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P082. Altered oligosaccharide structures reduce colitis induction in mice defective in glycosyltransferases

S. Shinzaki1, H. Iijima1, T. Inoue1, M. Tsujii1, E. Miyoshi2, T. Takehara1, 1Osaka University, Gastroenterology and Hepatology, Suita, Japan, 2Osaka University, Molecular Biochemistry and Clinical Investigation, Suita, Japan

Background

Oligosaccharide modifications induce various functional changes in immune cells. We previously reported that the galactose-deficient fraction in fucosylated IgG oligosaccharides is increased with a decrease in beta-1,4-galactosyltransferase I (B4GalTI) in patients with Crohn's disease (CD) (Shinzaki S. et al. Am J Gastroenterol 2008). Recent reports demonstrate that B cells and immunoglobulins have protective roles in inflammatory bowel diseases (IBD). The roles of oligosaccharide alterations in CD, however, have not been investigated yet. In the present study we investigated a possible role of oligosaccharide modification in the pathophysiology of colitis using mice defective in glycosyltransferases.

Methods

Colitis severity was compared between B4galt1+/− and B4galt1+/+ mice. B cells isolated from B4galt1+/− and B4galt1+/+ mice were adoptively transferred to recombination activating gene (Rag) 2−/− mice, in which colitis was induced by CD4+CD62L+ T cells. Cell-surface glycan profiles were determined by lectin microarray. Cytokine production was determined in a co-culture of various types of cells isolated from either B4galt1+/− or B4galt1+/+ mice.

Results

Dextran sodium sulfate (DSS) and trinitrobenzene sulfonic acid-induced colitis was significantly ameliorated in B4galt1+/− mice, which have galactose deficiency in IgG oligosaccharides (similar to that of patients with CD) compared with B4galt1+/+ mice. Amelioration of colitis was associated with an increased interleukin-10 (IL-10) production from macrophages in B4galt1+/− mice. The amelioration of colitis in B4galt1+/− mice was lost in the absence of IL-10, indicating that IL-10 is indispensable for the protection of colitis in B4galt1+/− mice. Colitis in Rag2−/− mice transferred with CD4+CD62L+ T cells was ameliorated by co-transfer of B cells isolated from B4galt1+/−, but not from B4galt1+/+ mice. Lectin microarray and flow cytometric analysis revealed increased expression of polylactosamines on B4galt1+/− B cells and macrophages in comparison with B4galt1+/+ cells. The production of IL-10 from macrophages was induced via their direct interaction with B4galt1+/− B cells by cross-linking cell-surface polylactosamines by galectins. Moreover, alpha-1,6-fucosyltransferase (Fut8) deficient mice, which lack core fucose, also showed amelioration of DSS colitis.

Conclusion

Altered oligosaccharide structures on immune cells modulate mucosal inflammation. Oligosaccharides in immune cells can be a potential therapeutic target for IBD.