Role of sulfated O-glycans expressed by high endothelial venule-like vessels in pathogenesis of chronic inflammatory gastrointestinal diseases.
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.
Department of Molecular Pathology, Shinshu University Graduate School of Medicine, Matsumoto, Japan. motokoba@shinshu-u.ac.jp
Motohiro
M
Kobayashi
Minoru
M
Fukuda
Jun
J
Nakayama
D000954:Antigens, Surface / Q000096:biosynthesis; D002908:Chronic Disease; D003093:Colitis, Ulcerative / Q000209:etiology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism*; D005756:Gastritis / Q000209:etiology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D016481:Helicobacter Infections / Q000150:complications* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D016480:Helicobacter pylori / Q000302:isolation & purification; D006801:Humans; D019041:L-Selectin / Q000378:metabolism; D016256:Lewis X Antigen / Q000031:analogs & derivatives; D008565:Membrane Proteins / Q000096:biosynthesis; D009844:Oligosaccharides / Q000096:biosynthesis* / Q000502:physiology; D011134:Polysaccharides / Q000096:biosynthesis* / Q000502:physiology; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism; D000080506:Sialyl Lewis X Antigen / Q000031:analogs & derivatives; D014699:Venules / Q000378:metabolism* / Q000473:pathology
C086949:6'-sulfated sialyl Lewis x; D000954:Antigens, Surface; C069886:L-selectin counter-receptors; D016256:Lewis X Antigen; D008565:Membrane Proteins; D009844:Oligosaccharides; D011134:Polysaccharides; D016201:Receptors, Lymphocyte Homing; D000080506:Sialyl Lewis X Antigen; D019041:L-Selectin