Netali Ben-Baruch Morgenstern1, Adina Y Ballaban1, Ting Wen1, Tetsuo Shoda1, Julie M Caldwell1, Kara Kliewer1, Jennifer M Felton1, J Pablo Abonia1, Vincent A Mukkada2, Philip E Putnam2, Scott M Bolton2, Daniel F Dwyer3, Nora A Barrett3, Marc E Rothenberg4. 1. Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 2. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 3. Jeff and Penny Vinik Center for Translational Immunology Research, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Mass; Department of Medicine, Harvard Medical School, Boston, Boston, Mass. 4. Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address: Rothenberg@cchmc.org.
Abstract
BACKGROUND: Mast cells (MCs) are pleiotropic cells that accumulate in the esophagus of patients with eosinophilic esophagitis (EoE) and are thought to contribute to disease pathogenesis, yet their properties and functions in this organ are largely unknown. OBJECTIVES: This study aimed to perform a comprehensive molecular and spatial characterization of esophageal MCs in EoE. METHODS: Esophageal biopsies obtained from patients with active EoE, patients with EoE in histologic remission, and individuals with histologically normal esophageal biopsies and no history of esophageal disease (ie, control individuals) were subject to single-cell RNA sequencing, flow cytometry, and immunofluorescence analyses. RESULTS: This study probed 39,562 single esophageal cells by single-cell RNA sequencing; approximately 5% of these cells were MCs. Dynamic MC expansion was identified across disease states. During homeostasis, TPSAB1highAREGhigh resident MCs were mainly detected in the lamina propria and exhibited a quiescent phenotype. In patients with active EoE, resident MCs assumed an activated phenotype, and 2 additional proinflammatory MC populations emerged in the intraepithelial compartment, each linked to a proliferating MKI67high cluster. One proinflammatory activated MC population, marked as KIThighIL1RL1highFCER1Alow, was not detected in disease remission (termed "transient MC"), whereas the other population, marked as CMA1highCTSGhigh, was detected in disease remission where it maintained an activated state (termed "persistent MC"). MCs were prominent producers of esophageal IL-13 mRNA and protein, a key therapeutic target in EoE. CONCLUSIONS: Esophageal MCs comprise heterogeneous populations with transcriptional signatures associated with distinct spatial compartmentalization and EoE disease status. In active EoE, they assume a proinflammatory state and locally proliferate, and they remain activated and poised to reinitiate inflammation even during disease remission.
BACKGROUND: Mast cells (MCs) are pleiotropic cells that accumulate in the esophagus of patients with eosinophilic esophagitis (EoE) and are thought to contribute to disease pathogenesis, yet their properties and functions in this organ are largely unknown. OBJECTIVES: This study aimed to perform a comprehensive molecular and spatial characterization of esophageal MCs in EoE. METHODS: Esophageal biopsies obtained from patients with active EoE, patients with EoE in histologic remission, and individuals with histologically normal esophageal biopsies and no history of esophageal disease (ie, control individuals) were subject to single-cell RNA sequencing, flow cytometry, and immunofluorescence analyses. RESULTS: This study probed 39,562 single esophageal cells by single-cell RNA sequencing; approximately 5% of these cells were MCs. Dynamic MC expansion was identified across disease states. During homeostasis, TPSAB1highAREGhigh resident MCs were mainly detected in the lamina propria and exhibited a quiescent phenotype. In patients with active EoE, resident MCs assumed an activated phenotype, and 2 additional proinflammatory MC populations emerged in the intraepithelial compartment, each linked to a proliferating MKI67high cluster. One proinflammatory activated MC population, marked as KIThighIL1RL1highFCER1Alow, was not detected in disease remission (termed "transient MC"), whereas the other population, marked as CMA1highCTSGhigh, was detected in disease remission where it maintained an activated state (termed "persistent MC"). MCs were prominent producers of esophageal IL-13 mRNA and protein, a key therapeutic target in EoE. CONCLUSIONS: Esophageal MCs comprise heterogeneous populations with transcriptional signatures associated with distinct spatial compartmentalization and EoE disease status. In active EoE, they assume a proinflammatory state and locally proliferate, and they remain activated and poised to reinitiate inflammation even during disease remission.
Authors: Duncan M Morgan; Bert Ruiter; Neal P Smith; Ang A Tu; Brinda Monian; Brandon E Stone; Navneet Virk-Hundal; Qian Yuan; Wayne G Shreffler; J Christopher Love Journal: Sci Immunol Date: 2021-08-13
Authors: Daniel F Dwyer; Jose Ordovas-Montanes; Samuel J Allon; Kathleen M Buchheit; Marko Vukovic; Tahereh Derakhshan; Chunli Feng; Juying Lai; Travis K Hughes; Sarah K Nyquist; Matthew P Giannetti; Bonnie Berger; Neil Bhattacharyya; Rachel E Roditi; Howard R Katz; Martijn C Nawijn; Marijn Berg; Maarten van den Berge; Tanya M Laidlaw; Alex K Shalek; Nora A Barrett; Joshua A Boyce Journal: Sci Immunol Date: 2021-02-26
Authors: J D Sherrill; K C Kiran; C Blanchard; E M Stucke; K A Kemme; M H Collins; J P Abonia; P E Putnam; V A Mukkada; A Kaul; S A Kocoshis; J P Kushner; A J Plassard; R A Karns; P J Dexheimer; B J Aronow; M E Rothenberg Journal: Genes Immun Date: 2014-06-12 Impact factor: 2.676
Authors: J Boesiger; M Tsai; M Maurer; M Yamaguchi; L F Brown; K P Claffey; H F Dvorak; S J Galli Journal: J Exp Med Date: 1998-09-21 Impact factor: 14.307