Tetsuo Shoda1, Ting Wen1, Julie M Caldwell1, Netali Ben-Baruch Morgenstern1, Garrett A Osswald1, Mark Rochman1, Lydia E Mack1, Jennifer M Felton1, J Pablo Abonia1, Nicoleta C Arva2, Dan Atkins3, Peter A Bonis4, Kelley E Capocelli5, Margaret H Collins6, Evan S Dellon7, Gary W Falk8, Nirmala Gonsalves9, Sandeep K Gupta10, Ikuo Hirano9, John Leung4, Paul A Menard-Katcher11, Vincent A Mukkada12, Philip E Putnam12, Amanda K Rudman Spergel13, Jonathan M Spergel14, Joshua B Wechsler15, Guang-Yu Yang16, Seema S Aceves17, Glenn T Furuta18, Marc E Rothenberg19. 1. Division of Allergy and Immunology, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 2. Department of Pathology, Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. 3. Section of Pediatric Allergy and Immunology, Children's Hospital Colorado, Aurora, Colorado. 4. Division of Gastroenterology, Tufts Medical Center, Boston, Massachusetts. 5. Department of Pathology, Children's Hospital Colorado, Aurora, Colorado. 6. Division of Pathology, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 7. Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina. 8. Division of Gastroenterology, Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 9. Division of Gastroenterology & Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. 10. Division of Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine, Indianapolis, Indiana. 11. Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado. 12. Division of Gastroenterology, Hepatology, and Nutrition, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 13. Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland. 14. Division of Allergy and Immunology, University of Pennsylvania Perelman School of Medicine/Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 15. Gastroenterology, Hepatology and Nutrition, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois. 16. Department of Pathology and Laboratory Medicine, Northwestern University, Chicago, Illinois. 17. Division of Allergy Immunology, Departments of Pediatrics and Medicine, University of California, San Diego, Rady Children's Hospital, San Diego, California. 18. Section of Pediatric Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado. 19. Division of Allergy and Immunology, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: Rothenberg@cchmc.org.
Abstract
BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) can progress to fibrostenosis by unclear mechanisms. Herein, we investigated gene dysregulation in fibrostenotic EoE, its association with clinical parameters and specific pathways, and the functional consequences. METHODS: Esophageal biopsies from subjects with EoE were collected across 11 Consortium of Eosinophilic Gastrointestinal Disease Researchers sites (n = 311) and 2 independent replication cohorts (n = 83). Inclusion criteria for fibrostenotic EoE were endoscopic rings, stricture, and/or a history of dilation. Endoscopic, histologic, and molecular features were assessed by the EoE Endoscopic Reference Score, EoE Histology Scoring System, EoE Diagnostic Panel, and RNA sequencing. Esophageal endothelial TSPAN12 expression and functional effects on barrier integrity and gene expression were analyzed in vitro. RESULTS: TSPAN12 was the gene most correlated with fibrostenosis (r = -0.40, P < .001). TSPAN12 was lower in fibrostenotic EoE and correlated with EoE Endoscopic Reference Score, EoE Diagnostic Panel, and EoE Histology Scoring System (r = 0.34-0.47, P < .001). Lower TSPAN12 associated with smaller esophageal diameter (r = 0.44, P = .03), increased lamina propria fibrosis (r = -0.41, P < .001), and genes enriched in cell cycle-related pathways. Interleukin (IL)-13 reduced TSPAN12 expression in endothelial cells. Conversely, anti-IL-13 therapy increased TSPAN12 expression. TSPAN12 gene silencing increased endothelial cell permeability and dysregulated genes associated with extracellular matrix pathways. Endothelial cell-fibroblast crosstalk induced extracellular matrix changes relevant to esophageal remodeling. CONCLUSIONS: Patients with fibrostenotic EoE express decreased levels of endothelial TSPAN12. We propose that IL-13 decreases TSPAN12, likely contributing to the chronicity of EoE by promoting tissue remodeling through fibroblast-endothelial cell crosstalk.
BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) can progress to fibrostenosis by unclear mechanisms. Herein, we investigated gene dysregulation in fibrostenotic EoE, its association with clinical parameters and specific pathways, and the functional consequences. METHODS: Esophageal biopsies from subjects with EoE were collected across 11 Consortium of Eosinophilic Gastrointestinal Disease Researchers sites (n = 311) and 2 independent replication cohorts (n = 83). Inclusion criteria for fibrostenotic EoE were endoscopic rings, stricture, and/or a history of dilation. Endoscopic, histologic, and molecular features were assessed by the EoE Endoscopic Reference Score, EoE Histology Scoring System, EoE Diagnostic Panel, and RNA sequencing. Esophageal endothelial TSPAN12 expression and functional effects on barrier integrity and gene expression were analyzed in vitro. RESULTS: TSPAN12 was the gene most correlated with fibrostenosis (r = -0.40, P < .001). TSPAN12 was lower in fibrostenotic EoE and correlated with EoE Endoscopic Reference Score, EoE Diagnostic Panel, and EoE Histology Scoring System (r = 0.34-0.47, P < .001). Lower TSPAN12 associated with smaller esophageal diameter (r = 0.44, P = .03), increased lamina propria fibrosis (r = -0.41, P < .001), and genes enriched in cell cycle-related pathways. Interleukin (IL)-13 reduced TSPAN12 expression in endothelial cells. Conversely, anti-IL-13 therapy increased TSPAN12 expression. TSPAN12 gene silencing increased endothelial cell permeability and dysregulated genes associated with extracellular matrix pathways. Endothelial cell-fibroblast crosstalk induced extracellular matrix changes relevant to esophageal remodeling. CONCLUSIONS: Patients with fibrostenotic EoE express decreased levels of endothelial TSPAN12. We propose that IL-13 decreases TSPAN12, likely contributing to the chronicity of EoE by promoting tissue remodeling through fibroblast-endothelial cell crosstalk.
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