Tenascin expression in inflammatory,dysplastic and neoplastic lesions of the human stomach

Wie studied the expression of tenascin (Tn) in human stomach. In the normal mucosa of the antrum and body, Tn reaction was only seen in the muscularis mucosae, in the region of the pyloric sphincter and in the duodenum, a Tn-immunoreactive rim was seen underlying surface epithelial cells. Antral gastritis, irrespective of the degree of inflammation, showed a rim-like Tn expression under the surface epithelial cells but no Tn reaction was seen in mild chronic gastritis of the body. In some moderate and severe examples of chronic gastritis a delicate Tn-reactive line was seen to underline the surface epithelium focally and the neck regions of gastric pits. Discontinuous Tn immunoreactivity was sometimes seen beneath hyperplastic epithelium in both parts of the stomach. A Tn-immunoreactive line was seldom seen surrounding glands showing intestinal metaplasia. In both benign and malignant ulcers prominent Tn immunoreaction was seen at the base of ulcers extending deep into the underlying muscularis. Only severely dysplastic lesions displayed Tn in the lamina propria, in close association with capillaries. In early forms of diffuse gastric cancer (DGCA) raggedly increased Tn staining was seen in the lamina propria underlying affected surface epithelial cells. In advanced forms of DGCA consistent Tn expression was seen in the tumour stroma. A distinct Tn reaction was seen surrounding invasive tumour cell nests of intestinal type gastric cancer (IGCA) in the submucosa, whereas in early forms of the tumour enhanced Tn reaction was noted predominantly in the upper part of the lamina propria in the vicinity of dysplastic elements. Notably, while most invading DGCA tumour cell nests showed no Tn in the submucosa and muscle cell layer, invading IGCA islets showed prominent expression of Tn. The most conspicuous Tn enhancement in the stomach is seen in invasive tumours and in ulcers suggesting that Tn is an important stromal component in malignant growth and in lesions undergoing active repair and remodelling.     

Pathophysiological role of human beta-defensins 2 in gastric mucosa

Human beta-defensins (HBDs) recognized in the stomach include HBD1, which is the constitutional human beta-defensin (HBD), and HBD-2 and HBD-4, which are inducible HBDs. HBD-2 is an antimicrobial peptide that is involved in host defences against bacterial infections, such as Helicobacter pylori (H.pylori) in infection of the gastric mucosal epithelium. We examined the pathophysiological role of HBD-2, besides their roles as antimicrobial peptides. The materials used for the study consisted of gastric mucosal tissue specimens collected endoscopically from patients with conditions such as chronic gastritis associated with H. pylori infection, and gastric ulcers and gastritis due to non-steroidal anti-inflammatory drugs (NSAIDs) with or without H. pylori infection. We investigated the expression of HBD-2 and NF-kappaB by RT-PCR and immunoblotting, and the relation between the localization of HBD-2 and follicular dendritic cells (FDCs) by immunohistochemistry. Expression of HBD-2 was recognized in all the mucosal tissue specimens, irrespective of the presence or absence of H. pylori infection. All of the mucosal specimens expressing HBD-2 also revealed expression of NF-kappaB. In consecutive immunohisto-chemical staining, while expression of HBD-2 was observed in the gastric mucosal epithelium, FDCs were found to be localized in the lamina propria mucosae under the epithelial cell layer. These data suggested that in addition to being antimicrobial peptides, HBD-2 may also have a pathophysiological role as proinflammatory mediators, and that the HBD may act as proinflammatory mediators in concert with the dendritic cells (DC) by transmitting a signal from the mucosal surface to the lamina propria mucosae, which seems to be the original site of gastric mucosal damage.     

Cyclooxygenase-2 expression in Helicobacter pylori-associated premalignant and malignant gastric lesions

Expression of cyclooxygenase-2 (COX-2) in various stages of the Helicobacter pylori-associated gastric carcinogenesis pathway has not been elucidated. We investigated the distribution and intensity of COX-2 expression in premalignant and malignant gastric lesions, and monitored the changes after H. pylori eradication. Gastric biopsies from H. pylori-infected patients with chronic active gastritis, gastric atrophy, intestinal metaplasia (IM), gastric adenocarcinoma, and noninfected controls were studied. Expression of COX-2 was evaluated by immunohistochemistry and in situ hybridization. Endoscopic biopsies were repeated 1 year after successful eradication of H. pylori in a group of IM patients for comparing COX-2 expression and progression of IM. In all H. pylori-infected patients, COX-2 expression was predominantly found in the foveolar and glandular epithelium and, to a lesser extent, in the lamina propria. In the noninfected group, only 35% of cases demonstrated weak COX-2 expression. Intensity of COX-2 was not significantly different between the chronic active gastritis, gastric atrophy, IM, and gastric adenocarcinoma groups. In 17 patients with IM, COX-2 expressions in the epithelial cells and stromal cells were reduced 1 year after H. pylori eradication. However, the changes in COX-2 expression did not correlate with progression/regression of IM. Both premalignant and malignant gastric lesions demonstrate strong COX-2 expression. Successful eradication of H. pylori leads to down-regulation of COX-2 expression but failed to reverse IM at 1 year.     

Microsomal prostaglandin E synthase (mPGES)-1, mPGES-2 and cytosolic PGES expression in human gastritis and gastric ulcer tissue

Recently, three different prostaglandin E2 synthases have been identified: microsomal prostaglandin E synthase (mPGES)-1, cytosolic PGES (cPGES), and mPGES-2; however, their role and connection to cyclooxygenase (COX)-2 in the gastric ulcer repair process remain unknown. Therefore, we examined mPGES-1, cPGES, and mPGES-2 expression and localization in the stomach in vitro and in vivo. Tissues were obtained from Helicobacter pylori (H. pylori)-infected patients and consisted of surgical resections of gastric ulcers, or biopsies of gastric ulcers or gastritis. mPGES-1 mRNA and protein expression levels were examined by real-time polymerase chain reaction (PCR) and Western blot analysis, respectively. mPGES-1, cPGES, and mPGES-2 localization were analyzed immunohistochemically. Induction of PGES expression in response to interleukin (IL)-1beta was examined in vitro in the cultured human gastric fibroblast line Hs262.St. Real-time PCR analysis of mPGES-1 mRNA expression in biopsy samples showed significantly higher expression levels in open than in closed gastric ulcer tissue. Western blot analysis showed mPGES-1 protein expression limited to open ulcer tissue, while mPGES-2 and cPGES immunoreactivities were seen in both open and closed ulcer tissue. Immunohistochemical analysis showed strong mPGES-1 expression in fibroblasts and macrophages of the ulcer bed, paralleling COX-2 expression. cPGES and mPGES-2 expression levels were seen in both fibroblasts of the ulcer bed and in epithelial cells. Furthermore, stronger cPGES and mPGES-2 immunoreactivities were seen in scattered mast cell-like cells and neuroendocrine-like cells, respectively. Induction of mPGES-1 expression in response to IL-1beta was seen in cultured gastric fibroblasts in vitro, and double immunostaining showed mPGES-1 coexpression with COX-2 in fibroblasts of the ulcer bed in vivo. In conclusion, mPGES-1, cPGES, and mPGES-2 are all expressed in gastric ulcer tissue, but only mPGES-1 parallels COX-2 expression in mesenchymal and inflammatory cells of the ulcer bed, suggesting a key role for this enzyme in the ulcer repair process.     

Superoxide dismutases in chronic gastritis

Human gastric diseases have shown significant changes in the activity and expression of superoxide dismutase (SOD) isoforms. The aim of this study was to detect Mn‐SOD activity and expression in the tissue of gastric mucosa, primarily in chronic gastritis (immunohistochemical Helicobacter pylori‐negative gastritis, without other pathohistological changes) and to evaluate their possible connection with pathohistological diagnosis. We examined 51 consecutive outpatients undergoing endoscopy for upper gastrointestinal symptoms. Patients were classified based on their histopathological examinations and divided into three groups: 51 patients (archive samples between 2004–2009) with chronic immunohistochemical Helicobacter pylori‐negative gastritis (mononuclear cells infiltration were graded as absent, moderate, severe) divided into three groups. Severity of gastritis was graded according to the updated Sydney system. Gastric tissue samples were used to determine the expression of Mn‐SOD with anti‐Mn‐SOD Ab immunohistochemically. The Mn‐SOD expression was more frequently present in specimens with severe and moderate inflammation of gastric mucosa than in those with normal mucosa. In patients with normal histological finding, positive immunoreactivity of Mn‐SOD was not found. Our results determine the changes in Mn‐SOD expression occurring in the normal gastric mucosa that had undergone changes in the intensity of chronic inflammatory infiltrates in the lamina propria.     

ABO (H) blood group antigen expression in gastric mucosa

The A, B, O (H) blood group antigens (BGA) are glycolipids present in the plasma membranes of many different epithelial cells. Alterations in BGA expression have been described in malignant tumors and premalignant lesions. We have studied ABO (H) BGA expression in paraffin sections of gastric specimens using immunofluorescence techniques with monoclonal antibodies. 102 patients were studied. 15 with normal mucosa (NM); 16 with duodenal ulcer (DU); 23 with gastric ulcer (GU); 11 with pernicious anaemia (PA) and 37 with adenocarcinoma (AC). The expression of BGA in normal gastric mucosa is detected in surface epithelium, mucoid cell neck glands and parietal cells as well as 2/3 of antral glands. BGA expression in DU gastritis is very similar to that seen in NM. In atrophic chronic gastritis associated with GU and PA there is a significant decrease in BGA expression. In patients with PA, BGA expression is greater in antral mucosa than in fundic mucosa. Loss of BGA expression is more pronounced in atrophic chronic gastritis surrounding AC. Intestinal metaplasia shows variable BGA expression. Our results support the hypothesis that loss of BGA expression by epithelial gastric mucosal cells may be related to alterations in cellular differentiation and premalignant potential.     

CXC chemokines Gro(alpha)/IL-8 and IP-10/MIG in Helicobacter pylori gastritis

Infection with Helicobacter pylori causes chronic active gastritis, which is characterized by neutrophils infiltrating the gastric epithelial layer and the underlying lamina propria as well as by T, B lymphocytes and macrophages accumulating in the lamina propria. In this study, the chemokine profile responsible for the recruitment of these inflammatory cells is investigated. Using both RNA/RNA in situ hybridization and immunohistochemistry, the expression of the neutrophil and/or lymphocyte-attractant CXC chemokines growth-related oncogene alpha (Gro(alpha)), IL-8, interferon-gamma (IFN-gamma)-inducible protein-10 (IP-10), monokine induced by IFN-gamma (MIG) and the CC chemokines macrophage inflammatory protein-1alpha (MIP-1alpha), -1beta, regulated on activation normal T cell expressed and secreted (RANTES) and monocyte chemoattractant protein-1 (MCP-1) is studied and microanatomically localized in the gastric mucosa. Macrophages in the lamina propria at sites with neutrophil infiltration and gastric epithelium infiltrated by neutrophils highly expressed the neutrophil-attractant chemokines Gro(alpha) and IL-8. Additionally, Gro(alpha) and IL-8 were expressed by neutrophils themselves localized within gastric epithelium, in the foveolar lumen and in the cellular debris overlying mucosal erosion. IP-10 and to a lower extent MIG, both selectively chemotactic for inflammatory T cells, were expressed by endothelial cells of gastric mucosal vessels and by mononuclear cells at sites with T cell infiltration. Expression of all other CC chemokines tested was significantly lower. These in vivo data indicate that a set of predominantly CXC chemokines modulates the inflammation in H. pylori gastritis. Gro(alpha) and IL-8 may play an important role in neutrophil trafficking from the mucosal vessel into the gastric epithelium, whereas IP-10 and MIG contribute to the recruitment of inflammatory T cells into the mucosa.     

Protective role of heat shock protein 27 in gastric mucosal injury

Heat shock protein 27 (HSP27) mediates cytoprotective effects through its function as a molecular chaperone and through the phosphorylation-dependent stabilization of actin filaments. The role of HSP27 in gastric ulcer formation and healing is, however, unknown. The expression of HSP27 was studied in human gastric tissue specimens obtained from patients with gastric ulcers and from healthy Helicobacter pylori-negative individuals, who received low-dose aspirin, rofecoxib, and the combination in a prospective study. The susceptibility of the gastric mucosa to indomethacin-induced lesions was further studied in transgenic mice overexpressing human HSP27 (Tg(huHSP27)) and compared with wild-type mice (Wt). The expression of HSP27, COX-1, and COX-2 was investigated in Tg(huHSP27) mice and Wt mice by immunohistochemistry and western blot analysis. While no specific changes in HSP27 expression were found following exposure of healthy human gastric mucosa to oral administration of aspirin or refocoxib, chronic gastric ulcers showed strong HSP27 expression at the ulcer base and margins. Here it was expressed by granulation tissue and regenerating surface epithelium. In Tg(huHSP27) mice, overexpression of HSP27 led to a significant decrease of indomethacin-induced erosions and ulcers compared with Wt mice. COX-1 and COX-2 levels did not change. HSP27 is involved in chronic gastric ulcer repair mechanisms in humans, while overexpression of human HSP27 in gastric epithelial cells in mice reduces the susceptibility to non-steroidal anti-inflammatory drug (NSAID)-induced gastric ulceration. This indicates that HSP27 expression is critical for mucosal protection in the stomach.     

Interleukin-12 expression is focally enhanced in the gastric mucosa of pediatric patients with Crohn's disease.

The stomach is frequently involved in children suffering from Crohn's disease (CD). Diagnosis of specific gastritis may be difficult when granulomas are absent. We have used in situ hybridization to examine the expression of interleukin (IL)-12, a key cytokine in the Th1 response. IL-12 p35 and p40 antisense probes were used to examine ileal specimens from 9 children with CD and gastric biopsies from 24 children (13 with CD, 6 with Helicobacter pylori chronic gastritis, and 5 with a normal gastric mucosa). In all patients with CD, many clusters of IL-12-positive cells were present in the lamina propria. This was the case in the ileal specimens as well as in gastric mucosa showing granulomatous gastritis or nongranulomatous gastritis. The same distribution patterns were found for the IL-12 p35 and p40. In three patients with Helicobacter pylori gastritis, few scattered IL-12-positive cells were found. No positive cells were found in the normal gastric mucosa. The focally enhanced IL-12 expression in the gastric mucosa of pediatric patients with CD, with or without specific lesions, suggests that both are indeed linked to the disease and supports the major part of IL-12 in initiating and maintaining of the cascade resulting in the Th1 responses.     

Histogenesis of gastric foveolar metaplasia following duodenal ulcer: a definite reparative lineage of Brunner's gland

AIMS: We aimed to clarify the histogenesis of gastric metaplasia in the duodenal mucosa, particularly in association with a reparative lineage of Brunner's glands. METHODS AND RESULTS: Using immunohistochemical methods with recently developed antimucin monoclonal antibodies (mAbs) that distinguish foveolar and deep mucins of the gastric type, as well as mAb MIB-1, the histogenesis of gastric metaplasia was investigated in the duodenal wall of 20 surgically resected specimens. In duodenal ulcers extending into Brunner's glands with destruction of the muscularis mucosae, proliferating cells positive for MIB-1 were scattered in Brunner's glands. Interestingly, a group of proliferating cells was often seen next to the ulcerated surface. These cells were also positive for M1 (gastric-foveolar type mucin) but negative for M2 (deep gastric and Brunner glands' mucin). In regenerating ducts through granulation tissue, the proliferating cell zone was elongated, above which foveolar-type cells positive for M1 but negative for M2 were detected, indicating that the G-zone is newly established in Brunner's glands at the floor of an ulcer to produce gastric-foveolar cells. Subsequently, an organoid growth of the normal stomach mucosa is completed in the duodenum. CONCLUSIONS: This study indicates a possible histogenetic pathway of gastric metaplasia in close association with a reparative lineage of Brunner's glands, suggesting that the occurrence of the gastric-foveolar type epi-thelium is not a simple expansion of Brunner's duct but a true metaplasia.     

Selective cyclooxygenase-2 blocker delays healing of esophageal ulcers in rats and inhibits ulceration-triggered c-Met/hepatocyte growth factor receptor induction and extracellular signal-regulated kinase 2 activation

Nonsteroidal anti-inflammatory drugs, both nonselective and cyclooxygenase-2 (COX-2) selective, delay gastric ulcer healing. Whether they affect esophageal ulcer healing remains unexplored. We studied the effects of the COX-2 selective inhibitor, celecoxib, on esophageal ulcer healing as well as on the cellular and molecular events involved in the healing process. Esophageal ulcers were induced in rats by focal application of acetic acid. Rats with esophageal ulcers were treated intragastrically with either celecoxib (10 mg/kg, once daily) or vehicle for 2 or 4 days. Esophageal ulceration triggered increases in: esophageal epithelial cell proliferation; expression of COX-2 (but not COX-1); hepatocyte growth factor (HGF) and its receptor, c-Met; and activation of extracellular signal-regulated kinase 2 (ERK2). Treatment with celecoxib significantly delayed esophageal ulcer healing and suppressed ulceration-triggered increases in esophageal epithelial cell proliferation, c-Met mRNA and protein expression, and ERK2 activity. In an ex vivo organ-culture system, exogenous HGF significantly increased ERK2 phosphorylation levels in esophageal mucosa. A structural analog of celecoxib, SC-236, completely prevented this effect. These findings indicate that celecoxib delays esophageal ulcer healing by reducing ulceration-induced esophageal epithelial cell proliferation. These actions are associated with, and likely mediated by, down-regulation of the HGF/c-Met-ERK2 signaling pathway.     

Cholinergic innervation of the simian oxyntic gastric mucosa

The innervation of the oxyntic gastric mucosa was studied by light and electron microscopy in the rhesus monkey. An abundant net of acetylcholinesterase-positive nerves was seen in the lamina propria, with many slender fibers noted close to the basal lamina of the glands. Electron microscopic observation disclosed the presence of nerve fibers containing axons and varicosities in the lamina propria, often in very close proximity to the epithelial glandular cells. Nerve endings partly enveloped by a Schwann cell were occasionally seen in direct contact with a parietal cell.     

Association between genetic polymorphisms in the cyclooxygenase-1 gene promoter and peptic ulcers in Japan

Cyclooxygenase-1 (COX-1) has been regarded as a constitutively expressed enzyme that generates prostaglandins for gastrointestinal integrity. We attempted to clarify the association between potentially functional polymorphisms (T-1676C and A-842G/C50T) in the COX-1 gene promoter and gastroduodenal disorders in a Japanese population. The study was performed with 480 stocked DNAs from subjects (gastric ulcers in 93 subjects and duodenal ulcers in 44) with no evidence of gastric malignancy. We employed the PCR-SSCP method to detect gene polymorphisms. The severity of histological chronic gastritis in antral biopsy specimens was classified according to the updated Sydney system. The T-1676C polymorphism was not associated with either gastric mucosal atrophy or infiltration of inflammatory cells into gastric mucosa. In non-NSAID (non-steroidal anti-inflammatory drug) users, male gender and Helicobacter pylori (HP) infection were significantly associated with both gastric and duodenal ulcers, whereas the -1676T allele carrier was significantly associated with only gastric ulcers (OR, 2.86; 95% CI, 1.29-6.34). In NSAID users, the number of -1676T alleles was significantly associated with developing gastroduodenal ulcers (OR, 5.80; 95% CI, 1.59-21.1), whereas male gender and HP infection were not. The -842T/ C50T polymorphism was not detected in any of the 480 Japanese subjects. In conclusion, a carrier of the -1676T allele in the COX-1 gene promoter, as well as HP infection and male gender, seem to be significant risk factors for developing gastric ulcers, and the number of -1676T alleles was also a significant risk factor for the NSAID-induced ulcer, whereas the frequency of the A-842G polymorphism was thought to be very rare in the Japanese population.     

Expression of apoptosis-related proteins in Barrett's metaplasia-dysplasia-carcinoma sequence: a switch to a more resistant phenotype

Barrett's esophagus, or columnar-lined esophagus (CLE), is a premalignant disorder in which the stratified squamous epithelium is replaced by metaplastic epithelium. To gain more insight into the process of carcinogenesis in CLE, we studied several factors involved in the apoptotic pathway in biopsies with gastric metaplasia (GM), intestinal metaplasia (IM), dysplasia, and/or adenocarcinoma. Immunohistochemistry was performed for Fas, Bcl-2, Bax, Bcl-xl, inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2). Fas staining was positive in the epithelium of all biopsies from patients with CLE but negative in normal gastric mucosa. Fas staining was positive in all tumor cells of the 8 cases containing adenocarcinoma. Bcl-2 was positive in lamina propria immune cells of all specimens. Bax staining was positive in the epithelium of all biopsies, including tumor cells. Bcl-xl was positive in dysplasia and tumor cells, but negative in 8 of 17 biopsies containing IM. iNOS was positive in 20 of 21 biopsies with IM and in 4 of 8 dysplasia biopsies. COX-2 was positive in 7 of 8 adenocarcinomas. We conclude that the apoptotic balance in the transformation from IM to adenocarcinoma switches to an antiapoptotic phenotype because of increased Bcl-xl expression and decreased Bax expression. Fas can be used as a marker for the differentiation of gastric mucosa and metaplasia in the esophagus. iNOS is highly positive in CLE-associated intestinal metaplasia. COX-2 is negative in nonmalignant CLE. Therefore, pharmacologic inhibition of COX-2 activity is unlikely to be effective in the preventing CLE-associated adenocarcinoma. There was no clear correlation between iNOS expression and activation of proapoptotic and antiapoptotic genes.     

免疫球蛋白A1和肝细胞生长因子与腹型过敏性紫癜患儿胃组织损伤关系的研究

目的探讨IgAl和肝细胞生长因子（HGF）在腹型过敏性紫癜（I-1SP）患儿胃肠道损伤中的作用。方法取临床有持续或反复腹痛的腹型HSP患儿胃黏膜组织的病例为腹型HSP组,取胃镜检查明确诊断为急性胃炎患儿胃黏膜组织的病例为非HSP胃炎组;取胃肿瘤患儿切除部分胃的远离肿瘤部分、并经病理证实为正常胃黏膜组织的病例为正常对照组。运用免疫组织化学非生物素二步法检测IgA、IgAl和HGF蛋白在各组胃黏膜组织中的表达情况。结果腹型HSP组20例,非HSP胃炎10例,正常对照组4例。①腹型HSP组胃黏膜组织IgA、IgAl蛋白主要表达于胃黏膜上皮的表面黏液细胞内和固有层管状腺间的间质细胞、炎症细胞内;其免疫分数显著高于非HSP胃炎组和正常对照组,IgA蛋白：（0．61±0．02）vs（0．55±0．04）和（0．14±0．03）,IgAl蛋白：（0．58±0．05）vs（0．38±0．03）和（0．13±0．05）;腹型HSP组IgAl／IgA免疫分数比值（0．94±0．02）亦显著高于非HSP胃炎组（0．69±0．06）;②腹型HSP组胃黏膜组织中HGF蛋白主要表达于胃黏膜固有层的管状腺细胞内,其免疫分数显著高于非HSP胃炎组和正常对照组,（0．16±0．03）vs（0．39±0．08）和（0．50±0．01）,差异有统计学意义;③腹型HSP组胃黏膜组织中IgAl与HGF蛋白的表达水平呈正相关（r=0．892,P〈0．01）。结论对于无典型皮疹的腹型HSP患儿,IgA!及HGF可能作为病理学指标对HSP诊断及鉴别提供新的依据。     

Russell body gastritis: an unusual, tumor-like lesion of the gastric mucosa

The case of an 80-year-old woman who presented with epigastric symptoms is reported. Upper gastrointestinal endoscopy displayed Candida esophagitis and a localized swelling of the fundic mucosa. Histologic examination of the gastric biopsy showed a distinctive accumulation of numerous uniform plasma cells filled with so-called Russell bodies. On low-power view, the lesion resembled a neoplastic process due to the marked expansion of the lamina propria with distension of fundic glands. However, immunohistochemistry confirmed a polyclonal pattern of the plasma cells. This unusual reactive lesion of the gastric mucosa has only rarely been described and has been termed Russell body gastritis.     

Structure of lamina propria lymphoid follicles and associated epithelium in the gastric mucosa during Helicobacter pylori infection in ulcer-bearing Mongolian gerbils

To develop a gerbil model of Helicobacter pylori-induced chronic active gastritis comparable in severity to human lesions, we made acetic acid-induced ulcer in the anterior antral wall and concurrently challenged 1 x 10(8) colony-forming units bacteria per os. At 30 and 60 days after inoculation, the number of viable bacteria colonizing on the surface epithelium of the gastric mucosa was larger in ulcer-bearing animals compared to non-bearing ones. Furthermore, in the former animals, neutrophil and mononuclear cell infiltration as well as lymphoid follicle formation in the lamina propria was more prominent. Electron microscopically, lymphoid follicle-associated epithelium displayed specialized structures. Namely, brush cells interposed between mucous epithelial cells and characterized by prominent microfilament bundles and many apical vesicles or caveola specifically embraced the cluster of intraepithelially invading lymphocytes and macrophage-like cells by the attenuated cytoplasm in an analogous manner to M cells in Peyer's patches. The present study has demonstrated that ulcer formation enhances both H. pylori colonization and lamina propria lymphoid follicle formation and suggested that follicle-associated epithelium might play roles in the delivery of intraluminal antigen.     

Involvement of myeloid dendritic cells in the development of gastric secondary lymphoid follicles in Helicobacter pylori-infected neonatally thymectomized BALB/c mice

We previously described an animal model of Helicobacter pylori-induced follicular gastritis in neonatally thymectomized (nTx) mice. However, it is still not clear whether antigen-presenting dendritic cells (DCs) in the stomach have a role in the development of secondary follicles in H. pylori-infected nTx mice. We investigated the distribution of DC subsets using this model and examined their roles. To identify lymphoid and myeloid DCs, sections were stained with anti-CD11c (pan-DC marker) in combination with anti-CD8alpha (lymphoid DC marker) or anti-CD11b (myeloid DC marker) and were examined with a confocal microscope. Expression of macrophage inflammatory protein 3alpha (MIP-3alpha), which chemoattracts immature DCs, was analyzed by real-time PCR and immunohistochemistry. Follicular dendritic cells (FDCs) were stained with anti-SKY28 antibodies. In noninfected nTx mice, a few myeloid and lymphoid DCs were observed in the bottom portion of the lamina propria, whereas in H. pylori-infected nTx mice, there was an increased influx of myeloid DCs throughout the lamina propria. FDC staining was also observed in the stomachs of members of the infected group. MIP-3alpha gene expression was upregulated in the infected nTx group, and the immunohistochemistry analysis revealed MIP-3alpha-positive epithelial cells. These data suggest that H. pylori infection upregulates MIP-3alpha gene expression in gastric epithelial cells and induces an influx of myeloid DCs in the lamina propria of the gastric mucosa in nTx mice. Myeloid DCs and FDCs might contribute to the development of gastric secondary lymphoid follicles in H. pylori-infected nTx mice.