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

eb病毒（Epstein-Barr virus， EBV）对人类B淋巴细胞和上皮细胞具有亲和性，在世界范围内广泛感染95%的人。我们也知道EBV是一种与伯基特淋巴瘤、霍奇金淋巴瘤、艾滋病相关淋巴瘤相关的致病试剂。EBV在感染B淋巴细胞并诱导其致瘤性时逃避免疫监视，但对EBV在人体内入侵的分子机制知之甚少。为了阐明这一机制，我们试图展示EBV潜伏基因产物如何在体内促进EBV诱导B细胞生长转化和活化。首先，我们培育了eb病毒核抗原（EBNA1）在B细胞特异性表达的转基因小鼠（tg）， EBV核抗原（EBNA1）通过稳定p53抑癌蛋白参与EBV基因组在细胞内的维持和生长转化。他们携带EBV EBNA1基因，在Ig增强子/多瘤即时早期基因启动子的控制下，使EBNA1在B细胞中的表达更特异性。EBNA1tg表现为脾脏和淋巴结增生，B细胞大量表达EBNA1蛋白。EBNA1tg与对照组的致瘤性发生率无差异，提示EBV的致瘤性可能取决于其他EBV潜伏基因如LMP1和EBNA1，也可能取决于人类遗传背景的多样性，即EBV易感性。二是如何建立体内系统，探索eb病毒对潜伏膜蛋白（latent membrane protein， LMP）诱导的B细胞生长转化的发病机制。数据表明，LMP1和LMP2a等LMP的表达抑制和修饰了B细胞的后期发育，特别是二级淋巴器官中滤泡B细胞向生发中心B细胞的转变。在这种情况下，很难确定LMP参与淋巴瘤的发生，发展为伯基特淋巴瘤，霍奇金淋巴瘤，这被认为是源于生发中心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LMP表达系统，早期B细胞发育在诱导LMP1表达方面存在缺陷，这表明LMP1在EBV感染中负责逃避宿主免疫监视。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