Julia L M Dunn1, Tetsuo Shoda1, Julie M Caldwell1, Ting Wen1, Seema S Aceves2, Margaret H Collins3, Evan S Dellon4, Gary W Falk5, John Leung6, Lisa J Martin7, Paul Menard-Katcher8, Amanda K Rudman-Spergel9, Jonathan M Spergel10, Joshua B Wechsler11, Guang-Yu Yang12, Glenn T Furuta13, Marc E Rothenberg14. 1. Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio. 2. Division of Allergy Immunology, University of California, San Diego, Calif; Rady Children's Hospital, San Diego, Calif. 3. Division of Pathology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati. 4. Center for Esophageal Diseases and Swallowing and Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC. 5. Division of Gastroenterology, Hospital of the University of Pennsylvania, Philadelphia, Pa. 6. Division of Gastroenterology, Tufts Medical Center, Boston, Mass. 7. Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio. 8. Division of Gastroenterology & Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colo. 9. Allergy, Asthma and Airway Biology Branch Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Md. 10. Division of Allergy and Immunology, Children's Hospital of Philadelphia, School of Medicine, University of Pennsylvania, Philadelphia, Pa. 11. Division of Gastroenterology, Hepatology and Nutrition, Lurie Children's Hospital of Chicago, Chicago, Ill. 12. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Ill. 13. Digestive Health Institute, Children's Hospital Colorado, Gastrointestinal Eosinophilic Diseases Program, University of Colorado School of Medicine, Aurora, Colo. 14. Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address: Rothenberg@cchmc.org.
Abstract
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.
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.
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