Basic pathogenesis of eosinophilic esophagitis

Abstract

Eosinophilic esophagitis (EE) is a newly recognized disease, which has largely been called idiopathic EE, emphasizing the poor understanding of its pathogenesis. EE is a severe disease of the esophagus characterized by an accumulation of eosinophils in the esophageal mucosa, and is highly associated with atopic disease. Nevertheless, the nomenclature "eosinophilic esophagitis" describes only the tip of the iceberg of a complex disorder, as the pathogenesis of EE involves multiple tissues, cell types, and genes, and derives from complex genetic and environmental factors. This article defines the fundamental knowledge available to date that characterizes the mechanisms by which certain etiological factors cause EE, reviewing human studies, murine models, and recent knowledge regarding the involvement of environmental, cellular, molecular, and genetic factors in the development of EE.

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Figure 1. Etiologic factors involved in EE development

More then 500 gene polymorphisms has been shown to be associated to allergic diseases and the genetic context generated by the presence of these polymorphisms predispose individuals to asthma, atopic dermatitis, food allergy…. Although allergic diseases are common in the population, all allergic patients does not develop EE suggesting that a specific genetic predisposition for EE might be required to develop EE. As such a complex interplay between single nucleotide polymorphisms increase the risk of a Th2 inflammation to occur in the esophagus. To date only one single nucleotide polymorphism (SNP), has been associated with EE. This SNP is located in the 3’UTR of the eotaxin-3 gene (T/G +2496). All together, this complex genetic background and the environmental exposures (food and aeroallergens) contribute to the development of EE.

Figure 2. Molecular pathogenesis of EE

EE involves the complex interaction of genetic factors and environmental exposures leading to a Th2-associated disease localized in the esophagus of predisposed patients. Such processes involve increased expression of Th2 cytokines, chemokines, and chemokine receptors by PBMC (IL-4, IL-13, IL-5) and eosinophils (IL-13, IL-5, CCR3). In the esophagus, increased expression of IL-13 and TGF-beta likely contributes to eotaxin-3 release by epithelial cells, as well as increased collagen production (fibrosis) and vascular activation (VCAM-1 expression). Finally, IgE, systematically or locally synthesized by B cells are detected on the surface of mast cells and likely contributes to mast cell activation by food antigens.