Basic Pathogenesis of Eosinophilic Esophagitis
Section snippets
Environmental pathogenesis: a Th2 disease
Epidemiologic studies provided the first indirect information about the pathogenesis of EE. The allergic component of EE was apparent from the strong association of EE with allergic diseases (Fig. 1). About 70% of EE patients have current or past allergic diseases, or a positive skin prick test, especially to a variety of foods [1]. Of note, only a minority of EE patients present with food anaphylaxis, indicating distinct mechanisms compared with classical-IgE-mediated mast cell and basophil
Genetic predisposition
As already described in other Th2 diseases, EE pathogenesis is likely to be associated with allergen sensitization in predisposed individuals (see Fig. 1). EE has a strong familial pattern based on the growing clinical literature and the authors' own patient data. Among pediatric patients with EE, approximately 8% have at least one sibling or parent with EE as well [1]. In addition, Patel and Falchuk [25] have recently reported three adult brothers with dysphagia who were found to have EE.
Molecular pathogenesis
Substantial evidence is accumulating that EE is associated with a Th2 type immune response and local or systemic Th2 cytokine overproduction. IL-5 is a cytokine involved in eosinophil production, survival, and activation. IL-5 mRNA is increased in the biopsies of EE patients compared with normal (NL) patients ([27], [28], [29] and unpublished data). Peripheral CD4 + T cells show an increase in intracellular IL-5 in the blood of EE patients, compared with nonatopic non-EE patients [9].
Cellular pathogenesis
While absent in the normal esophagus, eosinophils markedly accumulate in the esophagus of EE patients. A minimum of 15 eosinophils per high power field is now used as clinical diagnostic criteria for EE [35], [36], [37]. Analysis of the EE transcriptome reveals that the strong accumulation of esophageal eosinophils is not accompanied by an increase in eosinophil specific transcripts [24]. Recently, Locksley's group demonstrated that eosinophil granule protein mRNAs were detectable in the early
Summary and future direction
EE has a complex pathogenesis, in which multiple etiologic factors interact. The environmental factors and a predisposed genetic background certainly interplay in EE onset and pathogenesis. A gene polymorphism, eotaxin-3, has been shown to be associated with EE [24], and we predict that EE, like most Th2 diseases, is a polygenic disorder with multiple environmental factors strongly contributing to disease expression (see Fig. 1). Although advances have been made in the understanding of human
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This work was funded in part by the NIH #AI070235 and #AI45898 (M.E. Rothenberg), the Food Allergy and Anaphylaxis Network (FAAN) (M.E. Rothenberg), Campaign Urging Research for Eosinophil Disorders (CURED), the Buckeye Foundation (M.E. Rothenberg), The Food Allergy Project (M.E. Rothenberg), The American Heart Association #0,625,296B (C. Blanchard) and The Thrasher Research Fund NR-0014 (C. Blanchard).