Gastroenterology

Gastroenterology

Volume 154, Issue 2, January 2018, Pages 333-345
Gastroenterology

Eosinophilic Esophagitis
Pathophysiology of Eosinophilic Esophagitis

https://doi.org/10.1053/j.gastro.2017.06.065Get rights and content

Eosinophilic esophagitis is an emerging disease that is distinguished from gastroesophageal reflux disease by the expression of a unique esophageal transcriptome and the interplay of early life environmental factors with distinct genetic susceptibility elements at 5q22 (TSLP) and 2p23 (CAPN14). Rare genetic syndromes have uncovered the contribution of barrier disruption, mediated in part by defective desmosomes and dysregulated transforming growth factor beta production and signaling, to eosinophilic esophagitis pathophysiology. Experimental modeling has defined a cooperative role of activated eosinophils, mast cells, and the cytokines IL-5 and IL-13, mediated by allergic sensitization to multiple foods. Understanding these processes is opening the way to better treatment based on disrupting allergic inflammatory and type 2 cytokine–mediated responses, including anti-cytokine therapeutics and dietary therapy.

Section snippets

Genetic Etiology

The prevalence of EoE is approximately 1 in 2000 and has a known male predominance, with a male-to-female ratio approaching 3:1.4, 5 EoE has a strong hereditability pattern, with familial associations having relative risk ratios as high as 64-fold amongst brothers.6 Proband concordance in monozygotic twins is 58%, substantiating a genetic etiology.7 Several different studies, including candidate-gene identification and genome-wide association studies have identified multiple genes that are

Allergic Milieu Predisposes to Eosinophilic Inflammation

Multiple lines of evidence support an allergic etiology as an underlying mechanism for EoE. First, patients with EoE have a high incidence of concurrent atopic disease (Figure 3).5 Recent evidence shows that EoE is correlated with higher rates of asthma and airway hyperresponsiveness.17 Sensitization to cutaneous, ingested, and/or inhaled allergens is likely necessary in the development of EoE, and in some patients, seasonal allergens may play a role.18, 19, 20 Second, the success of dietary

Microbial Imbalance may Contribute to Esophagitis

Similar to patterns in other atopic diseases, an emerging body of evidence suggests a role for intestinal dysbiosis in the pathogenesis of EoE. Host commensal populations may be skewed toward a Th2 profile by early life events such as Caesarian section delivery and antibiotic exposure during infancy, which appear to increase the risk of EoE in both children and adults.54, 55, 56, 57 Of note, similar risk factors have been identified in other atopic conditions and inflammatory bowel disease.58

Eosinophil Transmigration and Activation

The esophageal epithelium is composed of non-keratinized, stratified squamous epithelium that is bathed by a layer of mucus and covers the rete pegs with its vascular elements. Though the normal gastrointestinal tract contains eosinophils in varying density in times of good health, the normal esophageal mucosa does not contain any eosinophils. Thus, identifying eosinophils and their progenitor cells in the esophageal mucosa indicates a pathogenic role for these cells in an inflammatory response.

Barrier Dysfunction Contributes to Esophageal Inflammation

The basal layer of esophageal tissues from patients with EoE becomes hyperplastic, and its integrity as a barrier structure is impaired, as evidenced by dilated intercellular spaces and spongiosis.12 Using impedance monitoring, van Rhijn et al79 demonstrated a significantly decreased esophageal barrier during active EoE compared with inactive EoE in adult subjects. Ussing chamber analyses identified similar findings with mucosal biopsies.12 Ultrastructural studies show not only increased

Esophageal Fibrosis and Strictures are a Chronic Feature of EoE

Emerging clinical evidence supports that the likely outcome of unbridled eosinophilia is esophageal fibrosis and stricture formation. Esophageal remodeling is defined by histologic parameters in the epithelium, including basal zone hyperplasia, dilated intercellular spaces, rete peg elongation, and desquamation, and by subepithelial lamina propria features such as increased vascularization and fibrosis.5, 85, 86, 87 The confounding aspect of this pathogenic process is why remodeling sometimes

Association With Other Conditions Provides Insight into Pathogenetic Mechanisms

Notably, EoE has known associations with several genetic conditions (Table 3), particularly connective tissue disorders with hypermobility syndromes, such as Loeys-Dietz syndrome and Ehlers-Danlos syndrome, hypermobility type.112 A common denominator between these 2 conditions is the increased production and/or signaling of TGF-β, which is thought to lead to increased contractility of smooth muscle, tissue remodeling, and Th2 responses.45, 86, 113 Another condition associated with increased

Conclusion

The recent formation of the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR, https://www.rarediseasesnetwork.org/cms/cegir), which is part of the Rare Diseases Clinical Research Network (RDCRN) of the National Institutes of Health, will undoubtedly lead to better understanding and treatment of EoE and related rare eosinophil-associated gastrointestinal diseases. CEGIR is focused on defining the natural history of eosinophilic gastrointestinal disorders, developing disease

Acknowledgments

The authors thank Shawna Hottinger for editorial assistance.

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    Conflicts of interest Unrelated to this manuscript, S.S.A. is a co-inventor with a UCSD patent on viscous budesonide, consults for regeneron, and has funding from Ferring Research Institute and the NIAID. M.E.R. is a consultant for Pulm One, Spoon Guru, Celgene, Shire, Astra Zeneca, GlaxoSmithKline, Allakos, Adare, Regeneron and Novartis and has an equity interest in the first three listed and Immune Pharmaceuticals, and royalties from reslizumab (Teva Pharmaceuticals). M.E.R. is an inventor of patents, owned by Cincinnati Children’s. The other authors disclose no conflicts.

    Funding This work was supported in part by NIH U19 AI070235, NIH R01 AI124355, R37 R37 A1045898, NIH K24DK100303, the Campaign Urging Research for Eosinophilic Disease (CURED) Foundation, the Buckeye Foundation, and the Sunshine Charitable Foundation and its supporters, Denise A. Bunning and David G. Bunning. The study is also funded by U54 AI117804, which is part of the Rare Disease Clinical Research Network (RDCRN), an initiative of the Office of Rare Disease Research (ORDR), NCATS, and is funded through collaboration between NCATS, NIAID and NIDDK, as well as the patient advocacy groups American Partnership for Eosinophilic Disorders (APFED), CURED and the Eosinophilic Family Coalition (EFC), which have collectively resulted in the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR).

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