Alterations in junctional proteins, inflammatory mediators and extracellular matrix molecules in eosinophilic esophagitis
Introduction
Eosinophilic esophagitis (EoE) is an increasingly prevalent atopic disease of the esophagus encountered in children and in adults. It is an inflammation of the esophagus that does not respond to acid suppression therapy. Its symptoms in childhood include nausea and vomiting, failure to thrive, dyspepsia, abdominal or chest pain and early satiety. Clinical presentation in adults includes dysphagia and food impactions that necessitate endoscopic intervention.
The esophagus is the only organ in the gut that does not normally contain eosinophils. However, eosinophils accumulate intensely in the esophagus in EoE, and their count in sections of mucosal biopsies (> 15 counts/high power microscopic field) remains a hallmark for the diagnosis of the disease [1]. Elimination of dietary antigens causes marked improvement of symptoms [2]. The allergen-induced eosinophilia causes basal cell hyperplasia, abscesses, epithelial fragility and damage. Long-term complications of the disease include tears, collagen deposition, fibrosis, strictures and esophageal narrowing [3].
Induction of an immune response in epithelia is generally caused by foreign antigens interacting with antigen presenting cells, which subsequently play a role in polarizing T cells to become Th1 or Th2 cells. Each of these subsets of T cells secretes an array of cytokines that determine the immune response to the antigen. Th1 cells are associated with secretion of IFN-gamma, TNF and IL-2. On the other hand, the cytokine profile in EoE, an increase in IL-5, IL-4, and IL-13, [4] is characteristic of a Th2 response. These cytokines are thought to upregulate the production of eotaxin-3 from esophageal epithelial cells. Eotaxin-3, acting as a chemotactic cytokine, is likely a major factor in activation and recruitment of eosinophils [5]. Eosinophils and other leukocytes migrate into the esophageal mucosa leading to epithelial injury and remodeling [6].
The aim of this study was to investigate the factors involved in esophageal tissue damage and remodeling in EoE. Our data indicated significant alterations in gene expression of cell adhesion molecules CD44 and CD45, collagen and extracellular matrix proteases. Notably, expression of the tight junction protein claudin-1 and the adherens junction protein E-cadherin was markedly reduced, while expression of the tight junction protein occludin was increased. Moreover, expression of the mesenchymal marker vimentin increased significantly indicating major remodeling and changes of the epithelial properties of the esophageal cells. This is the first report about alterations in extracellular matrix and adhesion molecules and in adherens and tight junction proteins in EoE.
Section snippets
Patient population
Biopsies were obtained from pediatric patients undergoing routine endoscopy procedures at East Tennessee Children Hospital (ETCH) after obtaining written consent. The study was approved by the Institutional Review Boards of ETCH and Tulane University. The exclusion criteria were: anti-coagulant medicines, non-steroidal anti-inflammatory drugs, esophageal varices, or general poor health. Diagnosis of EoE was established by the pathologist based on a minimum eosinophil count of > 15
Description of patients
Table 1 shows patient information including diagnostic results and medications used. Other pathologies of the GI tract are included when present. Biopsies used for research were from EoE patients having an eosinophil count of at least 20/hpf as determined by the pathologist. Thirteen out of sixteen EoE patients had been on acid suppression therapy for more than 4 weeks prior to the endoscopy confirming the presence of “eosinophilia non-responsive to PPI treatment” [1]. Three EoE patients had all
Discussion
EoE is an inflammatory disease of the esophagus characterized by heavy infiltration of eosinophils and other inflammatory cells, hyperproliferation of the basal cells, and remodeling of the epithelium. Although the atopic nature of the disease is well recognized the factors leading to the extensive epithelial remodeling are not well understood. We demonstrate here altered expression of a set of genes related to inflammatory cytokines and show for the first time altered expression of
Conclusion
We have identified a series of novel genes and proteins whose expression is modified in EoE. Our data indicate profound alterations in the cytokine profile and extracellular matrix and adhesion molecules. The distribution of tight and adherens junction proteins in EoE shows major changes that explain disruption in the barrier properties of the epithelium. Vimentin expression and fractionation are remarkable in EoE and are likely to play a role in the progression of the disease. Further
Conflict of interest
None.
Acknowledgments
The study was supported by a grant from Tulane University (Tulane Enhancement Grant).
Parts of this study were presented in an abstract form at the American Gastroenterology Association meeting, 2010 and NAPSGHAN, 2011.
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