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)

Autoimmune gastritis (AIG) is an experimental model that closely resembles human autoimmune gastritis, the underlying pathology of pernicious anemia. Pathogenic CD4+ T cells are reactive to the parietal cell autoantigen, H/K ATPase, and are controlled by CD4+CD25+ T cells in an immunosuppressive cytokine-independent manner. Comparison of CD4+CD25+ T cell-mediated suppression in other autoimmune models shows inconsistencies with respect to requirements of cytokines for immunosuppression. More recent data, however, indicate that the evidence for requirement of IL-10 and TGF-beta could be due to the complex nature of the T cells causing the disease as well as the role of induced regulatory T cell populations. AIG provides a well-defined model that may allow for better analysis of CD4+CD25+ T cell in vivo biology. Evidence from this model indicates that immune responses must be initiated and then CD4+CD25+ T cells are recruited to control the quality of the immune response.
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PMID:Autoimmune gastritis is a well-defined autoimmune disease model for the study of CD4+CD25+ T cell-mediated suppression. 1598 80

H+/K+-ATPase beta-subunit-deficient mice (129/Sv background) display numerous pathologies in the stomach. Expression of the mutation in BALB/cCrSlc mice results in the development of an aberrant 'mucus-rich' cell population. 'Mucus-rich' cells have been described in stomachs of mice with autoimmune gastritis, a disease mediated by CD4+ T cells. Other pathological features of autoimmune gastritis are similar to those in H+/K+ beta-deficient mice and include a mononuclear cell infiltrate in the gastric mucosa, non-functional or absent parietal cells, depletion of zymogenic cells, hypergastrinaemia, and gastric unit hypertrophy caused by immature cell hyperplasia. The present study investigates further the aberrant gastric 'mucus-rich' cell lineage and analyses the mRNA expression of mucus cell products TFF1 and TFF2. 'Mucus-rich' cells stained for both acidic and neutral mucins, and with a TFF2-specific antibody. Stomachs from both models expressed decreased TFF1 mRNA and reciprocally increased TFF2 mRNA. The involvement of gastrin in regulating trefoil mRNA expression was also investigated using gastrin-deficient mice. In contrast to previous findings, gastrin did not positively regulate TFF1 mRNA expression, but there was possible augmentation of TFF2. Additionally, a clear role for inflammation was established involving both polymorphonuclear and mononuclear cells in these models, and a link was found between mucosal hypertrophy and increased interleukin-11 (IL-11) expression.
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PMID:Reciprocal changes in trefoil 1 and 2 expression in stomachs of mice with gastric unit hypertrophy and inflammation. 1598 82

Murine autoimmune gastritis is one of the most well-defined organ-specific autoimmune diseases. CD4(+) T cells, which mediate the disease, recognize the highly abundant gastric H(+)/K(+) ATPase heterodimer. The H(+)/K(+) ATPase alpha subunit is also expressed in the thymus, in an aire-independent manner, whereas the H(+)/K(+) ATPase beta subunit is absent from the thymus. Analysis of both H(+)/K(+) ATPase-specific T cell receptor transgenic mice with different affinities for the gastric antigen and mice deficient in the H(+)/K(+) ATPase subunits has provided information on thymic and peripheral selection events. The H(+)/K(+) ATPase antigens play an important role in purging the repertoire of gastritogenic T cells, and recent data have suggested that this tolerance induction occurs primarily in the periphery. The gastritis system provides a powerful approach to determine the impact of peripheral antigen presentation in the target organ draining lymph node on tolerance and autoimmune disease.
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PMID:Shaping the T cell repertoire to a bona fide autoantigen: lessons from autoimmune gastritis. 1621 18

The stimulation of gastric acid secretion from parietal cells involves both intracellular calcium and cAMP signaling. To understand the effect of increased cAMP on parietal cell function, we engineered transgenic mice expressing cholera toxin (Ctox), an irreversible stimulator of adenylate cyclase. The parietal cell-specific H(+),K(+)-ATPase beta-subunit promoter was used to drive expression of the cholera toxin A1 subunit (CtoxA1). Transgenic lines were established and tested for Ctox expression, acid content, plasma gastrin, tissue morphology, and cellular composition of the gastric mucosa. Four lines were generated, with Ctox-7 expressing approximately 50-fold higher Ctox than the other lines. Enhanced cAMP signaling in parietal cells was confirmed by observation of hyperphosphorylation of the protein kinase A-regulated proteins LASP-1 and CREB. Basal acid content was elevated and circulating gastrin was reduced in Ctox transgenic lines. Analysis of gastric morphology revealed a progressive cellular transformation in Ctox-7. Expanded patches of mucous neck cells were observed as early as 3 mo of age, and by 15 mo, extensive mucous cell metaplasia was observed in parallel with almost complete loss of parietal and chief cells. Detection of anti-parietal cell antibodies, inflammatory cell infiltrates, and increased expression of the Th1 cytokine IFN-gamma in Ctox-7 mice suggested that autoimmune destruction of the tissue caused atrophic gastritis. Thus constitutively high parietal cell cAMP results in high acid secretion and a compensatory reduction in circulating gastrin. High Ctox in parietal cells can also induce progressive changes in the cellular architecture of the gastric glands, corresponding to the development of anti-parietal cell antibodies and autoimmune gastritis.
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PMID:Parietal cell hyperstimulation and autoimmune gastritis in cholera toxin transgenic mice. 1639 75

A deficiency of CD4+CD25+ regulatory T cells (CD25+ Tregs) in lymphopenic mice can result in the onset of autoimmune gastritis. The gastric H/K ATPase alpha (H/Kalpha) and beta (H/Kbeta) subunits are the immunodominant autoantigens recognized by effector CD4+ T cells in autoimmune gastritis. The mechanism by which CD25+ Tregs suppress autoimmune gastritis in lymphopenic mice is poorly understood. To investigate the antigenic requirements for the genesis and survival of gastritis-protecting CD25+ Tregs, we analyzed mice deficient in H/Kbeta and H/Kalpha, as well as a transgenic mouse line (H/Kbeta-tsA58 Tg line 224) that lacks differentiated gastric epithelial cells. By adoptive transfer of purified T cell populations to athymic mice, we show that the CD25+ Treg population from mice deficient in either one or both of H/Kalpha and H/Kbeta, or from the H/Kbeta-tsA58 Tg line 224 mice, is equally effective in suppressing the ability of polyclonal populations of effector CD4+ T cells to induce autoimmune gastritis. Furthermore, CD25+ Tregs, from either wild-type or H/Kalpha-deficient mice, dramatically reduced the expansion of pathogenic H/Kalpha-specific TCR transgenic T cells and the induction of autoimmune gastritis in athymic recipient mice. Proliferation of H/Kalpha-specific T cells in lymphopenic hosts occurs predominantly in the paragastric lymph node and was dependent on the presence of the cognate H/Kalpha Ag. Collectively, these studies demonstrate that the gastritis-protecting CD25+ Tregs do not depend on the major gastric Ags for their thymic development or their survival in the periphery, and that CD25+ Tregs inhibit the Ag-specific expansion of pathogenic T cells in vivo.
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PMID:CD4+CD25+ regulatory T cells inhibit the antigen-dependent expansion of self-reactive T cells in vivo. 1642 90

The development and introduction into clinical practice of proton pump inhibitors (PPIs) have influenced the management of acid-peptic disorders dramatically. PPIs inhibit the gastric hydrogen/potassium adenosine triphosphatase selectively and irreversibly which is the final step in acid secretion. PPIs are currently the most effective form of therapy in acid-peptic diseases. All PPIs are potent, effective and generally safe, but little different in equivalent doses. PPIs undergo hepatic metabolism by cytochrome P450 (CYP) system. Polymorphism of CYP2C19 influences the pharmacokinetics and pharmacodynamics of PPIs. Doses and dosing schemes of PPIs based on CYP2C19 genotype status is expected to increase the efficacy in clinical outcome. The major indication of PPIs are acid-related diseases such as peptic ulcers and their complications, gastroesophageal reflux diseases, Zollinger-Ellison syndrome and eradication of Helicobacter pylori with antibiotics and dyspepsia. The potency and cost-effectiveness of PPIs have extended their clinical uses. However, their widespread and long-term use may limit the therapeutic benefit between efficacy and clinical problems such as acid rebound hypersecretion, enhanced oxyntic gastritis, problems with carcinoids in rodents and long-term concern for gastric cancer development. Further studies are needed to minimize the side effects and to maximize the therapeutic effects of PPIs.
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PMID:[Clinical use of proton pump inhibitors in gastrointestinal diseases]. 1655 71

A cardinal feature of organ-specific autoimmunity is destructive pathology in the target organ. In human and experimental models of autoimmune gastritis, mononuclear cell infiltration and cellular destruction in the gastric mucosa are disease hallmarks. Strategies to cure autoimmune disease must not only establish immunological tolerance to autoantigen, but also rid the organ of pathogenic autoreactive cells. The present study has assessed the effect of prednisolone treatment in clearing the inflammatory infiltrate in experimental autoimmune gastritis and in preventing disease relapse in athymic compared with euthymic mice. Experimental autoimmune gastritis was induced by neonatal thymectomy or by transgenic expression of GM-CSF (PC-GMCSF mice). Groups of mice were treated with prednisolone (10 mg/kg per day) for 10 weeks or with prednisolone for 10 weeks followed by 10 weeks without prednisolone. Stomachs were examined for gross morphological changes, and by histology and immunohistochemistry for composition of inflammatory infiltrate and gastric mucosal integrity. Autoantibody to gastric H+/K+ ATPase was determined by ELISA. Prednisolone promoted remission of gastritis in both mouse models of experimental autoimmune gastritis, evident by reduction in stomach size, clearing of gastric inflammatory infiltrate, and regeneration of the gastric mucosa. Prednisolone withdrawal resulted in disease relapse in all PC-GMCSF mice, whereas approximately 40% of neonatal thymectomy mice retained normal stomach morphology and remained free of gastric pathology. It is concluded that prednisolone promotes remission and gastric mucosal regeneration in experimental autoimmune gastritis. Prolonged remission of autoimmune gastritis in some athymic mice suggests a role for the thymus in disease relapse.
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PMID:Prednisolone promotes remission and gastric mucosal regeneration in experimental autoimmune gastritis. 1671 Aug 33

With the steadily increasing occurrence of antibiotic resistance in bacteria, there is a great need for new antibacterial compounds. The approach described here involves targeting virulence-related bacterial type IV secretion systems (TFSSs) with small-molecule inhibitors. The cag TFSS of Helicobacter pylori was chosen as a model, and novel inhibitors directed against the cag VirB11-type ATPase Cagalpha were identified. The cag genes encode proteins that are components of a contact-dependent secretion system used by the bacterium to translocate the effector molecule CagA into host cells. Translocated CagA is associated with severe gastritis, and carcinoma. Furthermore, functional TFSSs and immunodominant CagA play a role in interleukin (IL)-8 induction, which is an important factor for chronic inflammation. Inhibitors of Cagalpha were identified by high-throughput screening of chemical libraries that comprised 524 400 small molecules. The ATPase activity of Cagalpha was inhibited by the selected compounds in an in vitro enzymic assay using the purified enzyme. The most active compound, CHIR-1, reduced TFSS function to an extent that cellular effects on AGS cells mediated by CagA were virtually undetectable, while reduced levels of IL-8 induction were observed. Gastric colonization by CHIR-1-pre-treated bacteria was found to be impaired in a dose-dependent manner using a mouse model of infection. Small-molecule Cagalpha inhibitors, the first described inhibitors of a TFSS, are potential candidates for the development of new antibacterial compounds that may lead to alternative medical treatments. The compounds are expected to impose weak selective pressure, since they target virulence functions. Moreover, the targeted virulence protein is conserved in a variety of bacterial pathogens. Additionally, TFSS inhibitors are potent tools to study the biology of TFSSs.
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PMID:Inhibitors of Helicobacter pylori ATPase Cagalpha block CagA transport and cag virulence. 1700 73

Overlapping neural, hormonal, and paracrine pathways finely regulate gastric acid secretion. In rats and guinea pigs, most of the intrinsic neural innervation to the gastric mucosa originates in the myenteric plexus. In contrast, human stomachs have a clearly defined submucosal plexus that contains a variety of transmitters including nitric oxide, vasoactive intestinal peptide (VIP), gastrin-releasing peptide (GRP), substance P, and calcitonin gene-related peptide (CGRP). Although GRP is known to participate in meal-stimulated acid secretion by releasing gastrin in a variety of laboratory animals, recent studies were unable to demonstrate a role for endogenous GRP in meal-stimulated gastrin secretion in humans. Pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the secretin-glucagon-VIP family, has been localized to gastric mucosal neurons and may participate in vagally mediated acid secretion. Two novel peptides, ghrelin and leptin, have been localized to the stomach. Peripheral administration of ghrelin stimulates and of leptin inhibits acid secretion. The binding of secretagogues to parietal cells generates changes in second messengers that regulate the translocation and activation of the proton pump, HK-ATPase. In resting cells, HK-ATPase is contained within cytoplasmic tubulovesicles in an inactive form. At stimulation, the tubulovesicles fuse with the apical canaliculi and the HK-ATPase is incorporated into the apical membrane where it actively pumps H ions in exchange for K. Acute infection with Helicobacter pylori results in hypochlorhydria, whereas chronic infection can cause either hypo- or hyperchlorhydria, depending on the distribution of the infection and the degree of corpus gastritis. Recent studies suggest that inflammatory cytokines, produced in response to the organism, can play a role in the perturbations in acid and gastrin secretion induced by H. pylori.
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PMID:Gastric secretion. 1703 42

Researchers have developed murine lymphopenic, non-lymphopenic, transgenic, spontaneous and infectious agent based models to induce an experimental autoimmune gastritis (EAG) for the study of human organ-specific autoimmune disease. These models result in a chronic inflammatory mononuclear cell infiltrate in the gastric mucosa, destruction of parietal and zymogenic cells with autoantibodies reactive to the gastric parietal cells and the gastric H+/K+ ATPase (ATP4), arguably hallmarks of a human autoimmune gastritis (AIG). In the case of AIG, it is well documented that, in addition to parietal cell antibodies being detected in up to 90% of patients, up to 70% have intrinsic factor antibodies with the later antibodies considered highly specific to patients with pernicious anemia. This is the first report specifically investigating the occurrence of intrinsic factor antibodies, cobalamin deficiency and pernicious anemia in EAG models. We conclude, in contrast to AIG, that, in the three EAG models examined, intrinsic factor is not selected as a critical autoantigen.
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PMID:Murine experimental autoimmune gastritis models refractive to development of intrinsic factor autoantibodies, cobalamin deficiency and pernicious anemia. 1703 94


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