Persistent desmoglein-1 downregulation and periostin accumulation in histologic remission of eosinophilic esophagitis - 18/10/24

Doi : 10.1016/j.jaci.2024.09.016

Hannes Hoelz, MD ^a, Tim Faro ^a, Marie-Luise Frank ^a, Ignasi Forné, PhD ^b, Daniela Kugelmann, MD ^c, Anja Jurk ^a, Simon Buehler ^a, Kolja Siebert ^a, Monica Matchado, PhD ^d, Tobias Straub, PhD ^e, Annett Hering ^f,^g, Guido Piontek ^h, Susanna Mueller, MD ^h, Sibylle Koletzko, MD ^a,ⁱ, Markus List, PhD ^j,^k, Katja Steiger, MD ^f,^g, Martina Rudelius, MD ^h, Jens Waschke, MD ^c, Tobias Schwerd, MD ^a,^⁎
^a Department of Pediatrics, Dr von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany
^b Protein Analysis Unit, Biomedical Center Munich, LMU Munich, Munich, Germany
^c Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Munich, Germany
^d Experimental Bioinformatics, TUM School of Life Sciences, Technical University of Munich, Freising, Germany
^e Biomedical Center Munich, Bioinformatics Core Facility, LMU Munich, Munich, Germany
^f Institute of Pathology, School of Medicine and Health, Technische Universität München, Munich, Germany
^g Comparative Experimental Pathology, School of Medicine and Health, Technische Universität München, Munich, Germany
^h Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
ⁱ Department of Pediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland
^j Data Science in Systems Biology, TUM School of Life Sciences, Technical University of Munich, Freising, Germany
^k Munich Data Science Institute (MDSI), Technical University of Munich, Garching, Germany

^∗Corresponding author: Tobias Schwerd, MD, Pediatric Gastroenterology and Hepatology, Dr von Hauner Children’s Hospital, University Hospital, LMU Munich, Lindwurmstr 4, 80337 Munich, Germany.Pediatric Gastroenterology and HepatologyDr von Hauner Children’s HospitalUniversity HospitalLMU MunichLindwurmstr 4Munich80337Germany

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Friday 18 October 2024

Graphical abstract

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Abstract

Background

Patients with eosinophilic esophagitis (EoE) require long-lasting resolution of inflammation to prevent fibrostenosis and dysphagia. However, the dissociation between symptoms and histologic improvement suggests persistent molecular drivers despite histologic remission.

Objective

We characterized persisting molecular alterations in pediatric patients with EoE using tissue transcriptomics and proteomics.

Methods

Esophageal biopsy samples (n = 247) collected prospectively during 189 endoscopies from pediatric patients with EoE (n = 36, up to 11 follow-up endoscopies) and pediatric controls (n = 44, single endoscopies) were subjected to bulk transcriptomics (n = 96) and proteomics (n = 151). Intercellular junctions (desmoglein-1/3, desmoplakin, E-cadherin) and epithelial-to-mesenchymal transition (vimentin:E-cadherin ratio) were assessed by immunofluorescence staining.

Results

Active EoE (≥15 eosinophils per high-power field [eos/hpf]), inactive EoE (<15 eos/hpf), and deep-remission EoE (0 eos/hpf) were diagnosed in 107 of 185, 78 of 185, and 41 of 185 biopsy samples, respectively. Among the dysregulated genes (up-/downregulated 310/112) and proteins (up-/downregulated 68/16) between active EoE and controls, 17 genes, and 6 proteins remained dysregulated in inactive EoE. Using persistently upregulated genes (n = 9) and proteins (n = 3) only, such as ALOX15, CXCL1, CXCL6, CTSG, CDH26, PRRX1, CLC, EPX, and periostin (POSTN), was sufficient to separate inactive EoE and deep-remission biopsy samples from control tissue. While 32 differentially expressed genes persisted in deep-remission EoE compared to controls, the proteome normalized except for persistently upregulated POSTN. Epithelial-to-mesenchymal transition normalized in inactive EoE, whereas desmosome recovery remained impaired as a result of desmoglein-1 downregulation.

Conclusion

The analysis of molecular changes shows persistent EoE-associated esophageal dysregulation despite histologic remission. These data expand our understanding of inflammatory processes and possible mechanisms that underlie tissue remodeling in EoE.

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Key words : Eosinophilic esophagitis, proteome, transcriptome, epithelial barrier dysfunction, fibrosis

Abbreviations used : CLC, DAP, DEG, DSG, ED, EDP, EMT, EoE, eos, EPX, EREFS, FC, FD, GERD, hpf, PCA, PEC, POSTN, PPI, Vim/Ecad