RESUMEN
The parietal cell (PC) plays an important role in normal gastric physiology and in common diseases of the stomach. Although the genes involved in acid secretion are well known, there is limited molecular information about other aspects of PC function. We have generated a comprehensive database of genes expressed preferentially in PCs relative to other gastric mucosal cell lineages. PCs were purified from FVB/N mouse stomachs by lectin panning. cRNA generated from PC-enriched (PC(+)) and PC-depleted (PC(-)) populations were used to query oligonucleotide-based microarrays. False-positive signals were filtered by using a new algorithm for noise reduction and selected results independently audited by real-time quantitative reverse transcription (RT)-PCR. The annotated database of 240 genes reveals previously unappreciated aspects of cellular function, including factors that may mediate PC regulation of gastric stem cell proliferation. PC(+) and PC(-) expression profiles were also prepared from germ-free mice 2 and 8 weeks after colonization with a clinical isolate of Helicobacter pylori (Hp)--the pathogen that produces acid-peptic disease (gastritis, ulcers) in humans. Whereas PC(+) gene expression was remarkably constant, the PC(-) fractions demonstrated a robust, evolving host response, with increased expression of genes involved in cell motility/migration, extracellular matrix interactions, and IFN responses. The consistency of PC(+) gene expression allowed identification of a cohort of 92 genes enriched in PCs under all conditions studied. These genes provide a molecular profile that can be used to define this epithelial lineage under a variety of physiologic, pharmacologic, and pathologic stimuli.
Asunto(s)
Expresión Génica , Helicobacter pylori/fisiología , Células Parietales Gástricas/microbiología , Animales , Bases de Datos Factuales , Modelos Animales de Enfermedad , Femenino , Vida Libre de Gérmenes , Infecciones por Helicobacter/microbiología , Masculino , Metaanálisis como Asunto , Ratones , Células Parietales Gástricas/citologíaRESUMEN
Mathematical modeling has helped develop hypotheses about the role of microbial and host parameters in the initial and subsequent phases of Helicobacter pylori colonization. Transgenic mice have been used to test the hypothesis that the outcome of colonization is influenced by whether bacteria can adhere to available epithelial cell receptors. Complementary use of modeling and experimental approaches should facilitate studies of H. pylori pathogenesis.
Asunto(s)
Infecciones por Helicobacter/microbiología , Helicobacter pylori/fisiología , Helicobacter pylori/patogenicidad , Mucosa Intestinal/microbiología , Animales , Infecciones por Helicobacter/patología , Helicobacter pylori/genética , Humanos , Ratones , Ratones Transgénicos , Modelos BiológicosRESUMEN
Helicobacter pylori infection of the human stomach is associated with altered acid secretion, loss of acid-producing parietal cells, and, in some hosts, adenocarcinoma. We have used a transgenic mouse model to study the effects of parietal cell ablation on H. pylori pathogenesis. Ablation results in amplification of the presumptive gastric epithelial stem cell and its immediate committed daughters. The amplified cells produce sialylated oncofetal carbohydrate antigens that function as receptors for H. pylori adhesins. Attachment results in enhanced cellular and humoral immune responses. NeuAc alpha 2,3Gal beta 1,4 glycoconjugates may not only facilitate persistent H. pylori infection in a changing gastric ecosystem, but by promoting interactions with lineage progenitors and/or initiated cells contribute to tumorigenesis in patients with chronic atrophic gastritis.
Asunto(s)
Mucosa Gástrica/metabolismo , Glicoconjugados/metabolismo , Helicobacter pylori/metabolismo , Células Parietales Gástricas/fisiología , Animales , Antígenos de Neoplasias/metabolismo , Adhesión Bacteriana , División Celular , Linaje de la Célula , Células Epiteliales/microbiología , Femenino , Mucosa Gástrica/citología , Mucosa Gástrica/microbiología , Mucosa Gástrica/ultraestructura , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/crecimiento & desarrollo , Helicobacter pylori/inmunología , Helicobacter pylori/patogenicidad , Lectinas/metabolismo , Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Ácido N-Acetilneuramínico/metabolismo , Células Madre/citología , Células Madre/metabolismo , Células Madre/microbiología , Células Madre/ultraestructuraRESUMEN
Genetically defined in vivo models are needed to assess the importance of target cell attachment in bacterial pathogenesis. Gastric colonization by Helicobacter pylori in human populations is common and persistent, and has various outcomes including peptic ulcers and cancer. The impact of attachment on the course of infection was examined in transgenic mice expressing a human receptor for H. pylori in their gastric epithelium. Persistent infection by a clinical isolate occurred at comparable microbial densities in transgenic and nontransgenic littermates. However, microbial attachment in transgenic mice resulted in production of autoantibodies to Lewisx carbohydrate epitopes shared by bacteria and acid-secreting parietal cells, chronic gastritis, and parietal cell loss. This model should help identify bacterial and host genes that produce attachment-related pathology.
Asunto(s)
Adhesinas Bacterianas/metabolismo , Adhesión Bacteriana/fisiología , Mucosa Gástrica/microbiología , Mucosa Gástrica/fisiopatología , Infecciones por Helicobacter , Infecciones por Helicobacter/fisiopatología , Helicobacter pylori/fisiología , Antígenos del Grupo Sanguíneo de Lewis/metabolismo , Adulto , Animales , Moléculas de Adhesión Celular/biosíntesis , Modelos Animales de Enfermedad , Mucosa Gástrica/metabolismo , Técnicas de Transferencia de Gen , Infecciones por Helicobacter/metabolismo , Humanos , Antígenos del Grupo Sanguíneo de Lewis/genética , Ratones , Ratones TransgénicosRESUMEN
Sixty-four consecutive patients which on upper gastrointestinal endoscopy had endoscopic signs of atrophic body gastritis were investigated with standard histology examinations of gastric biopsies, serology and/or culture for Helicobacter pylori and with standard blood chemistry profile. A histologic diagnosis of atrophy could be made in only 27 of the 64 patients (42%). Of these 27 patients, 5 had the pernicious anaemia (PA) type (19%), 22 had not (81%). Past and/or present H. pylori infection was found in 16/22 non-PA patients (73%) but in none of the PA patients (p = 0.00572). The present study thus confirms earlier findings that non-PA type atrophic body gastritis is more common than the PA type and suggests that, as opposed to PA-type atrophy, it is related to H. pylori infection.
Asunto(s)
Gastritis Atrófica/microbiología , Infecciones por Helicobacter/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Anemia Perniciosa/diagnóstico , Anticuerpos Antibacterianos/inmunología , Endoscopía Gastrointestinal , Ensayo de Inmunoadsorción Enzimática , Femenino , Gastrinas/sangre , Gastritis Atrófica/patología , Infecciones por Helicobacter/patología , Helicobacter pylori/inmunología , Helicobacter pylori/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , RadioinmunoensayoRESUMEN
Serum IgG antibodies of Helicobacter pylori were detected in single-dilution ELISA using glycine extracted material. Among 148 endoscopy patients 59% displayed antibodies; as expected, a higher occurrence (90%) was found in patients with positive gastric culture for H. pylori than in culture negative patients (37%). Among 68 blood donors the frequency of H. pylori antibodies was 28%. In 73 children less than 15 years of age examined for unrelated disorders the occurrence was 4%. By immunoblotting using the same extract, 3 prominent bands, 29K, 54K and 60K and several weak bands were identified. These were formed by 57%, 92%, and 65%, respectively, of the ELISA positive patient sera. Comparing culture positive and negative patients, the 3 bands occurred more often among the culture positive subjects though between 18 and 61% of the sera from culture negative patients gave either of the bands. When comparing the glycine extracts of 4 different H. pylori strains with separate haemagglutinating patterns no differences in the position of the major bands emerged. By absorption experiments no immunological cross-reactivity with components of Escherichia coli, Klebsiella pneumoniae, Campylobacter jejuni or C. fetus was found. Thus, the glycine extract seemed specific for the detection of antibodies to H. pylori.