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. 2004 Dec 21;101(51):17807-12.
doi: 10.1073/pnas.0407503101. Epub 2004 Dec 9.

Induction of peripheral lymph node addressin in human gastric mucosa infected by Helicobacter pylori

Motohiro Kobayashi  1 , Junya Mitoma, Naoshi Nakamura, Tsutomu Katsuyama, Jun Nakayama, Minoru Fukuda
Affiliations

Induction of peripheral lymph node addressin in human gastric mucosa infected by Helicobacter pylori

Motohiro Kobayashi et al. Proc Natl Acad Sci U S A. .

Abstract

Helicobacter pylori infects over half the world's population and is a leading cause of peptic ulcer and gastric cancer. H. pylori infection results in chronic inflammation of the gastric mucosa, and progression of chronic inflammation leads to glandular atrophy and intestinal metaplasia. However, how this chronic inflammation is induced or maintained is not well known. Here, we show that chronic inflammation caused by H. pylori infection is highly correlated with de novo synthesis of peripheral lymph node addressin (PNAd) presented on high-endothelial venule (HEV)-like vessels. The number of HEV-like vessels dramatically increases as chronic inflammation progresses. We found that the PNAd is bound by L-selectin.IgM chimeric protein, and decorated by NCC-ST-439 antibody, which is suggested to recognize both nonsulfated and 6-sulfated sialyl Lewis X on core 2 branched O-glycans, and MECA-79 antibody, which reacts with 6-sulfo N-acetyllactosamine on extended core 1 O-glycans. These results indicate that PNAd on HEV-like vessels present in the gastric mucosa subsequent to H. pylori infection is similar to those on HEVs present in the secondary lymphoid organs, which are essential for lymphocyte circulation. Moreover, eradication of H. pylori is associated with the disappearance of HEV-like vessels in the gastric mucosa. By contrast, very few PNAd were found in the gastric mucosa of patients with chemical gastritis caused by nonsteroidal antiinflammatory drugs. These results strongly suggest that PNAd in HEV-like vessels plays a critical role in lymphocyte recruitment during chronic inflammation induced by H. pylori infection.

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Figures

Fig. 1.
Fig. 1.
FACS analysis of transfected CHO cells expressing sialyl Lewis X or 6-sulfo sialyl Lewis X on extended core 1 or core 2 branched O-glycans (32) and structures of MECA-79 and NCC-ST-439 epitopes are shown. (A) MECA-79 binds CHO cells expressing 6-sulfo sialyl Lewis X on extended core 1 (CHO-PSGL-1·C1·F7·LSST) but not sialyl Lewis X (CHO-PSGL-1·C1·F7). NCC-ST-439 binds CHO cells expressing sialyl Lewis X (CHO-PSGL-1·C2·F7) and 6-sulfo sialyl Lewis X (CHO-PSGL-1·C2·F7·LSST) on core 2 branched O-glycans but barely binds those expressing sialyl Lewis X or 6-sulfo sialyl Lewis X on extended core 1 O-glycans. HECA-452 binds all cells tested, but its reactivity apparently depends on the expression level of extended core 1 O-glycans. (B) L-selectin ligand containing 6-sulfo sialyl Lewis X on core 2 branch and extended core 1 structure is shown. The epitopes for NCC-ST-439 and MECA-79 are shown in boxes.
Fig. 2.
Fig. 2.
MECA-79, HECA-452, and NCC-ST-439 antigens in a HEV-like vessel in the gastric mucosa with H. pylori-associated chronic active gastritis. Serial sections were subjected to immunostaining with anti-CD31, anti-CD34, MECA-79, HECA-452, and NCC-ST-439 antibodies and to a binding assay with L-selectin·IgM and E-selectin·IgM chimeric proteins in the absence or presence of 1 mM EDTA. HE, hematoxylin and eosin staining. (Bar, 10 μm.)
Fig. 3.
Fig. 3.
Gastric mucosa of different degrees of chronic inflammation and association of HEV-like vessels with progression of inflammation. (A) (Upper) Gastric mucosa at a mild stage barely expresses HEV-like vessels with minimum recruitment of lymphocytes. (Lower) Gastric mucosa at a marked stage express a significant number of recruited lymphocytes (arrowheads) around HEV-like vessels. (B) The number of MECA-79+ or HECA-452+ vessels is positively correlated with the progression of chronic inflammation. Each group consists of 11 (normal), 42 (mild), 67 (moderate), and 23 (marked) patients. (C) The number of patients exhibiting ≥1% MECA-79+ or HECA-452+ vessels is highly correlated with the progression of chronic inflammation. *, P < 0.05; **, P < 0.01; ***, P < 0.001; NS, not significant. (Bar, 50 μm.)
Fig. 4.
Fig. 4.
Disappearance of HEV-like vessels in the gastric mucosa after eradication of H. pylori. Gastric mucosa infected by H. pylori was examined before and 2 months after a treatment to eradicate H. pylori. (A) Before the treatment, HEV-like vessels detected by MECA-79 and HECA-452 antibodies were abundant, and large numbers of mononuclear cells (lymphocytes) were present around these vessels. (B) After eradication of H. pylori, HEV-like vessels were no longer present and few mononuclear cells were present. (Bar, 100 μm.)
Fig. 5.
Fig. 5.
Few HEV-like vessels are associated with chemical gastritis caused by NSAIDs. (A and B) Gastric mucosa obtained from two rheumatoid arthritis patients taking NSAIDs. In both patients, typical chemical gastritis phenotype, such as foveolar hyperplasia (asterisks) and vasodilatation and congestion (arrowheads), is evident. (B) MECA-79+ HEV-like vessels are associated only with substantial lymphocyte recruitment (arrows), which is rather atypical for chemical gastritis. Images for HE ×800, CD34, MECA-79, and HECA-452 are further enlarged in the same scale to show details. (Bar, 50 μm.)
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