Interleukin-15 Expression Is Increased in Human Eosinophilic Esophagitis and Mediates Pathogenesis in Mice
Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA. Gastroenterology
(Impact Factor: 16.72).
04/2010; 139(1):182-93.e7. DOI: 10.1053/j.gastro.2010.03.057
Quantitative microarray analyses have shown increased expression of interleukin-15 (IL-15) messenger RNA in the esophagus of patients with eosinophilic esophagitis (EoE), a recently recognized allergic disorder with poorly understood pathogenesis.
Quantitative polymerase chain reaction and enzyme-linked immunosorbent assay analyses were performed to examine protein and transcript levels in tissue samples from patients with EoE. Tissues from IL-15Ra-deficient and wild-type (control) mice were also examined. Tissue eosinophilia was determined by immunostaining for major basic protein and flow cytometry for cell-surface receptors.
Quantitative polymerase chain reaction analyses showed that levels of IL-15 and its receptor IL-15Ra were increased approximately 6- and approximately 10-fold, respectively, in tissues from patients with EoE and approximately 3- and approximately 4-fold, respectively, in mice with allergen-induced EoE. A >2-fold increase in serum IL-15 protein levels was also detected in human EoE samples compared with those from healthy individuals. Human IL-15 messenger RNA levels correlated with esophageal eosinophilia (P < .001). IL-15Ra-deficient mice were protected from allergen-induced esophageal eosinophilia compared with controls (P < .001), even though similar levels of airway eosinophilia were observed in all mice. IL-15 activated STAT5 and CD4(+) T cells to produce cytokines that act on eosinophils. Incubation of primary esophageal epithelial cells from mice and humans with IL-15 caused a dose-dependent increase in the mRNA expression and protein levels of eotaxin-1, -2, and -3.
IL-15 mediates in the pathogenesis of EoE. IL-15 activates CD4(+) T cells to produce cytokines that act on eosinophils.
Available from: Steven Leach
- "Recently, Zhu et al. (79) found that IL-15 is involved in the induction of eosinophil-selective cytokines and chemokines by CD4+ T cells. This study found a 6- to 10-fold increase in the levels of both IL-15 and its receptor IL-15Rα in esophageal tissues, and a twofold increase in serum IL-15 protein levels in patients with EoE. "
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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.
Available from: Canonica Walter
- "In humans, an increase of IL-15 and its receptor (IL-15R) at the tissue, correlates with the eosinophilia in the mucosa. In animal models of EoE, the deletion of the gene for IL-15R seems to protect from eosinophilic infiltration . "
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ABSTRACT: Eosinophilic esophagitis is a chronic inflammatory disease of the esophagus, immune/antigens mediated, whose incidence is increasing both in adults and pediatric population. It is clinically characterised by symptoms related to esophageal dysfunction and associated with eosinophil-predominant esophageal inflammation. The role of atopy has been clearly demonstrated both in epidemiological and experimental studies and has important implications for diagnosis and therapy. In fact, many evidences show that food and inhalant allergens represent the most important factors involved in the progress of the disease. Several studies have reported that, in a range between 50 and 80%, patients with eosinophilic esophagitis have a prior history of atopy, and for them, the presence of allergic rhinitis, asthma or atopic dermatitis is frequent. Skin tests are able to identify in most patients the allergens involved, allowing a correct dietary approach in order to achieve the remission of symptoms and the biopsy normalization.
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ABSTRACT: Eosinophilic esophagitis (EoE) is a relatively new entity with a significant amount of increased recognition over the last decade. The mainstay treatments of EoE are designed to eliminate the causative allergens or to reduce their effects on the esophageal mucosa. Common treatments include dietary modification, proton pump inhibitors, systemic and topical corticosteroids, and endoscopic treatments. As the pathogenesis of EoE is explored, new and novel treatments are being studied that target specific pathways and chemokines identified in as precipitating agents of EoE. This is a rapidly evolving field with significant ongoing research and clinical studies. Our review will therefore focus on current and novel treatment approaches to the disease.
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