Coordinate Interaction between IL-13 and Epithelial Differentiation Cluster Genes in Eosinophilic Esophagitis

Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
The Journal of Immunology (Impact Factor: 4.92). 03/2010; 184(7):4033-41. DOI: 10.4049/jimmunol.0903069
Source: PubMed


We have previously proposed that the pathogenesis of eosinophilic esophagitis (EE) is mediated by an IL-13-driven epithelial cell response associated with marked gene dysregulation including eotaxin-3 overproduction. In this study, we compared epithelial responses between healthy patients and those with EE, aiming to uncover molecular explanations for EE pathogenesis. Esophageal epithelial cells could be maintained for up to five passages, with 67% and 62% of cell lines reaching confluence in healthy controls and EE cases, respectively. Both sets of epithelial cells avidly responded to IL-13 at similar levels as assessed by eotaxin-3 production. Acidic pH increased cellular release of eotaxin-3 (4.6 +/- 1.98 ng/ml versus 12.46 +/- 2.90 ng/ml at pH 7.4 and 4, respectively; p < 0.05). Numerous epidermal differentiation complex (EDC) genes, such as filaggrin and SPRR3, were downregulated both in IL-13-stimulated esophageal epithelial cells and in EE biopsies specimens compared with healthy controls. Whereas the filaggrin loss of function mutation 2282del4 was overrepresented in EE compared with control individuals (6.1% versus 1.3% respectively; p = 0.0172), the decreased filaggrin expression was uniformly seen in all EE cases in vivo. Indeed, expression of the EDC genes filaggrin and involucrin was strongly decreased directly by IL-13. These results establish that the epithelial response in EE involves a cooperative interaction between IL-13 and expression of EDC genes.

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    • "It may act to maintain a favorable environment for allergic immune responses by recruiting T-lymphocytes, enhancing the proliferation of eosinophils in the bone marrow and inducing B-cell class switching to IgE production (66). Additionally, mast-cell-derived proteoglycans such as heparin are known to potentiate eotaxin-induced eosinophil recruitment in vivo (67), highlighting a key combinatory role amongst eosinophils and mast cells in EoE pathogenesis. "
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    ABSTRACT: Eosinophilic esophagitis (EoE) is an emerging disease characterized by esophageal eosinophilia (>15eos/hpf), lack of responsiveness to acid-suppressive medication and is managed by allergen elimination and anti-allergy therapy. Although the pathophysiology of EoE is currently unsubstantiated, evidence implicates food and aeroallergen hypersensitivity in genetically predisposed individuals as contributory factors. Genome-wide expression analyses have isolated a remarkably conserved gene-expression profile irrespective of age and gender, suggesting a genetic contribution. EoE has characteristics of mainly TH2 type immune responses but also some TH1 cytokines, which appear to strongly contribute to tissue fibrosis, with esophageal epithelial cells providing a hospitable environment for this inflammatory process. Eosinophil-degranulation products appear to play a central role in tissue remodeling in EoE. This remodeling and dysregulation predisposes to fibrosis. Mast-cell-derived molecules such as histamine may have an effect on enteric nerves and may also act in concert with transforming growth factor-β to interfere with esophageal musculature. Additionally, the esophageal epithelium may facilitate the inflammatory process under pathogenic contexts such as in EoE. This article aims to discuss the contributory factors in the pathophysiology of EoE.
    Full-text · Article · May 2014 · Frontiers in Pediatrics
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    • "Increasing numbers of patients with EoE have been reported in Western countries,(25–28) while many cases of EGE have been reported in Japan.(1,2) It is considered that Th2-mediated allergic response and Th2-type cytokines, including IL-5, 13, 15, and eotaxines, are involved in development of these diseases.(29–33) "
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    ABSTRACT: Recent studies have suggested that decrease in Helicobacter pylori infection may predispose to allergic diseases. However, there are few reports of the relationships of eosinophilic gastrointestinal disorders (EGIDs), especially eosinophilic gastroenteritis (EGE), with H. pylori infection. We investigated the possible influence of H. pylori infection on EGIDs in Japanese patients. We performed a case-control study to investigate the prevalence of H. pylori infection in patients with EGIDs. Eighteen with eosinophilic esophagitis (EoE) and 22 with EGE were enrolled. For each patient, 3 age- and gender-matched normal controls (n = 120) were randomly selected from a population who received a medical check-up between April 2010 and December 2011 at the Shimane Institute of Health Science. The mean ages of the EoE and EGE patients were 50.9 ± 17 and 49.2 ± 20 years, respectively. Males were more frequently seen in the EoE group, while there was no significant gender difference in regard to EGE. Of the patients with EoE, 22.3% were infected with H. pylori, as compared to 55.5% of their age- and sex-matched normal controls. The odds ratio for EoE patients to have an H. pylori infection was 0.22 (p<0.05). In addition, 22.7% of the patients with EGE and 48.5% of their matched controls were infected with H. pylori, with odds ratio for EGE patients to have an H. pylori infection shown to be 0.31 (p<0.05). In conclusion, the prevalence of H. pylori infection was significantly lower in EGE and EoE patients in Japan as compared to normal control subjects.
    Full-text · Article · Jul 2013 · Journal of Clinical Biochemistry and Nutrition
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    • "In particular, IL-5 and eotaxin are involved in chemotaxis of eosinophils whereas IL-13 interacts with epithelial-differentiation cluster genes which determine tissue remodeling in human EoE [23], [24]. These results, in parallel with the measurement of cytokines in the supernatant of in vitro reactivated spleen cells after provocation by PPE, are consistent with the data summarized by Rothenberg et al. [25] and recently published by his coworkers [23], [24], [26], which confirmed the increase of these cytokines during human EoE. In our analysis of the kinetics of induction of digestive lesions by peanut regimen, histological data and IL-5 mRNA expression showed that digestive lesions were the most marked after 10 days of sustained oral peanut exposure. "
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    ABSTRACT: Food allergy may affect the gastrointestinal tract and eosinophilia is often associated with allergic gastrointestinal disorders. Allergy to peanuts is a life-threatening condition and effective and safe treatments still need to be developed. The present study aimed to evaluate the effects of sustained oral exposure to peanuts on the esophageal and jejunal mucosa in sensitized mice. We also evaluated the effects of desensitization with epicutaneous immunotherapy (EPIT) on these processes. Mice were sensitized by gavages with whole peanut protein extract (PPE) given with cholera toxin. Sensitized mice were subsequently exposed to peanuts via a specific regimen and were then analysed for eosinophilia in the esophagus and gut. We also assessed mRNA expression in the esophagus, antibody levels, and peripheral T-cell response. The effects of EPIT were tested when intercalated with sensitization and sustained oral peanut exposure. Sustained oral exposure to peanuts in sensitized mice led to severe esophageal eosinophilia and intestinal villus sub-atrophia, i.e. significantly increased influx of eosinophils into the esophageal mucosa (136 eosinophils/mm(2)) and reduced villus/crypt ratios (1.6±0.15). In the sera, specific IgE levels significantly increased as did secretion of Th2 cytokines by peanut-reactivated splenocytes. EPIT of sensitized mice significantly reduced Th2 immunological response (IgE response and splenocyte secretion of Th2 cytokines) as well as esophageal eosinophilia (50 eosinophils/mm(2), p<0.05), mRNA expression of Th2 cytokines in tissue--eotaxin (p<0.05), IL-5 (p<0.05), and IL-13 (p<0.05)--GATA-3 (p<0.05), and intestinal villus sub-atrophia (2.3±0.15). EPIT also increased specific IgG2a (p<0.05) and mRNA expression of Foxp3 (p<0.05) in the esophageal mucosa. Gastro-intestinal lesions induced by sustained oral exposure in sensitized mice are efficaciously treated by allergen specific EPIT.
    Full-text · Article · Feb 2012 · PLoS ONE
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Questions & Answers about this publication

  • Joseph Sherrill added an answer in Agarose:
    How shall I detect 15 bp of difference on gel?

    I want to detect 15 bp of difference in DNA fragments of 350-385 bp length. Which method will be most useful? Agarose, PAGE or primer labeling and genotyping?

    Joseph Sherrill

    Hi Pankaj

    You can run your samples on a high(er) percentage (2-3%) TAE-agarose gel. To make the gel without bubbles, microwave in a pressurized container (ie, Pyrex bottle with lid fully tightened) and slowly release the lid once the agarose has fully melted. My previous lab used this method (RFLP) to genotype a 4bp deletion in the filaggrin gene.