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

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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.