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

爱泼斯坦-巴尔病毒(Epstein-Barr Virus，EBV)是一种嗜人B淋巴细胞和上皮细胞的病毒，广泛感染全球95%的人类。众所周知，EBV是一种与Burkitt淋巴瘤、霍奇金淋巴瘤和艾滋病相关淋巴瘤有关的致病试剂。当EBV感染B淋巴细胞并诱导其致瘤性时，它可以逃脱免疫监视，但人们对EBV侵袭人类的分子机制知之甚少。首先，我们建立了B细胞特异性表达EBV核抗原(EBNA1)的转基因小鼠(TG)，EBNA1参与了EBV基因组在细胞内的维持，并通过稳定P53抑癌蛋白参与了生长转化。携带EB病毒EBNA1基因，在Ig增强子/多瘤即刻早期基因启动子的控制下，使EBNA1在B细胞中表达，S…更具体地说。EBNA1Tg表现为脾和淋巴结增生，B细胞大量表达EBNA1蛋白。EBNA1tg组的致瘤性与对照组无差异，提示EBV的致瘤性可能依赖于另一个EBV潜伏基因LMP1和EBNA1，并可能依赖于人类遗传背景的多样性，这可能是EBV的易感性。第二个方面是如何建立体内系统，以研究EBV在潜伏膜蛋白(LMP)诱导的B细胞生长转化中的发病机制。结果表明，LMP包括LMP1和LMP2a的表达抑制和调节了B细胞发育的晚期，尤其是次级淋巴器官中滤泡B细胞向生发中心B细胞的转变。在这种背景下，很难确定LMP参与了发生Burkitt淋巴瘤的淋巴生成过程，Burkitt淋巴瘤是霍奇金淋巴瘤，被认为来自生发中心B细胞。Lb克服了这些困难，我们在小鼠体内建立了更复杂的药物诱导的LMP表达系统，在小鼠的早期B细胞发育不能诱导LMP1表达的情况下，提示LMP1在EBV感染中负责逃避宿主的免疫监视。较少

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