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Biomedical subjects

L M Judd

Publications and source records attributed to L M Judd.

7 recordsLinked to original sources
PubMed2006

Differentiation of the Gastric Mucosa IV. Role of trefoil peptides and IL-6 cytokine family signaling in gastric homeostasis.

Gastric trefoil peptides mediate mucosal repair by stimulating cell migration, inhibiting apoptosis and inflammation, and likely augmenting the barrier function of mucus. One of these, tff1, is a gastric-specific tumor suppressor gene, which when repressed is associated with gastric cancer progression. IL-6 family cytokines play an important role in maintaining gastric homeostasis by regulating tff1 and other mediators of mucosal proliferation, inflammation, angiogenesis, and apoptosis. In this review the signaling cascades downstream of the common IL-6 cytokine family coreceptor gp130 that contribute to control of this homeostasis are described, as are the pathological outcomes of imbalancing these pathways.

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PubMed2005

Reciprocal changes in trefoil 1 and 2 expression in stomachs of mice with gastric unit hypertrophy and inflammation.

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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PubMed2001

Requirements for autoimmune responses to mouse gastric autoantigens.

Autoimmune gastritis, in which the H+/K(+)-ATPase of parietal cells is the major antigen, is one of the most common autoimmune diseases. Here we examined if specific properties of the H+/K(+)-ATPase or parietal cells are involved in rendering them autoimmune targets. The model antigens beta-galactosidase and ovalbumin (OVA) were expressed in parietal cells of transgenic mice. On experimental induction of autoimmune gastritis by neonatal thymectomy, autoantibodies to beta-galactosidase developed in mice expressing beta-galactosidase in parietal cells, a response that was independent of either the response to the gastric H+/K(+)-ATPase or gastric inflammation. In contrast, mice that expressed OVA in parietal cells did not exhibit an antibody response to OVA after thymectomy. However, increasing the frequency of anti-OVA T lymphocytes in OVA-expressing mice resulted in autoantibodies to OVA and gastritis. These studies indicate that parietal cells can present a variety of antigens to the immune system. Factors such as the identity and expression level of the autoantigen and the frequency of autoreactive T cells play a role in determining the prevalence and outcome of the particular immune response. In addition, as not all mice of a particular genotype displayed autoimmunity, random events are involved in determining the target of autoimmune recognition.

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PubMed2001

Regulation of gastric epithelial cell development revealed in H(+)/K(+)-ATPase beta-subunit- and gastrin-deficient mice.

The gastric H(+)/K(+)-ATPase is essential for normal development of parietal cells. Here we have directly assessed the role of the H(+)/K(+)-ATPase beta-subunit (H/K-beta) on epithelial cell development by detailed quantitation of the epithelial cell types of the gastric mucosa of H/K-beta-deficient mice. H/K-beta-deficient mice had a 3.1-fold increase in the number of immature cells per gastric unit; however, the numbers of surface mucous and parietal cells were similar to those in the gastric units of wild-type mice. The effect of elevated gastrin levels in the H/K-beta-deficient mice was determined by producing mice that are also deficient in gastrin. We demonstrated that the increased production of immature cells and resulting hypertrophy is caused by the overproduction of gastrin. However, the depletion of zymogenic cells, which is another feature of H/K-beta-deficient mice, is independent of hypergastrinemia. Significantly, parietal cells of H/K-beta- and gastrin-deficient mice had abnormal secretory membranes and were devoid of resting tubulovesicular membranes. Together these data suggest a homeostatic mechanism limiting the number of immature cells that can develop into end-stage epithelial cells and indicate a direct role for H/K-beta in the development of mature parietal cells.

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PubMed1999

Gastric H(+),K(+)-adenosine triphosphatase beta subunit is required for normal function, development, and membrane structure of mouse parietal cells.

BACKGROUND & AIMS: Parietal cells of the gastric mucosa contain a complex and extensive secretory membrane system that harbors gastric H(+),K(+)-adenosine triphosphatase (ATPase), the enzyme primarily responsible for acidification of the gastric lumen. We have produced mice deficient in the H(+),K(+)-ATPase beta subunit to determine the role of the protein in the biosynthesis of this membrane system and the biology of gastric mucosa. METHODS: Mice deficient in the H(+), K(+)-ATPase beta subunit were produced by gene targeting. RESULTS: The stomachs of H(+),K(+)-ATPase beta subunit-deficient mice were achlorhydric. Histological and immunocytochemical analyses with antibodies to the H(+),K(+)-ATPase alpha subunit revealed that parietal cell development during ontogeny was retarded in H(+), K(+)-ATPase beta subunit-deficient mice. In 15-day-old mice, cells with secretory canaliculi were observed in wild-type but not in H(+), K(+)-ATPase beta subunit-deficient mice. Parietal cells of H(+), K(+)-ATPase beta subunit-deficient mice 17 days and older contained an abnormal canaliculus that was dilated and contained fewer and shorter microvilli than normal. In older parietal cells, the abnormal canaliculus was massive (25 micrometer in diameter) and contained few microvilli. We did not observe typical tubulovesicular membranes in any parietal cell from H(+),K(+)-ATPase beta subunit-deficient mice. Histopathologic alterations were only observed in the stomach. CONCLUSIONS: The H(+),K(+)-ATPase beta subunit is required for acid-secretory activity of parietal cells in vivo, normal development and cellular homeostasis of the gastric mucosa, and attainment of the normal structure of the secretory membranes.

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PubMed1999

Autoimmune gastritis results in disruption of gastric epithelial cell development.

We have investigated the underlying basis of the lesion in murine autoimmune gastritis, a model of the human disease pernicious anemia. The disease is mediated by T lymphocytes and characterized by selective depletion of parietal and zymogenic cells from the gastric unit (gland) together with gastric epithelial cell hyperplasia. The gastric units of gastritic stomachs contained 2.3-fold more cells than normal and accumulated rapidly dividing, short-lived gastric epithelial stem cells and mucous neck cells. Most of these immature cells failed to differentiate into end-stage cells but rather appeared to die by apoptosis. We also found no correlation between anti-parietal cell autoantibody titers and the degree of gastric pathology, providing further evidence that autoantibodies do not play a direct role in the pathogenesis of gastritis. Taken together, the normal developmental pathways of the gastric mucosa are disrupted in autoimmune gastritis, resulting in an amplification of immature cell types. The differentiation of these immature cells appears to be blocked, contributing to depletion of end-stage cells. This scenario provides an explanation for depletion of not only parietal cells but also zymogenic cells even though they are not directly targeted by the immune system.

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