Helicobacter pylori chronically colonizes the stomach and duodenum and causes peptic ulcers or gastric adenocarcinoma in 10 to 20% of infected individuals. We hypothesize that the inability of patients to clear H. pylori infections is a consequence of active suppression of the immune response. Here we show that H. pylori-infected individuals have increased frequencies of CD4؉ CD25 high T cells in both the stomach and duodenal mucosa compared to uninfected controls. These cells have the phenotype of regulatory T cells, as they express The gastrointestinal mucosa is in constant contact with both harmless and harmful antigens. The immune system has to discriminate between these antigens to maintain a balance between active defense and the prevention of immunopathology. In mouse models, naturally occurring CD4 ϩ CD25 ϩ regulatory T cells (T reg cells) have been implicated in playing an important role in suppressing immune responses to the normal intestinal flora (28) as well as to pathogens (22,25). However, little is currently known about the role of T reg cells in the human gastrointestinal mucosa.Most studies of human T reg cells have been performed with cells isolated from peripheral blood (2, 17, 32), but CD4 ϩ CD25ϩ cells with suppressor activity have also been demonstrated in the thymus (29), cord blood (36), synovial fluid (4), tonsils (32), and a few types of tumors (19,37). Human T cells have a more variable expression of CD25 (the interleukin-2 receptor ␣-chain) than do mouse T cells, and only those that express CD25 with the highest intensities (CD25 high ) are suppressive (2, 4). T cells expressing intermediate levels of CD25 (CD25 low ) are instead activated effector or memory T cells and lack a regulatory function. T reg cells suppress the activity of other T cells via a contact-dependent mechanism, but the molecules directly mediating this suppression have still not been clearly identified (22). However, the Foxp3 gene (FOXP3 in humans), which encodes the transcription factor scurfin, has recently been demonstrated to be a key regulatory gene for the development and function of T reg cells (10,15,16). Humans with defects in the FOXP3 gene experience strong activation of the immune system, leading to multiorgan autoimmune disease, inflammatory bowel disease, allergies, and severe infections, collectively known as the IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-linked inheritance syndrome) (11). FOXP3/Foxp3 is expressed by CD4 ϩ CD25ϩ T reg cells in humans and mice, and the transduction of CD25 Ϫ cells from mice with this gene converts the cells into regulatory cells. Although recent data indicate that FOXP3 gene expression can be induced in CD25Ϫ cells under special conditions (5, 9, 33, 34), these induced FOXP3-expressing cells also have a suppressive capacity, suggesting that a tight link exists between FOXP3 expression and a regulatory function.We are currently investigating the role of T reg cells in chronic Helicobacter pylori infection (20,25). Although H. pylori colo...

Helicobacter pylori infects the stomach and duodenal mucosa. T cells are important components of the H. pylori-induced immune response, but little is currently known about how these cells are recruited to the infected mucosa. Here, we have characterized stomach and duodenal T cells isolated from H. pylori-infected and noninfected subjects with regard to subtype, expression of homing and chemokine receptors, and in vitro reactivity to H. pylori antigens. Higher numbers of CD4؉ but similar numbers of CD8 ؉ lamina propria T cells were isolated from stomach biopsies from H. pylori-positive compared to H. pylori-negative individuals. CD4 Helicobacter pylori colonizes the mucus layer and the epithelium in the stomach as well as areas of gastric metaplasia in the duodenum. Most infected individuals remain asymptomatic, but 10 to 15% of those infected develop peptic ulcers, and 1 to 2% develop gastric cancer (13). H. pylori infection induces gastritis with infiltration of neutrophils, macrophages, dendritic cells, as well as B and T cells into the stomach lamina propria (13, 38). A majority of H. pylori-infected individuals also develop duodenitis (16, 44), but less is known about the duodenal immune responses to the infection.T cells seem to play an important role in the immunity against H. pylori. The mucosal inflammation induced by H. pylori is T-cell dependent, as H. pylori infection does not induce gastritis in T-cell-deficient mice, unless T cells are transferred to the mice (10). However, the natural T-cell responses to H. pylori are not protective, as the infection normally remains for life. Recent studies indicate that regulatory T cells suppress the T-cell responses to H. pylori infection, thereby contributing to the persistent bacterial colonization (25,26,36). However, vaccination can induce partial protection against Helicobacter infections in mice, and CD4 ϩ T cells have been shown to be important for this protection. Thus, protection cannot be achieved in mice lacking CD4 ϩ T cells, whereas protection can be induced in the absence of B cells or CD8 ϩ T cells (12,31,42). The natural T-cell response to H. pylori is of the Th1 type (23), and this type of response also seems to be involved in vaccine-induced protection against the infection (3).To achieve protection after vaccination, T cells have to be recruited to the stomach mucosa. Thus, Michetti et al. demonstrated that immunization-induced protection against H. felis infection is abolished by administration of antibodies that block the interaction between the ␣ 4 ␤ 7 integrin expressed by gut-homing lymphocytes and the mucosal addressin cellular adhesion molecule 1 (MAdCAM-1) expressed on endothelial cells in intestinal as well as gastric mucosa (28). Less is known about how T cells are recruited to the gastrointestinal mucosa during natural H. pylori infection. However, indirect evidence suggests that the homing receptors ␣ 4 ␤ 7 and L-selectin both mediate homing of H. pylori-specific T cells to H. pyloriinfected human mucosa. Thus, circulating T cell...

The aim of this study was to evaluate the axial and radial distribution of histological markers including hyperplasia of the basal cell layer, elongation of the papillae and dilatation of the intercellular spaces of the squamous epithelium in patients with nonerosive reflux disease compared to controls and to relate this to the macroscopic topography in erosive reflux disease. Two different study populations were included in this report. Endoscopic esophageal biopsies were taken from 21 healthy control subjects and 21 nonerosive reflux disease patients before and after 4 weeks of esomeprazole therapy. Endoscopic still images from 50 erosive reflux disease patients were reviewed for the radial orientation of LA grade A and/or B esophagitis (Los Angeles criteria for grading of reflux esophagitis). The 3 o'clock position of the squamocolumnar junction showed significantly thicker basal cell layer (P=0.011) and more intercellular space dilatation (P=0.01) in nonerosive reflux disease patients compared to the 9 o'clock position. Only a significant difference in dilatation of the intercellular spaces (P=0.018) between nonerosive reflux disease patients and controls were observed in the 3 o'clock region at the squamocolumnar junction, whereas 1-2 cm orally, all three histological criteria differed significantly (P

Helicobacter pylori infection results in a substantial increase in MMP-9 and MMP-2 activity in the gastric mucosa, probably contributed to in large part by tissue-resident macrophages, while no changes were seen in the TIMP levels. The net increase in gastric MMP activity is likely to contribute to tissue damage during H. pylori-associated gastritis.

Introduction: Dilatation of intercellular spaces of the esophageal squamous epithelium has been suggested as a marker of early acid reflux-induced damage. This change is a potentially useful addition to histomorphological changes that represent so called minimal endoscopic lesions. We have assessed dilatation of intercellular spaces with regard to: (1) interobserver variability, and (2) whether the incidence of this varies between ‘red streaks’ and the adjacent normal looking squamous epithelium. Methods: Esophageal biopsies from 44 patients with chronic gastro-esophageal reflux (GERD) were evaluated. At endoscopy, these patients had one or more red streaks on the tops of the mucosal folds in the distal esophagus. Biopsies were taken from the red streaks and from the normal-appearing mucosa 1 cm lateral to the red streaks. Biopsies were assessed in a blinded fashion by two independent pathologists (MV & RF). Criteria for assessing intercellular space dilatation were evaluated and agreed on prior to the study. Results: Good interobserver agreement was recorded (kappa = 0.82 at the streaks and 0.77 for the control tissues) for absence/presence of intercellular space dilatation. Red streak and control biopsies differed significantly (p = 0.0001), with respect to presence of dilated intercellular spaces, with 90.5 % of the former demonstrating this as present compared to 56.1% in the controls. Conclusion: This study supports the concept that esophageal mucosal minimal changes due to reflux is localised and that dilatation of intercellular spaces is an early sign of reflux-induced epithelial damage. The low interobserver variability in the assessment of intercellular space dilatation suggests that this may be a useful variable for assessment of early signs of acid-reflux induced damage to the squamous epithelium of the esophagus by use of light microscopy.