FUNCTIONS OF VEROTOXIN RECEPTOR GB3 (CD77) IN B CELL FUNCTIONS

Globotriaosyl神经酰胺（Gb 3或CD 77）和潜在的含有Gala-4Gal残基的其他鞘糖脂是verotoxins（VT）的受体。VT的（也称为志贺样毒素）产生的E。大肠杆菌血清型0157：H7和其它血清型在出血性结肠炎和溶血性尿毒综合征（HUS）的发展中被认为是致病因子，溶血性尿毒综合征是儿科急性肾衰竭的主要原因。Gb 32在多种人类细胞类型上表达，包括小儿肾小球和生殖中心B淋巴细胞。以前，我们鉴定了CD 19上的VT样序列和干扰素-α受体的IFNAR-1亚基，并且我们已经证明了Gb 3在伯基特淋巴瘤细胞（具有与生发中心B细胞相似的表型的B细胞）中在CD 19介导的粘附和干扰素-α诱导的生长抑制中的作用。最近，我们已经确定了人鼠MHC II类蛋白的verotoxin样序列。因此，Gb 3和MHC II类蛋白之间的相互作用可以发挥主要作用，在抗原呈递的淋巴细胞4s与生发中心表型。本研究的长期目标是全面地确定VT受体Gb 3在人类感染产VT大肠杆菌时免疫应答中的作用以及VT介导的免疫系统致病作用。杆菌拟议的研究的具体目标是确定潜在的Gb 3结合位点的CD 19和MHC II类蛋白使用分子建模技术，确定是否Gb 3与MHC II类分子在伯基特淋巴瘤细胞中相互作用，并调查小鼠作为一个模型的作用，Gb 3在B细胞功能。

Globotriaosyl ceramide (Gb3 or CD77), and potentially other glycosphingolipids which contain Gala-4Gal residues, are receptors for verotoxins (VT's). VT's (also called Shiga-like toxins) produced by E. coli serotype 0157:H7 and other serotypes have been implicated as causative agents in the development of hemorrhagic colitis and the hemolytic uremic syndrome (HUS), which is the leading cause of pediatric acute renal failure. Gb32 is expressed on a variety of human cell types including those of pediatric glomeruli and germinal center B lymphocytes. Previously, we identified VT-like sequences on CD19 and the IFNAR-1 subunit of the interferon-alpha receptor, and we have demonstrated roles for Gb3 in CD19-mediated adhesion and interferon- alpha-induced growth inhibition in Burkitt's lymphoma cells, B cells with a phenotype similar to that of germinal center B cells. Recently we have identified verotoxin-like sequences on human murine MHC class II proteins. Therefore, interactions between Gb3 and MHC class II proteins could play a major role in antigen presentation by lymphocyt4s with a germinal center phenotype. The long term objective of this research is to determine in a comprehensive manner the roles of the VT receptor Gb3 in immune responses and the pathogenic effects on the immune system mediated by VT during human infection with VT-producing E. coli. The specific aims of the proposed research are to identify potential Gb3-binding sites on CD19 and MHC class II proteins using molecular modeling techniques, determine if Gb3 interacts with MHC class II molecules in Burkitt's lymphoma cells, and investigate the mouse as a model for the role of Gb3 in B cell functions.