Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Murine autoimmune gastritis, induced by neonatal thymectomy, is characterized by a mononuclear infiltrate within the gastric mucosa, loss of parietal and zymogenic cells and circulating autoantibodies to the gastric H/K ATPase. The infiltrate contains both CD4+ and CD8+ T cells. Here we have investigated the roles of CD4+ and CD8+ T cells in the development of gastritis by in vivo treatment with depleting rat anti-CD4 and anti-CD8 monoclonal antibodies. Depletion of CD4+ T cells decreased the incidence of gastric mononuclear infiltrates from 63% (5/8), observed in normal rat immunoglobulin G (IgG)-injected mice, to 8% (1/12) and also abolished the production of antigastric autoantibodies. In contrast, depletion of CD8+ T cells did not reduce the incidence of gastritis. The absence of CD8+ T cells in the infiltrate of the stomach of anti-CD8(+)-treated mice was confirmed by immunocytochemistry. These results argue that neonatal thymectomy-induced autoimmune gastritis is mediated by CD4+ T cells and that CD8+ T cells do not play a significant role in the development of the gastric lesion.
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PMID:CD4+ T cells, but not CD8+ T cells, are required for the development of experimental autoimmune gastritis. 964 Feb 52

Autoimmune gastritis is the underlying pathological lesion of pernicious anemia in humans. The lesion is characterized by a chronic inflammatory infiltrate in the gastric mucosa with loss of parietal and zymogenic cells. It is associated with circulating autoantibodies to the gastric H/K-ATPase, the enzyme responsible for acidification of gastric juice. Experimental models of autoimmune gastritis have previously been produced in mice after a variety of manipulations, including thymectomy. Here we report for the first time a spontaneous mouse model of autoimmune gastritis in C3H/He mice. The spontaneous gastritis is also accompanied by circulating autoantibodies to the gastric H/K-ATPase. The spontaneous mouse model should be useful for studies directed toward the immunopathogenesis and treatment of autoimmune gastritis.
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PMID:Spontaneous autoimmune gastritis in C3H/He mice: a new mouse model for gastric autoimmunity. 977 63

Thymectomy at day 3 of life (d3Tx) results in the development of organ-specific autoimmunity. We have recently shown that d3Tx BALB/c mice which develop autoimmune gastritis contain CD4+ T cells specific for the gastric parietal cell proton pump, H/K ATPase. Here, we demonstrate that freshly explanted gastric lymph node (LN) cells from d3Tx mice react significantly to the H/K ATPase alpha chain, but only marginally to the beta chain. Two H/K ATPase-reactive T cell lines were derived from the gastric LN of d3Tx mice. Both are CD4+, TCR alpha/beta-, and I-Ad restricted, and recognize distinct peptides from the H/K ATPase alpha chain. One cell line secretes Th1 and the other Th2 cytokines, but both are equally potent in inducing gastritis with distinct profiles of cellular infiltration in nu/nu recipient animals. Neither of the cell lines induced disease in normal BALB/c recipients and transfer of disease to nu/nu recipients was blocked by co-transfer of normal BALB/c spleen cells containing CD4+ CD25+ cells. Although CD4+ CD25+ T cells are thought to emigrate from the thymus after day 3 of life, they could be identified in LN of 2-day-old animals. The capacity of CD4+ CD25+ T cells to abrogate the pathogenic activity in vivo of both activated Th1/Th2 lines strongly suggests that this suppressor T cell population may have a therapeutic role in other models of established autoimmunity. The availability of well-characterized lines of autoantigen-specific T cells should greatly facilitate the analysis of the mechanism of action and target of the CD4+ CD25+ immunoregulatory cells.
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PMID:Post-thymectomy autoimmune gastritis: fine specificity and pathogenicity of anti-H/K ATPase-reactive T cells. 1006 84

Peptic ulcer disease (PUD) is thought to result from an imbalance between aggressive (excessive) {especially gastric acid and pepsin} and protective (diminished) factors (gastric mucus and bicarbonate, prostaglandins and others) in the stomach. Recent attention has focused on the role of Helicobacter pylori as a cause of chronic active gastritis and a pathogenic factor in PUD. Antiulcer medications with proven efficacy in the treatment of acute PUD include histamine 2 (H 2)-receptor antagonists, H +/K +-ATPase (proton pump) inhibitors, antacids, sucralfate and prostaglandin analogues. The advent of proton pump inhibitors in particular has resulted in effective therapy for ulcers that previously would have been considered refractory. H 2-receptor antagonists and sucralfate are also useful for maintenance therapy of PUD. Recent interest has focused on strategies aimed at eradicating H. pylori and the ensuing change in the natural history of PUD, specifically a marked decrease in ulcer recurrence. In contrast, with standard treatment regimens there is a high rate of ulcer relapse (50 to 90%) after acute ulcer healing. Eradication of H. pylori has until now required a triple drug regimen of bismuth and 2 antibiotics, and is too cumbersome for routine use. It is likely, however, that treatment aimed at eradicating H. pylori will be routine in the near future and will represent a cost-effective alternative to standard long term maintenance therapy.
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PMID:Formulary management of antiulcer drugs: clinical considerations. 1014 96

We have previously shown that autoimmune gastritis can be elicited in mice by immunization with the gastric parietal cell H/K ATPase alpha beta heterodimer and that tolerance specifically induced to the H/K ATPase beta-subunit protects mice from the development of gastritis. Here we have identified the immunodominant gastritogenic epitope of the H/K ATPase beta-subunit (H/Kbeta). Epitope mapping was carried out with a panel of 21 overlapping peptides that spanned the entire sequence of the gastric H/K ATPase beta-subunit. T cells from gastric H/K ATPase-immunized mice responded to only one of the overlapping peptides, namely H/Kbeta253-277. Furthermore, a single subcutaneous immunization of 6-week-old BALB/c mice with the ATPase beta-subunit peptides resulted in a T-cell response to only H/Kbeta253-277. Multiple immunization with the overlapping H/K ATPase peptides demonstrated that H/Kbeta253-277 was capable of inducing a mononuclear infiltrate specifically within the gastric mucosa. We conclude that H/Kbeta253-277 is the dominant gastritogenic epitope of the gastric H/K ATPase.
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PMID:Identification of a gastritogenic epitope of the H/K ATPase beta-subunit. 1023 89

We purified a compound with strong inhibitory effect on H+, K(+)-ATPase from Paeoniae radix, which has been used in Japan for the treatment of gastritis and peptic ulcers. The compound was identified as 1,2,3,4,6,-penta-o-galloyl-beta-D-glucose by proton nuclear magnetic resonance, carbon-13 nuclear magnetic resonance, and fast atomic bombardment mass spectrometry. The IC50 of the compound for H+, K(+)-ATPase was 166 nmol/l. Kinetic analyses indicated that the inhibition of the enzyme by pentagalloylglucose was noncompetitive with respect to K+. Pentagalloylglucose had relatively weak inhibitory effects for Mg(+)-ATPase (IC50: > 10 mumol/l) and Na+, K(+)-ATPase (IC50: 2.7 mumol/l). Pentagalloylglucose also inhibited the accumulation of [14C]aminopyrine in parietal cells that had been isolated from guinea pig stomach and stimulated by 10 mumol/l histamine (IC50: 7.8 mumol/l) and 1 mmol/l dbc-AMP (IC50: 10 mumol/l). These results suggest that pentagalloylglucose is a potent inhibitor of H+, K(+)-ATPase and may be responsible for inhibition of acid secretion by Paeoniae radix.
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PMID:Pentagalloylglucose, an antisecretory component of Paeoniae radix, inhibits gastric H+, K(+)-ATPase. 1066 Aug 6

The catalytic alpha and glycoprotein beta subunits of the gastric H/K ATPase are major molecular targets in human and mouse autoimmune gastritis. We have previously shown that the H/K ATPase beta subunit is required for the initiation of mouse gastritis and identified a gastritogenic H/K ATPase beta subunit peptide (H/Kbeta253-277). Here we report the generation of MHC class II-restricted TCR transgenic mice using V(alpha)9 and V(beta)8.3 TCR chains with specificity for the gastritogenic H/Kbeta253-277 peptide. We found an 8-fold reduction in CD4(+) T cells in the thymus of the transgenic mice. Despite the reduction in intrathymic CD4(+) T cells, V(beta)8. 3-expressing T cells comprised the majority (>90%) of peripheral spleen and lymph node T cells. These peripheral T cells retained their capacity to proliferate in vitro to the H/Kbeta253-277 peptide. Using the responsive T cells, we have restricted the gastritogenic T cell epitope to H/Kbeta261-274. Despite the capacity of the peripheral T cells to proliferate in vitro to the peptide, the majority ( approximately 80%, 13 of 16) of transgenic mice remained free of gastritis while a minority (20%, three of 16) spontaneously developed an invasive and destructive gastritis. Our results confirm that H/Kbeta261-274 is a gastritogenic peptide. The data also suggest that CD4 T cell tolerance to the gastritogenic peptide in the transgenic mice is maintained by a combination of intrathymic and peripheral tolerance mechanisms.
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PMID:Tolerance and autoimmunity to a gastritogenic peptide in TCR transgenic mice. 1070 Apr 69

Recent studies suggest a significant association of Helicobacter pylori (H.p.) gastritis and antigastric autoimmunity. Sera of H.p. infected patients exhibit antigastric autoantibodies with high prevalence (over 50 percent of the cases) and with antiluminal and/or anticanalicular binding patterns on gastric mucosa. Models for the pathogenesis of this H.p. associated autoimmunity are antigenic mimicry or Th 1-induced expression of MHC class II and costimulatory molecules on gastric epithelial cells. The anticanalicular autoantibodies binding to gastric parietal cells show fine specificities for the alpha- and for the beta-subunit of the gastric H, K-ATPase, which correspond to the findings in classical autoimmune gastritis. They are significantly correlated with higher grades of corpus gastritis as well as morphologic and functional glandular atrophy of the corpus. The development of this antigastric autoimmunity apparently is a relevant pathogenic factor of the host reaction and might be crucial for the different types and outcomes of H.p. gastritis.
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PMID:[Helicobacter pylori infections and autoimmunity: the interplay in the pathogenesis of gastritis]. 1071 95

The gastric H+/K+ ATPase is the causative autoantigen recognized by CD4+ T cells that mediate autoimmune gastritis. Pathogenic CD4+ T cells are regulated by CD25+CD4+ T cells. Here, it is proposed that waves of activation and migration of antigen presenting cells and CD4+ T cells to and from the target organ and draining lymph node result in tissue damage.
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PMID:The causative H+/K+ ATPase antigen in the pathogenesis of autoimmune gastritis. 1087 77

Autoimmune gastritis in humans is a chronic inflammatory disease of the stomach accompanied by specific destruction of gastric parietal and zymogenic cells resulting in pernicious anemia. Human gastritis can be accurately reproduced in mice and is characterised by autoantibodies to the alpha- and beta-subunits of the gastric H/K ATPase (the enzyme responsible for gastric acid secretion) and cellular destruction of parietal and zymogenic cells within the gastric gland. Studies with these mouse models have given us our current concepts of the immunopathogenesis of the gastritis. Mouse models have shown that a T cell response is generated to the alpha- and beta-subunits of the H/K ATPase and that an immune response to the beta-subunit seems to be required for disease initiation. Using these models, we have defined key events associated with a damaging autoimmune response to the gastric H/K ATPase. The mechanisms associated with the cellular destruction associated with autoimmune gastritis are not know, but may involve signaling through death inducing pathways such as the Fas/FasL and TNF/TNFR pathways. This knowledge should permit us to develop strategies to prevent and treat the gastritis.
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PMID:Immunopathology of autoimmune gastritis: lessons from mouse models. 1096 31


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