inducing LMP1 expression suggesting that LMP1 is responsible for escaping host immunosurveillance in the EBV infection. Less