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Pitsios C, Rossi CM. Allergen immunotherapy and eosinophilic esophagitis: friends or foes? Curr Opin Allergy Clin Immunol 2024; 24:504-509. [PMID: 39270037 DOI: 10.1097/aci.0000000000001029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/15/2024]
Abstract
PURPOSE OF REVIEW The connection between eosinophilic esophagitis (EoE) and food and airborne allergens is complex. Exposure to allergens (mainly food) is often the trigger for EoE flares. The development of EoE has been described as a side effect of allergen immunotherapy, especially oral immunotherapy (OIT, with food allergens), while isolated cases of EoE have been reported during sublingual immunotherapy (SLIT, with extracts of aeroallergens). RECENT FINDINGS EoE is currently recognized as a common side effect of OIT, while a solid correlation between SLIT and EoE is missing. Animal models have been developed to study the pathophysiological link between sensitization to aeroallergens and the induction of EoE and will probably provide an interpretation of why there are cases of EoE developed during SLIT. Recent findings in animal models suggest a genetic connection to EoE development after sensitization and re-exposure to airborne allergens. Subcutaneous allergen immunotherapy does not have a causative effect on EoE; on the contrary, a beneficial effect on EoE has been reported. Moreover, epicutaneous immunotherapy with a vector containing milk has also been used to treat children with milk-induced EoE. SUMMARY Discovering the immune links between allergens and EoE will further guide the proper use of allergen immunotherapy and help define future strategies for the management of EoE.
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Affiliation(s)
- Constantinos Pitsios
- Medical School, University of Cyprus
- Allergy Outpatient Clinic, General Hospital of Nicosia, Nicosia, Cyprus
| | - Carlo Maria Rossi
- Department of Internal Medicine, IRCCS San Matteo Hospital Foundation
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
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2
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S2k guideline Gastroesophageal reflux disease and eosinophilic esophagitis of the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1786-1852. [PMID: 39389106 DOI: 10.1055/a-2344-6282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
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Ridolo E, Nicoletta F, Lombardi C, Passalacqua G, Senna G, Canonica GW. Eosinophilic esophagitis and inhalant antigens: Pointing out the roles of allergic rhinitis, immunotherapy and biologic treatment. World Allergy Organ J 2024; 17:100968. [PMID: 39386073 PMCID: PMC11462258 DOI: 10.1016/j.waojou.2024.100968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 08/16/2024] [Accepted: 08/27/2024] [Indexed: 10/12/2024] Open
Abstract
Eosinophilic esophagitis (EoE) and allergic rhinitis (AR) usually represent the latest manifestations of the atopic march, sharing a common type 2 inflammation response. A relevant prevalence of AR in EoE cohorts has been widely confirmed. An increasing literature assessed the involvement of aeroantigens in EoE pathogenesis, focusing foremost on the seasonality of new diagnoses, symptoms, and response to therapy. Unfortunately, no diriment direction has been achieved, probably due to the retrospective design of the studies so far available, which chose surrogate markers of EoE activity (mostly the date of new diagnosis) which may be affected by geographical, logistic and personal factors, probably not dependent by the disease itself. EoE exacerbations reported in the context of the pollen levels (preferably pollen counts) may represent a more reliable marker. AR might promote the onset and the re-exacerbation of EoE through mechanisms that are both local (ie, massive exposure to airborne antigens mediated by post-nasal drip) and systemic (type 2 inflammation). Furthermore, AR may facilitate EoE onset by predisposing to pollen food allergic syndrome (PFAS), and EoE patients with PFAS reported higher rate of AR, thus suggesting a bond among these 3 conditions whose causative relationship have still to be ascertained. In addition, because of its shifting activity from Th2 to Th1 inflammation, several case reports focused on the effect of allergen immunotherapy (AIT) employed to treat AR in EoE patients. Also in this instance, no certainties could be guaranteed, although sublingual immunotherapy (SLIT) is more frequently reported to exacerbate EoE, while SCIT is mostly described as a remission adjuvant. The real life experience reported from our allergy service appears to confirm such hypothesis. Finally, a watchful eye should be reserved to monoclonal antibodies as a potential future option for concomitant EoE and AR. In light of all this, an attentive evaluation of allergic history of EoE patients should be relevant. Future perspectives should be addressed on prospective studies targeted to shed light on causative relations among airborne antigens, AR and EoE, and to viable comprehensive treatments.
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Affiliation(s)
- Erminia Ridolo
- Department of Internal Medicine, University of Parma, 43121 Parma, Italy
| | | | - Carlo Lombardi
- Departmental Unit of Allergology, Clinical Immunology and Pneumology, Fondazione Poliambulanza, Brescia, Italy
| | - Giovanni Passalacqua
- Allergy and Respiratory Diseases, DIMI Department of Internal Medicine, University of Genoa, Ospedale Policlinico San Martino, Genoa, Italy
| | - Gianenrico Senna
- Asthma Center and Allergy Unit, University of Verona and General Hospital, Verona, Italy
| | - Giorgio Walter Canonica
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Personalized Medicine, Asthma and Allergy, Humanitas Clinical and Research Center, IRCCS, Rozzano, Italy
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Melhem H, Niess JH. Eosinophilic Esophagitis and Inflammatory Bowel Disease: What Are the Differences? Int J Mol Sci 2024; 25:8534. [PMID: 39126102 PMCID: PMC11313654 DOI: 10.3390/ijms25158534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/19/2024] [Accepted: 07/20/2024] [Indexed: 08/12/2024] Open
Abstract
Eosinophilic esophagitis (EoE) and inflammatory bowel disease (IBD) are chronic inflammatory disorders of the gastrointestinal tract, with EoE predominantly provoked by food and aeroallergens, whereas IBD is driven by a broader spectrum of immunopathological and environmental triggers. This review presents a comprehensive comparison of the pathophysiological and therapeutic strategies for EoE and IBD. We examine the current understanding of their underlying mechanisms, particularly the interplay between environmental factors and genetic susceptibility. A crucial element in both diseases is the integrity of the epithelial barrier, whose disruption plays a central role in their pathogenesis. The involvement of eosinophils, mast cells, B cells, T cells, dendritic cells, macrophages, and their associated cytokines is examined, highlighting the importance of targeting cytokine signaling pathways to modulate immune-epithelial interactions. We propose that advances in computation tools will uncover the significance of G-protein coupled receptors (GPCRs) in connecting immune and epithelial cells, leading to novel therapies for EoE and IBD.
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Affiliation(s)
- Hassan Melhem
- Gastroenterology Group, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland
| | - Jan Hendrik Niess
- Gastroenterology Group, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland
- Department of Gastroenterology and Hepatology, University Digestive Healthcare Center, Clarunis, 4002 Basel, Switzerland
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Pilat JM, Jacobse J, Buendia MA, Choksi YA. Animal models of eosinophilic esophagitis. J Leukoc Biol 2024; 116:349-356. [PMID: 38507307 PMCID: PMC11518583 DOI: 10.1093/jleuko/qiae043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 02/06/2024] [Accepted: 02/09/2024] [Indexed: 03/22/2024] Open
Abstract
Eosinophilic esophagitis is a chronic inflammatory disorder of the esophagus. Over the past 25 yr, great strides have been made toward understanding its pathogenesis, in part due to studies in several types of animal models. The vast majority of these models have been characterized in mice. In this review, we summarize the histopathological features of eosinophilic esophagitis recapitulated by these animal models, as well as discuss their strengths and weaknesses.
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Affiliation(s)
- Jennifer M. Pilat
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, 1075 Medical Research Building IV, B-2215 Garland Ave, Nashville, TN 37232, United States
| | - Justin Jacobse
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, 1075 Medical Research Building IV, B-2215 Garland Ave, Nashville, TN 37232, United States
- Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
- Division of Molecular Pathogenesis, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, United States
- Veterans Affairs Tennessee Valley Healthcare System, 1310 24th Ave S, Nashville, TN 37232, United States
| | - Matthew A. Buendia
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Vanderbilt University Medical Center, 2200 Children’s Way, Nashville, TN 37232, United States
| | - Yash A. Choksi
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, 1075 Medical Research Building IV, B-2215 Garland Ave, Nashville, TN 37232, United States
- Veterans Affairs Tennessee Valley Healthcare System, 1310 24th Ave S, Nashville, TN 37232, United States
- Program in Cancer Biology, School of Medicine, Vanderbilt University, 1075 Medical Research Building IV, B-2215 Garland Ave, Nashville, TN 37232, United States
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, 1030 Medical Research Building IV, 2215 Garland Ave, Nashville, TN 37232, United States
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Laky K, Frischmeyer-Guerrerio PA. Development and dysfunction of structural cells in eosinophilic esophagitis. J Allergy Clin Immunol 2024; 153:1485-1499. [PMID: 38849184 PMCID: PMC11626564 DOI: 10.1016/j.jaci.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 04/18/2024] [Accepted: 04/18/2024] [Indexed: 06/09/2024]
Abstract
Eosinophilic esophagitis (EoE) is a disorder characterized by dysfunction and chronic local inflammation of the esophagus. The incidence and prevalence of EoE are increasing worldwide. The mechanisms responsible are poorly understood, and effective treatment options are limited. From the lumen outward, the esophagus comprises stratified squamous epithelium, lamina propria, and muscle. The tissue-specific nature of EoE strongly suggests that structural cells in the esophagus are involved in the EoE diathesis. Epithelial basal cell hyperplasia and dilated intercellular spaces are cardinal features of EoE. Some patients with EoE develop lamina propria fibrosis, strictures, or esophageal muscle dysmotility. Clinical symptoms of EoE are only weakly correlated with peak eosinophil count, implying that other cell types contribute to EoE pathogenesis. Epithelial, endothelial, muscle, and fibroblast cells can each initiate inflammation and repair, regulate tissue resident immune cells, recruit peripheral leukocytes, and tailor adaptive immune cell responses. A better understanding of how structural cells maintain tissue homeostasis, respond to cell-intrinsic and cell-extrinsic stressors, and exacerbate and/or resolve inflammatory responses in the esophagus is needed. This knowledge will facilitate the development of more efficacious treatment strategies for EoE that can restore homeostasis of both hematopoietic and structural elements in the esophagus.
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Affiliation(s)
- Karen Laky
- Food Allergy Research Section, Laboratory of Allergic Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
| | - Pamela A Frischmeyer-Guerrerio
- Food Allergy Research Section, Laboratory of Allergic Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
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Furuta GT, Dellon ES, Straumann A, Gonsalves N, Rothenberg ME, Hirano I. Building and implementing a research infrastructure for eosinophilic gastrointestinal diseases. J Allergy Clin Immunol 2024; 153:1536-1539. [PMID: 38849187 PMCID: PMC11550568 DOI: 10.1016/j.jaci.2024.04.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 04/22/2024] [Accepted: 04/23/2024] [Indexed: 06/09/2024]
Affiliation(s)
- Glenn T Furuta
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, Colo.
| | - Evan S Dellon
- Center for Esophageal Diseases and Swallowing, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Alex Straumann
- Department of Gastroenterology, University Hospital Zurich, Zurich, Switzerland
| | - Nimi Gonsalves
- Kenneth Griffin Esophageal Center, Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - Marc E Rothenberg
- Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Ikuo Hirano
- Kenneth Griffin Esophageal Center, Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Ill
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Li D, Wei Y, Wang J, Wang B. Animal models of eosinophilic esophagitis, review and perspectives. Animal Model Exp Med 2024; 7:127-135. [PMID: 38369973 PMCID: PMC11079148 DOI: 10.1002/ame2.12391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 01/11/2024] [Indexed: 02/20/2024] Open
Abstract
Eosinophilic oesophagitis (EoE) is an allergen/immune-mediated chronic esophageal disease characterized by esophageal mucosal eosinophilic infiltration and esophageal dysfunction. Although the disease was originally attributed to a delayed allergic reaction to allergens and a Th2-type immune response, the exact pathogenesis is complex, and the efficacy of existing treatments is unsatisfactory. Therefore, the study of the pathophysiological process of EOE has received increasing attention. Animal models have been used extensively to study the molecular mechanism of EOE pathogenesis and also provide a preclinical platform for human clinical intervention studies of novel therapeutic agents. To maximize the use of existing animal models of EOE, it is important to understand the advantages or limitations of each modeling approach. This paper systematically describes the selection of experimental animals, types of allergens, and methods of sensitization and excitation during the preparation of animal models of EoE. It also discusses the utility and shortcomings of each model with the aim of providing the latest perspectives on EoE models and leading to better choices of animal models.
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Affiliation(s)
- Dong Li
- Department of DermatologyHuazhong University of Science and Technology Tongji Medical College Tongji HospitalWuhanChina
| | - Yujia Wei
- Department of DermatologyHuazhong University of Science and Technology Tongji Medical College Tongji HospitalWuhanChina
| | - Jing Wang
- Health Management CenterHuazhong University of Science and Technology Tongji Medical College Tongji HospitalWuhanChina
| | - Bo Wang
- Department of GastroenterologyHuazhong University of Science and Technology Tongji Medical College Tongji HospitalWuhanChina
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Yadavalli CS, Upparahalli Venkateshaiah S, Verma AK, Kathera C, Duncan PS, Vaezi M, Paul RJ, Mishra A. Vasoactive Intestinal Peptide Receptor, CRTH2, Antagonist Treatment Improves Eosinophil and Mast Cell-Mediated Esophageal Remodeling and Motility Dysfunction in Eosinophilic Esophagitis. Cells 2024; 13:295. [PMID: 38391908 PMCID: PMC10886969 DOI: 10.3390/cells13040295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/30/2024] [Accepted: 02/01/2024] [Indexed: 02/24/2024] Open
Abstract
BACKGROUND AND AIMS Ultrasonography has shown that eosinophils accumulate in each segment of the esophageal mucosa in human EoE, ultimately promoting esophageal motility dysfunction; however, no mechanistic evidence explains how or why this accumulation occurs. METHODS Quantitative PCR, ELISA, flow cytometry, immunostaining, and immunofluorescence analyses were performed using antibodies specific to the related antigens and receptors. RESULTS In deep esophageal biopsies of EoE patients, eosinophils and mast cells accumulate adjacent to nerve cell-derived VIP in each esophageal segment. qRT-PCR analysis revealed five- to sixfold increases in expression levels of VIP, CRTH2, and VAPC2 receptors and proteins in human blood- and tissue-accumulated eosinophils and mast cells. We also observed a significant correlation between mRNA CRTH2 levels and eosinophil- and nerve cell-derived VIPs in human EoE (p < 0.05). We provide evidence that eosinophil and mast cell deficiency following CRTH2 antagonist treatment improves motility dysfunction in a chronic DOX-inducible CC10-IL-13 murine model of experimental EoE. CONCLUSIONS CRTH2 antagonist treatment is a novel therapeutic strategy for inflammatory cell-induced esophageal motility dysfunction in IL-13-induced chronic experimental EoE.
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Affiliation(s)
- Chandra Sekhar Yadavalli
- Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center, School of Medicine, Tulane University, New Orleans, LA 70112, USA; (C.S.Y.); (S.U.V.); (C.K.)
| | - Sathisha Upparahalli Venkateshaiah
- Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center, School of Medicine, Tulane University, New Orleans, LA 70112, USA; (C.S.Y.); (S.U.V.); (C.K.)
| | - Alok K. Verma
- Division of Gastroenterology, Cincinnati Childrens Medical Center, Cincinnati, OH 45229, USA;
| | - Chandrasekhar Kathera
- Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center, School of Medicine, Tulane University, New Orleans, LA 70112, USA; (C.S.Y.); (S.U.V.); (C.K.)
| | - Pearce S. Duncan
- Division of Gastroenterology, School of Medicine, Tulane University, New Orleans, LA 70118, USA;
| | - Michael Vaezi
- Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, TN 37232, USA;
| | - Richard J. Paul
- Division of Physiology, Cincinnati University, Cincinnati, OH 45220, USA;
| | - Anil Mishra
- Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center, School of Medicine, Tulane University, New Orleans, LA 70112, USA; (C.S.Y.); (S.U.V.); (C.K.)
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Girkin JLN, Sokulsky LA, Starkey MR, Hansbro PM, Foster PS, Collison AM, Mattes J. A unique role for IL-13 in inducing esophageal eosinophilia through MID-1 and STAT6. FRONTIERS IN ALLERGY 2023; 4:1248432. [PMID: 38026128 PMCID: PMC10657859 DOI: 10.3389/falgy.2023.1248432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 10/17/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction Eosinophilic esophagitis (EoE) is associated with allergen-driven inflammation of the esophagus and an upregulated Th2 cytokine signature. Recombinant interleukin (IL)-13 (rIL-13) administration to mice induces some of the hallmark features of EoE, including increased eotaxin expression and eosinophil recruitment. Inflammation in EoE has previously been shown to depend on the expression of TRAIL and MID-1, which reduced protein phosphatase 2A (PP2A) activity. The relationship between IL-13 and TRAIL signalling in esophageal eosinophilia is currently unknown. Objective To investigate the interaction between IL-13-driven eosinophil infiltration and TRAIL or MID-1 in the esophagus. Method We administered rIL-13 to wild type (WT), TRAIL-deficient (Tnsf10-/-) or STAT6-deficient (STAT6-/-) mice and targeted MID-1 with small interfering RNA. Results rIL-13 administration to mice increased TRAIL and MID-1 expression in the esophagus while reducing PP2A activity. TRAIL deficient, but not STAT6 deficient mice demonstrated increased MID-1 expression and PP2A reduction upon IL-13 challenge which correlated with eosinophil infiltration into the esophagus. Silencing MID-1 expression with siRNA completely ablated IL-13 induced eosinophil infiltration of the esophagus, restored PP2A activity, and reduced eotaxin-1 expression. Conclusion IL-13-driven eosinophil infiltration of the esophagus induced eosinophilia and eotaxin-1 expression in a STAT6-dependent and MID-1-dependent manner. This study highlights a novel mechanism employed by IL-13 to perpetuate eosinophil infiltration.
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Affiliation(s)
- Jason L. N. Girkin
- The Priority Research Centre for Healthy Lungs and The Asthma and Breathing Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia
| | - Leon A. Sokulsky
- The Priority Research Centre, GrowUpWell and The Asthma and Breathing Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia
| | - Malcolm R. Starkey
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Philip M. Hansbro
- The Priority Research Centre, GrowUpWell and The Asthma and Breathing Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia
- Centre for Inflammation, Faculty of Science, School of Life Sciences, Centenary Institute and University of Technology Sydney, Sydney, NSW, Australia
| | - Paul S. Foster
- The Priority Research Centre, GrowUpWell and The Asthma and Breathing Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia
| | - Adam M. Collison
- The Priority Research Centre for Healthy Lungs and The Asthma and Breathing Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia
| | - Joerg Mattes
- The Priority Research Centre for Healthy Lungs and The Asthma and Breathing Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia
- The Department of Respiratory and Sleep Medicine, John Hunter Children's Hospital, Newcastle, NSW, Australia
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Massironi S, Mulinacci G, Gallo C, Elvevi A, Danese S, Invernizzi P, Vespa E. Mechanistic Insights into Eosinophilic Esophagitis: Therapies Targeting Pathophysiological Mechanisms. Cells 2023; 12:2473. [PMID: 37887317 PMCID: PMC10605530 DOI: 10.3390/cells12202473] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 10/12/2023] [Accepted: 10/16/2023] [Indexed: 10/28/2023] Open
Abstract
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized by eosinophilic infiltration of the esophagus. It arises from a complex interplay of genetic predisposition (susceptibility loci), environmental triggers (allergens and dietary antigens), and a dysregulated immune response, mainly mediated by type 2 T helper cell (Th2)-released cytokines, such as interleukin (IL)-4, IL-5, and IL-13. These cytokines control eosinophil recruitment and activation as well as tissue remodeling, contributing to the characteristic features of EoE. The pathogenesis of EoE includes epithelial barrier dysfunction, mast cell activation, eosinophil degranulation, and fibrosis. Epithelial barrier dysfunction allows allergen penetration and promotes immune cell infiltration, thereby perpetuating the inflammatory response. Mast cells release proinflammatory mediators and promote eosinophil recruitment and the release of cytotoxic proteins and cytokines, causing tissue damage and remodeling. Prolonged inflammation can lead to fibrosis, resulting in long-term complications such as strictures and dysmotility. Current treatment options for EoE are limited and mainly focus on dietary changes, proton-pump inhibitors, and topical corticosteroids. Novel therapies targeting key inflammatory pathways, such as monoclonal antibodies against IL-4, IL-5, and IL-13, are emerging in clinical trials. A deeper understanding of the complex pathogenetic mechanisms behind EoE will contribute to the development of more effective and personalized therapeutic strategies.
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Affiliation(s)
- Sara Massironi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (G.M.); (C.G.); (A.E.)
- School of Medicine and Surgery, University of Milano-Bicocca, 20125 Milan, Italy
| | - Giacomo Mulinacci
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (G.M.); (C.G.); (A.E.)
- School of Medicine and Surgery, University of Milano-Bicocca, 20125 Milan, Italy
| | - Camilla Gallo
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (G.M.); (C.G.); (A.E.)
- School of Medicine and Surgery, University of Milano-Bicocca, 20125 Milan, Italy
| | - Alessandra Elvevi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (G.M.); (C.G.); (A.E.)
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (G.M.); (C.G.); (A.E.)
- School of Medicine and Surgery, University of Milano-Bicocca, 20125 Milan, Italy
| | - Edoardo Vespa
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, 20132 Milan, Italy
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Yadavalli CS, Upparahalli Venkateshaiah S, Kumar S, Kandikattu HK, Oruganti L, Kathera CS, Mishra A. Allergen-induced NLRP3/caspase1/IL-18 signaling initiate eosinophilic esophagitis and respective inhibitors protect disease pathogenesis. Commun Biol 2023; 6:763. [PMID: 37524769 PMCID: PMC10390481 DOI: 10.1038/s42003-023-05130-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 07/10/2023] [Indexed: 08/02/2023] Open
Abstract
The current report describes a stepwise mechanistic pathway of NLRP3/caspase1/IL-18-regulated immune responses operational in eosinophilic esophagitis (EoE). We show that esophageal epithelial cells and macrophage-derived NLRP3 regulated IL-18 initiate the disease and induced IL-5 facilitates eosinophil growth and survival. We also found that A. fumigatus-exposed IL-18-/- mice or IL-18-neutralized mice are protected from EoE induction. Most importantly, we present that intravascular rIL-18 delivery to ΔdblGATA mice and CD2-IL-5 mice show the development of EoE characteristics feature like degranulated and intraepithelial eosinophils, basal cell hyperplasia, remodeling and fibrosis. Similarly, we show an induced NLRP3-caspase1-regulated IL-18 pathway is also operational in human EoE. Lastly, we present the evidence that inhibitors of NLRP3 and caspase-1 (MCC950, BHB, and VX-765) protect A. fumigatus- and corn-extract-induced EoE pathogenesis. In conclusion, the current study provides a new understanding by implicating NLRP3/caspase1-regulated IL-18 pathway in EoE pathogenesis. The study has the clinical significance and novel therapeutic strategy, which depletes only IL-18-responsive pathogenic eosinophils, not naïve IL-5-generated eosinophils critical for maintaining innate immunity.
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Affiliation(s)
- Chandra Sekhar Yadavalli
- John W. Deming Department of Medicine, Tulane Eosinophilic Disorders Center (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA, USA
| | - Sathisha Upparahalli Venkateshaiah
- John W. Deming Department of Medicine, Tulane Eosinophilic Disorders Center (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA, USA
| | - Sandeep Kumar
- John W. Deming Department of Medicine, Tulane Eosinophilic Disorders Center (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA, USA
- Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Hemanth Kumar Kandikattu
- John W. Deming Department of Medicine, Tulane Eosinophilic Disorders Center (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA, USA
| | - Lokanatha Oruganti
- John W. Deming Department of Medicine, Tulane Eosinophilic Disorders Center (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA, USA
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA
| | - Chandra Sekhar Kathera
- John W. Deming Department of Medicine, Tulane Eosinophilic Disorders Center (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA, USA
| | - Anil Mishra
- John W. Deming Department of Medicine, Tulane Eosinophilic Disorders Center (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA, USA.
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13
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S2k-Leitlinie Gastroösophageale Refluxkrankheit und eosinophile Ösophagitis der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) – März 2023 – AWMF-Registernummer: 021–013. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2023; 61:862-933. [PMID: 37494073 DOI: 10.1055/a-2060-1069] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/28/2023]
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Fuller AD, Karami AL, Kabir MF, Klochkova A, Jackson JL, Mu A, Tan Y, Klein-Szanto AJ, Whelan KA. Eosinophilic esophagitis-associated epithelial remodeling may limit esophageal carcinogenesis. FRONTIERS IN ALLERGY 2023; 4:1086032. [PMID: 37064719 PMCID: PMC10090679 DOI: 10.3389/falgy.2023.1086032] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 02/28/2023] [Indexed: 03/31/2023] Open
Abstract
Introduction Under homeostatic conditions, esophageal epithelium displays a proliferation/differentiation gradient that is generated as proliferative basal cells give rise to suprabasal cells then terminally differentiated superficial cells. This proliferation/differentiation gradient is often perturbed in esophageal pathologies. Basal cell hyperplasia may occur in patients with gastroesophageal reflux disease (GERD), a condition in which acid from the stomach enters the esophagus, or eosinophilic esophagitis (EoE), an emerging form of food allergy. While GERD is a primary risk factor for esophageal cancer, epidemiological data suggests that EoE patients do not develop esophageal cancer. Methods In order to investigate the impact of EoE and esophageal cancer specifically on the cellular landscape of esophageal epithelium, we perform single cell RNA-sequencing in murine models of EoE and esophageal cancer, specifically esophageal squamous cell carcinoma (ESCC). We further evaluate modules of co-expressed genes in EoE- and ESCC-enriched epithelial cell clusters. Finally, we pair EoE and ESCC murine models to examine the functional relationship between these pathologies. Results In mice with either EoE or ESCC, we find expansion of cell populations as compared to normal esophageal epithelium. In mice with EoE, we detect distinct expansion of 4 suprabasal populations coupled with depletion of 2 basal populations. By contrast, mice with ESCC display unique expansion of 2 basal populations and 1 suprabasal population, as well as depletion of 2 suprabasal populations. Senescence, glucocorticoid receptor signaling, and granulocyte-macrophage colony-stimulating factor pathways are associated with EoE-enriched clusters while pathways associated with cell proliferation and metabolism are identified in ESCC-enriched clusters. Finally, our in vivo data demonstrate that exposure to EoE inflammation limits tumor burden of esophageal carcinogenesis. Discussion Our findings provide the first functional investigation of the relationship between EoE and esophageal cancer and suggest that esophageal epithelial remodeling events occurring in response to EoE inflammation may limit esophageal carcinogenesis. This investigation may have future implications for leveraging allergic inflammation-associated alterations in epithelial biology to prevent and/or treat esophageal cancer.
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Affiliation(s)
- Annie D. Fuller
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Adam L. Karami
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Mohammad Faujul Kabir
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Alena Klochkova
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Jazmyne L. Jackson
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Anbin Mu
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Yinfei Tan
- Genomics Facility, Fox Chase Cancer Center, Philadelphia, PA, United States
| | | | - Kelly A. Whelan
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
- Department of Cancer & Cellular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
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15
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Iwaya M, Kobayashi S, Nakayama Y, Kato S, Kurasawa S, Sado T, Iwaya Y, Uehara T, Ota H. Number and distribution of eosinophils and lymphocytes in the Japanese pediatric gastrointestinal tract: in search of a definition for "abnormally increased eosinophils". World J Pediatr 2023; 19:251-260. [PMID: 36436182 DOI: 10.1007/s12519-022-00646-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 10/19/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND Primary eosinophilic gastrointestinal disorders (EGIDs) constitute chronic allergic inflammation. The number of eosinophils is one of the diagnostic criteria; more than 20 eosinophils per high-power field (HPF) in the gastrointestinal (GI) tract are considered abnormal in Japan. However, the quantity of eosinophils considered normal varies according to anatomical location and geographical region; such values have not been reported in Japanese pediatric patients, nor have the numbers of lymphocytes in the normal pediatric stomach. To establish a reference for defining diagnostic criteria for EGIDs, we evaluated the number of eosinophils in the normal Japanese pediatric GI tract. METHODS We examined 131 biopsy cases without significant clinical history, endoscopic abnormality, or histological abnormality. Immunohistochemical analysis of CD3 and CD20 was performed. RESULTS The mean eosinophil density was highest in the cecum (49.5 ± 22.4 per HPF). Counts of more than 20 eosinophils per HPF were observed in the duodenum [bulb (20.0 ± 9.6) and second portion (30.0 ± 15.8)], terminal ileum (38.3 ± 22.7), cecum (49.5 ± 22.4), ascending colon (42.3 ± 25.3), transverse colon (29.4 ± 17.0), and descending colon (32.2 ± 17.9). Counts of fewer than 10 eosinophils per HPF were observed in the stomach and rectum; a count of fewer than one eosinophil per HPF was observed in the esophagus. More than 100 CD3-positive T cells per HPF were observed in the stomach. CONCLUSIONS The mean numbers of eosinophils in the bowel were greater than 20 per HPF. For Japanese pediatrics, the current threshold eosinophil count should be revised.
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Affiliation(s)
- Mai Iwaya
- Department of Laboratory Medicine, Shinshu University Hospital, 3-1-1 Asahi, Matsumoto , Nagano, Japan.
| | - Shota Kobayashi
- Department of Laboratory Medicine, Shinshu University Hospital, 3-1-1 Asahi, Matsumoto , Nagano, Japan
| | - Yoshiko Nakayama
- Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
| | - Sawako Kato
- Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
| | - Shingo Kurasawa
- Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tomomitsu Sado
- Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yugo Iwaya
- Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takeshi Uehara
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Hiroyoshi Ota
- Department of Clinical Laboratory Sciences, School of Health Sciences, Shinshu University, Matsumoto, Japan
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16
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Laky K, Kinard JL, Li JM, Moore IN, Lack J, Fischer ER, Kabat J, Latanich R, Zachos NC, Limkar AR, Weissler KA, Thompson RW, Wynn TA, Dietz HC, Guerrerio AL, Frischmeyer-Guerrerio PA. Epithelial-intrinsic defects in TGFβR signaling drive local allergic inflammation manifesting as eosinophilic esophagitis. Sci Immunol 2023; 8:eabp9940. [PMID: 36608150 PMCID: PMC10106118 DOI: 10.1126/sciimmunol.abp9940] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Allergic diseases are a global health challenge. Individuals harboring loss-of-function variants in transforming growth factor-β receptor (TGFβR) genes have an increased prevalence of allergic disorders, including eosinophilic esophagitis. Allergic diseases typically localize to mucosal barriers, implicating epithelial dysfunction as a cardinal feature of allergic disease. Here, we describe an essential role for TGFβ in the control of tissue-specific immune homeostasis that provides mechanistic insight into these clinical associations. Mice expressing a TGFβR1 loss-of-function variant identified in atopic patients spontaneously develop disease that clinically, immunologically, histologically, and transcriptionally recapitulates eosinophilic esophagitis. In vivo and in vitro, TGFβR1 variant-expressing epithelial cells are hyperproliferative, fail to differentiate properly, and overexpress innate proinflammatory mediators, which persist in the absence of lymphocytes or external allergens. Together, our results support the concept that TGFβ plays a fundamental, nonredundant, epithelial cell-intrinsic role in controlling tissue-specific allergic inflammation that is independent of its role in adaptive immunity.
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Affiliation(s)
- Karen Laky
- Food Allergy Research Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jessica L Kinard
- Food Allergy Research Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jenny Min Li
- Food Allergy Research Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ian N Moore
- Infectious Disease Pathogenesis Section, Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Justin Lack
- Collaborative Bioinformatics Resource, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.,Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Elizabeth R Fischer
- Electron Microscopy Unit, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA
| | - Juraj Kabat
- Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Rachel Latanich
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Nicholas C Zachos
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Ajinkya R Limkar
- Inflammation Immunobiology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Katherine A Weissler
- Food Allergy Research Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Robert W Thompson
- Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Thomas A Wynn
- Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Harry C Dietz
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
| | - Anthony L Guerrerio
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Pamela A Frischmeyer-Guerrerio
- Food Allergy Research Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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17
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Underwood B, Troutman TD, Schwartz JT. Breaking down the complex pathophysiology of eosinophilic esophagitis. Ann Allergy Asthma Immunol 2023; 130:28-39. [PMID: 36351516 PMCID: PMC10165615 DOI: 10.1016/j.anai.2022.10.026] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/30/2022] [Accepted: 10/31/2022] [Indexed: 11/08/2022]
Abstract
Eosinophilic esophagitis (EoE) is a chronic and progressive immune-mediated disease of the esophagus associated with antigen-driven type 2 inflammation and symptoms of esophageal dysfunction. Our understanding of EoE pathophysiology has evolved since its initial recognition more than 20 years ago and has translated into diagnostic and novel therapeutic approaches that are affecting patient care. The mechanisms underlying disease development and progression are influenced by diverse factors, such as genetics, age, allergic comorbidities, and allergen exposures. Central to EoE pathophysiology is a dysregulated feed-forward cycle that develops between the esophageal epithelium and the immune system. Allergen-induced, type 2-biased immune activation by the esophageal epithelium propagates a cycle of impaired mucosal barrier integrity and allergic inflammation, eventually leading to tissue remodeling and progressive organ dysfunction. Herein, we review the current understanding of fundamental pathophysiological mechanisms contributing to EoE pathogenesis.
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Affiliation(s)
- Brynne Underwood
- Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Ty D Troutman
- Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Justin T Schwartz
- Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
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18
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Manresa MC, Miki H, Miller J, Okamoto K, Dobaczewska K, Herro R, Gupta RK, Kurten R, Aceves SS, Croft M. A Deficiency in the Cytokine TNFSF14/LIGHT Limits Inflammation and Remodeling in Murine Eosinophilic Esophagitis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 209:2341-2351. [PMID: 36288906 PMCID: PMC10130236 DOI: 10.4049/jimmunol.2200326] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 09/27/2022] [Indexed: 01/04/2023]
Abstract
Eosinophilic esophagitis (EoE) is a chronic type 2 allergic disease, with esophageal tissue remodeling as the mechanism behind clinical dysphagia and strictures. IL-13 is thought to be a central driver of disease, but other inflammatory factors, such as IFNs and TNF superfamily members, have been hypothesized to play a role in disease pathogenesis. We recently found that the cytokine TNFSF14/LIGHT is upregulated in the esophagus of patients with EoE and that LIGHT promotes inflammatory activity in esophageal fibroblasts. However, the global effects of LIGHT on EoE pathogenesis in vivo remain unknown. We investigated the impact of a LIGHT deficiency in a murine model of EoE driven by house dust mite allergen. Chronic intranasal challenge with house dust mite promoted esophageal eosinophilia and increased CD4+ T cell numbers and IL-13 and CCL11 production in wild-type mice. Esophageal remodeling was reflected by submucosal collagen accumulation, increased muscle density, and greater numbers of fibroblasts. LIGHT-/- mice displayed normal esophageal eosinophilia, but exhibited reduced frequencies of CD4 T cells, IL-13 expression, submucosal collagen, and muscle density and a decrease in esophageal accumulation of fibroblasts. In vitro, LIGHT increased division of human esophageal fibroblasts and selectively enhanced IL-13-mediated expression of a subset of inflammatory and fibrotic genes. These results show that LIGHT contributes to various features of murine EoE, impacting the accumulation of CD4 T cells, IL-13 production, fibroblast proliferation, and esophagus remodeling. These findings suggest that LIGHT may be, to our knowledge, a novel therapeutic target for the treatment of EoE.
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Affiliation(s)
- Mario C Manresa
- Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA
| | - Haruka Miki
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA
| | - Jacqueline Miller
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA
| | - Kevin Okamoto
- Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA
| | - Katarzyna Dobaczewska
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA
| | - Rana Herro
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA
| | - Rinkesh K Gupta
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA
| | - Richard Kurten
- Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR
- Arkansas Children's Hospital Research Institute, Little Rock, AR; and
| | - Seema S Aceves
- Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA
- Rady Children's Hospital, San Diego, CA
| | - Michael Croft
- Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA;
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA
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19
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Zhao W, Wang B, Zhang L, Jin H. Eosinophils Infiltration in Esophageal Muscularis Propria Induces Achalasia-like Esophageal Motility Disorder in Mice. Biomolecules 2022; 12:biom12121865. [PMID: 36551293 PMCID: PMC9775547 DOI: 10.3390/biom12121865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 12/08/2022] [Accepted: 12/09/2022] [Indexed: 12/15/2022] Open
Abstract
Eosinophil infiltration in esophageal muscularis propria is common in achalasia (AC). This study aims to evaluate the effect of eosinophil infiltration in muscularis propria of the esophagus on esophageal motility in mice. A mouse model with eosinophil infiltration in the esophageal muscle layer was established by long term Ovalbumin (OVA) exposure. The histopathology features of esophageal muscularis propria as well as parameters of esophageal motility, such as lower esophageal sphincter pressure (LESP) and esophageal emptying, were compared between model and control group. In addition, the histopathology and motility of esophagus at each time point in the model group were compared. The esophageal motor function severely deteriorated in the model group, mimicking the abnormal esophageal motility of AC, with more eosinophils and fewer SOX-10-IR cells in esophageal muscularis propria in the model group, compared with control. With the prolongation of OVA treatment, esophageal motility disorder was aggravated, accompanied by increased eosinophils in the the muscle layer of esophagus and decreased SOX-10-IR cells in the model group. In addition, the eosinophil count was negatively correlated with SOX-10-IR cells. Long-term exposure to OVA assisted by alum may induce eosinophil infiltration in esophageal muscularis propria, reduced SOX-10-IR cells and abnormal esophageal motility, which simulates the functional and histopathological features of some AC patients. This suggests that eosinophil infiltration in esophageal muscularis propria may play a role in the pathogenesis of a subgroup of AC.
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Affiliation(s)
| | | | - Lili Zhang
- Correspondence: (L.Z.); (H.J.); Tel./Fax: +86-2260362608 (H.J.)
| | - Hong Jin
- Correspondence: (L.Z.); (H.J.); Tel./Fax: +86-2260362608 (H.J.)
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20
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Rothenberg ME. Scientific journey to the first FDA-approved drug for eosinophilic esophagitis. J Allergy Clin Immunol 2022; 150:1325-1332. [PMID: 36209816 PMCID: PMC9742179 DOI: 10.1016/j.jaci.2022.09.027] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/11/2022] [Accepted: 09/07/2022] [Indexed: 11/06/2022]
Abstract
When eosinophilia was first associated with esophagitis, it was thought to reflect gastroesophageal reflux disease, especially given the efficacy of reflux medications to abate esophageal eosinophilia in many individuals. Subsequent studies demonstrated disease remittance with amino acid-based formulas and conversely induction of esophageal eosinophilia in mice following allergen challenge. These results, along with the finding that proton pump inhibitors alleviated esophageal eosinophilia by an anti-inflammatory mechanism, turned attention away from an acid-induced pathogenesis and established eosinophilic esophagitis (EoE) as a separate disease entity driven by allergic inflammation. The disease underpinnings were elucidated by analysis of esophageal transcriptomic profiling, revealing gene signatures orchestrated by type 2 cytokine signaling, mainly IL-13. Preclinical studies showed that IL-13 overproduction was sufficient to induce EoE-like changes in mice and human ex vivo systems and conversely that inhibiting IL-13 signaling attenuated these processes. An early proof-of-principle study with a humanized anti-IL-13 mAb in patients with EoE revealed correction of the EoE transcriptome and attenuation of esophageal eosinophilia, providing a rationale for advancing anti-type 2 cytokine therapy for EoE. Dupilumab, a precision therapeutic mAb that blocks the shared IL-13 and IL-4 receptor, is the first drug to advance through clinical trials and receive US Food and Drug Administration approval for EoE. The ability of dupilumab to improve clinical, histologic, endoscopic, and molecular features of EoE and garner US Food and Drug Administration approval is a victory for science, rare diseases, patients, and advocacy and provides a framework for developing additional EoE treatments and approved treatments for eosinophilic gastrointestinal disease beyond the esophagus.
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Affiliation(s)
- Marc E Rothenberg
- Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine.
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21
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Maskey A, Srivastava K, Soffer G, Dunkin D, Yuan Q, Li XM. Induction of Severe Eosinophilic Esophagitis and Multi-Organ Inflammation by Airborne Allergens is Associated with IL-4/IL-13 and CCL11 but Not IgE in Genetic Susceptible Mice. J Inflamm Res 2022; 15:5527-5540. [PMID: 36176352 PMCID: PMC9514888 DOI: 10.2147/jir.s372449] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 08/18/2022] [Indexed: 11/23/2022] Open
Abstract
Background Eosinophilic Esophagitis (EoE) is an increasingly common chronic inflammatory disease. The pathological mechanisms underlying EoE are largely unknown. Objective We sought to understand the mechanisms underlying aeroallergen-induced EoE in Sharpin gene deficient (Sharpin-/-) mice that is prone to inflammatory response. Methods Sharpin-/-mice were exposed with Aspergillus fumigatus and ovalbumin intranasally every alternate day for 4 weeks. Wild type (WT) naïve mice, WT exposed, and un-exposed Sharpin-/- mice were controls. Histopathological analysis was performed by H&E, trichrome and major basic protein staining. Total and specific IgE, IgG, and IgA levels were measured by ELISA and Th2 cytokine and CCL11 chemokine gene expression were determined. Results Airborne allergen exposed Sharpin-/- mice showed severe eosinophilic inflammation in the esophagus (p < 0.001), and markedly increased epithelial thickening (p < 0.0001) compared to WT normal controls, whereas airborne allergen exposed WT mice and unexposed Sharpin-/- mice only showed mild eosinophilic inflammation in the esophagus. These exposed Sharpin-/- mice also showed over 7-fold increase in blood eosinophils (p < 0.0001), 60-fold increase in eosinophils in bronchoalveolar lavage fluid (p < 0.0001) and 4-fold increase in eosinophils in the skin (p < 0.0001) compared to normal controls. Surprisingly, exposed Sharpin-/- mice did not show elevation of serum total or antigen-specific IgE levels but reduced total IgA and IgG levels than normal controls There was a marked increase in IL-4, IL-13 and CCL11 gene expression in esophageal tissue (p < 0.001) in exposed Sharpin-/- mice compared to WT normal mice. Conclusion Th2 cytokines and chemokines, but not IgE may play an important pathologic role in aeroallergen-induced EoE. This study may provide insight into new therapeutics for EoE.
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Affiliation(s)
- Anish Maskey
- Department of Pathology, Microbiology & Immunology, New York Medical College, Valhalla, NY, USA
| | - Kamal Srivastava
- Department of Pathology, Microbiology & Immunology, New York Medical College, Valhalla, NY, USA.,General Nutraceutical Technology, LLC, Elmsford, NY, USA
| | - Gary Soffer
- Department of Allergy and Immunology, Yale University, New Haven, CT, USA
| | - David Dunkin
- Division of Pediatric Gastroenterology and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Qian Yuan
- Pediatric Gastroenterology and Nutrition, Mass General Hospital for Children, Boston, MA, USA
| | - Xiu-Min Li
- Department of Pathology, Microbiology & Immunology, New York Medical College, Valhalla, NY, USA.,Department of Otolaryngology, New York Medical College, Valhalla, NY, USA
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22
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Khokhar D, Marella S, Idelman G, Chang JW, Chehade M, Hogan SP. Eosinophilic esophagitis: Immune mechanisms and therapeutic targets. Clin Exp Allergy 2022; 52:1142-1156. [PMID: 35778876 PMCID: PMC9547832 DOI: 10.1111/cea.14196] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 06/08/2022] [Accepted: 06/20/2022] [Indexed: 01/26/2023]
Abstract
Eosinophilic esophagitis (EoE) is an emerging chronic inflammatory disease of the oesophagus and is clinically characterized by upper gastrointestinal (GI) symptoms including dysphagia and esophageal food impaction. Histopathologic manifestations, which include intraepithelial eosinophilic inflammation and alterations of the esophageal squamous epithelium, such as basal zone hyperplasia (BZH) and dilated intercellular spaces (DIS), are thought to contribute to esophageal dysfunction and disease symptoms. Corroborative clinical and discovery science-based studies have established that EoE is characterized by an underlying allergic inflammatory response, in part, related to the IL-13/CCL26/eosinophil axis driving dysregulation of several key epithelial barrier and proliferative regulatory genes including kallikrein (KLK) serine proteases, calpain 14 (CAPN14) and anoctamin 1 (ANO1). The contribution of these inflammatory and proliferative processes to the clinical and histological manifestations of disease are not fully elucidated. Herein, we discuss the immune molecules and cells that are thought to underlie the clinical and pathologic manifestations of EoE and the emerging therapeutics targeting these processes for the treatment of EoE.
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Affiliation(s)
- Dilawar Khokhar
- Division of Allergy and ImmunologyUniversity of MichiganAnn ArborMichiganUSA
- Mary H Weiser Food Allergy CenterUniversity of MichiganAnn ArborMichiganUSA
| | - Sahiti Marella
- Mary H Weiser Food Allergy CenterUniversity of MichiganAnn ArborMichiganUSA
- Department of PathologyUniversity of MichiganAnn ArborMichiganUSA
| | - Gila Idelman
- Mary H Weiser Food Allergy CenterUniversity of MichiganAnn ArborMichiganUSA
| | - Joy W. Chang
- Division of Gastroenterology, Department of Internal MedicineUniversity of MichiganAnn ArborMichiganUSA
| | - Mirna Chehade
- Mount Sinai Center for Eosinophilic DisordersIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Simon P. Hogan
- Mary H Weiser Food Allergy CenterUniversity of MichiganAnn ArborMichiganUSA
- Department of PathologyUniversity of MichiganAnn ArborMichiganUSA
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Shah MZ, Polk BI. Eosinophilic Esophagitis. Immunol Allergy Clin North Am 2022; 42:761-770. [DOI: 10.1016/j.iac.2022.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Mishra A. Long term Th2 cytokines immunotherapy beneficial for EoE pediatric patients? INTERNATIONAL JOURNAL OF PUBLIC HEALTH AND AWARENESS 2022; 5:9-11. [PMID: 36212388 PMCID: PMC9541019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Eosinohilic esophagitis (EoE) and gastroesophageal reflux diseases (GERD) are closely related esophageal disorders, and both accumulate eosinophils in the esophagus. However, origin of both these diseases are very different. The evidence indicates that acid reflux is the main cause of GERD; whereas EoE is induced in response to food or environment allergens exposed accumulation of inflammatory cells like eosinophils, mast cells and T cell subsets. EoE is a global problem, and effect even 1 year old children to adult population. Currently, mepolizumab (anti-IL-5) neutralization therapy sdata showed reduced epithelial layer eosinophilia in EoE,1, 2 and most recently FDA approved FDA has also approved Dupixent (anti-IL4R and anti-IL-13) for EoE following Phase 3 randomized, double-blind, placebo-controlled trial. The efficacy and safety of Dupixent 300 mg weekly patients 12 year or older on limited patient number, 69% and 64% reduction in EoE symptoms from baseline compared to 32% and 41% for placebo (FDA, 2022). In this commentary, we raised few concerns to be considered on these therapies based on the significance of IL-5, IL-4 in maintaining the innate immunity of the young children are mostly effected by EoE that require long term immunotherapy of mepolizumab (anti-IL-5) or Dupixent (anti-IL4R and anti-IL-13).
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Affiliation(s)
- Anil Mishra
- John W. Deming Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, LA, USA
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25
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de Souza TA, Carneiro AP, Narciso AS, Barros CP, Alves DA, Marson LB, Tunala T, de Alcântara TM, de Paiva Maia YC, Briza P, Ferreira F, Goulart LR. Eosinophilic esophagitis auxiliary diagnosis based on a peptide ligand to eosinophil cationic protein in esophageal mucus of pediatric patients. Sci Rep 2022; 12:12226. [PMID: 35851408 PMCID: PMC9289663 DOI: 10.1038/s41598-022-16293-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 07/07/2022] [Indexed: 11/09/2022] Open
Abstract
Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus characterized by increased number of eosinophils. Currently, EoE diagnosis is based on endoscopic procedures for histopathological examination, eosinophils' counting and, often, in clinical practice, the challenge is the differentiation between EoE and gastroesophageal reflux disease (GERD). Our aim was to develop novel peptide ligand to Eosinophil cationic protein (ECP) present in EoE biopsies of patients with potential to be used for detection. We performed a comparative proteomic analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) of esophageal biopsies from pediatric patients with eosinophilic esophagitis, gastroesophageal reflux disease and control individuals. Then, phage display technology was used to select peptides against specific up-regulated protein from EoE patients. Twelve phage clones were selected after three biopanning rounds, and the best phage clone reactivity was evaluated by phage-ELISA assay using esophageal mucus samples from 94 pediatric patients. Mass spectrometry showed that eosinophil cationic protein (ECP) was one of the most up-regulated proteins in EoE patients, which is an eosinophil granule protein usually deposited on tissues to mediate remodeling, but in excess may cause fibrosis and hypertrophy, especially in allergic responses. A highly reactive ECP-ligand peptide (E5) was able to distinguish reactive mucus of EoE patients from GERD and the control individuals by Phage-ELISA, achieving a sensitivity of 84.62%, and a specificity of 82.72%. This is the first study that successfully demonstrated an antibody-like peptide targeting ECP at the esophagus mucus as a useful auxilliary tool for EoE diagnosis with a significant association with atopic disorders and dysphagia.ClinicalTrials.gov no.: NCT03069573.
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Affiliation(s)
- Tafarel Andrade de Souza
- Laboratory of Nanobiotechnology Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Federal University of Uberlandia, Uberlandia, MG, Brazil.
| | - Ana Paula Carneiro
- Laboratory of Nanobiotechnology Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Federal University of Uberlandia, Uberlandia, MG, Brazil
| | - Andreia S Narciso
- Laboratory of Nanobiotechnology Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Federal University of Uberlandia, Uberlandia, MG, Brazil
| | - Cristina P Barros
- Pediatric Department, Federal University of Uberlandia, Uberlandia, MG, Brazil
| | - Douglas Alexsander Alves
- Laboratory of Nanobiotechnology Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Federal University of Uberlandia, Uberlandia, MG, Brazil
| | - Luciane B Marson
- Pediatric Department, Federal University of Uberlandia, Uberlandia, MG, Brazil
| | - Tatiane Tunala
- Pathology Laboratory, Clinical Hospital, Federal University of Uberlandia, Uberlandia, MG, Brazil
| | - Tânia M de Alcântara
- Pathology Laboratory, Clinical Hospital, Federal University of Uberlandia, Uberlandia, MG, Brazil
| | - Yara Cristina de Paiva Maia
- Laboratory of Nanobiotechnology Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Federal University of Uberlandia, Uberlandia, MG, Brazil.,Nutrition and Molecular Biology Research Goup, School of Medicine, Federal University of Uberlandia, Uberlandia, MG, Brazil
| | - Peter Briza
- Department of Biosciences, University of Salzburg, Salzburg, Austria
| | - Fatima Ferreira
- Department of Biosciences, University of Salzburg, Salzburg, Austria
| | - Luiz R Goulart
- Laboratory of Nanobiotechnology Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Federal University of Uberlandia, Uberlandia, MG, Brazil
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26
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Uchida AM, Ro G, Garber JJ, Peterson KA, Round JL. Models and Tools for Investigating Eosinophilic Esophagitis at the Bench. Front Immunol 2022; 13:943518. [PMID: 35874718 PMCID: PMC9296852 DOI: 10.3389/fimmu.2022.943518] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 06/10/2022] [Indexed: 11/23/2022] Open
Abstract
Eosinophilic esophagitis (EoE) is an increasingly common food allergy disease of the esophagus that received its medical designation code in 2008. Despite this recency, great strides have been made in the understanding of EoE pathophysiology and type 2 immunity through basic and translational scientific investigations conducted at the bench. These advances have been critical to our understanding of disease mechanisms and generating new hypotheses, however, there currently is only one very recently approved FDA-approved therapy for EoE, leaving a great deal to be uncovered for patients with this disease. Here we review some of the innovative methods, models and tools that have contributed to the advances in EoE discovery and suggest future directions of investigation to expand upon this foundation.
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Affiliation(s)
- Amiko M. Uchida
- Division of Gastroenterology, Hepatology and Nutrition, University of Utah School of Medicine, Salt Lake City, UT, United States
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, United States
- *Correspondence: Amiko M. Uchida,
| | - Gabrielle Ro
- Division of Gastroenterology, Hepatology and Nutrition, University of Utah School of Medicine, Salt Lake City, UT, United States
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, United States
| | - John J. Garber
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston MA, United States
| | - Kathryn A. Peterson
- Division of Gastroenterology, Hepatology and Nutrition, University of Utah School of Medicine, Salt Lake City, UT, United States
| | - June L. Round
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, United States
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27
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Upparahalli Venkateshaiah S, Yadavalli CS, Kandikattu HK, Kumar S, Oruganti L, Mishra A. Molecules involved in the development of Barrett's esophagus phenotype in chronic eosinophilic esophagitis. Am J Physiol Gastrointest Liver Physiol 2022; 323:G31-G43. [PMID: 35437997 PMCID: PMC9190763 DOI: 10.1152/ajpgi.00321.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 03/15/2022] [Accepted: 04/10/2022] [Indexed: 01/31/2023]
Abstract
This paper aims to investigate the molecules involved in development of Barrett's esophagus (BE) in human eosinophilic esophagitis (EoE). Histopathological, immunohistochemical, real-time PCR Immuno blot, and ELISA analyses are performed to identify the signature genes and proteins involved in the progression of BE in EoE. We detected characteristic features of BE like intermediate columnar-type epithelial cells, induced BE signature genes like ErbB3, CDX1, ErbB2IP in the esophageal mucosa of patients with EoE. In addition, we had observed several BE-associated proteins such as TFF3, p53 and the progression markers like EGFR, p16, MICA, MICB, and MHC molecules in esophageal biopsies of patients with chronic EoE. Interestingly, we also detected mucin-producing columnar cells and MUC-2, MUC-4, and MUC5AC genes and proteins along with induced IL-9 in patients with chronic EoE. A strong correlation of IL-9 with mucin genes is observed that implicated a possible role for IL-9 in the transformation of esophageal squamous epithelial cells to columnar epithelial cells in patients with EoE. These findings indicate that IL-9 may have an important role in BE development in patients with chronic EoE. We also discovered that IL-9 stimulates mucin-producing and barrier cell transcripts and proteins such CK8/18, GATA4, SOX9, TFF1, MUC5AC, and tight junction proteins in primary esophageal epithelial cells when exposed to IL-9. Taken together, these findings provide evidence that indeed IL-9 has a role in the initiation and progression of BE characteristics like development of mucin-producing columnar epithelial cells in patients with chronic EoE.NEW & NOTEWORTHY Intermediate columnar-type epithelial cells are observed in biopsies of patients with EoE. Induced BE signature genes (CK8/18, CDX1 GATA4, SOX9, and Occludin) were observed in patients with chronic EoE. Induction of IL-9 and its correlation with eosinophils mucin-producing genes and proteins was observed in patients with EoE. Induced IL-9 may be responsible for the development of BE in patients with chronic EoE.
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Affiliation(s)
- Sathisha Upparahalli Venkateshaiah
- Section of Pulmonary Diseases, John W. Deming Department of Medicine, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, Louisiana
| | - Chandra Sekhar Yadavalli
- Section of Pulmonary Diseases, John W. Deming Department of Medicine, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, Louisiana
| | - Hemanth Kumar Kandikattu
- Section of Pulmonary Diseases, John W. Deming Department of Medicine, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, Louisiana
| | - Sandeep Kumar
- Section of Pulmonary Diseases, John W. Deming Department of Medicine, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, Louisiana
| | - Lokanatha Oruganti
- Section of Pulmonary Diseases, John W. Deming Department of Medicine, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, Louisiana
| | - Anil Mishra
- Section of Pulmonary Diseases, John W. Deming Department of Medicine, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, Louisiana
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Tanzer J, Meng D, Ohsaki A, Caldwell JM, Mingler MK, Rothenberg ME, Oyoshi MK. Laundry detergent promotes allergic skin inflammation and esophageal eosinophilia in mice. PLoS One 2022; 17:e0268651. [PMID: 35759448 PMCID: PMC9236249 DOI: 10.1371/journal.pone.0268651] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 05/04/2022] [Indexed: 11/24/2022] Open
Abstract
The prevalence of allergic diseases is on the rise, yet the environmental factors that contribute to this increase are still being elucidated. Laundry detergent (LD) that contains cytotoxic ingredients including microbial enzymes continuously comes into contact with the skin starting in infancy. An impaired skin barrier has been suggested as a route of allergic sensitization. We hypothesized that exposure of skin to LD damages the skin barrier resulting in systemic sensitization to allergens that enter through the impaired skin barrier. Mouse skin samples exposed in vitro to microbial proteases or LD exhibited physical damage, which was more pronounced in neonatal skin as compared to adult skin. Exposure of the skin to microbial proteases in vitro resulted in an increase in the levels of interleukin (IL)-33 and thymic stromal lymphopoietin (TSLP). BALB/c wild type mice epicutaneously exposed to LD and ovalbumin (OVA) showed an increase in levels of transepidermal water loss, serum OVA-specific immunoglobulin (Ig) G1 and IgE antibodies, and a local increase of Il33, Tslp, Il4 and Il13 compared with LD or OVA alone. Following intranasal challenge with OVA, mice epicutaneously exposed to LD showed an increase in allergen-induced esophageal eosinophilia compared with LD or OVA alone. Collectively, these results suggest that LD may be an important factor that impairs the skin barrier and leads to allergen sensitization in early life, and therefore may have a role in the increase in allergic disease.
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Affiliation(s)
- Jamie Tanzer
- Harvard College, Cambridge, MA, United States of America
| | - Di Meng
- Division of Pediatric Allergy, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Charlestown, MA, United States of America
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States of America
| | - Asa Ohsaki
- Division of Immunology, Boston Children’s Hospital, Boston, MA, United States of America
| | - Julie M. Caldwell
- Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children’s Hospital, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America
| | - Melissa K. Mingler
- Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children’s Hospital, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America
| | - Marc E. Rothenberg
- Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children’s Hospital, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America
| | - Michiko K. Oyoshi
- Division of Pediatric Allergy, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Charlestown, MA, United States of America
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States of America
- Division of Immunology, Boston Children’s Hospital, Boston, MA, United States of America
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29
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Rossi CM, Lenti MV, Merli S, Licari A, Votto M, Marseglia GL, Di Sabatino A. Primary eosinophilic gastrointestinal disorders and allergy: Clinical and therapeutic implications. Clin Transl Allergy 2022; 12:e12146. [PMID: 35620572 PMCID: PMC9125508 DOI: 10.1002/clt2.12146] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 03/28/2022] [Accepted: 03/29/2022] [Indexed: 12/14/2022] Open
Abstract
Primary eosinophilic gastrointestinal disorders (EGID) are increasingly prevalent, immune‐mediated, chronic conditions which primarily affect pediatric and young adult patients, leading to substantial disease burden, and poor quality of life. EGID may either involve single portions of the gastrointestinal tract (i.e., esophagus, stomach, small bowel, and colon) or a combination. Their strong association with allergic disorders has been recently recognized, and although their shared pathophysiological basis remains partly elusive, this feature greatly impacts the diagnostic and treatment work‐up. We herein critically discuss the current knowledge on the association of EGID and allergic disorders, including atopic dermatitis, allergic rhinitis, allergic asthma, and food or drug allergy. In particular, we reviewed the literature focusing on their epidemiology, pathophysiological basis and mechanisms, and diagnostic strategies. Finally, we discuss the currently ongoing clinical trials targeting EGID and allergic diseases, including, among others the monoclonal antibodies dupilumab, mepolizumab, benralizumab, and lirentelimab.
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Affiliation(s)
- Carlo Maria Rossi
- First Department of Internal Medicine IRCCS Fondazione Policlinico San Matteo University of Pavia Pavia Italy
| | - Marco Vincenzo Lenti
- First Department of Internal Medicine IRCCS Fondazione Policlinico San Matteo University of Pavia Pavia Italy
| | - Stefania Merli
- First Department of Internal Medicine IRCCS Fondazione Policlinico San Matteo University of Pavia Pavia Italy
| | - Amelia Licari
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences University of Pavia Fondazione IRCCS Policlinico San Matteo Pavia Italy
| | - Martina Votto
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences University of Pavia Fondazione IRCCS Policlinico San Matteo Pavia Italy
| | - Gian Luigi Marseglia
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences University of Pavia Fondazione IRCCS Policlinico San Matteo Pavia Italy
| | - Antonio Di Sabatino
- First Department of Internal Medicine IRCCS Fondazione Policlinico San Matteo University of Pavia Pavia Italy
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30
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Mishra A, Majid D, Kandikattu HK, Yadavalli CS, Upparahalli Venkateshaiah S. Role of IL-18-transformed CD274-expressing eosinophils in promoting airway obstruction in experimental asthma. Allergy 2022; 77:1165-1179. [PMID: 34800294 DOI: 10.1111/all.15180] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/30/2021] [Accepted: 10/18/2021] [Indexed: 01/21/2023]
Abstract
BACKGROUND IL-5-dependent residential and IL-18-transformed pathogenic eosinophils have been reported; however, the role of IL-18-transformed CD274-expressing pathogenic eosinophils compared to IL-5-generated eosinophils in promoting airway obstruction in asthma has not yet been examined. METHODS Eosinophils are detected by tissue anti-MBP and anti-EPX immunostaining, CD274 expression by flow cytometry, and airway resistance using the Buxco FinePointe RC system. RESULTS We show that A. fumigatus-challenged wild-type mice, and different gene-deficient mice including naïve CC10-IL-18-transgenic mice, accumulate mostly peribronchial and perivascular CD274-expressing eosinophils except naïve CD2-IL-5-transgenic mice. Additionally, we show that CD2-IL-5 transgenic mice following rIL-18 treatment accumulate high number of CD274-expressing perivascular and peribronchial eosinophils with induced collagen, goblet cell hyperplasia and airway resistance compared to saline-challenged CD2-IL5 transgenic mice. Furthermore, we also show that even A. fumigatus-challenged IL-5 -/- mice and rIL-18 given ΔdblGATA mice accumulate CD274-expressing eosinophil-associated asthma pathogenesis including airway obstruction. Most importantly, we provide evidence that neutralization of CD274 and IL-18 in A. fumigatus-challenged mice ameliorate experimental asthma. Taken together, the data presented are clinically significant in establishing that anti-IL-18 neutralization is a novel immunotherapy to restrict asthma pathogenesis. CONCLUSIONS We demonstrate that IL-18 is critical for inducing asthma pathogenesis, and neutralization of CD274 is a potential immunotherapeutic strategy for asthma.
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Affiliation(s)
- Anil Mishra
- John W. Deming Department of Medicine Tulane Eosinophilic Disorders Center (TEDC) Section of Pulmonary Diseases Tulane University School of Medicine New Orleans Louisina USA
| | - Dewan Majid
- John W. Deming Department of Medicine Tulane Eosinophilic Disorders Center (TEDC) Section of Pulmonary Diseases Tulane University School of Medicine New Orleans Louisina USA
| | - Hemanth Kumar Kandikattu
- John W. Deming Department of Medicine Tulane Eosinophilic Disorders Center (TEDC) Section of Pulmonary Diseases Tulane University School of Medicine New Orleans Louisina USA
| | - Chandra Sekhar Yadavalli
- John W. Deming Department of Medicine Tulane Eosinophilic Disorders Center (TEDC) Section of Pulmonary Diseases Tulane University School of Medicine New Orleans Louisina USA
| | - Sathisha Upparahalli Venkateshaiah
- John W. Deming Department of Medicine Tulane Eosinophilic Disorders Center (TEDC) Section of Pulmonary Diseases Tulane University School of Medicine New Orleans Louisina USA
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31
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Garcia E, Ladak Z, Landry T, Wollin M, Persad ARL, Sergi CM, Huynh HQ, Persad R, Persad S. Epithelial-mesenchymal transition, regulated by β-catenin and Twist, leads to esophageal wall remodeling in pediatric eosinophilic esophagitis. PLoS One 2022; 17:e0264622. [PMID: 35239721 PMCID: PMC8893662 DOI: 10.1371/journal.pone.0264622] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 02/14/2022] [Indexed: 01/07/2023] Open
Abstract
Eosinophilic Esophagitis (EoE) is an antigen-triggered inflammatory condition of the esophageal lining characterized by eosinophilic infiltration. EoE is associated with significant remodeling, and although this remodeling is reversed by current treatment regimens, symptoms of EoE and associated remodeling reappear upon cessation of therapies. We hypothesized that structural remodeling of cell-cell adhesion is a key factor in the pathogenesis of EoE and that epithelial to mesenchymal transition (EMT) was a viable molecular process to lead to this remodeling. Endoscopically obtained biopsy samples from 18 EoE and 18 control pediatric patients were evaluated by transmission electron microscopy to measure intercellular spaces (IS) between cells. Biopsy samples from all groups were analyzed for cellular levels of cell-cell adhesion proteins: E-cadherin, zonula occludens associated protein-1 (ZO-1), and N-cadherin. We also analyzed for cellular levels and localization two of transcription factors, Twist1 and β-catenin, that are associated with promoting EMT. The IS was significantly increased in the EoE group compared to the control. We observed a significant decrease in E-cadherin and ZO-1 levels and a concomitant increase in N-cadherin levels in EoE samples compared to control. Further, while there was no significant change in cellular levels of β-catenin, we observed an altered localization of the protein from the cell membrane in control tissue to a nuclear/perinuclear localization in EoE. We observed higher levels of the transcription factor Twist1 in the EoE group compared to normal which was localized mainly at the nucleus. Our results suggest that the integrity of normally sealed esophageal epithelia is compromised in the EoE patients compared to control subjects, and this is due to alterations in the expression of cell adhesion molecules at the esophageal epithelium. Our data also suggest that EMT, potentially regulated by transcription factors β-catenin and Twist1, may be responsible for the molecular alteration which leads to the remodeling of esophageal epithelia in EoE.
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Affiliation(s)
- Elizabeth Garcia
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Zeenat Ladak
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Takaaki Landry
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Michael Wollin
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Amit R. L. Persad
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Consolato M. Sergi
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Hien Q. Huynh
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | | | - Sujata Persad
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
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Racca F, Pellegatta G, Cataldo G, Vespa E, Carlani E, Pelaia C, Paoletti G, Messina MR, Nappi E, Canonica GW, Repici A, Heffler E. Type 2 Inflammation in Eosinophilic Esophagitis: From Pathophysiology to Therapeutic Targets. Front Physiol 2022; 12:815842. [PMID: 35095572 PMCID: PMC8790151 DOI: 10.3389/fphys.2021.815842] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 12/09/2021] [Indexed: 12/11/2022] Open
Abstract
Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease of the esophagus characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation, whose incidence is rising. It significantly affects patients’ quality of life and, if left untreated, results in fibrotic complications. Although broad consensus has been achieved on first-line therapy, a subset of patients remains non-responder to standard therapy. The pathogenesis of EoE is multifactorial and results from the complex, still mostly undefined, interaction between genetics and intrinsic factors, environment, and antigenic stimuli. A deep understanding of the pathophysiology of this disease is pivotal for the development of new therapies. This review provides a comprehensive description of the pathophysiology of EoE, starting from major pathogenic mechanisms (genetics, type 2 inflammation, epithelial barrier dysfunction, gastroesophageal reflux, allergens, infections and microbiota) and subsequently focusing on the single protagonists of type 2 inflammation (involved cells, cytokines, soluble effectors, surface proteins and transcription factors) that could represent present and future therapeutic targets, while summarizing previous therapeutic approaches in literature.
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Affiliation(s)
- Francesca Racca
- Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- *Correspondence: Francesca Racca,
| | - Gaia Pellegatta
- Digestive Endoscopy Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Giuseppe Cataldo
- Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Edoardo Vespa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Digestive Endoscopy Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Elisa Carlani
- Digestive Endoscopy Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Corrado Pelaia
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, Catanzaro, Italy
| | - Giovanni Paoletti
- Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Maria Rita Messina
- Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Emanuele Nappi
- Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Giorgio Walter Canonica
- Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Alessandro Repici
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Digestive Endoscopy Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Enrico Heffler
- Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
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33
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Ghezzi M, Pozzi E, Abbattista L, Lonoce L, Zuccotti GV, D’Auria E. Barrier Impairment and Type 2 Inflammation in Allergic Diseases: The Pediatric Perspective. CHILDREN (BASEL, SWITZERLAND) 2021; 8:1165. [PMID: 34943362 PMCID: PMC8700706 DOI: 10.3390/children8121165] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/30/2021] [Accepted: 11/30/2021] [Indexed: 01/02/2023]
Abstract
Allergic diseases represent a global burden. Although the patho-physiological mechanisms are still poorly understood, epithelial barrier dysfunction and Th2 inflammatory response play a pivotal role. Barrier dysfunction, characterized by a loss of differentiation, reduced junctional integrity, and altered innate defence, underpins the pathogenesis of allergic diseases. Epithelial barrier impairment may be a potential therapeutic target for new treatment strategies Up now, monoclonal antibodies and new molecules targeting specific pathways of the immune response have been developed, and others are under investigation, both for adult and paediatric populations, which are affected by atopic dermatitis (AD), asthma, allergic rhinitis (AR), chronic rhinosinusitis with nasal polyps (CRSwNP), or eosinophilic esophagitis (EoE). In children affected by severe asthma biologics targeting IgE, IL-5 and against IL-4 and IL-13 receptors are already available, and they have also been applied in CRSwNP. In severe AD Dupilumab, a biologic which inhibits both IL-4 and IL-13, the most important cytokines involved in inflammation response, has been approved for treatment of patients over 12 years. While a biological approach has already shown great efficacy on the treatment of severe atopic conditions, early intervention to restore epithelial barrier integrity, and function may prevent the inflammatory response and the development of the atopic march.
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Affiliation(s)
- Michele Ghezzi
- Allergology and Pneumology Unit, V. Buzzi Children’s Hospital, 20154 Milan, Italy;
| | - Elena Pozzi
- Department of Pediatrics, V. Buzzi Children’s Hospital, 20154 Milan, Italy; (E.P.); (L.A.); (L.L.); (G.V.Z.)
| | - Luisa Abbattista
- Department of Pediatrics, V. Buzzi Children’s Hospital, 20154 Milan, Italy; (E.P.); (L.A.); (L.L.); (G.V.Z.)
| | - Luisa Lonoce
- Department of Pediatrics, V. Buzzi Children’s Hospital, 20154 Milan, Italy; (E.P.); (L.A.); (L.L.); (G.V.Z.)
| | - Gian Vincenzo Zuccotti
- Department of Pediatrics, V. Buzzi Children’s Hospital, 20154 Milan, Italy; (E.P.); (L.A.); (L.L.); (G.V.Z.)
- Department of Biomedical and Clinical Science “L. Sacco”, University of Milan, 20157 Milan, Italy
| | - Enza D’Auria
- Allergology and Pneumology Unit, V. Buzzi Children’s Hospital, 20154 Milan, Italy;
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Barni S, Arasi S, Mastrorilli C, Pecoraro L, Giovannini M, Mori F, Liotti L, Saretta F, Castagnoli R, Caminiti L, Cianferoni A, Novembre E. Pediatric eosinophilic esophagitis: a review for the clinician. Ital J Pediatr 2021; 47:230. [PMID: 34809686 PMCID: PMC8609874 DOI: 10.1186/s13052-021-01178-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 10/27/2021] [Indexed: 12/16/2022] Open
Abstract
Eosinophilic esophagitis (EoE) is a chronic clinical-pathologic disease characterized by eosinophilic infiltration of the esophageal epithelium with esophageal dysfunction symptoms.EoE can occur at any age and has different clinical manifestations depending on the age onset.To date, esophago-gastroduodenal endoscopy (EGD) with biopsy is the gold-standard for EoE diagnosis.According to the recent consensus guidelines, proton pump inhibitors, corticosteroids and elimination diets could be a first-line therapy option. The aim of the treatment is clinical and histological remission for preventing long-lasting untreatable fibrosis.A multidisciplinary approach (allergist, gastroenterology, dietitian, and pathologist) is recommended for managing patients affected by EoE, given the complexity of its treatment.This review will provide a practical guide to assist pediatricians treating children with EoE.Moreover, it highlights the unmet needs in diagnosis and treatment that require urgent attention from the scientific community in the aim of improving the management of patients with EoE.
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Affiliation(s)
- Simona Barni
- Allergy Unit, Department of Pediatrics, Meyer Children’s University Hospital, Florence, Italy
| | - Stefania Arasi
- Predictive and Preventive Medicine Research Unit, Multifactorial and Systemic Diseases Research Area, Pediatric Allergy Unit, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
| | - Carla Mastrorilli
- Pediatric Unit and Emergency, University Hospital Consortium Corporation Polyclinic of Bari, Pediatric Hospital Giovanni XXIII, Bari, Italy
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Luca Pecoraro
- Department of Medicine, University of Verona, Policlinico GB Rossi, Verona, Italy
- Pediatric Unit, ASST Mantua, Mantua, Italy
| | - Mattia Giovannini
- Allergy Unit, Department of Pediatrics, Meyer Children’s University Hospital, Florence, Italy
| | - Francesca Mori
- Allergy Unit, Department of Pediatrics, Meyer Children’s University Hospital, Florence, Italy
| | - Lucia Liotti
- Pediatric Unit, Senigallia Hospital, Senigallia, Italy
| | - Francesca Saretta
- Pediatric Department, Latisana-Palmanova Hospital, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy
| | - Riccardo Castagnoli
- Department of Pediatrics, Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
| | - Lucia Caminiti
- Department of Human Pathology in Adult and Development Age “Gaetano Barresi”, Allergy Unit, Department of Pediatrics, AOU Policlinico Gaetano Martino, Messina, Italy
| | - Antonella Cianferoni
- Pediatrics Department, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
- Allergy and Immunology Division, The Children’s Hospital of Philadelphia, Philadelphia, USA
| | - Elio Novembre
- Allergy Unit, Department of Pediatrics, Meyer Children’s University Hospital, Florence, Italy
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Zubeldia-Varela E, Barker-Tejeda TC, Blanco-Pérez F, Infante S, Zubeldia JM, Pérez-Gordo M. Non-IgE-Mediated Gastrointestinal Food Protein-Induced Allergic Disorders. Clinical Perspectives and Analytical Approaches. Foods 2021; 10:foods10112662. [PMID: 34828942 PMCID: PMC8623505 DOI: 10.3390/foods10112662] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 10/27/2021] [Indexed: 12/21/2022] Open
Abstract
Non-IgE-mediated gastrointestinal food allergy (non-IgE-GI-FA) is the name given to a series of pathologies whose main entities are food protein-induced allergic proctocolitis (FPIAP), food protein-induced enteropathy (FPE), and food protein-induced enterocolitis syndrome (FPIES). These are more uncommon than IgE-mediated food allergies, their mechanisms remain largely unknown, and their diagnosis is mainly done by clinical history, due to the lack of specific biomarkers. In this review, we present the latest advances found in the literature about clinical aspects, the current diagnosis, and treatment options of non-IgE-GI-FAs. We discuss the use of animal models, the analysis of gut microbiota, omics techniques, and fecal proteins with a focus on understanding the pathophysiological mechanisms of these pathologies and obtaining possible diagnostic and/or prognostic biomarkers. Finally, we discuss the unmet needs that researchers should tackle to advance in the knowledge of these barely explored pathologies.
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Affiliation(s)
- Elisa Zubeldia-Varela
- Department of Basic Medical Sciences, Facultad de Medicina, Institute of Applied Molecular Medicine (IMMA), Universidad San Pablo-CEU, CEU Universities, ARADyAL, 28660 Madrid, Spain; (E.Z.-V.); (T.C.B.-T.)
- Centre for Metabolomics and Bioanalysis (CEMBIO), Department of Chemistry and Biochemistry, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, 28660 Madrid, Spain
| | - Tomás Clive Barker-Tejeda
- Department of Basic Medical Sciences, Facultad de Medicina, Institute of Applied Molecular Medicine (IMMA), Universidad San Pablo-CEU, CEU Universities, ARADyAL, 28660 Madrid, Spain; (E.Z.-V.); (T.C.B.-T.)
- Centre for Metabolomics and Bioanalysis (CEMBIO), Department of Chemistry and Biochemistry, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, 28660 Madrid, Spain
| | - Frank Blanco-Pérez
- VPr1 Research Group “Molecular Allergology”, Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, 63225 Langen, Germany;
| | - Sonsoles Infante
- Allergy Paediatric Unit, Allergy Service, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain; (S.I.); (J.M.Z.)
- Gregorio Marañón Health Research Institute (IiSGM), 28007 Madrid, Spain
| | - José M. Zubeldia
- Allergy Paediatric Unit, Allergy Service, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain; (S.I.); (J.M.Z.)
- Gregorio Marañón Health Research Institute (IiSGM), 28007 Madrid, Spain
- Rare Diseases Networking Biomedical Research Centre (CIBERER, U-761), Carlos III Institute of Health, 28029 Madrid, Spain
| | - Marina Pérez-Gordo
- Department of Basic Medical Sciences, Facultad de Medicina, Institute of Applied Molecular Medicine (IMMA), Universidad San Pablo-CEU, CEU Universities, ARADyAL, 28660 Madrid, Spain; (E.Z.-V.); (T.C.B.-T.)
- Correspondence: ; Tel.: +34-91-372-4700 (ext. 14675)
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Havlichek D, Choung RS, Murray JA. Eosinophilic Gastroenteritis: Using Presenting Findings to Predict Disease Course. Clin Transl Gastroenterol 2021; 12:e00394. [PMID: 34620754 PMCID: PMC8500667 DOI: 10.14309/ctg.0000000000000394] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 07/12/2021] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Studies on eosinophilic gastroenteritis have identified broad spectrums of disease. We aimed to characterize subtypes of disease and ascertain outcomes of each group. METHODS This is a retrospective cohort study from a large tertiary medical center including 35 patients diagnosed with eosinophilic gastroenteritis from 2007 to 2018. We defined 2 groups of patients based on clinical and laboratory findings at presentation. Severe disease was defined as having weight loss at time of presentation, hypoalbuminemia at presentation, serosal disease involvement, or anemia at diagnosis. The remaining patients were labeled as mild disease group. We collected and compared demographic data, clinical features, laboratory findings, an allergy history, and disease course of both cohorts. RESULTS Among 35 patients with eosinophilic gastroenteritis, 18 patients met the criteria for severe disease and 17 patients for mild disease. Of the patients with severe eosinophilic gastroenteritis, 6 (38%) had remission without chronic symptoms, whereas 10 (63%) had chronic symptoms requiring chronic medical therapy. Of the mild group, 12 patients (80%) had disease remission without chronic medications. An allergy history was more common in the severe disease group (83%) compared with the mild disease group (45%). Prednisone and open capsule budesonide were the most commonly used treatment medications in both groups. DISCUSSION Patients with eosinophilic gastroenteritis may be characterized into 2 forms. Patients with weight loss at time of presentation, hypoalbuminemia at presentation, serosal disease involvement, or anemia at diagnosis were associated with a chronic disease course requiring chronic medications.
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Affiliation(s)
- Daniel Havlichek
- Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA;
| | - Rok Seon Choung
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
| | - Joseph A. Murray
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
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Immunogenetic, Molecular and Microbiotic Determinants of Eosinophilic Esophagitis and Clinical Practice-A New Perspective of an Old Disease. Int J Mol Sci 2021; 22:ijms221910830. [PMID: 34639170 PMCID: PMC8509128 DOI: 10.3390/ijms221910830] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/01/2021] [Accepted: 10/05/2021] [Indexed: 12/19/2022] Open
Abstract
Eosinophilic oesophagitis (EoE) is a chronic, allergic disease associated with a T-lymphocyte response inducing esophageal eosinophilic infiltration in the esophagus. Inflammation and tissue fibrosis are responsible for the main clinical symptoms such as food impaction and dysphagia. The etiopathogenesis is multifactorial in which genetic and environmental factors coexist. The most common trigger is a non-IgE-mediated food allergy to milk, wheat, egg, soybean, nuts, fish, and seafood. The second factor we focus on is the contribution of genetic variation to the risk of EoE, describing the expression profile of selected genes associated with eosinophilic oesophagitis. We raise the topic of treatment, aiming to eliminate inflammation through an elimination diet and/or use of pharmacologic therapy with the use of proton pump inhibitors or steroids and endoscopic procedures to dilate the esophagus. We demonstrate that early diagnosis and effective treatment prevent the development of food impaction and decreased quality of life. The increasing presence of EoE requires bigger awareness among medical specialists concerning clinical features, the course of EoE, diagnostic tools, and management strategies.
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Kim SH, Kesar V, Grider D, Nguyen V. A Rare Case of Eosinophilic Gastroenteritis Isolated in the Muscularis Propria of the Small Bowel. Cureus 2021; 13:e18790. [PMID: 34804656 PMCID: PMC8592308 DOI: 10.7759/cureus.18790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/13/2021] [Indexed: 11/08/2022] Open
Abstract
Eosinophilic gastroenteritis (EG) is an autoimmune disorder that involves infiltration of eosinophils in the bowel wall of the stomach and/or intestine, resulting in various gastrointestinal symptoms. The majority of cases are diagnosed by findings of increased eosinophils on mucosal biopsies. We describe a rare type of eosinophilic gastroenteritis with eosinophilic infiltration involving only the muscularis propria layer. This elusive diagnosis was made after a full-thickness intestinal wall biopsy. This predominantly muscular type eosinophilic gastroenteritis can cause intestinal obstruction or perforation. Similar to the predominantly mucosal type eosinophilic gastroenteritis, this type of eosinophilic gastroenteritis responds to low-dose or topical corticosteroids.
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Affiliation(s)
- Seo Hyun Kim
- Gastroenterology, Virginia Tech Carilion School of Medicine, Roanoke, USA
| | - Varun Kesar
- Gastroenterology, Carilion Roanoke Memorial Hospital, Roanoke, USA
| | - Douglas Grider
- Pathology, Carilion Roanoke Memorial Hospital, Roanoke, USA
- Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, USA
| | - Vu Nguyen
- Gastroenterology, University Hospitals Cleveland Medical Center, Cleveland, USA
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Cianferoni A, Jensen E, Davis CM. The Role of the Environment in Eosinophilic Esophagitis. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2021; 9:3268-3274. [PMID: 34507708 DOI: 10.1016/j.jaip.2021.07.032] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 07/26/2021] [Accepted: 07/26/2021] [Indexed: 12/17/2022]
Abstract
Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease clinicopathologically characterized by esophageal dysfunction. EoE is characterized by eosinophilic histologic inflammation indistinguishable from other atopic diseases such as asthma, eczema, or allergic rhinitis, which often co-occur in patients with EoE. This suggest a possible shared pathophysiology and triggers in the development of EoE with other atopic conditions. Although the evidence of EoE being linked to exposure to allergenic foods is strong, the connection between EoE and aeroallergens is less understood. In this review, we will discuss clinical, epidemiological, and animal studies that investigate how environmental allergens influence the clinical manifestations of EoE and its seasonality. It is also known that the developing immune system is significantly shaped by early-life exposures, pollution, climate change, and those factors that are known to influence development of asthma. We therefore also describe the evidence for and the gaps in our knowledge of the role of early-life exposures, pollution, and climate change in the development of EoE.
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Affiliation(s)
- Antonella Cianferoni
- Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa
| | - Elizabeth Jensen
- Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC
| | - Carla M Davis
- Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas.
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Manohar M, Kandikattu HK, Upparahalli Venkateshaiah S, Yadavalli CS, Mishra A. Eosinophils in the pathogenesis of pancreatic disorders. Semin Immunopathol 2021; 43:411-422. [PMID: 33783592 PMCID: PMC8249347 DOI: 10.1007/s00281-021-00853-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 03/18/2021] [Indexed: 12/19/2022]
Abstract
Eosinophils comprise approximately 1-4% of total blood leukocytes that reside in the intestine, bone marrow, mammary gland, and adipose tissues to maintain innate immunity in healthy individuals. Eosinophils have four toxic granules known as major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN), and upon degranulation, these granules promote pathogenesis of inflammatory diseases like allergy, asthma, dermatitis, and gastrointestinal disorders. Additionally, the role of eosinophils is underscored in exocrine disorders including pancreatitis. Chronic pancreatitis (CP) is an inflammatory disorder that occurs due to the alcohol consumption, blockage of the pancreatic duct, and trypsinogen mutation. Eosinophil levels are detected in higher numbers in both CP and pancreatic cancer patients compared with healthy individuals. The mechanistic understanding of chronic inflammation-induced pancreatic malignancy has not yet been reached and requires further exploration. This review provides a comprehensive summary of the epidemiology, pathophysiology, evaluation, and management of eosinophil-associated pancreatic disorders and further summarizes current evidence regarding risk factors, pathophysiology, clinical features, diagnostic evaluation, treatment, and prognosis of eosinophilic pancreatitis (EP) and pancreatic cancer.
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Affiliation(s)
- Murli Manohar
- School of Medicine, Gastrointestinal and Hepatology Division, Stanford University, Stanford, CA, 94304, USA
| | - Hemanth Kumar Kandikattu
- John W. Deming Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Sathisha Upparahalli Venkateshaiah
- John W. Deming Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Chandra Sekhar Yadavalli
- John W. Deming Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Anil Mishra
- John W. Deming Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, LA, 70112, USA.
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Mahon M, Romo ND, de Vos G, Levanon D. Race-specific characteristics in pediatric eosinophilic esophagitis in an urban inner-city clinic. Ann Allergy Asthma Immunol 2021; 127:349-353. [PMID: 34004276 DOI: 10.1016/j.anai.2021.05.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/04/2021] [Accepted: 05/09/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Manifestations of pediatric eosinophilic esophagitis (EoE) are varied and dictated by multiple factors. The influence of race is limited to small observational cohorts of dichotomized data (Whites vs non-Whites) or single-racial analysis. OBJECTIVE To better understand phenotypic variability in the manifestation and atopic sensitization of pediatric EoE, from the perspective of race. METHODS Retrospective observational cohort study performed at a tertiary referral center. Subjects were included if less than 21 years old, with suggestive clinical features and histopathologic (>15 eosinophils/high-power field [hpf]) confirmation of EoE. Statistical computation was performed using Stata/IC 11 on variables of interest. RESULTS A total of 34 subjects were included in the analysis. The median (interquartile range [IQR]) age for initial atopy was 2 (1-5) years. The median (IQR) age for EoE diagnosis was 5 (3-8) years. Age of EoE diagnosis was higher for Black or African Americans than non-Black or African Americans (P = .01). Between the racial groups, there was no difference in the total number of food sensitizations (P = .13), yet environmental allergy testing revealed that Black or African Americans were more likely to be sensitized for weeds (P = .03), dog (P = .009), and mold (P = .006). On histopathologic analysis, Black or African American subjects were found to have more prominent midesophageal eosinophilia at median 50/hpf (20-80/hpf), whereas Hispanic or LatinXs have more prominent lower esophageal eosinophilia at median 40/hpf (IQR, 20-40/hpf), compared with the other races (P = .04 and P = .04, respectively). CONCLUSION Black or African Americans are more likely to present at an older age, have aeroallergen sensitization, and have more prominent midesophageal eosinophilia.
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Affiliation(s)
- Mark Mahon
- Lewis M. Fraad Department of Pediatrics, Albert Einstein College of Medicine, NYC Health and Hospitals/Jacobi Medical Center, Bronx, New York.
| | - Noé D Romo
- Lewis M. Fraad Department of Pediatrics, Albert Einstein College of Medicine, NYC Health and Hospitals/Jacobi Medical Center, Bronx, New York
| | - Gabriele de Vos
- Lewis M. Fraad Department of Pediatrics, Albert Einstein College of Medicine, NYC Health and Hospitals/Jacobi Medical Center, Bronx, New York
| | - Daniela Levanon
- Lewis M. Fraad Department of Pediatrics, Albert Einstein College of Medicine, NYC Health and Hospitals/Jacobi Medical Center, Bronx, New York
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Upparahalli Venkateshaiah S, Rayapudi M, Kandikattu HK, Yadavalli CS, Mishra A. Blood mRNA levels of T cells and IgE receptors are novel non-invasive biomarkers for eosinophilic esophagitis (EoE). Clin Immunol 2021; 227:108752. [PMID: 33945873 DOI: 10.1016/j.clim.2021.108752] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 04/28/2021] [Accepted: 04/30/2021] [Indexed: 12/12/2022]
Abstract
Eosinophilic esophagitis (EoE) is often misdiagnosed as GERD; therefore, the goal of the current study is to establish a non-invasive diagnostic and monitoring biomarker that differentiated GERD from EoE. Reports indicates that IL-15 responsive iNKT cells and tissue specific IgE have a critical in EoE pathogenesis, not in GERD. Therefore, we tested the hypothesis that the panel of IL-15-responsive T cell and IgE receptors may be novel non-invasive biomarkers for EoE. Accordingly, the receptors of IL-15 responsive T cells (Vα24, Jα18, γδT, αβT) and IgE (FcεRI & FcεRII) were examined. The data indicates that blood mRNA levels of Vα24, Jα18, γδ T, αβ T and FcεRI are significantly reduced in EoE compared to the GERD patients and normal individuals. The ROC curve analysis indicated FcεRII, Jα18 and δ TCR are the positive predictors that discriminate EoE from GERD. Thus, these molecules will be a novel non-invasive diagnostic biomarker for EoE.
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Affiliation(s)
- Sathisha Upparahalli Venkateshaiah
- John W. Deming Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, LA, USA
| | - Madhavi Rayapudi
- Allergy and Immunology Division, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH 45229, USA
| | - Hemanth Kumar Kandikattu
- John W. Deming Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, LA, USA
| | - Chandra Sekhar Yadavalli
- John W. Deming Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, LA, USA
| | - Anil Mishra
- John W. Deming Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, LA, USA.
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Upparahalli Venkateshaiah S, Manohar M, Kandikattu HK, Mishra A. Experimental Modeling of Eosinophil-Associated Diseases. Methods Mol Biol 2021; 2241:275-291. [PMID: 33486743 DOI: 10.1007/978-1-0716-1095-4_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Eosinophils are an important subtype of leukocytes derived from bone marrow multipotent hematopoietic stem cells and represent about 1% of leukocytes in circulating blood. In homeostatic conditions, eosinophils reside in the intestine to maintain the balance of immune responses by communicating with gut microbes without causing inflammation. However, under the stressed or diseased condition, eosinophils degranulate, releasing their granule-derived cytotoxic proteins that are involved in inflammatory responses. Various eosinophil-associated inflammatory diseases are eosinophilic esophagitis (EoE), eosinophilic gastroenteritis (EG), and eosinophilic colitis (EC), together called EGID, asthma, hypereosinophilic syndrome, and eosinophilic pneumonia (EP). Eosinophil degranulation results in the release of their four toxic proteins [major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN)] which promote disease pathogenesis. Pancreatitis is the inflammatory disease of the pancreas that arises due to blockage of the pancreatic duct, trypsinogen mutation, alcohol consumption, and repeated occurrence of pancreatitis leading to chronic pancreatitis (CP); subsequently some CP patients may also develop pancreatic cancer. The presence of eosinophils is now shown in various case reports with acute, recurrent acute, and chronic pancreatitis and pancreatic cancer indicating the role of eosinophils in the pathogenesis of various pancreatic inflammatory disorders. However, the details of eosinophil accumulation during pancreatic diseases are not well explored and need further attention. Overall, the chapter provides the current understanding of reported eosinophils associated with inflammatory diseases like EGID diseases, asthma, and pancreatic disorders, i.e., acute, chronic pancreatitis, and pancreatic cancer. This knowledge will be helpful for future studies to develop novel treatment options for the eosinophils associated diseases. Therefore, more efforts are needed to perform preclinical and clinical studies in this field for the successful development of eosinophil-targeting treatments for a variety of eosinophil-associated diseases.
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Affiliation(s)
- Sathisha Upparahalli Venkateshaiah
- John W. Deming Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, LA, USA
| | - Murli Manohar
- John W. Deming Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, LA, USA
| | - Hemanth Kumar Kandikattu
- John W. Deming Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, LA, USA
| | - Anil Mishra
- John W. Deming Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, LA, USA.
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Kandikattu HK, Venkateshaiah SU, Verma AK, Mishra A. Tacrolimus (FK506) treatment protects allergen-, IL-5- and IL-13-induced mucosal eosinophilia. Immunology 2021; 163:220-235. [PMID: 33512727 DOI: 10.1111/imm.13314] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 12/16/2020] [Accepted: 01/18/2021] [Indexed: 02/06/2023] Open
Abstract
Eosinophils are a common clinical feature associated with chronic allergic diseases, and elemental diets, systemic steroids, anti-IL-5 and anti-IL-13 treatment have shown some therapeutic promise. Herein, we present evidence that pre- and post-intraperitoneal administration of tacrolimus (FK506) is very effective in reducing CCR3/Siglec-F+ eosinophils in Aspergillus-challenged asthma and EoE, CD2-IL-5 induced global eosinophilia, and DOX regulated IL-13-induced asthma. We used flow cytometry and anti-major basic protein (MBP) immunostaining to examine eosinophils in the spleen, bone marrow, BALF, lung, oesophagus and intestine. Additionally, we also performed ELISA and Western blot analyses to show that tacrolimus treatment also reduces the levels of eosinophil-specific cytokines IL-4, IL-5, IL-13 and TGF-β, eosinophil-specific chemokines Eotaxin-1 and Eotaxin-2, and progenitors of target RCAN1 mRNA and protein levels. Additionally, the current investigations also show that the TGF-β-mediated oesophageal and lung fibrosis is also reduced in Aspergillus-challenged, CD2-IL-5 transgenic and DOX-responsive IL-13 mice. Mechanistically, we show that tacrolimus in vitro treatment inhibited bone marrow-derived eosinophil proliferation and viability by promoting eosinophil apoptosis that may be associated with downregulation of RCAN1. Taken together, we provide in vivo and in vitro evidence that tacrolimus ameliorates eosinophil levels and associated pathogenesis in allergen-, IL-5- and IL-13-induced EoE, EG and asthma pathogenesis. Considering tacrolimus side-effects and reactivity to several other drugs, we propose the topical use of tacrolimus for paediatric and low-dose oral for adult patients as a novel therapeutic strategy for the clinical trial to reduce mucosal eosinophilia first in steroid-refractory or elemental diet non-responsive adult EoE, EG and asthma patients.
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Affiliation(s)
- Hemanth Kumar Kandikattu
- Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center, Tulane University School of Medicine, New Orleans, LA, USA
| | - Sathisha Upparahalli Venkateshaiah
- Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center, Tulane University School of Medicine, New Orleans, LA, USA
| | - Alok Kumar Verma
- Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center, Tulane University School of Medicine, New Orleans, LA, USA
| | - Anil Mishra
- Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center, Tulane University School of Medicine, New Orleans, LA, USA
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45
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Sciumè GD, Visaggi P, Sostilio A, Tarducci L, Pugno C, Frazzoni M, Ricchiuti A, Bellini M, Giannini EG, Marchi S, Savarino V, de Bortoli N. Eosinophilic esophagitis: novel concepts regarding pathogenesis and clinical manifestations. Minerva Gastroenterol (Torino) 2021; 68:23-39. [PMID: 33435660 DOI: 10.23736/s2724-5985.20.02807-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Eosinophilic esophagitis is a chronic disease whose incidence and prevalence are increasing, based on a genetic-driven interaction between environment and immune system. Several gene loci involved in the development of the disease have been identified. A two-step mechanism has been hypothesized: a thymic stromal lymphopoietin-induced allergic sensitization followed by upregulation of CAPN14-related esophageal-specific pathways. Environment seems to have a larger effect than genetic variants. Factors that could play a role are allergens, drugs, colonizing bacteria and possibly Helicobacter Pylori infection. Acting on these modifiable risk factors may be a tool to prevent the disease. EoE is characterized by a typical eosinophilic infiltrate limited to the esophageal epithelium, supported by a Th2-mediated immune response, found in other atopic conditions. The key of the pathogenesis is the disfunction of the epithelial barrier which allow the interaction between allergens and inflammatory cells. Eosinophilic-predominant inflammation leads to the typical wall remodeling, histologically characterized by epithelial and smooth muscle hyperplasia, lamina propria fibrosis and neo-angiogenesis. These alterations find their clinical expression in the pattern of symptoms: dysphagia, food impaction, chest pain, heartburn.
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Affiliation(s)
- Giusi D Sciumè
- Division of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Pierfrancesco Visaggi
- Division of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Andrea Sostilio
- Division of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Luca Tarducci
- Division of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Camilla Pugno
- Division of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Marzio Frazzoni
- Digestive Pathophysiology Unit, Baggiovara Hospital, Modena, Italy
| | - Angelo Ricchiuti
- Division of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Massimo Bellini
- Division of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Edoardo G Giannini
- Gastrointestinal Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Santino Marchi
- Division of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Vincenzo Savarino
- Gastrointestinal Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Nicola de Bortoli
- Division of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy -
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46
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Doyle AD, Masuda MY, Kita H, Wright BL. Eosinophils in Eosinophilic Esophagitis: The Road to Fibrostenosis is Paved With Good Intentions. Front Immunol 2020; 11:603295. [PMID: 33335531 PMCID: PMC7736408 DOI: 10.3389/fimmu.2020.603295] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 11/03/2020] [Indexed: 12/15/2022] Open
Abstract
Eosinophilic esophagitis (EoE) is an antigen-driven disease associated with epithelial barrier dysfunction and chronic type 2 inflammation. Eosinophils are the defining feature of EoE histopathology but relatively little is known about their role in disease onset and progression. Classically defined as destructive, end-stage effector cells, eosinophils (a resident leukocyte in most of the GI tract) are increasingly understood to play roles in local immunity, tissue homeostasis, remodeling, and repair. Indeed, asymptomatic esophageal eosinophilia is observed in IgE-mediated food allergy. Interestingly, EoE is a potential complication of oral immunotherapy (OIT) for food allergy. However, we recently found that patients with peanut allergy may have asymptomatic esophageal eosinophilia at baseline and that peanut OIT induces transient esophageal eosinophilia in most subjects. This is seemingly at odds with multiple studies which have shown that EoE disease severity correlates with tissue eosinophilia. Herein, we review the potential role of eosinophils in EoE at different stages of disease pathogenesis. Based on current literature we suggest the following: (1) eosinophils are recruited to the esophagus as a homeostatic response to epithelial barrier disruption; (2) eosinophils mediate barrier-protective activities including local antibody production, mucus production and epithelial turnover; and (3) when type 2 inflammation persists, eosinophils promote fibrosis.
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Affiliation(s)
- Alfred D Doyle
- Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, United States
| | - Mia Y Masuda
- Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, United States
| | - Hirohito Kita
- Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, United States.,Department of Immunology, Mayo Clinic Arizona, Scottsdale, AZ, United States
| | - Benjamin L Wright
- Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, United States.,Division of Pulmonology, Phoenix Children's Hospital, Phoenix, AZ, United States
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47
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Collison AM, Sokulsky LA, Nightingale S, Percival E, LeFevre A, Meredith J, Krauss S, Foster PS, Mattes J. In vivo targeting of miR-223 in experimental eosinophilic oesophagitis. Clin Transl Immunology 2020; 9:e1210. [PMID: 33282292 PMCID: PMC7683276 DOI: 10.1002/cti2.1210] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 08/19/2020] [Accepted: 10/20/2020] [Indexed: 01/03/2023] Open
Abstract
Objectives Eosinophilic oesophagitis (EoE) is characterised by oesophageal inflammation, fibrosis and dysfunction. Micro (mi)-RNAs interfere with pro-inflammatory and pro-fibrotic transcriptional programs, and miR-223 was upregulated in oesophageal mucosal biopsy specimens from EoE patients. The therapeutic potential of modulating miR-223 expression in vivo has not been determined. We aimed to elucidate the relevance of oesophageal miR-223 expression in an in vivo model of EoE by inhibiting miR-223 tissue expression. Methods The expression of miR-223 and the validated miR-223 target insulin-like growth factor receptor 1 (IGF1R) protein was determined in our paediatric cohort of EoE patients. A murine model of Aspergillus fumigatus-induced EoE was employed, and oesophagi were assessed for miR-233, IGF1R, T lymphocyte type 2 (T2) cytokine expression and eosinophil infiltration. Mice were treated with antagomirs targeting miR-223 or resveratrol targeting its upstream regulator Midline-1(MID-1). Results There was an inverse relationship between an increased expression of miR-223 and a decreased IGF1R protein concentration in biopsy specimens from EoE patients. TNF-related apoptosis-inducing ligand deficiency, MID-1 inhibition and resveratrol treatment suppressed miR-223 expression. Furthermore, inhibition of miR-223 and treatment with resveratrol in the oesophagus resulted in an amelioration of EoE hallmark features including eosinophilic infiltration, oesophageal circumference and a reduction in T2 cytokine expression. Conclusion miR-223 has a key role in the perpetuation of EoE hallmark features downstream of TNF-related apoptosis-inducing ligand and MID-1 in an experimental model. These studies highlight a potentially critical role of miRNA function in EoE aetiology. miR-223 expression in the oesophagus may be therapeutically modulated by resveratrol, providing a potential new therapeutic option to be explored in EoE patients for this increasingly prevalent condition.
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Affiliation(s)
- Adam M Collison
- Experimental and Translational Respiratory Medicine Group Newcastle NSW Australia.,Priority Research Centre GrowUpWell The University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia
| | - Leon A Sokulsky
- Experimental and Translational Respiratory Medicine Group Newcastle NSW Australia.,Priority Research Centre GrowUpWell The University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia.,Priority Research Centre for Healthy Lungs The University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia
| | - Scott Nightingale
- Priority Research Centre GrowUpWell The University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia.,Paediatric Gastroenterology Department John Hunter Children's Hospital Newcastle NSW Australia
| | - Elizabeth Percival
- Experimental and Translational Respiratory Medicine Group Newcastle NSW Australia.,Priority Research Centre GrowUpWell The University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia
| | - Anna LeFevre
- Priority Research Centre GrowUpWell The University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia
| | - Joseph Meredith
- Priority Research Centre GrowUpWell The University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia
| | - Sybille Krauss
- Faculty IV: School of Science and Technology Institute of Biology Department Human Biology/Neurobiology University of Siegen Siegen Germany
| | - Paul S Foster
- Priority Research Centre for Healthy Lungs The University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia
| | - Joerg Mattes
- Experimental and Translational Respiratory Medicine Group Newcastle NSW Australia.,Priority Research Centre GrowUpWell The University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia.,Paediatric Respiratory & Sleep Medicine Department Newcastle Children's Hospital Kaleidoscope Newcastle NSW Australia
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48
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Arias Á, Lucendo AJ. Epidemiology and risk factors for eosinophilic esophagitis: lessons for clinicians. Expert Rev Gastroenterol Hepatol 2020; 14:1069-1082. [PMID: 32749898 DOI: 10.1080/17474124.2020.1806054] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION The rapid expansion in the epidemiology of eosinophilic esophagitis (EoE) is being documented, along with cumulative research assessing environmental exposures associated with EoE and susceptibility due to genetic variants. AREAS COVERED Incidence rates for EoE of 5-10 new cases per 100,000 inhabitants annually have shown an increase in recent reports of up to 20 in some countries; the highest prevalence being reported for Europe and North America, where EoE now affects more than 1 out of 1,000 people. EoE has been shown to be associated with several disorders, Th2-mediated atopies being the most common. Patients with EoE exhibit increased frequency of asthma, allergic rhinitis and eczema, and EoE has been considered as a late component of the atopic march. Risk variants in TSLP, CAPN14 and LRCC32 genes, among others, have all been related to EoE, and interact with prenatal and early life exposure potentially modifying abundance and composition of gut microbiome. Dysregulated interactions between bacteria and mucosal immunity emerge as leading causes of EoE. EXPERT OPINION The expanding epidemiology of EoE, the resources needed and subsequent increasing healthcare costs require additional effort to optimize cost-effective management and unveil mechanisms that enhance the development of future preventive strategies.
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Affiliation(s)
- Ángel Arias
- Research Unit, Hospital General Mancha Centro , Alcázar De San Juan, Spain.,Centro De Investigación Biomédica En Red De Enfermedades Hepáticas Y Digestivas (Ciberehd) , Madrid, Spain.,Instituto De Investigación Sanitaria La Princesa , Madrid, Spain
| | - Alfredo J Lucendo
- Centro De Investigación Biomédica En Red De Enfermedades Hepáticas Y Digestivas (Ciberehd) , Madrid, Spain.,Instituto De Investigación Sanitaria La Princesa , Madrid, Spain.,Department of Gastroenterology, Hospital General De Tomelloso , Ciudad Real, Spain
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49
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Koumbourlis AC, Belessis Y, Cataletto M, Cutrera R, DeBoer E, Kazachkov M, Laberge S, Popler J, Porcaro F, Kovesi T. Care recommendations for the respiratory complications of esophageal atresia-tracheoesophageal fistula. Pediatr Pulmonol 2020; 55:2713-2729. [PMID: 32716120 DOI: 10.1002/ppul.24982] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/18/2020] [Accepted: 07/22/2020] [Indexed: 12/11/2022]
Abstract
Tracheoesophageal fistula (TEF) with esophageal atresia (EA) is a common congenital anomaly that is associated with significant respiratory morbidity throughout life. The objective of this document is to provide a framework for the diagnosis and management of the respiratory complications that are associated with the condition. As there are no randomized controlled studies on the subject, a group of experts used a modification of the Rand Appropriateness Method to describe the various aspects of the condition in terms of their relative importance, and to rate the available diagnostic methods and therapeutic interventions on the basis of their appropriateness and necessity. Specific recommendations were formulated and reported as Level A, B, and C based on whether they were based on "strong", "moderate" or "weak" agreement. The tracheomalacia that exists in the site of the fistula was considered the main abnormality that predisposes to all other respiratory complications due to airway collapse and impaired clearance of secretions. Aspiration due to impaired airway protection reflexes is the main underlying contributing mechanism. Flexible bronchoscopy is the main diagnostic modality, aided by imaging modalities, especially CT scans of the chest. Noninvasive positive airway pressure support, surgical techniques such as tracheopexy and rarely tracheostomy are required for the management of severe tracheomalacia. Regular long-term follow-up by a multidisciplinary team was considered imperative. Specific templates outlining the elements of the clinical respiratory evaluation according to the patients' age were also developed.
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Affiliation(s)
- Anastassios C Koumbourlis
- Division of Pulmonary & Sleep Medicine, Children's National Hospital, George Washington University School of Medicine & Health Sciences, Washington, District of Columbia
| | - Yvonne Belessis
- Department of Respiratory Medicine, Sydney Children's Hospital Randwick, Randwick, New South Wales, Australia
| | - Mary Cataletto
- Division of Pediatric Pulmonary Medicine, New York University, Winthrop University Hospital, Mineola, New York
| | - Renato Cutrera
- Academic Department of Pediatrics (DPUO), Pediatric Pulmonology & Respiratory Intermediate Care Unit, Sleep and Long Term Ventilation Unit, Pediatric Hospital "Bambino Gesù" Research Institute, Rome, Italy
| | - Emily DeBoer
- Department of Pediatrics, Section of Pulmonary and Sleep Medicine, University of Colorado Denver, Children's Hospital Colorado Breathing Institute, Aurora, Colorado
| | - Mikhail Kazachkov
- Department of Pediatric Pulmonology, Gastroesophageal, Upper Airway and Respiratory Diseases Center, New York University School of Medicine, New York, New York
| | - Sophie Laberge
- Department of Pediatrics, Division of Respiratory Medicine, Sainte-Justine University Hospital Center, Université de Montréal, Montreal, Quebec, Canada
| | - Jonathan Popler
- Division of Pediatric Pulmonology, Children's Healthcare of Atlanta, Atlanta, Georgia
| | - Federica Porcaro
- Department of Pediatrics, Pediatric Pulmonology & Respiratory Intermediate Care Unit, Sleep and Long-Term Ventilation Unit, Bambino Gesù Children's Hospital, Rome, Italy
| | - Thomas Kovesi
- Pediatrics, Division of Respirology, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada
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50
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Roh JH, Ryoo E, Tchah H. Clinical Manifestations of Eosinophilic Esophagitis in Children and Adolescents: A Single-Center, Matched Case-Control Study. Pediatr Gastroenterol Hepatol Nutr 2020; 23:319-328. [PMID: 32704493 PMCID: PMC7354874 DOI: 10.5223/pghn.2020.23.4.319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 11/15/2019] [Accepted: 11/30/2019] [Indexed: 11/14/2022] Open
Abstract
PURPOSE To examine the prevalence and clinical manifestations of eosinophilic esophagitis (EoE) in Korea children. METHODS The study was designed as a 1:2 matching case-control study. Using information from the endoscopic database of a tertiary center, we retrospectively reviewed the medical records of patients aged 18 years or younger who underwent upper gastrointestinal endoscopy between January 2014 and December 2017. A total of 21 patients were diagnosed with EoE based on current diagnostic criteria. In addition, 42 controls with normal esophageal biopsy findings matched to each EoE case by sex, age (±1 months), and season were randomly selected during the study period. RESULTS The mean age of EoE diagnosis was 12.1±4.0 years and the male-to-female ratio was 2:1. The proportion of allergic diseases in patients with EoE (28.6%) was higher than that in the controls (6.8%) (p=0.04). Most EoE patients tested for allergy were positive for at least one antigen, which was significantly different to the controls (88.2% vs. 47.4%, p=0.01). Characteristic endoscopic findings of EoE were noted in 19 patients (90.5%), but 2 patients (9.5%) showed normal esophageal mucosa. The clinical symptoms of EoE were improved by a proton-pump inhibitor in 10 patients (50.0%), and by an H2 blocker in 9 patients (45.0%). Only one patient (5.0%) required inhaled steroids. CONCLUSION While EoE is rare in the Korean pediatric population, the results of this study will improve our understanding of the clinical manifestations of the disease.
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Affiliation(s)
- Ji Hyeon Roh
- Department of Pediatrics, Gachon University Gil Medical Center, Incheon, Korea
| | - Eell Ryoo
- Department of Pediatrics, Gachon University Gil Medical Center, Incheon, Korea
| | - Hann Tchah
- Department of Pediatrics, Gachon University Gil Medical Center, Incheon, Korea
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