Epicutaneous Antigen Exposure Primes for Experimental Eosinophilic Esophagitis in Mice

doi:10.1053/j.gastro.2005.06.027

Gastroenterology

Volume 129, Issue 3, September 2005, Pages 985-994

https://doi.org/10.1053/j.gastro.2005.06.027 Get rights and content

Background & Aims: Eosinophilic esophagitis (EE) is frequently associated with atopic disease, including dermatitis and asthma. Data are emerging that atopic skin may provide an early entry point for antigen sensitization. We aimed to test the hypothesis that epicutaneous exposure to antigen primes for subsequent respiratory antigen-induced EE. Methods: Wild-type and genetically engineered mice were subjected to epicutaneous antigen sensitization and the development of experimental EE, and immune responses were examined. Results: We show that exposure to antigen via the epicutaneous route primes for marked eosinophilic inflammation in the esophagus triggered by a single airway antigen challenge. The development of experimental EE is associated with significant skin eosinophilia, accelerated bone marrow eosinophilopoiesis, blood eosinophilia, and large increases in serum antigen-specific immunoglobulin G1/immunoglobulin E using ovalbumin or Aspergillus fumigatus as the epicutaneous antigen. Mechanistic analysis with gene-targeted mice showed that interleukin-5 was required for esophageal eosinophilia and that interleukin-4, interleukin-13, and STAT6 contributed to a lesser extent. Conclusions: These findings provide the first evidence that epicutaneous exposure to allergens potently primes for EE via a Th2-dependent mechanism.

Section snippets

Mice

Four- to 8-week-old BALB/c mice (National Cancer Institute, Frederick, MD), STAT6- deficient BALB/c mice (Jackson Laboratory, Bar Harbor, ME), and IL-5–deficient (originally obtained from Drs K. Matthaei and P. S. Foster, John Curtin School of Medical Research, Australian National University, Canberra, Australia), IL-13–deficient, IL-4/IL-13 double-deficient, and their littermate F6 BALB/c controls (originally obtained from A. MacKenzie, Medical Research Council Laboratory of Molecular Biology,

Epicutaneous OVA Induces Cutaneous and Systemic Th2 Responses

Previous studies have shown that epicutaneous exposure to the food antigen OVA induces AD-like eosinophilic inflammation locally in the skin accompanied by production of Th2-associated Ig and lymphocyte responses.15, 16, 40, 45 Furthermore, following a single respiratory OVA challenge, epicutaneously sensitized mice developed marked lung inflammation.16, 18 Related to this observation, we tested several hypotheses concerning EE. First, we were interested in determining if epicutaneous

Discussion

Eosinophil infiltration into the esophagus is a commonly observed medical problem in patients with diverse conditions, including gastroesophageal reflux disease, drug reactions, eosinophilic gastroenteritis, and primary EE.1, 2, 3, 4, 5, 6, 7, 8, 9, 10 Importantly, recent clinical studies have suggested that these disorders (especially primary EE) are occurring with increasing frequency.6, 9 Additionally, the level of eosinophils in the esophagus negatively correlates with response to

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Eosinophilic esophagitis (EoE) is a chronic type 2 inflammatory disease characterized by an eosinophilic inflammatory infiltrate in the esophagus, leading to remodeling, stricture formation, and fibrosis. Triggered by food and aeroallergens, type 2 cytokines interleukin (IL)-4, IL-13, IL-5 produced by CD4+ T helper 2 cells (Th2), eosinophils, mast cells, basophils, and type 2 innate lymphoid cells alter the esophageal epithelial barrier and increase inflammatory cell tissue infiltration. Clustering analysis based on the expression of type 2 inflammatory genes demonstrated the diversity of EoE endotypes. Despite the availability of treatment options for patients with EoE, which include dietary restriction, proton pump inhibitors, swallowed topical steroids, and esophageal dilation, there are still no Food and Drug Administration–approved medications for this disease; as such, there are clear unmet medical needs for these patients. A number of novel biologic therapies currently in clinical trials represent a promising avenue for targeted therapeutic approaches in EoE. This review summarizes our current knowledge on the role of type 2 inflammatory cells and mediators in EoE disease pathogenesis, as well as the future treatment landscape targeting underlying inflammation in EoE.

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: Supported in part by National Institutes of Health grants R01 AI42242 and AI45898 and the Burroughs Welcome Fund Translational Research Grant (to M.E.R.).

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Basic–alimentary tractEpicutaneous Antigen Exposure Primes for Experimental Eosinophilic Esophagitis in Mice

Section snippets

Mice

Epicutaneous OVA Induces Cutaneous and Systemic Th2 Responses

Discussion

J Allergy Clin Immunol

Am J Med

Am J Gastroenterol

Gastroenterology

Gastrointest Endosc

Gastroenterology

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Pediatr

J Allergy Clin Immunol

J Allergy Clin Immunol

Gastroenterology

Am J Pathol

Clin Gastroenterol Hepatol

J Allergy Clin Immunol

J Allergy Clin Immunol

The role of the eosinophil in gastrointestinal diseases

Curr Opin Gastroenterol

Eosinophilic esophagitis in children and adults

J Pediatr Gastroenterol Nutr

Eosinophilic esophagitis

N Engl J Med

IL-5 promotes eosinophil trafficking to the esophagus

J Immunol

Atopic dermatitis and asthmaparallels in the evolution of treatment

Pediatrics

New insights into atopic dermatitis

J Clin Invest

Increased airways responsiveness in mice depends on local challenge with antigen

Am J Respir Crit Care Med

Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice

J Clin Invest

Th2 responses induced by epicutaneous or inhalational protein exposure are differentially dependent on IL-4

J Clin Invest

CCR3 is essential for skin eosinophilia and airway hyperresponsiveness in a murine model of allergic skin inflammation

J Clin Invest

Basic–alimentary tract
Epicutaneous Antigen Exposure Primes for Experimental Eosinophilic Esophagitis in Mice