alpha-Neup5Ac-(2--3)-beta-D-Galp-(1--4)-[alpha-L-Fucp-(1--3)]-D-GlcpNAc and Gastritis

Helicobacter pylori is a Gram-negative bacterium that infects over 50% of the world's population. This organism causes various gastric diseases such as chronic gastritis, peptic ulcer, and gastric cancer. H. pylori possesses lipopolysaccharides that share structural similarity to Lewis blood group antigens in gastric mucosa. Such antigenic mimicry could result in immune tolerance against antigens of this pathogen. On the other hand, H. pylori colonizes gastric mucosa by utilizing adhesins that bind Lewis blood group antigen-related carbohydrates expressed on gastric epithelial cells. After colonization, H. pylori induces acute inflammatory responses mainly by neutrophils. This acute phase is gradually replaced by a chronic inflammatory response. In chronic gastritis, lymphocytes infiltrate the lamina propria, and such infiltration is facilitated by the interaction between L-selectin on lymphocytes and peripheral lymph node addressin (PNAd), which contains 6-sulfo sialyl Lewis X-capped O-glycans, on high endothelial venule (HEV)-like vessels. H. pylori barely colonizes gland mucous cell-derived mucin where alpha1,4-GlcNAc-capped O-glycans exist. In vitro experiments show that alpha1,4-GlcNAc-capped O-glycans function as a natural antibiotic to inhibit H. pylori growth. These findings show that distinct sets of carbohydrates expressed in the stomach are closely associated with pathogenesis and prevention of H. pylori-related diseases, providing therapeutic potentialities based on specific carbohydrate modulation.

Topics: Adhesins, Bacterial; Animals; Chronic Disease; Gastric Mucosa; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; L-Selectin; Lewis X Antigen; Lipopolysaccharides; Molecular Mimicry; Mucin-2; Neutrophils; O Antigens; Oligosaccharides; Peptic Ulcer; Polysaccharides; Sialyl Lewis X Antigen; Stomach Neoplasms

Lymphocyte homing is mediated by a cascade of adhesive interactions between circulating lymphocytes and specialized endothelial cells comprising high endothelial venules (HEVs). Sulfated O-glycans expressed on HEVs, collectively called peripheral lymph node addressin (PNAd), interact with L-selectin expressed on lymphocytes, contributing to the initial step of the lymphocyte homing. In chronic inflammatory states, PNAd is induced on HEV-like vessels but absent in non-lymphoid tissues under normal conditions. Such HEV-like vessels have been observed in various chronic inflammatory diseases including rheumatoid arthritis, lymphocytic thyroiditis, Helicobacter pylori-associated chronic gastritis, and inflammatory bowel disease (IBD), and implicated in lymphocyte recruitment in those diseases. In H. pylori-associated chronic gastritis, PNAd-expressing HEV-like vessels are induced, and the progression of chronic inflammation is highly correlated with appearance of these vessels. Furthermore, eradication of H. pylori by antibiotics resulted in disappearance of PNAd. These results indicate that inhibition of PNAd formation could have therapeutic effect by attenuating lymphocyte recruitment. In ulcerative colitis (UC), PNAd-expressing HEV-like vessels are induced, preferentially in the active phase, and T cells, particularly CD4(+) T cells, are closely associated with these vessels, suggesting that T cell recruitment via PNAd-expressing HEV-like vessels plays at least a partial role in UC pathogenesis. Additionally, N-acetylglucosamine-6-O-sulfotransferase 1 (GlcNAc6ST-1) is suggested to be a candidate to regulate PNAd induction on HEV-like vessels in UC. These results provide a potential therapeutic strategy to treat UC by blocking T cell adhesion to PNAd-expressing HEV-like vessels. Inhibition or down-regulation of GlcNAc6ST-1 may be an alternative.

Topics: Antigens, Surface; Chronic Disease; Colitis, Ulcerative; Endothelial Cells; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; L-Selectin; Lewis X Antigen; Membrane Proteins; Oligosaccharides; Polysaccharides; Receptors, Lymphocyte Homing; Sialyl Lewis X Antigen; Venules

High endothelial venule (HEV)-like vessels have been observed in gastric B cell lymphoma of mucosa-associated lymphoid tissue type (MALT lymphoma), as well as in its preceding lesion, chronic Helicobacter pylori gastritis. Previously we reported that glycans on HEV-like vessels in the latter lesion served as L-selectin ligands, although their function is unclear. We have investigated sialyl Lewis X (sLeX)-related glycoepitopes and found that MECA-79(-) /HECA-452(+) /NCC-ST-439(+) HEV-like vessels preferentially mark gastric MALT lymphoma compared to chronic H. pylori gastritis. We then constructed CHO cell lines expressing potential MECA-79(-) /HECA-452(+) /NCC-ST-439(+) glycans, as well as other sLeX-type glycans, on CD34 and evaluated L-selectin binding to those cells, using L-selectin-IgM chimera binding and lymphocyte adhesion assays. L-selectin-IgM chimeras bound to CHO cells expressing 6-sulpho-sLeX attached to core 2-branched O-glycans with or without 6-sulpho-sLeX attached to extended core 1 O-glycans, but only marginally to other CHO cell lines. By contrast, CHO cells expressing 6-sulpho-sLeX attached to extended core 1 and/or core 2-branched O-glycans, as well as non-sulphated sLeX attached to core 2-branched O-glycans, showed substantial lymphocyte binding, while binding was negligible on lines expressing 6-sulpho- and non-sulphated sLeX attached to N-glycans and non-sulphated sLeX attached to extended core 1 O-glycans. These results indicate that MECA-79(-) /HECA-452(+) /NCC-ST-439(+) glycans, specifically, 6-sulpho- and non-sulphated sLeXs attached to core 2-branched O-glycans, expressed on HEV-like vessels in gastric MALT lymphoma function as L-selectin ligands and likely contribute to H. pylori-specific T cell recruitment in the progression of gastric MALT lymphoma.

Topics: Animals; Cell Adhesion; CHO Cells; Cricetinae; Cricetulus; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Immunoglobulin M; L-Selectin; Lewis X Antigen; Ligands; Lymphatic Vessels; Lymphocytes; Lymphoma, B-Cell, Marginal Zone; Neoplasm Proteins; Polysaccharides; Sialyl Lewis X Antigen; Stomach Neoplasms

Helicobacter pylori infects over half the population worldwide and is a leading cause of chronic gastritis and gastric cancer. However, the mechanism by which this organism induces inflammation and carcinogenesis is not fully understood. In the present study we used insulin-gastrin (INS-GAS) transgenic mice that fully develop gastric adenocarcinoma after infection of H. pylori-related Helicobacter felis. Histological examination revealed that more than half of those mice developed invasive adenocarcinoma after 8 months of infection. These carcinomas were stained by NCC-ST-439 and HECA-452 that recognize 6-sulfated and non-sulfated sialyl Lewis X. Lymphocytic infiltration predominantly to submucosa was observed in most H. felis-infected mice, and this was associated with the formation of peripheral lymph node addressin (PNAd) on high endothelial venule (HEV)-like vessels detected by MECA-79. Time-course analysis of gene expression by using gene microarray revealed upregulation of several inflammation-associated genes including chemokines, adhesion molecules, surfactant protein D (SP-D), and CD74 in the infected stomach. Immunohistochemical analysis demonstrated that SP-D is expressed in hyperplasia and adenocarcinoma whereas CD74 is expressed in adenocarcinoma in situ and invasive carcinoma. These results as a whole indicate that H. felis induces HEV-like vessels and inflammation-associated chemokines and chemokine receptors, followed by adenocarcinoma formation.

Topics: Adenocarcinoma; Animals; Antigens, Differentiation, B-Lymphocyte; Female; Gastric Mucosa; Gastrins; Gastritis; Gene Expression Profiling; Glycosyltransferases; Helicobacter felis; Helicobacter Infections; Histocompatibility Antigens Class II; Hyperplasia; Immunohistochemistry; Insulin; Lymphocytes; Male; Mice; Mice, Transgenic; Oligonucleotide Array Sequence Analysis; Oligosaccharides; Pulmonary Surfactant-Associated Protein D; Sialyl Lewis X Antigen; Stomach; Stomach Neoplasms; Up-Regulation

Helicobacter pylori adherence in the human gastric mucosa involves specific bacterial adhesins and cognate host receptors. Here, we identify sialyl-dimeric-Lewis x glycosphingolipid as a receptor for H. pylori and show that H. pylori infection induced formation of sialyl-Lewis x antigens in gastric epithelium in humans and in a Rhesus monkey. The corresponding sialic acid-binding adhesin (SabA) was isolated with the "retagging" method, and the underlying sabA gene (JHP662/HP0725) was identified. The ability of many H. pylori strains to adhere to sialylated glycoconjugates expressed during chronic inflammation might thus contribute to virulence and the extraordinary chronicity of H. pylori infection.

Topics: Adhesins, Bacterial; Amino Acid Sequence; Animals; Bacterial Adhesion; Carbohydrate Sequence; Carrier Proteins; Gastric Mucosa; Gastritis; Genes, Bacterial; Glycoconjugates; Helicobacter Infections; Helicobacter pylori; Humans; Lewis X Antigen; Macaca mulatta; Mice; Mice, Transgenic; Molecular Sequence Data; Oligosaccharides; Sialic Acids; Sialyl Lewis X Antigen