Eosinophil infiltration into the esophagus is a commonly observed medical problem in patients with diverse diseases including gastroesophageal reflux, drug reactions, allergic eosinophilic esophagitis, eosinophilic gastroenteritis, and primary eosinophilic esophagitis (2
). Recent clinical studies have suggested that the level of eosinophils in the esophagus negatively correlates with response to conventional gastroesophageal reflux therapy (36
). Additionally, the clinical symptoms and the eosinophilic infiltrations can be ameliorated by a food allergen elimination diet or anti-inflammatory therapy (cromoglycate or glucocorticoids) in some patients (9
). This suggests that sensitized individuals may develop esophageal eosinophilic inflammation in response to exposure to food allergens. However, the role of allergens in the induction of eosinophilia in the esophagus has been debated, since there is no direct causal evidence proving this linkage (6
). We now demonstrate that exposure of anesthetized mice to repeated challenges of aeroallergens using a standard protocol to induce allergic airway inflammation promotes marked eosinophilic esophagitis. The accumulation of eosinophils, especially intraepithelial eosinophils, the detection of extracellular granules, and epithelial cell hyperplasia mimic the pathophysiological changes observed in individuals with various forms of eosinophilic esophagitis (6
). Of note, the detection of protein-laden free eosinophil granules is a common pathological observation in human eosinophilic inflammation (33
). It is likely that sensitization occurs by pulmonary exposure, since oral or intragastric allergen exposure alone fails to elicit eosinophilia. In support of this, intranasal inoculation to nonanesthetized mice, which bypasses allergen delivery to the lung, failed to induce pulmonary and esophageal eosinophilic inflammation. Mechanistically, it is interesting to speculate that sensitization occurs through the respiratory tract (lung), and when the sensitized mice are subsequently exposed to the oral allergens deposited by the intranasal application, they develop a hypersensitivity response that leads to eosinophil infiltration into the esophagus. Taken together, this study suggests that aeroallergens may contribute to the development of eosinophilic esophagitis in sensitized atopic patients.
In this study we also demonstrate that IL-5 has a central role in regulating eosinophil accumulation in the esophagus. In the absence of IL-5 (by analysis of gene-targeted mice or anti–IL-5–treated mice), esophageal eosinophilia is markedly reduced. Thus, the esophagus likely uses similar pathways, involving CD4+
T cells and IL-5, for the induction of eosinophilic inflammation as those operational during allergic pulmonary inflammation. The lack of allergen-induced epithelial hyperplasia in IL-5–deficient mice suggests an etiological role for eosinophils in promoting epithelial proliferation. Eosinophils are sources of a variety of cytokines, including growth factors (e.g., TGF-α and -β), that may be involved in promoting epithelial hyperplasia (12
). In addition to regulating eosinophilopoiesis, IL-5 primes eosinophils to have enhanced responsiveness to chemokines such as eotaxin (37
). We have also demonstrated that, following allergen challenge, the accumulation of eosinophils in the esophagus is dependent in part upon eotaxin. However, eotaxin-deficient mice still show markedly elevated eosinophil levels in the esophagus compared with base-line wild-type mice or mice treated with placebo alone. This indicates the cooperation of eotaxin with other eosinophil-active chemoattractants in the regulation of eosinophil trafficking to the esophagus. Consistent with this, eosinophils respond to a variety of chemokines including other CCR3 ligands (monocyte chemoattractant protein-2 [MCP-2] and MCP-3, RANTES, and eotaxin-2 and -3) (12
). Thus, the requirements for IL-5 and eotaxin in regulating eosinophils in the esophagus are similar to their respective roles in the lungs.
In summary, these investigations dissect the cellular and molecular mechanisms involved in eosinophil homing into the esophagus. We demonstrate that intranasal allergen exposure induces marked eosinophil infiltration into the esophagus. This suggests that eosinophilic esophagitis can be mediated by extrinsic allergens and establishes a causal link between the development of allergic hypersensitivity in the respiratory tract and in the esophagus, implicating an etiologic role for aeroallergens in the pathogenesis of esophagitis. We propose that aeroallergens may be contributing to the pathogenesis of esophageal inflammation in a subset of patients with primary eosinophilic esophagitis and gastroesophageal reflux disorders. These results suggest that a subgroup of patients with eosinophilic esophagitis may benefit from control of aeroallergen sensitization and/or exposure. Furthermore, the demonstration that IL-5, which is required for pulmonary eosinophilia, is also required for eosinophil infiltration in the esophagus further substantiates immunological cooperativity between the immune responses in the lung and esophagus. It has long been debated whether eosinophils have a pathological role in gastrointestinal inflammatory disorders. The demonstration that allergen-induced epithelial hyperplasia is ablated in IL-5 gene-targeted mice indicates that eosinophils are likely to be causally related to gastrointestinal pathology. These data suggest that anti–IL-5 therapy, which is currently being tested for the treatment of asthma, may be a rational approach for the treatment of eosinophilic esophageal disorders. It is hoped that this novel experimental regime for the induction of eosinophilic esophagitis will facilitate future investigations designed to understand the pathophysiology and treatment of inflammatory disorders of the esophagus.