Esophageal type 2 cytokine expression heterogeneity in eosinophilic esophagitis in a multisite cohort

doi:10.1016/j.jaci.2020.01.051

Journal of Allergy and Clinical Immunology

Volume 145, Issue 6, June 2020, Pages 1629-1640.e4

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https://doi.org/10.1016/j.jaci.2020.01.051 Get rights and content

Background

There is strong evidence for a role of type 2 cytokines in the pathogenesis of eosinophilic esophagitis (EoE); however, heterogeneity in type 2 gene expression has not been examined.

Objective

We examined type 2 immunity–associated gene expression in esophageal biopsy specimens, aiming to determine the degree of cytokine heterogeneity and its potential clinical significance.

Methods

Patients (n = 312) were recruited from 10 sites associated with the Consortium of Eosinophilic Gastrointestinal Disease Researchers. In addition to histologic and endoscopic assessment, esophageal biopsy specimens were examined for expression of 96 genes within the EoE diagnostic panel.

Results

Five subgroups of patients with active EoE were identified by unsupervised clustering based on expression of IL4, IL5, IL13, C-C motif chemokine ligand 26 (CCL26), thymic stromal lymphopoietin (TSLP), Charcot-Leyden crystal (CLC), C-C motif chemokine receptor 3 (CCR3), and CPA3. These groups differed in age (P < .02) and EoE diagnostic panel score (P < 1.08E–30) but not in eosinophil levels. The group V patients had the highest expression of IL5, TSLP, and CCL26 and genes associated with tissue remodeling, such as COL8A1, actin γ-2 (ACTG2), and tetraspanin 12 (TSPAN12). IL5 and IL13 were highly expressed in group IV; however, groups IV and V differed in age (34 vs 14 years [P < .05]). Groups II and III, which exhibited intermediate expression of IL5 and CPA3, were differentiated by high TSLP and IL13 in group III.

Conclusion

We observed heterogeneous type 2 gene expression among patients with active EoE. Type 2 gene overexpression was not directly proportional to disease features; this was especially true for tissue remodeling events. These findings highlight a clinical opportunity for leveraging molecular endotypes to implement personalized medicine in EoE.

Graphical abstract

Section snippets

Patient recruitment

This study was conducted within the context of CEGIR, a national collaborative network of 16 academic centers caring for adults and children with eosinophilic gastrointestinal disorders (see Table E1 in this article’s Online Repository at www.jacionline.org). The CEGIR clinical trial, Outcomes Measures in Eosinophilic Gastrointestinal Disorders across the Ages (OMEGA), is a longitudinal cohort study aimed at understanding the natural history of EoE, eosinophilic gastritis, and eosinophilic

Characteristics of Patients with EoE

Patient age ranged from 4 to 71 years, with mean age of 26 years (Table I). A majority of the patients were male (67%) (Table I). A subset of patients were taking a proton-pump inhibitor, practicing dietary elimination, and receiving topical steroid therapy (Table I). Patients with active EoE had a mean value of 50 eosinophils per hpf, whereas patients with inactive EoE had a mean value of 3 eosinophils per hpf (Table I). The EDP total score differed in the active and inactive groups (123 vs

Discussion

Herein, we have examined the relationship between type 2 gene expression and EoE-related disease features. In this study, we examined heterogeneous expression of the type 2 cytokines IL-5 and IL-13 because of their known roles in promoting eosinophil survival and activation through both direct and indirect mechanisms and the emerging set of therapies that target these cytokines and/or their receptors.⁵^,¹¹^,¹³^,¹⁴^,¹⁸ We have identified subgroups of patients with active EoE that have low,

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: CEGIR (U54 AI117804) is part of the Rare Diseases Clinical Research Network, an initiative of the Office of Rare Diseases Research, National Center for Advancing Translational Sciences; it is cofunded by the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Center for Advancing Translational Sciences. CEGIR is also supported by patient advocacy groups, including the American Partnership for Eosinophilic Disorders and the Campaign Urging Research for Eosinophilic Disease.

: Disclosure of potential conflict of interest: M. E. Rothenberg is a consultant for Pulm One, Spoon Guru, Celgene, AstraZeneca, Allakos, and ClostraBio and has an equity interest in Pulm One, Spoon Guru, and ClostraBio and royalties from reslizumab (Teva Pharmaceuticals); he is also an inventor of patents, owned by Cincinnati Children’s. G. W. Falk has received research support from Celgene/Receptos, Regeneron, Shire, and Adare. M. H. Collins is a consultant for Allakos, AstraZeneca, Esocap, Shire/Takeda, Regeneron, and Receptos/Celgene and has received research funding from Shire/Takeda, Regeneron, and Receptos/Celgene. E. S. Dellon is a consultant for Adare, Aimmune, Alivio, Allakos, AstraZeneca, Banner, Calypso, Enumeral, Esocap, Gossamer Bio, GSK, Receptos/Celegene, Regeneron, Robarts, Salix, and Shire/Takeda; the recipient of research funding from Adare, Allakos, Meritage, Miraca, Nutricia, Receptos/Celgene, Regeneron, and Shire/Takeda; and the recipient of educational grants from Allakos, Banner, and Holoclara. S. S. Aceves is a consultant for Regeneron and AImmune; an inventor of oral viscous budesonide, patented by the University of California, San Diego, and licensed by Shire; and the recipient of research funding from Ferring Research Institute. J. M. Spergel is a consultant for Regeneron and DBV Technology; his research is supported by the National Institutes of Health, EATS Foundation, AImmune Therapeutics, FARE, and DBV Technology. G. T. Furuta is a consultant for Shire and a cofounder of EnteroTrack. The rest of the authors declare that they have no relevant conflicts of interest.

^∗: Amanda K. Rudman-Spergel's co-authorship of this publication does not necessarily constitute endorsement by the National Institute of Allergy and Infectious Diseases, the National Institutes of Health, or any other agency of the United States government.

^‡: A list of participants in the CEGIR study is provided in this article’s Online Repository (available at www.jacionline.org).

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Food allergy and gastrointestinal diseaseEsophageal type 2 cytokine expression heterogeneity in eosinophilic esophagitis in a multisite cohort

Background

Objective

Methods

Results

Conclusion

Graphical abstract

Section snippets

Patient recruitment

Characteristics of Patients with EoE

Discussion

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

J Allergy Clin Immunol

Lancet Gastroenterol Hepatol

Gastroenterology

Mucosal Immunol

J Allergy Clin Immunol

Mucosal Immunol

Gastroenterology

Gastroenterology

J Allergy Clin Immunol

Clin Gastroenterol Hepatol

Gastrointest Endosc

Cytokine

J Allergy Clin Immunol

Eosinophilic esophagitis is characterized by a non-IgE-mediated food hypersensitivity

Allergy

Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults

United European Gastroenterol J

Allergic esophagitis in children: a clinicopathological entity

Am J Surg Pathol

A striking local esophageal cytokine expression profile in eosinophilic esophagitis

J Allergy Clin Immunol

Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease

Nat Genet

Mepolizumab and exacerbations of refractory eosinophilic asthma

N Engl J Med

Food allergy and gastrointestinal disease
Esophageal type 2 cytokine expression heterogeneity in eosinophilic esophagitis in a multisite cohort