Epithelial origin of eosinophilic esophagitis

Area of Science:

• Gastroenterology
• Immunology
• Epithelial Biology

Background:

• Eosinophilic esophagitis (EoE) is a chronic esophageal inflammatory disease driven by allergens.
• The esophageal epithelium plays a central role in EoE pathogenesis.
• Genetic susceptibility loci and transcriptome data highlight epithelial dysfunction in EoE.

Purpose of the Study:

• To investigate the role of protease and protease inhibitor imbalances in the esophageal epithelium in EoE.
• To elucidate the function of SPINK7 in esophageal homeostasis and EoE.
• To propose a model for EoE pathogenesis involving epithelial barrier defects and innate immunity.

Main Methods:

• Analysis of EoE transcriptome for dysregulated genes.
• Examination of gene products from EoE susceptibility loci (calpain 14, thymic stromal lymphopoietin).
• Assessment of epithelial barrier function and cytokine production in relation to SPINK7 expression.

Main Results:

• EoE susceptibility genes encode epithelial-derived proteins.
• Impaired epithelial barrier function is crucial in EoE.
• Loss of SPINK7 expression in EoE leads to increased proteolytic activity, impaired barrier function, and cytokine release.

Conclusions:

• The esophagus functions as an anti-inflammatory sensing organ.
• Protease/protease inhibitor imbalances in the esophageal epithelium are key to EoE.
• Defects in epithelial innate immunity pathways contribute to EoE development.