Eosinophilic esophagitis (EE) is an emerging disorder with a poorly understood pathogenesis. In order to define disease mechanisms, we took an empirical approach analyzing esophageal tissue by a genome-wide microarray expression analysis. EE patients had a striking transcript signature involving 1% of the human genome that was remarkably conserved across sex, age, and allergic status and was distinct from that associated with non-EE chronic esophagitis. Notably, the gene encoding the eosinophil-specific chemoattractant eotaxin-3 (also known as CCL26) was the most highly induced gene in EE patients compared with its expression level in healthy individuals. Esophageal eotaxin-3 mRNA and protein levels strongly correlated with tissue eosinophilia and mastocytosis. Furthermore, a single-nucleotide polymorphism in the human eotaxin-3 gene was associated with disease susceptibility. Finally, mice deficient in the eotaxin receptor (also known as CCR3) were protected from experimental EE. These results implicate eotaxin-3 as a critical effector molecule for EE and provide insight into disease pathogenesis.

Eosinophils can regulate local immune and inflammatory responses, and their accumulation in the blood and tissue is associated with several inflammatory and infectious diseases. As such, therapies aimed at eosinophils may help control diverse diseases, including atopic disorders such as asthma and allergy, and diseases not primarily associated with eosinophils such as autoimmunity and malignancy. Recently, eosinophil-targeted therapeutic agents aimed at blocking specific steps involved in eosinophil development, migration and activation have entered clinical testing and have produced encouraging results and insights into the role of eosinophils. Herein, we describe recent advances in the development of first generation eosinophil-targeted therapies and highlight strategies for using personalized medicine approaches for eosinophilic disorders.

The airways are lined by several distinct epithelial cells that play unique roles in pulmonary homeostasis; however, the mechanisms controlling their differentiation in health and disease are poorly understood. The winged helix transcription factor, FOXA2, is expressed in the foregut endoderm and in subsets of respiratory epithelial cells in the fetal and adult lung. Because targeted mutagenesis of the Foxa2 gene in mice is lethal before formation of the lung, its potential role in lung morphogenesis and homeostasis has not been determined. We selectively deleted Foxa2 in respiratory epithelial cells in the developing mouse lung. Airspace enlargement, goblet cell hyperplasia, increased mucin and neutrophilic infiltration were observed in lungs of the Foxa2-deleted mice. Experimental goblet cell hyperplasia caused by ovalbumin sensitization,interleukin 4 (IL4), IL13 and targeted deletion of the gene encoding surfactant protein C (SP-C), was associated with either absent or decreased expression of Foxa2 in airway epithelial cells. Analysis of lung tissue from patients with a variety of pulmonary diseases revealed a strong inverse correlation between FOXA2 and goblet cell hyperplasia. FOXA2 is required for alveolarization and regulates airway epithelial cell differentiation in the postnatal lung.

Background & Aims-Eosinophilic esophagitis (EE) is an increasingly recognized disease that mimics gastro-esophageal reflux disease. Recently, EE has been associated with esophageal remodeling, but the mechanisms involved are poorly understood. We hypothesized that the development of EE in patients and in an experimental murine model would be associated with eosinophil-mediated tissue remodeling.

Eosinophilic esophagitis (EE) is an emerging disease associated with both food and respiratory allergy characterized by extensive esophageal tissue remodeling and abnormal esophageal gene expression including increased IL-13. We investigated the ability of increased airway IL-13 to induce EE-like changes. Mice that overexpress an IL-13 transgene in the lung (but not esophagus) accumulated esophageal IL-13 and developed prominent esophageal remodeling with epithelial hyperplasia, angiogenesis, collagen deposition and increased circumference. IL-13-induced marked changes in esophageal transcripts overlapped with the human EE esophageal transcriptome. IL-13-induced esophageal eosinophilia was eotaxin-1 (but not eotaxin-2) dependent but remodeling occurred independent of eosinophils, as demonstrated by studying eosinophil lineage-deficient IL-13 transgenic mice. IL-13-induced remodeling was significantly enhanced by IL-13Rα2 gene deletion, indicating an inhibitory effect of IL-13Rα2. In the murine system, there was partial overlap between IL-13-induced genes in the lung and esophagus, yet the transcriptomes were also divergent at the tissue level. In human esophagus, IL-13 levels correlated with the magnitude of the EE transcriptome. In conclusion, inducible airway expression of IL-13 results in an esophageal gene expression and extensive tissue remodeling pattern that resembles human EE. Notably, we have identified a pathway for inducing EE-like changes that is IL-13-driven, eosinophil-independent and suppressed by IL-13Rα2.