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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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2
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Mager LF, Krause T, McCoy KD. Interaction of microbiota, mucosal malignancies, and immunotherapy-Mechanistic insights. Mucosal Immunol 2024; 17:402-415. [PMID: 38521413 DOI: 10.1016/j.mucimm.2024.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 03/09/2024] [Accepted: 03/17/2024] [Indexed: 03/25/2024]
Abstract
The microbiome has emerged as a crucial modulator of host-immune interactions and clearly impacts tumor development and therapy efficacy. The microbiome is a double-edged sword in cancer development and therapy as both pro-tumorigenic and anti-tumorigenic bacterial taxa have been identified. The staggering number of association-based studies in various tumor types has led to an enormous amount of data that makes it difficult to identify bacteria that promote tumor development or modulate therapy efficacy from bystander bacteria. Here we aim to comprehensively summarize the current knowledge of microbiome-host immunity interactions and cancer therapy in various mucosal tissues to find commonalities and thus identify potential functionally relevant bacterial taxa. Moreover, we also review recent studies identifying specific bacteria and mechanisms through which the microbiome modulates cancer development and therapy efficacy.
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Affiliation(s)
- Lukas F Mager
- Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Canada; Department of Internal Medicine I, Faculty of Medicine, University of Tübingen, Germany; M3 Research Center for Malignom, Metabolome and Microbiome, Faculty of Medicine University Tübingen, Germany
| | - Tim Krause
- Department of Internal Medicine I, Faculty of Medicine, University of Tübingen, Germany; M3 Research Center for Malignom, Metabolome and Microbiome, Faculty of Medicine University Tübingen, Germany
| | - Kathy D McCoy
- Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Canada.
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3
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Ocampo AA, Genta RM, Dellon ES. Mast Cell Esophagitis: A Novel Entity in Patients with Unexplained Esophageal Symptoms. Dysphagia 2024; 39:360-368. [PMID: 37605054 PMCID: PMC10879451 DOI: 10.1007/s00455-023-10616-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 08/10/2023] [Indexed: 08/23/2023]
Abstract
It is not known whether esophageal mast cells may be a cause of unexplained esophageal symptoms. We aimed to determine the prevalence of esophageal mastocytosis in patients without other underlying causes of symptoms and assess the relationship between symptoms and mast cells. In this retrospective study, we identified adults with esophageal symptoms, a normal endoscopy, normal esophageal biopsies, and no definitive diagnosis during clinical evaluation. We quantified mast cell density (mast cells/mm2) in archived esophageal biopsies using tryptase immunohistochemistry, and compared mast cell levels by clinical features and physiologic testing. In the 87 patients identified (mean age 37, 72% female, 63% white, 92% non-Hispanic), common symptoms were dysphagia (76%), heartburn (71%), and chest pain (25%). Overall, the mean esophageal epithelial mast cell count was 83.0 ± 51.8 mast cells/mm2; 60% of patients had ≥ 60 mast/mm2, and 17% had ≥ 120 masts/mm2. There were no differences in mast cell counts by type of esophageal testing. Mast cell levels did not differ significantly by type of symptoms, atopic status, medications, smoking status, or alcohol use. There were also no major differences in clinical characteristics by mast cell quartiles or thresholds. In conclusion, esophageal mast cell infiltration was common in patients with symptoms unexplained by prior testing, and levels were higher than previously published values for patients with no underlying esophageal condition. Mast cell esophagitis could be a novel cause of unexplained esophageal symptoms in a subset of patients, though it reamins to be determined if such patients benefit from mast cell-targeted treatment.
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Affiliation(s)
- Adolfo A Ocampo
- Division of Gastroenterology and Hepatology, Department of Medicine, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, CB#7080, Bioinformatics Building, 130 Mason Farm Rd.,UNC-CH, Chapel Hill, NC, 27599-7080, USA
| | - Robert M Genta
- Inform Diagnostics, Irving, TX, USA
- Departments of Pathology and Medicine (Gastroenterology), Baylor College of Medicine, Houston, TX, USA
| | - Evan S Dellon
- Division of Gastroenterology and Hepatology, Department of Medicine, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, CB#7080, Bioinformatics Building, 130 Mason Farm Rd.,UNC-CH, Chapel Hill, NC, 27599-7080, USA.
- Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease,, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
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4
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Leech T, Peiris M. Mucosal neuroimmune mechanisms in gastro-oesophageal reflux disease (GORD) pathogenesis. J Gastroenterol 2024; 59:165-178. [PMID: 38221552 PMCID: PMC10904498 DOI: 10.1007/s00535-023-02065-9] [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: 08/24/2023] [Accepted: 11/30/2023] [Indexed: 01/16/2024]
Abstract
Gastro-oesophageal reflux disease (GORD) is a chronic condition characterised by visceral pain in the distal oesophagus. The current first-line treatment for GORD is proton pump inhibitors (PPIs), however, PPIs are ineffective in a large cohort of patients and long-term use may have adverse effects. Emerging evidence suggests that nerve fibre number and location are likely to play interrelated roles in nociception in the oesophagus of GORD patients. Simultaneously, alterations in cells of the oesophageal mucosa, namely epithelial cells, mast cells, dendritic cells, and T lymphocytes, have been a focus of GORD research for several years. The oesophagus of GORD patients exhibits both macro- and micro-inflammation as a response to chronic acidic reflux at the epithelium. In other conditions of the GI tract, such as IBS and IBD, well-characterised bidirectional processes between immune cells and mucosal nerve fibres contribute to pathogenesis and symptom generation. Sensory alterations in these conditions such as nerve fibre outgrowth and hypersensitivity can be driven by inflammatory processes, which promote visceral pain signalling. This review will examine what is currently known of the molecular pathways linking inflammation and sensory perception leading to the development of GORD symptoms and explore potentially relevant mechanisms in other GI regions which may indicate new areas in GORD research.
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Affiliation(s)
- Tom Leech
- Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK
| | - Madusha Peiris
- Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK.
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5
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Dellon ES. Eosinophilic Esophagitis: What's in a Name? Dig Dis Sci 2024; 69:330-334. [PMID: 38060168 DOI: 10.1007/s10620-023-08205-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/10/2023] [Indexed: 12/08/2023]
Affiliation(s)
- Evan S Dellon
- , CB #7080, Bioinformatics Bldg., 130 Mason Farm Road, Chapel Hill, NC, 27599-7080, USA.
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6
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Chen J, Oshima T, Tomita T, Fukui H, Shinzaki S. Regulatory T cells Are Increased and Correlate With Mast Cells in Eosinophilic Esophagitis. J Neurogastroenterol Motil 2024; 30:29-37. [PMID: 38173156 PMCID: PMC10774801 DOI: 10.5056/jnm23040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 05/30/2023] [Accepted: 06/26/2023] [Indexed: 01/05/2024] Open
Abstract
Background/Aims The incidence of eosinophilic esophagitis (EoE) has been increasing recently. The role of regulatory T cells (Tregs) and correlations with other inflammatory cells in EoE remain unknown. We aim to clarify the role of Tregs and their correlations with inflammatory cells in EoE patients. Methods Biopsies from controls and EoE patients before and after treatments were analyzed. Eosinophil infiltration was evaluated by hematoxylin and eosin staining. Immunohistochemical staining was performed to examine infiltration of T cells, Tregs, and mast cells. Gene expressions of chemokines were evaluated by reverse transcription-quantitative polymerase chain reaction. Results Tregs and mast cells were increased in the esophageal epithelial layers of EoE patients. After treatments, Tregs and mast cells were decreased when histologic remission was achieved. Infiltration of Tregs correlated significantly with numbers of eosinophils and mast cells. Filaggrin mRNA was decreased in patients with EoE before treatment and upregulated after treatment, even when histologic remission was not achieved. Conclusions Tregs were increased in esophageal epithelium of patients with EoE, and correlated with mast cell infiltration.
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Affiliation(s)
- Junji Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Tadayuki Oshima
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Toshihiko Tomita
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Hirokazu Fukui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Shinichiro Shinzaki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo Medical University, Nishinomiya, Japan
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Arias-González L, Rodríguez-Alcolado L, Laserna-Mendieta EJ, Navarro P, Lucendo AJ, Grueso-Navarro E. Fibrous Remodeling in Eosinophilic Esophagitis: Clinical Facts and Pathophysiological Uncertainties. Int J Mol Sci 2024; 25:927. [PMID: 38256003 PMCID: PMC10815180 DOI: 10.3390/ijms25020927] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 01/08/2024] [Accepted: 01/09/2024] [Indexed: 01/24/2024] Open
Abstract
Eosinophilic esophagitis (EoE) is a chronic, progressive, type 2 inflammatory disease with increasing global prevalence. An eosinophil-predominant inflammation that permeates the epithelium and deeper esophageal layers characterizes the disease. Several cytokines, mainly derived from inflammatory T-helper 2 (Th2) cells and epithelial cells, are involved in perpetuating inflammatory responses by increasing surface permeability and promoting tissue remodeling characterized by epithelial-mesenchymal transition (EMT) and collagen deposition. This leads to esophageal strictures and narrow caliber esophagi, which are proportional a patient's age and untreated disease length. Pathophysiological mechanisms leading to EoE have been described in recent years, and transforming growth factor beta (TGF)-beta have been involved in fibrotic phenomena in EoE. However, evidence on the dependence of these phenomena on TGF-beta is scarce and contradictory. This review provides state-of-the art knowledge on intimate mechanisms of esophageal fibrosis in EoE and its clinical consequences.
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Affiliation(s)
- Laura Arias-González
- Department of Gastroenterology, Hospital General de Tomelloso, Vereda de Socuéllamos s/n, 13700 Tomelloso, Spain; (L.A.-G.); (L.R.-A.); (E.J.L.-M.); (P.N.); (E.G.-N.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
- Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), 45071 Toledo, Spain
- Instituto de Investigación Sanitaria Princesa, 28006 Madrid, Spain
| | - Leticia Rodríguez-Alcolado
- Department of Gastroenterology, Hospital General de Tomelloso, Vereda de Socuéllamos s/n, 13700 Tomelloso, Spain; (L.A.-G.); (L.R.-A.); (E.J.L.-M.); (P.N.); (E.G.-N.)
- Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), 45071 Toledo, Spain
| | - Emilio J. Laserna-Mendieta
- Department of Gastroenterology, Hospital General de Tomelloso, Vereda de Socuéllamos s/n, 13700 Tomelloso, Spain; (L.A.-G.); (L.R.-A.); (E.J.L.-M.); (P.N.); (E.G.-N.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
- Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), 45071 Toledo, Spain
- Instituto de Investigación Sanitaria Princesa, 28006 Madrid, Spain
| | - Pilar Navarro
- Department of Gastroenterology, Hospital General de Tomelloso, Vereda de Socuéllamos s/n, 13700 Tomelloso, Spain; (L.A.-G.); (L.R.-A.); (E.J.L.-M.); (P.N.); (E.G.-N.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
- Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), 45071 Toledo, Spain
| | - Alfredo J. Lucendo
- Department of Gastroenterology, Hospital General de Tomelloso, Vereda de Socuéllamos s/n, 13700 Tomelloso, Spain; (L.A.-G.); (L.R.-A.); (E.J.L.-M.); (P.N.); (E.G.-N.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
- Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), 45071 Toledo, Spain
- Instituto de Investigación Sanitaria Princesa, 28006 Madrid, Spain
| | - Elena Grueso-Navarro
- Department of Gastroenterology, Hospital General de Tomelloso, Vereda de Socuéllamos s/n, 13700 Tomelloso, Spain; (L.A.-G.); (L.R.-A.); (E.J.L.-M.); (P.N.); (E.G.-N.)
- Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), 45071 Toledo, Spain
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8
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Maslenkina KS, Motylev EN, Guschin MY, Vandysheva RA, Mikhaleva LM. [Pathomorphological criteria and features of immune response in eosinophilic esophagitis and reflux esophagitis]. Arkh Patol 2024; 86:5-12. [PMID: 38319266 DOI: 10.17116/patol2024860115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2024]
Abstract
BACKGROUND Eosinophilic esophagitis (EoE) is an immune-mediated disease, manifested by dysphagia and characterized by intraepithelial infiltration: more than 15 eosinophils per field of view at x400 magnification, and requiring differential diagnosis with reflux esophagitis (RE). OBJECTIVE To access the implication of EoE histologic scoring system (EoEHSS) for differential diagnosis of EoE and RE and to characterize features of immune response in these diseases. MATERIAL AND METHODS 38 patients with EoE and 38 patients with RE were enrolled in the study. All the patients had esophagogastroduodenoscopy with biopsy. Biopsy specimens were stained with H&E and combined PAS/Alcian blue staining. Immunohistochemical evaluation was conducted with antibodies to CD3, CD4, CD8, CD20, CD56 and CD68. RESULTS Grade score of EoEHSS in EoE was 2.4 times more than in RE (p<0.05). Stage score in EoE was 2.75 more than in RE (p<0.05). Intraepithelial count of CD3+ T-lymphocytes comprised 87 (76-95.5) in high-power view in EoE and 45 (38.5-48.5) in high-power view in RE. Intraepithelial count of CD4+ T-lymphocytes was 35 (28-41.5) in high-power view in EoE and 19 (16.5- 22.5) in high-power view in RE. Intraepithelial count of CD8+ T-lymphocytes comprised 59 (50.5-67.5) in high-power field in EoE and 27 (24-28.5) in high-power field in RE. CONCLUSION The use of the EoEHSS histological rating scale for eosinophilic esophagitis is effective in the differential diagnosis of EoE and EC. Predominant cells in intraepithelial infiltrate are CD3+ T-lymphocytes both in EoE and RE, CD8+ cells prevail over CD4+ cells. In EoE intraepithelial count of CD3+ T-lymphocytes is 1.93 times more, count of intraepithelial CD4+ lymphocytes is 1.84 times more and count of CD8+ lymphocytes is 2.19 times more than in RE.
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Affiliation(s)
- K S Maslenkina
- A.P. Avtsyn Research Institute of Human Morphology Petrovsky National Research Center of Surgery, Moscow, Russia
| | - E N Motylev
- A.P. Avtsyn Research Institute of Human Morphology Petrovsky National Research Center of Surgery, Moscow, Russia
| | - M Yu Guschin
- A.P. Avtsyn Research Institute of Human Morphology Petrovsky National Research Center of Surgery, Moscow, Russia
| | - R A Vandysheva
- A.P. Avtsyn Research Institute of Human Morphology Petrovsky National Research Center of Surgery, Moscow, Russia
| | - L M Mikhaleva
- A.P. Avtsyn Research Institute of Human Morphology Petrovsky National Research Center of Surgery, Moscow, Russia
- Russian Medical Academy of Continuous Professional Education, Moscow, Russia
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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: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [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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10
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Grando M, De Pauli S, Miotti G, Balbi M, Zeppieri M. Adult eosinophilic esophagitis and advances in its treatment. World J Methodol 2023; 13:59-66. [PMID: 37456973 PMCID: PMC10348084 DOI: 10.5662/wjm.v13.i3.59] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/24/2023] [Accepted: 05/15/2023] [Indexed: 06/20/2023] Open
Abstract
Eosinophilic esophagitis (EoE) is a chronic eosinophil inflammation that seems to be T helper type 2 antigen-driven. The disease is one of several eosinophilic gastrointestinal disorders in which there appears to be inflammation of the gastrointestinal tract without any apparent underlying causes. Differential diagnosis needs to be made with gastroesophageal reflux, which is characterized by chronic inflammation due to gastric refluxate from disorders related to motility. EoE, however, is considered a chronic allergic inflammatory disorder related to destructive tissue remodeling. There seems to be a higher prevalence of EoE in Western countries. It is typically found in atopic male individuals. Physiopathological risk factors include atopy, environmental factors, esophageal epithelial barrier dysfunctions, etc. EoE can cause several symptoms that include retrosternal burning sensation, dysphagia, food impaction, chronic reflux symptoms, nausea, and vomiting. Early diagnosis, which requires a biopsy to assess for esophageal inflammation, is essential for proper treatment. The aim of our brief overview is to summarize the current literature regarding the characteristics, diagnosis, complications, mechanisms of pathology, clinical features, influence of comorbidities, and treatment in patients with EoE.
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Affiliation(s)
- Martina Grando
- Department of Internal Medicine, Azienda Sanitaria Friuli Occidentale, San Vito al Tagliamento 33078, Italy
| | - Silvia De Pauli
- Department of Internal Medicine, Azienda Sanitaria Friuli Occidentale, Pordenone 33170, Italy
| | - Giovanni Miotti
- Department of Plastic Surgery, University Hospital of Udine, Udine 33100, Italy
| | - Massimiliano Balbi
- Department of Internal Medicine, Azienda Sanitaria Friuli Occidentale, San Vito al Tagliamento 33078, Italy
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
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11
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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: 22] [Impact Index Per Article: 11.0] [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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12
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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: 37] [Impact Index Per Article: 18.5] [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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13
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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: 41] [Impact Index Per Article: 13.7] [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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14
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Clinicopathologic Correlations in Eosinophilic Gastrointestinal Disorders. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2021; 9:3258-3266. [DOI: 10.1016/j.jaip.2021.06.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/04/2021] [Accepted: 06/07/2021] [Indexed: 12/17/2022]
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15
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Kaymak T, Hruz P, Niess JH. Immune system and microbiome in the esophagus: implications for understanding inflammatory diseases. FEBS J 2021; 289:4758-4772. [PMID: 34213831 PMCID: PMC9542113 DOI: 10.1111/febs.16103] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 05/20/2021] [Accepted: 07/01/2021] [Indexed: 12/15/2022]
Abstract
The gastrointestinal tract is the largest compartment of the body's immune system exposed to microorganisms, structural components and metabolites, antigens derived from the diet, and pathogens. Most studies have focused on immune responses in the stomach, the small intestine, and the colon, but the esophagus has remained an understudied anatomic immune segment. Here, we discuss the esophagus' anatomical and physiological distinctions that may account for inflammatory esophageal diseases.
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Affiliation(s)
- Tanay Kaymak
- Department of Biomedicine, University of Basel, Switzerland
| | - Petr Hruz
- Clarunis - University Center for Gastrointestinal and Liver Diseases Basel, Switzerland
| | - Jan Hendrik Niess
- Department of Biomedicine, University of Basel, Switzerland.,Clarunis - University Center for Gastrointestinal and Liver Diseases Basel, Switzerland
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16
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Philpott H, Lee SZ, Arrington A, McGee SJ, Dellon ES. Impact of food challenge on local oesophageal immunophenotype in eosinophilic oesophagitis. Clin Exp Allergy 2021; 50:463-470. [PMID: 32012383 DOI: 10.1111/cea.13578] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 11/24/2019] [Accepted: 12/02/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Eosinophilic oesophagitis (EoE) is caused by the ingestion of food antigens. Dietary avoidance can result in clinical and histological remission, while food reintroduction can cause recurrence. It is uncertain if food antigen processing and immune activation occurs locally, in the oesophagus. Therefore, we performed a comparative study of the density of cell surface proteins (known to be involved with antigen presentation) on oesophageal tissue prior to, and following food antigen induced disease recurrence. A secondary aim was to consider novel biomarkers. METHOD Adult patients with a diagnosis of EoE, who had achieved histological remission with an elimination diet (<15 eosinophils per high power field at oesophageal biopsy), and who underwent food challenge with proven recurrence were included. Immunohistochemistry/immunofluorescence for CD1a, CD3, CD28, CD40, CD69, CD80, CD138, CXCR3 and HLA-DR was performed. Staining intensity of each biomarker (pixels/mm2 ) was quantified by semi-automated analysis (Studio-FL software). RESULTS Fourteen cases of EoE (pre and post food challenge), 6 GORD and 5 healthy controls were included. HLA-DR, CD3, CD28, CD40 and CD 138 significantly increased with food reintroduction (P = <0.05). CD1a, CD 69, CD 80 and CXCR3 did not measurably change. CONCLUSION The presence of cell surface proteins typically associated with antigen presentation (following food antigen induced recurrence) suggests immune activation occurs in the oesophagus, and the relative lack of langerhans cells (CD1a) may indicate this cell type is unimportant. The cell surface protein CD 138 increases with disease recurrence, is not elevated in GORD or healthy controls, and has promise as a biomarker.
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Affiliation(s)
- Hamish Philpott
- Department of Gastroenterology NALHN, Adelaide, University of Adelaide, Adelaide, SA, Australia
| | - Shawn Zhenhui Lee
- Department of Gastroenterology NALHN, Adelaide, University of Adelaide, Adelaide, SA, Australia
| | - Ashley Arrington
- Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Sarah J McGee
- Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Evan S Dellon
- Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA
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17
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Lucendo AJ, López-Sánchez P. Targeted Therapies for Eosinophilic Gastrointestinal Disorders. BioDrugs 2021; 34:477-493. [PMID: 32472465 DOI: 10.1007/s40259-020-00427-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The growing recognition of eosinophilic gastrointestinal disorders has revealed the limitations of current treatment (mainly based on dietary modification and corticosteroids), and include refractoriness, high recurrence rates, and the need for long-term therapy. Research efforts, mainly in eosinophilic esophagitis (EoE), have unveiled essential pathophysiological mechanisms leading to these disorders, which bear some similarities to those of atopic manifestations and are shared by eosinophilic gastroenteritis (EGE) and eosinophilic colitis (EC). Novel targeted therapies, some imported from bronchial asthma and atopic dermatitis, are currently being assessed in EoE. The most promising are monoclonal antibodies, including those targeting interleukin (IL)-13 (cendakimab) and IL-4 (dupilumab), with phase 3 trials currently ongoing. The potential of anti-integrin therapy (vedolizumab) and Siglec-8 blockers (antolimab) in EGE are also promising. Non-biological therapies for eosinophilic gut disorders, which include preventing the activation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and chemoattractant receptor expressed on T helper 2 cells (CRTH2) signaling pathways, and other potential targets that deserve investigation in eosinophilic gut disorders, are reviewed.
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Affiliation(s)
- Alfredo J Lucendo
- Department of Gastroenterology, Hospital General de Tomelloso, Vereda de Socuéllamos, s/n.,, 13700, Tomelloso, Ciudad Real, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. .,Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
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18
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Ju JY, Stelow EB, Courville EL. Normal gastrointestinal tract inflammatory cells and review of select benign hematolymphoid proliferations. Semin Diagn Pathol 2021; 38:6-13. [PMID: 33726961 DOI: 10.1053/j.semdp.2021.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 02/10/2021] [Accepted: 02/22/2021] [Indexed: 11/11/2022]
Abstract
The luminal gastrointestinal tract can be a site of robust immune response in which reactive lymphoproliferative processes can sometimes be difficult to distinguish from lymphoma. In this article, we review gastrointestinal tract normal resident inflammatory cells and common nonneoplastic lymphoproliferative responses with emphasis on their differential and links to lymphoma. Topics that are covered include lymphocytic esophagitis, gastric chronic inflammation, mucosa-associated lymphoid tissue, and ulceration, small intestinal lymphoid hyperplasia, celiac disease, microscopic colitis, inflammatory bowel disease, primary immunodeficiency, graft-versus-host disease, and anti-programmed cell death protein-1 effect. We additionally present the less common differential of histiocytic processes within the gastrointestinal tract. The aim of this paper is to serve as a reference for practicing pathologists facing lymphoid, lymphoplasmacytic, or histiocytic processes in the luminal gastrointestinal tract. We hope to help the practicing pathologist distinguish benign from malignant entities and identify features requiring further workup.
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Affiliation(s)
- Jennifer Y Ju
- Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific St, Box 357470, Seattle, WA, United States
| | - Edward B Stelow
- Department of Pathology, University of Virginia, 1215 Lee Street, Box 800214, Charlottesville, VA, United States
| | - Elizabeth L Courville
- Department of Pathology, University of Virginia, 1215 Lee Street, Box 800214, Charlottesville, VA, United States.
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19
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Mennini M, Tambucci R, Riccardi C, Rea F, De Angelis P, Fiocchi A, Assa'ad A. Eosinophilic Esophagitis and Microbiota: State of the Art. Front Immunol 2021; 12:595762. [PMID: 33679739 PMCID: PMC7933523 DOI: 10.3389/fimmu.2021.595762] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 01/04/2021] [Indexed: 12/12/2022] Open
Abstract
Eosinophilic esophagitis (EoE) is a chronic, food-triggered, immune-mediated disease of the oesophagus, clinically characterized by symptoms referred to oesophagal dysfunction, and histologically defined by an eosinophil productive inflammation of the oesophagal mucosa, among other cell types. The involvement of an adaptive Th2-type response to food antigens in EoE was known since 2000; several cytokines and chemokines promote food-specific responses, during which local production of IgE, but also IgG4 derived from plasma cells in lamina propria of oesophagal mucosa might play an important role. Evidence pointing towards a possible role for the innate immunity in EoE has arisen recently. Together, this evidence gives rise to a potential role that the innate immune system in general, and also the microbial pattern recognition receptors (PRRs) might play in EoE pathogenesis. Among PRRs, Toll-like receptors (TLRs) are type-I transmembrane receptors expressed both on epithelial and lamina propria cells with the capacity to distinguish between pathogen and commensal microbes. As TLRs in the different intestinal epithelia represent the primary mechanism of epithelial recognition of bacteria, this evidence underlines that oesophagal TLR-dependent signaling pathways in EoE support the potential implication of microbiota and the innate immune system in the pathogenesis of this disease. The oesophagal mucosa hosts a resident microbiota, although in a smaller population as compared with other districts of the gastrointestinal tract. Few studies have focused on the composition of the microbiota of the normal oesophagus alone. Still, additional information has come from studies investigating the oesophagal microbiota in disease and including healthy patients as controls. Our review aims to describe all the evidence on the oesophagal and intestinal microbiota in patients with EoE to identify the specific features of dysbiosis in this condition.
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Affiliation(s)
- Maurizio Mennini
- Division of Allergy, Bambino Gesù Children's Hospital-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Renato Tambucci
- Digestive Endoscopy and Surgery Unit, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy
| | - Carla Riccardi
- Division of Allergy, Bambino Gesù Children's Hospital-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Francesca Rea
- Digestive Endoscopy and Surgery Unit, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy
| | - Paola De Angelis
- Digestive Endoscopy and Surgery Unit, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy
| | - Alessandro Fiocchi
- Division of Allergy, Bambino Gesù Children's Hospital-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Amal Assa'ad
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
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20
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Moiseff R, Olson N, Suriawinata AA, Rothstein RI, Lisovsky M. CD8 T-Cell-Predominant Lymphocytic Esophagitis is One of the Major Patterns of Lymphocytic Inflammation in Gastroesophageal Reflux Disease. Arch Pathol Lab Med 2020; 145:1138-1143. [PMID: 33373450 DOI: 10.5858/arpa.2020-0430-oa] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/30/2020] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Published reports have suggested an association of lymphocytic esophagitis (LyE) with gastroesophageal reflux disease (GERD) and primary motility disorders and have also shown that GERD and motility disorders frequently overlap. These findings make it difficult to determine the true relationship between LyE and GERD, which may be confounded by the presence of motility disorders with LyE. OBJECTIVE.— To characterize patterns of lymphocytic inflammation in patients with GERD that have no motility abnormalities. DESIGN.— We identified 161 patients seen at our institution from 1998 to 2014, who were diagnosed with GERD, had normal esophageal motility, and available esophageal biopsies. LyE was defined as peripapillary lymphocytosis with rare or absent granulocytes. CD4 and CD8 immunophenotype of lymphocytes was evaluated using immunohistochemistry. RESULTS.— We found increased intraepithelial lymphocytes in 13.7% of patients with GERD. Two major patterns and 1 minor pattern of lymphocytic inflammation were observed as follows: (1) LyE (in 6.8% [11 of 161] of patients and typically focal), (2) dispersed lymphocytes in an area of reflux esophagitis (in 5.6% [9 of 161] and typically diffuse), and (3) peripapillary lymphocytes in an area of reflux esophagitis (in 1.2% [2 of 161]). CD8 T cells significantly outnumbered CD4 T cells in 91% of patients with lymphocytic esophagitis and 100% of patients with dispersed lymphocytes (9 of 9) or peripapillary lymphocytes (2 of 2) in the area of reflux esophagitis. CONCLUSIONS.— These findings suggest that LyE is one of the major patterns of lymphocytic inflammation in GERD. CD8 T-cell-predominant immunophenotype may be useful as a marker of GERD in the differential diagnosis of LyE.
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Affiliation(s)
- Robin Moiseff
- From the Department of Pathology (Moiseff, Olson, Suriawinata, Lisovsky)
| | - Nicholas Olson
- From the Department of Pathology (Moiseff, Olson, Suriawinata, Lisovsky).,Olson is currently located at Physicians Laboratory in Sioux Falls, South Dakota
| | | | - Richard I Rothstein
- and Section of Gastroenterology and Hepatology (Rothstein), at Dartmouth-Hitchcock Medical Center and Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
| | - Mikhail Lisovsky
- From the Department of Pathology (Moiseff, Olson, Suriawinata, Lisovsky)
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21
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Ryu S, Lee KH, Tizaoui K, Terrazzino S, Cargnin S, Effenberger M, Shin JI, Kronbichler A. Pathogenesis of Eosinophilic Esophagitis: A Comprehensive Review of the Genetic and Molecular Aspects. Int J Mol Sci 2020; 21:ijms21197253. [PMID: 33008138 PMCID: PMC7582808 DOI: 10.3390/ijms21197253] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 09/24/2020] [Accepted: 09/28/2020] [Indexed: 01/21/2023] Open
Abstract
Eosinophilic esophagitis (EoE) is a relatively new condition described as an allergic-mediated disease of the esophagus. Clinically, it is characterized by dysphagia, food impaction, and reflux-like symptoms. Multiple genome-wide association studies (GWAS) have been conducted to identify genetic loci associated with EoE. The integration of numerous studies investigating the genetic polymorphisms in EoE and the Mendelian diseases associated with EoE are discussed to provide insights into the genetic risk of EoE, notably focusing on CCL26 and CAPN14. We focus on the genetic loci investigated thus far, and their classification according to whether the function near the loci is known. The pathophysiology of EoE is described by separately presenting the known function of each cell and molecule, with the major contributors being eosinophils, Th2 cells, thymic stromal lymphopoietin (TSLP), transforming growth factor (TGF)-β1, and interleukin (IL)-13. This review aims to provide detailed descriptions of the genetics and the comprehensive pathophysiology of EoE.
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Affiliation(s)
- Seohyun Ryu
- Yonsei University College of Medicine, Seoul 03722, Korea;
| | - Keum Hwa Lee
- Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Korea;
| | - Kalthoum Tizaoui
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, 1068 Tunis, Tunisia;
| | - Salvatore Terrazzino
- Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, 28100 Novara, Italy; (S.T.); (S.C.)
| | - Sarah Cargnin
- Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, 28100 Novara, Italy; (S.T.); (S.C.)
| | - Maria Effenberger
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, 6020 Innsbruck, Austria;
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Korea;
- Correspondence: ; Tel.: +82-2-2228-2050
| | - Andreas Kronbichler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, 6020 Innsbruck, Austria;
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22
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Mastracci L, Grillo F, Parente P, Unti E, Battista S, Spaggiari P, Campora M, Scaglione G, Fassan M, Fiocca R. Gastro-esophageal reflux disease and Barrett's esophagus: an overview with an histologic diagnostic approach. Pathologica 2020; 112:117-127. [PMID: 33179616 PMCID: PMC7931578 DOI: 10.32074/1591-951x-162] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 06/29/2020] [Indexed: 12/12/2022] Open
Abstract
The first part of this overview on non-neoplastic esophagus is focused on gastro-esophageal reflux disease (GERD) and Barrett's esophagus. In the last 20 years much has changed in histological approach to biopsies of patients with gastro-esophageal reflux disease. In particular, elementary histologic lesions have been well defined and modality of evaluation and grade are detailed, their sensitivity and specificity has been evaluated and their use has been validated by several authors. Also if there is not a clinical indication to perform biopsies in patient with GERD, the diagnosis of microscopic esophagitis, when biopsies are provided, can be performed by following simple rules for evaluation which allow pathologists to make the diagnosis with confidence. On the other hand, biopsies are required for the diagnosis of Barrett's esophagus. This diagnosis is the synthesis of endoscopic picture (which has to be provided with the proper description on extent and with adequate biopsies number) and histologic pattern. The current guidelines and expert opinions for the correct management of these diagnosis are detailed.
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Affiliation(s)
- Luca Mastracci
- Anatomic Pathology, San Martino IRCCS Hospital, Genova, Italy
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Italy
| | - Federica Grillo
- Anatomic Pathology, San Martino IRCCS Hospital, Genova, Italy
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Italy
| | - Paola Parente
- Unit of Pathology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, (FG), Italy
| | - Elettra Unti
- UOC Anatomia Patologica, ARNAS Ospedali Civico-Di Cristina-Benfratelli, Palermo, Italy
| | - Serena Battista
- SOC di Anatomia Patologica, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy
| | - Paola Spaggiari
- Department of Pathology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Milan, Italy
| | - Michela Campora
- Anatomic Pathology, San Martino IRCCS Hospital, Genova, Italy
| | | | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Italy
| | - Roberto Fiocca
- Anatomic Pathology, San Martino IRCCS Hospital, Genova, Italy
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Italy
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23
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Lu CY, Hsieh MS, Wei KC, Ezmerli M, Kuo CH, Chen W. Gastrointestinal involvement of primary skin diseases. J Eur Acad Dermatol Venereol 2020; 34:2766-2774. [PMID: 32455473 DOI: 10.1111/jdv.16676] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 05/11/2020] [Indexed: 12/14/2022]
Abstract
Less is known about gastrointestinal (GI) involvement of primary skin diseases due to the difference in embryology, histology, microbiology and physiology between integument and alimentary tract. Oesophagus, following the oropharyngeal mucosa, is the most common GI segment affected by primary skin diseases, especially by eosinophilic oesophagitis, lichen planus and autoimmune bullous dermatoses like pemphigus vulgaris, mucosal membrane pemphigoid and epidermolysis bullosa acquisita. Eosinophilic oesophagitis is an emerging chronic atopic disease with oesophageal dysfunction as the typical presentation, and oesophageal narrowing, rings and stricture as late complications. Oesophageal lichen planus mainly involves the proximal to mid-oesophagus in elderly aged women with long-term oral mucosal lesions. In acute attack of pemphigus vulgaris, oesophageal involvement is not uncommon but often neglected and may cause sloughing oesophagitis (oesophagitis dissecans superficialis) with acute GI bleeding in rare cases. GI manifestation of hereditary bradykininergic angio-oedema with colicky acute abdomen mostly affects small intestine, usually in the absence of pruritus or urticaria, and is more severe and long-lasting than the acquired histaminergic form. Strong evidence supports association between inflammatory bowel disease, especially Crohn disease, and hidradenitis suppurativa/acne inversa. Patients with vitiligo need surveillance of autoimmune liver disease, autoimmune atrophic gastritis or coeliac disease when corresponding symptoms become suspect. Melanoma is the most common primary tumour metastatic to the GI tract, with small intestine predominantly targeted. Gastrointestinal involvement is not uncommon in disseminated mycosis fungoides. Extramammary Paget's disease is an intraepidermal adenocarcinoma of controversial origin, and a high association between the anogenital occurrence and colorectal adenocarcinoma has been reported. As GI tract is the largest organ system with multidimensional functions, dermatologists in daily practice should be aware of the gastrointestinal morbidities related to primary skin diseases for an early diagnosis and treatment.
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Affiliation(s)
- C-Y Lu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - M-S Hsieh
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan
| | - K-C Wei
- Department of Dermatology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - M Ezmerli
- Department of Dermatology, Faculty of Medicine in Rabigh, Kingdom of Saudi Arabia, King Abdulaziz University, Jeddah, Saudi Arabia
| | - C-H Kuo
- Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan
| | - W Chen
- Center for Research & Development, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan.,Department of Dermatology and Allergy, Technical University of Munich, Munich, Germany
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24
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Lucendo AJ. Pharmacological treatments for eosinophilic esophagitis: current options and emerging therapies. Expert Rev Clin Immunol 2020; 16:63-77. [PMID: 31842634 DOI: 10.1080/1744666x.2019.1705784] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction: The epidemiology of eosinophilic esophagitis (EoE) has increased rapidly to represent a common cause of chronic and recurrent esophageal symptoms. Current treatment options have limitations so the development of novel therapies is a matter of growing interest.Areas covered: This article provides an up-to-date discussion of current therapies and investigational options for EoE. Established anti-inflammatory treatments for EoE at present include dietary therapy, proton pump inhibitors and swallowed topic steroids, which should be combined with endoscopic dilation in case of strictures. Refractoriness, high recurrence rates, and need for long-term therapies have promoted the investigation of novel, esophageal-targeted formulas of topic corticosteroids, and monoclonal antibodies (including mepolizumab, reslizumab, QAX576, RPC4046, dupilumab, omalizumab, infliximab, and vedolizumab) for EoE, with some having been demonstrated as effective and safe in the short term. Several additional promising therapies are also discussed.Expert opinion: Several therapeutic targets have shown efficacy and will be approved to treat EoE, especially corticosteroid-sparing options and those for patients with multiple Th2-associated diseases. Personalized therapeutic strategies for initial and maintenance treatments of EoE must be rationally designed, to reduce the burden of disease and answer meaningfully the needs of all stakeholders involved in EoE.
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Affiliation(s)
- Alfredo J Lucendo
- Department of Gastroenterology, Hospital General de Tomelloso, Tomelloso, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain.,Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
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25
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Arias Á, Lucendo AJ. Molecular basis and cellular mechanisms of eosinophilic esophagitis for the clinical practice. Expert Rev Gastroenterol Hepatol 2019; 13:99-117. [PMID: 30791784 DOI: 10.1080/17474124.2019.1546120] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Eosinophilic esophagitis (EoE) is a chronic, allergen-driven inflammatory esophageal disease characterized by predominantly eosinophilic inflammation leading to esophageal dysfunction. Recent efforts to understand EoE have increased our knowledge of the disease. Areas covered: Multiple cells, molecules, and genes interplay with early life environmental factors in the pathophysiology of EoE to converge in the esophageal epithelium at the center of disease pathogenesis. Epithelial cells constitute a mayor cytokine source for TSLP and Calpain-14; an impaired epithelial barrier function allowing penetration of food and microbiota-derived antigens is involved in triggering and maintaining inflammation. Eosinophil and mast cell-derived products, including TGFβ, together with IL-1β and TNFα, promote epithelial mesenchymal transition in EoE, contributing to tissue remodeling by synthetizing and depositing extracellular matrix in subepithelial layers. This article aims to provide a state-of-the-art update on the pathophysiology of EoE applied to clinical practice, and latest research and developments with potential interest to improve the diagnosis and treatment of patients with EoE are revised. Expert commentary: Preliminary approaches have provided promising results toward incorporating minimally invasive methods for patient diagnosis and monitoring in clinical practice. Early diagnosis and optimized therapies will allow for personalized medicine in EoE.
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Affiliation(s)
- Ángel Arias
- a Research Unit , Hospital General La Mancha Centro , Alcázar de San Juan , Spain.,b Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) , Madrid , Spain
| | - Alfredo J Lucendo
- b Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) , Madrid , Spain.,c Department of Gastroenterology , Hospital General de Tomelloso , Ciudad Real , Spain
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26
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Mucosal inflammation in Candida esophagitis has distinctive features that may be helpful diagnostically. Mod Pathol 2018; 31:1653-1660. [PMID: 29921901 DOI: 10.1038/s41379-018-0060-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Revised: 02/28/2018] [Accepted: 03/24/2018] [Indexed: 12/13/2022]
Abstract
The diagnosis of Candida esophagitis can be challenging when the epithelium containing Candida filamentous forms is not readily seen or is entirely sloughed away. Mucosal inflammation could be helpful diagnostically, if distinctive. However it is thought to be nonspecific in Candida esophagitis. The goal of this retrospective study was to identify features of mucosal inflammation helpful in alerting a pathologist to the possibility of Candida esophagitis when Candida mycelia are not readily observed. The study group consisted of 99 consecutive cases of Candida esophagitis and a control group of 64 consecutive cases of reflux esophagitis diagnosed at our institution from 2008-2016. Band-like superficial intraepithelial neutrophils and increased intraepithelial lymphocytes were observed in 75 and 67% of Candida esophagitis cases, respectively and only in 14 and 19% of reflux esophagitis cases, respectively (p < .0001). Intraepithelial lymphocytes were peripapillary or CD4-predominant in 75% of Candida esophagitis cases with increased lymphocytes, in contrast to 17% of reflux esophagitis cases (p = .0011). Concurrent presence of intraepithelial neutrophils and increased lymphocytes showed increased specificity for Candida esophagitis and was observed in 61% of patients with Candida esophagitis and only in 2% of patients with reflux esophagitis (p < .0001). In addition, superficial band-like neutrophils were observed concurrently with increased peripapillary lymphocytes or CD4-predominant lymphocytes in 35 and 50% of Candida esophagitis cases, respectively, in contrast to no reflux esophagitis cases. Basal cell hyperplasia and elongation of stromal papillae were frequent in both groups. The data suggest that when Candida microorganisms are not readily observed, concurrent presence of superficial band-like neutrophils and increased lymphocytes may be indicative of Candida etiology of active esophagitis.
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Abstract
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus associated with an atopic predisposition which appears to be increasing in prevalence over the last few decades. Symptoms stem from fibrosis, swelling, and smooth muscle dysfunction. In the past two decades, the etiology of EoE has been and is continuing to be revealed. This review provides an overview of the effects of genetics, environment, and immune function including discussions that touch on microbiome, the role of diet, food allergy, and aeroallergy. The review further concentrates on the pathophysiology of the disease with particular focus on the important concepts of the molecular etiology of EoE including barrier dysfunction and allergic hypersensitivity.
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Affiliation(s)
- Benjamin P Davis
- Department of Internal Medicine, Division of Immunology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA, 52246, USA.
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28
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Toll-like receptors-mediated pathways activate inflammatory responses in the esophageal mucosa of adult eosinophilic esophagitis. Clin Transl Gastroenterol 2018; 9:147. [PMID: 29691386 PMCID: PMC5915448 DOI: 10.1038/s41424-018-0017-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 02/16/2018] [Accepted: 02/22/2018] [Indexed: 12/19/2022] Open
Abstract
Objectives Esophageal microbiota and regulation of adaptive immunity are increasingly being investigated in eosinophilic esophagitis (EoE). Toll-like receptors (TLRs) play a central role in the initiation and maintenance of innate immune activity. Our objective was to characterize the esophageal and duodenal innate immune response in EoE and its modulation by dietary therapy. Methods Esophageal and duodenal biopsy samples were collected from 10 adults with untreated EoE, before and after effective treatment with a six-food elimination diet (SFED), and 10 controls with normal esophagus. In all cases, bacterial load (by mRNA expression of 16S), TLRs, mucins, transcription factors, interleukins, components of the NKG2D system, and innate immunity effectors were assessed by qPCR. Protein expression of TLRs were also determined by immunofluorescence. Results Bacterial load and TLR1, TLR2, TLR4, and TLR9 were overexpressed on biopsies with active EoE compared with controls. Muc1 and Muc5B genes were downregulated while Muc4 was overexpressed. Upregulation of MyD88 and NFκB was found together with IL-1β, IL-6, IL-8, and IL-10 mediators and PER-1, iNOS, and GRZA effectors. NG-K2D components (KLRK1, IL-15, MICB) were also upregulated. In all cases, changes in active EoE were normalized following SFED and mucosal healing. Duodenal samples also showed increased expressions of TLR-1, TLR-2, and TLR-4, but not 16S or any other mediators nor effectors of inflammation. Conclusions Esophageal TLR-dependent signaling pathways in EoE support the potential implication of microbiota and the innate immune system in the pathogenesis of this disease.
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Clayton F, Peterson K. Eosinophilic Esophagitis: Pathophysiology and Definition. Gastrointest Endosc Clin N Am 2018; 28:1-14. [PMID: 29129294 DOI: 10.1016/j.giec.2017.07.011] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Eosinophilic esophagitis is an adaptive immune response to patient-specific antigens, mostly foods. Eosinophilic esophagitis is not solely IgE-mediated and is likely characterized by Th2 lymphocytes with an impaired esophageal barrier function. The key cytokines and chemokines are thymic stromal lymphopoeitin, interleukin-13, CCL26/eotaxin-3, and transforming growth factor-β, all involved in eosinophil recruitment and remodeling. Chronic food dysphagia and food impactions, the feared late complications, are related in part to dense subepithelial fibrosis, likely induced by interleukin-13 and transforming growth factor-β.
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Affiliation(s)
- Frederic Clayton
- Department of Pathology, The University of Utah, Huntsman Cancer Hospital, 1950 Circle of Hope, Room N3100, Salt Lake City, UT 84112, USA
| | - Kathryn Peterson
- Division of Gastroenterology, The University of Utah, 30 North 1900 East SOM 4R118, Salt Lake City, UT 84132, USA.
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30
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Lucendo AJ, Arias Á, Molina-Infante J, Arias-González L. The role of endoscopy in eosinophilic esophagitis: from diagnosis to therapy. Expert Rev Gastroenterol Hepatol 2017; 11:1135-1149. [PMID: 28803528 DOI: 10.1080/17474124.2017.1367664] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Eosinophilic esophagitis (EoE) has arisen as a common disorder in current clinical and endoscopic gastroenterology practice. Areas covered: A comprehensive review of the literature to summarize and update different aspects related with the use of endoscopy in the diagnostic workout and treatment of pediatric and adult EoE patients is conducted. Expert commentary: Endoscopic features in EoE are frequently subtle, so were inadverted in some initial reports of the disease. Literature has described a wide number of EoE-associated features, systematized in the EREFS classification, which standardized the grade and severity of exudates, rings, edema, furrows, and strictures. The insufficient reliability of these features to predict eosinophilic inflammation still makes biopsies essential in diagnosing or monitoring EoE. EoE causes half of the food impactions requiring endoscopy; food impaction leads to EoE diagnosis in up to half of cases. Long term consequences of EoE include esophageal remodeling leading to strictures and narrowing, thus impairing symptoms and needs dilation. Recognizing the risks from dilation in EoE required carrying out a safe technique to avoid the high complication rate reported in the early literature. Endoscopic dilation should be considered in patients with esophageal narrowing and dysphagia/food impaction unresponsive to diet or drugs-based anti-inflammatory treatment.
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Affiliation(s)
- Alfredo J Lucendo
- a Department of Gastroenterology , Hospital General de Tomelloso , Tomelloso , Spain.,b Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) , Madrid , Spain
| | - Ángel Arias
- b Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) , Madrid , Spain.,c Research Support Unit , Hospital General Mancha Centro , Alcázar de San Juan , Spain
| | - Javier Molina-Infante
- b Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) , Madrid , Spain.,d Department of Gastroenterology , Hospital San Pedro de Alcántara , Cáceres , Spain
| | - Laura Arias-González
- a Department of Gastroenterology , Hospital General de Tomelloso , Tomelloso , Spain.,b Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) , Madrid , Spain
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31
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Werneck-Silva AL, Pagliari C, Patzina RA, Takakura CFH, Duarte MI. Esophageal mucosa in HIV infection: A"deeper" look at this little spoken organ. J Gastroenterol Hepatol 2017; 32:1832-1838. [PMID: 28387430 DOI: 10.1111/jgh.13800] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 03/23/2017] [Accepted: 03/31/2017] [Indexed: 01/10/2023]
Abstract
BACKGROUND AND AIM Although the esophagus is a common site of opportunistic infection in AIDS patients, little is known about the impact of HIV as well as opportunistic infection in the esophageal mucosa. Our aim is to analyze the esophageal immune profile in HIV+ patients with different immunological status with and without the opportunistic Candida infection. METHODS Immunohistochemistry to CD4+ and CD8+ T-cells, γ-interferon, transforming growth factor-β, interleukin (IL)-4, IL-6, IL-13, and IL-17 was performed in esophageal samples of 40 chronically HIV+ patients under highly active antiretroviral therapy (16 with Candida esophagitis, 12 virologically non-supressed with blood CD4 count < 500, and 12 virologically suppressed with blood CD4 count > 500; the latter two groups without esophageal candidiasis). The controls were 12 HIV-negative healthy individuals. RESULTS Esophageal CD4+ T-cell expression in HIV+ patients did not differ from the control group (P = 0.50). Mucosal CD8+ T-cell expression was significantly increased in HIV+ patients (P = 0.0018). Candida esophagitis and virologically non-supressed HIV+ patients with CD4 < 500 showed an increased expression of IL-17 and IL-6 with fewer expressions of γ-interferon, more attenuated in the latter group. Transforming growth factor-β was increased only in virologically suppressed HIV+ patients with CD4 > 500. IL-4 and IL-13 were similar to the control group. CONCLUSION In contrast to CD8+ T-cell expression, esophageal CD4+ T-cell expression does not reflect the HIV+ patient's immunological status. T-helper 17 (Th17) response seems to play a role in the esophageal mucosa of virologically non-supressed HIV+ patients with blood CD4 < 500. Candida esophagitis showed a Th1/Th17 response but seems to be dominantly regulated by the Th17 pathway.
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Affiliation(s)
- Ana Luiza Werneck-Silva
- Casa da AIDS-Infectious Disease Division, University of São Paulo, São Paulo, Brazil
- Department of Gastroenterology, Clinical Division, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Carla Pagliari
- Laboratório da Disciplina de Patologia de Moléstias Transmissíveis, University of São Paulo, São Paulo, Brazil
| | - Roseli A Patzina
- Disciplina de Patologia, University of São Paulo, São Paulo, Brazil
| | | | - Maria Irma Duarte
- Laboratório da Disciplina de Patologia de Moléstias Transmissíveis, University of São Paulo, São Paulo, Brazil
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32
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Caldwell JM, Paul M, Rothenberg ME. Novel immunologic mechanisms in eosinophilic esophagitis. Curr Opin Immunol 2017; 48:114-121. [PMID: 28965008 DOI: 10.1016/j.coi.2017.08.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 08/03/2017] [Accepted: 08/16/2017] [Indexed: 12/16/2022]
Affiliation(s)
- Julie M Caldwell
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Ave., Cincinnati, OH 45229, United States
| | - Misu Paul
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Ave., Cincinnati, OH 45229, United States
| | - Marc E Rothenberg
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Ave., Cincinnati, OH 45229, United States.
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33
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Caldwell JM, Collins MH, Kemme KA, Sherrill JD, Wen T, Rochman M, Stucke EM, Amin L, Tai H, Putnam PE, Jiménez-Dalmaroni MJ, Wormald MR, Porollo A, Abonia JP, Rothenberg ME. Cadherin 26 is an alpha integrin-binding epithelial receptor regulated during allergic inflammation. Mucosal Immunol 2017; 10:1190-1201. [PMID: 28051089 PMCID: PMC5496811 DOI: 10.1038/mi.2016.120] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 11/10/2016] [Indexed: 02/04/2023]
Abstract
Cadherins (CDH) mediate diverse processes critical in inflammation, including cell adhesion, migration, and differentiation. Herein, we report that the uncharacterized cadherin 26 (CDH26) is highly expressed by epithelial cells in human allergic gastrointestinal tissue. In vitro, CDH26 promotes calcium-dependent cellular adhesion of cells lacking endogenous CDHs by a mechanism involving homotypic binding and interaction with catenin family members (alpha, beta, and p120), as assessed by biochemical assays. Additionally, CDH26 enhances cellular adhesion to recombinant integrin α4β7 in vitro; conversely, recombinant CDH26 binds αE and α4 integrins in biochemical and cellular functional assays, respectively. Interestingly, CDH26-Fc inhibits activation of human CD4+ T cells in vitro including secretion of IL-2. Taken together, we have identified a novel functional CDH regulated during allergic responses with unique immunomodulatory properties, as it binds α4 and αE integrins and regulates leukocyte adhesion and activation, and may thus represent a novel checkpoint for immune regulation and therapy via CDH26-Fc.
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Affiliation(s)
- Julie M. Caldwell
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Ave., Cincinnati, OH 45229 USA
| | - Margaret H. Collins
- Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Ave., Cincinnati, OH 45229 USA
| | - Katherine A. Kemme
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Ave., Cincinnati, OH 45229 USA
| | - Joseph D. Sherrill
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Ave., Cincinnati, OH 45229 USA
| | - Ting Wen
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Ave., Cincinnati, OH 45229 USA
| | - Mark Rochman
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Ave., Cincinnati, OH 45229 USA
| | - Emily M. Stucke
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Ave., Cincinnati, OH 45229 USA
| | - Lissa Amin
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Ave., Cincinnati, OH 45229 USA
| | - Haitong Tai
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Ave., Cincinnati, OH 45229 USA
| | - Philip E. Putnam
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Ave., Cincinnati, OH 45229 USA
| | - Maximiliano J. Jiménez-Dalmaroni
- Department of Biological Chemistry, John Innes Centre, The Sainsbury Laboratory, Norwich Research Park, Norwich, NR4 7UH, United Kingdom
| | - Mark R. Wormald
- The Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom
| | - Aleksey Porollo
- Center for Autoimmune Genomics and Etiology, Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Ave., Cincinnati, OH 45229 USA
| | - J. Pablo Abonia
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Ave., Cincinnati, OH 45229 USA
| | - ME Rothenberg
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Ave., Cincinnati, OH 45229 USA,To whom correspondence should be addressed: Marc Rothenberg, M.D., Ph.D., Cincinnati Children’s Hospital Medical Center, Division of Allergy and Immunology, 3333 Burnet Ave. ML7028, Cincinnati, Ohio 45229 USA. Phone: 513.802.0257; Fax: 513.636.3310;
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Abstract
The goal of this Review is to discuss the clinical approach to patients who do not respond to treatment for eosinophilic oesophagitis (EoE). Refractory EoE is challenging to manage as there are limited data to guide decision-making. In this Review, refractory EoE is defined as persistent eosinophilia in the setting of incomplete resolution of the primary presenting symptoms and incomplete resolution of endoscopic findings following a PPI trial, and after treatment with either topical steroids or dietary elimination. However, this definition is controversial. This Review will examine these controversies, explore how frequently non-response is observed, and highlight potential explanations and predictors of non-response. Non-response is common and affects a large proportion of patients with EoE. It is important to systematically assess multiple possible causes of non-response, as well as consider treatment complications and an incorrect diagnosis of EoE. If non-response is confirmed, second-line treatments are required. Although the overall response rate for second-line therapy is disappointing, with only half of patients eventually responding, there are several promising agents that are currently under investigation, and the future is bright for new treatment modalities for refractory EoE.
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Affiliation(s)
- Evan S Dellon
- Center for Esophageal Diseases and Swallowing, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, CB# 7080, Bioinformatics Building, 130 Mason Farm Road, Chapel Hill, North Carolina 27599-7080, USA
- Center for Gastrointestinal Biology and Diseases, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, CB# 7080, Bioinformatics Building, 130 Mason Farm Road, Chapel Hill, North Carolina 27599-7080, USA
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Runge TM, Eluri S, Woosley JT, Shaheen NJ, Dellon ES. Control of inflammation decreases the need for subsequent esophageal dilation in patients with eosinophilic esophagitis. Dis Esophagus 2017; 30:1-7. [PMID: 29206905 PMCID: PMC5906132 DOI: 10.1093/dote/dox042] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 04/04/2017] [Indexed: 12/11/2022]
Abstract
It is unknown if successful control of esophageal inflammation in eosinophilic esophagitis (EoE) decreases the need for subsequent esophageal dilation. We aimed to determine whether histologic response to topical steroid treatment decreases the likelihood and frequency of subsequent esophageal dilation. We conducted a retrospective cohort study. Patients with an incident diagnosis of EoE were included if they had an initial esophageal dilation, received topical steroids, and had a subsequent endoscopy with biopsies. The number of dilations performed in each group was determined, and histologic responders (<15 eos/hpf) were compared to nonresponders. The 55 EoE patients included (27 responders and 28 nonresponders) underwent a mean of 3.0 dilations over a median follow-up of 19 months. Responders required fewer dilations than nonresponders (1.6 vs. 4.6, P = 0.03), after adjusting for potential confounders. Despite undergoing significantly fewer dilations, responders achieved a similar increase in esophageal diameter with dilation (4.9 vs. 5.0 mm; P = 0.92). In EoE patients undergoing esophageal dilation at baseline, control of inflammation with topical steroids was associated with a 65% decrease in the number of subsequent dilations to maintain the same esophageal caliber. This suggests that inflammation control is an important goal in patients with fibrostenotic changes of EoE.
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Affiliation(s)
- T M Runge
- Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.,Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - S Eluri
- Center for Esophageal Diseases and Swallowing,U niversity of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.,Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - J T Woosley
- Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - N J Shaheen
- Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.,Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - E S Dellon
- Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.,Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease ,University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
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LOMAZI EA, BRANDALISE NA, SERVIDONI MDFPC, CARDOSO SR, MEIRELLES LR. MAST CELLS DISTINGUISH EOSINOPHILIC ESOPHAGITIS IN PEDIATRIC PATIENTS. ARQUIVOS DE GASTROENTEROLOGIA 2017; 54:192-196. [DOI: 10.1590/s0004-2803.201700000-23] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Accepted: 03/01/2017] [Indexed: 01/07/2023]
Abstract
ABSTRACT BACKGROUND: Mast cells exert a substantial role in gastrointestinal allergic diseases. Therefore, it is reasonable to presume that mast cell may aid diagnosis in eosinophilic gastroenteropathy. OBJECTIVE: To evaluate whether mast cell count in the esophageal epithelium can discriminate eosinophilic esophagitis, proton-pump inhibitor (PPI)-responsive eosinophilic esophagitis and gastroesophageal reflux esophagitis. METHODS: Retrospectively we reviewed the files of 53 consecutive patients (age: 7.8 years; range: 8-14 years) with definitive diagnose established during clinical follow up in a universitary outpatient clinic as follow: eosinophilic esophagitis (N=23), PPI-responsive eosinophilic esophagitis (N=15) and gastroesophageal reflux esophagitis (N=15). Eosinophil count in the esophageal epithelium in slides stained with H-E was reviewed and immunohistochemistry for mast cell tryptase was performed. RESULTS: Count of eosinophils/high-power field (HPF) higher than 15 were found in 14 out of 15 reflux esophagitis patients. The mean count of eosinophils/HPF was similar in eosinophilic esophagitis patients and in those with PPI-responsive eosinophilic esophagitis (42 and 39 eosinophils/HPF, respectively, P=0.47). Values of mast cell tryptase (+) were higher in eosinophilic esophagitis [median: 25 mast cells/HPF; range (17-43) ] and in PPI-responsive eosinophilic esophagitis patients [25 (16-32) ], compared to reflux esophagitis [4 (2-14) ], P<0.001. There was no difference between the mean count of mast cells/HPF in the esophageal epithelium of eosinophilic esophagitis patients and PPI-responsive eosinophilic esophagitis patients, respectively, 26 and 24 mast cells/HPF, P=0.391. CONCLUSION: Tryptase staining of mast cells differentiates eosinophilic esophagitis from reflux esophagitis.
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Blanchard C, Simon D, Schoepfer A, Straumann A, Simon HU. Eosinophilic esophagitis: unclear roles of IgE and eosinophils. J Intern Med 2017; 281:448-457. [PMID: 28425585 DOI: 10.1111/joim.12568] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the oesophagus. Recognized as a distinct entity only two decades ago, the emergence of the disease along with the availability of new technologies has rapidly opened new research avenues and outlined the main features of the pathogenesis of EoE. Yet, each advance in our understanding of the disease has raised new questions about the previous consensus. Currently, new subsets of the disease challenge our diagnostic criteria. For instance, it was believed that EoE did not respond to proton pump inhibitor (PPI) therapy; however, it has now been shown that a substantial proportion of EoE patients indeed respond to PPIs. In addition, a new subset of patients not even presenting eosinophil infiltrates in the oesophagus has also been described. Moreover, approaches for better understanding the heritability of the disease bring into question the dogma of predominant genetic involvement. Furthermore, the specificity and sensitivity of allergy testing for targeted food avoidance is highly controversial, and the production of specific antibodies in EoE now includes IgG4 in addition to IgE. In conclusion, EoE is perceived as 'a moving target' and the aim of this review was to summarize the current understanding of EoE pathogenesis.
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Affiliation(s)
- C Blanchard
- Nestlé Research Center, Lausanne, Switzerland
| | - D Simon
- Department of Dermatology, Inselspital, Bern University Hospital, Bern, Switzerland
| | - A Schoepfer
- Division of Gastroenterology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
| | - A Straumann
- Swiss EoE Clinic and EoE Research Network, Olten, Switzerland
| | - H-U Simon
- Institute of Pharmacology, University of Bern, Bern, Switzerland
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Lingblom C, Wallander J, Ingelsten M, Bergquist H, Bove M, Saalman R, Welin A, Wennerås C. Eosinophils from eosinophilic oesophagitis patients have T cell suppressive capacity and express FOXP3. Clin Exp Immunol 2017; 187:455-465. [PMID: 27921303 PMCID: PMC5290232 DOI: 10.1111/cei.12898] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Revised: 10/21/2016] [Accepted: 11/02/2016] [Indexed: 01/07/2023] Open
Abstract
Eosinophilic esophagitis (EoE) is an antigen-driven T cell-mediated chronic inflammatory disease where food and environmental antigens are thought to have a role. Human eosinophils express the immunoregulatory protein galectin-10 and have T cell suppressive capacity similar to regulatory T cells (Tregs ). We hypothesized that one function of eosinophils in EoE might be to regulate the T cell-driven inflammation in the oesophagus. This was tested by evaluating the suppressive capacity of eosinophils isolated from the blood of adult EoE patients in a mixed lymphocyte reaction. In addition, eosinophilic expression of forkhead box protein 3 (FOXP3), the canonical transcription factor of Tregs , was determined by conventional and imaging flow cytometry, quantitative polymerase chain reaction (qPCR), confocal microscopy and immunoblotting. It was found that blood eosinophils from EoE patients had T cell suppressive capacity, and that a fraction of the eosinophils expressed FOXP3. A comparison of EoE eosinophils with healthy control eosinophils indicated that the patients' eosinophils had inferior suppressive capacity. Furthermore, a higher percentage of the EoE eosinophils expressed FOXP3 protein compared with the healthy eosinophils, and they also had higher FOXP3 protein and mRNA levels. FOXP3 was found in the cytosol and nucleus of the eosinophils from both the patients and healthy individuals, contrasting with the strict nuclear localization of FOXP3 in Tregs . To conclude, these findings suggest that the immunoregulatory function of eosinophils may be impaired in EoE.
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Affiliation(s)
- C. Lingblom
- Department of Infectious DiseasesHead and Neck Surgery, Sahlgrenska Academy, University of GothenburgGöteborgSweden
| | - J. Wallander
- Department of Infectious DiseasesHead and Neck Surgery, Sahlgrenska Academy, University of GothenburgGöteborgSweden
| | - M. Ingelsten
- Department of Infectious DiseasesHead and Neck Surgery, Sahlgrenska Academy, University of GothenburgGöteborgSweden
| | - H. Bergquist
- Department of ENTHead and Neck Surgery, Sahlgrenska Academy, University of GothenburgGöteborgSweden
| | - M. Bove
- Department of ENTHead and Neck Surgery, NÄL HospitalTrollhättanSweden
| | - R. Saalman
- Department of PediatricsInstitution of Clinical Sciences, Sahlgrenska Academy, University of GothenburgGöteborgSweden
| | - A. Welin
- Department of Rheumatology and Inflammation ResearchSahlgrenska Academy, University of GothenburgGöteborgSweden
| | - C. Wennerås
- Department of Infectious DiseasesHead and Neck Surgery, Sahlgrenska Academy, University of GothenburgGöteborgSweden
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Marietta EV, Geno DM, Smyrk TC, Becker A, Alexander JA, Camilleri M, Murray JA, Katzka DA. Presence of intraepithelial food antigen in patients with active eosinophilic oesophagitis. Aliment Pharmacol Ther 2017; 45:427-433. [PMID: 27878833 PMCID: PMC6944330 DOI: 10.1111/apt.13877] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Revised: 10/29/2016] [Accepted: 11/03/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Although eosinophilic oesophagitis (EoE) is putatively mediated by an abnormal response to food antigen, the oesophagus is considered relatively impermeable to large molecules. AIM To assess whether food antigens penetrate the oesophageal mucosa in patients with EoE. METHODS Anti-gliadin staining was performed in three groups: active EoE, inactive EoE and EoE patients on a low or gluten free diet. To appraise the specificity of our results, we also performed gliadin staining on six patients without oesophageal disease who were consuming gluten. The groups with EoE on gluten also underwent endoscopic infusion with gluten containing soy sauce and repeat biopsies during the endoscopy. We measured eosinophil density, dilated intercellular spaces (on a 0-4+ scale) and gliadin in oesophageal mucosa by immunofluorescence. RESULTS Patients with active EoE had significantly greater epithelial density of anti-gliadin staining when compared to inactive EoE (P < 0.0065) and gluten-free patients (P < 0.0008) at baseline and after soy infusion. Gliadin was not detected in non-EoE control patients. The distribution of gliadin was both cytoplasmic and nuclear. There was good correlation of dilated intercellular spaces grade and total gliadin staining intensity (r = 0.577, P = 0.0077). Acute oesophageal perfusion of a commercial gliadin-rich soy sauce did not lead to an increase in gliadin staining in active or inactive EoE. CONCLUSION These findings suggest, although do not prove, that antigen penetration in active eosinophilic oesophagitis might be facilitated by impairment of epithelial integrity.
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Affiliation(s)
- E V Marietta
- Departments of Medicine/Gastroenterology and Pathology, Mayo Clinic, Rochester, MN, USA
| | - D M Geno
- Departments of Medicine/Gastroenterology and Pathology, Mayo Clinic, Rochester, MN, USA
| | - T C Smyrk
- Departments of Medicine/Gastroenterology and Pathology, Mayo Clinic, Rochester, MN, USA
| | - A Becker
- Departments of Medicine/Gastroenterology and Pathology, Mayo Clinic, Rochester, MN, USA
| | - J A Alexander
- Departments of Medicine/Gastroenterology and Pathology, Mayo Clinic, Rochester, MN, USA
| | - M Camilleri
- Departments of Medicine/Gastroenterology and Pathology, Mayo Clinic, Rochester, MN, USA
| | - J A Murray
- Departments of Medicine/Gastroenterology and Pathology, Mayo Clinic, Rochester, MN, USA
| | - D A Katzka
- Departments of Medicine/Gastroenterology and Pathology, Mayo Clinic, Rochester, MN, USA
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The Inflammatory Milieu of Eosinophilic Esophagitis: A Contemporary Review With Emphasis in Putative Immunohistochemistry and Serologic Markers. Appl Immunohistochem Mol Morphol 2016; 26:435-444. [PMID: 27801733 DOI: 10.1097/pai.0000000000000450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Eosinophilic esophagitis is a chronic disease characterized by esophageal dysfunction, frequent clinical history of atopy, and eosinophilic inflammation of the esophagus. Within the esophageal mucosa, there is a wide variety of immune mediators, chemotactic factors, mediators of transcription, and markers of epithelial differentiation and integrity that are overexpressed or underexpressed in eosinophilic esophagitis, offering many candidates for biomarkers with diagnostic or prognostic potential. In this review, we summarize the results from studies performed so far to evaluate the detection of these markers by immunohistochemistry on esophageal biopsies. In addition, we briefly describe some attempts to identify markers that could be detected in serum to be used to diagnose or monitor the disease without the need of a biopsy.
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Arias Á, Lucendo AJ, Martínez-Fernández P, González-Castro AM, Fortea M, González-Cervera J, Yagüe-Compadre JL, Mota-Huertas T, Vicario M. Dietary treatment modulates mast cell phenotype, density, and activity in adult eosinophilic oesophagitis. Clin Exp Allergy 2016; 46:78-91. [PMID: 25640519 DOI: 10.1111/cea.12504] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Revised: 11/11/2014] [Accepted: 11/14/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND Mast cells (MCs) are abundant in the inflammatory infiltrate in eosinophilic oesophagitis (EoE), but decrease with disease remission. However, their phenotype, role in the pathophysiology of the disease, and modulation after effective dietary therapy are still unclear. OBJECTIVE To define the phenotype of oesophageal MCs, their modulation through dietary therapy, and their association with clinical manifestations of EoE. METHODS Oesophageal mucosal samples from 10 adult patients with EoE obtained before and after effective six-food elimination diet (SFED) therapy, as well as from 10 control subjects were analysed. Eosinophil and MC density were quantified. Gene expression of chemoattractants for eosinophils (CCL11, CCL24, and CCL26), MCs (SCF), and their receptors (CCR3 and SCFR, respectively) were assessed by means of qPCR. Gene and protein expression of specific MC proteases (CPA3, CMA, and TPSB2) were evaluated with qPCR and immunofluorescence. Clinical manifestations and atopic background were recorded. RESULTS MC density was significantly increased in EoE compared with controls, decreasing after dietary treatment (18.6 to 1.44 cells/hpf, respectively; P < 0.001). The MCTC subtype predominated in the oesophageal mucosa (90%) in both patients with EoE and controls. Gene expression of MC-related proteases, eotaxins, and SCF were up-regulated in patients with EoE, but significantly decreased after therapy, regardless of atopic background. Epithelial peaks of MCs and eosinophils were significantly associated (ρ = 0.80) in EoE and correlated with the symptom score (ρ = 0.78). Gene expression of MC proteases and eotaxins also correlated with the symptom score (P < 0.05). CONCLUSIONS AND CLINICAL RELEVANCE MC and its proteases seem to play a relevant role in the pathophysiology and symptoms of EoE, which can be reversed after effective dietary treatment.
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Affiliation(s)
- Á Arias
- Research Unit, Hospital General La Mancha Centro, Alcázar de San Juan, Spain
| | - A J Lucendo
- Department of Gastroenterology, Hospital General de Tomelloso, Tomelloso, Spain
| | - P Martínez-Fernández
- Idipaz Research Laboratory, Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Madrid, Spain.,Center for Biomedical Research on Rare Diseases (CIBERER), Instituto Carlos III, Madrid, Spain
| | - A M González-Castro
- Digestive Diseases Research Unit, Laboratory of Neuro-immuno-gastroenterology, Department of Gastroenterology, Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d´Hebron, Barcelona, Spain
| | - M Fortea
- Digestive Diseases Research Unit, Laboratory of Neuro-immuno-gastroenterology, Department of Gastroenterology, Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d´Hebron, Barcelona, Spain
| | | | - J L Yagüe-Compadre
- Department of Pathology, Hospital General La Mancha Centro, Alcázar de San Juan, Spain
| | - T Mota-Huertas
- Department of Pathology, Hospital General La Mancha Centro, Alcázar de San Juan, Spain
| | - M Vicario
- Digestive Diseases Research Unit, Laboratory of Neuro-immuno-gastroenterology, Department of Gastroenterology, Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d´Hebron, Barcelona, Spain.,Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Spain
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Lisovsky M, Westerhoff M, Zhang X. Lymphocytic esophagitis: a histologic pattern with emerging clinical ramifications. Ann N Y Acad Sci 2016; 1381:133-138. [PMID: 27635640 DOI: 10.1111/nyas.13260] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 08/22/2016] [Accepted: 08/23/2016] [Indexed: 02/05/2023]
Abstract
The clinical significance of lymphocytic esophagitis (LyE), which is characterized by the prominence of peripapillary intraepithelial lymphocytes (IELs) without significant granulocytosis, remains poorly understood. During the last few years, plausible clinical correlates and novel approaches for stratification of LyE have started to emerge. Association with Crohn's disease has been established in children, but is not observed in adults. In adults, the form of LyE showing CD4+ -predominant IELs has been recently found to be associated with non-achalasia primary motility abnormalities. GERD is another possible association. The most common clinical manifestations of adult LyE are dysphagia and normal endoscopic appearance of the esophagus. LyE should be reported by pathologists in order to distinguish it from its mimics, such as eosinophilic esophagitis, and to assist in directing the next steps in evaluation for known associated diseases, such as Crohn's disease or motility disorders.
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Affiliation(s)
- Mikhail Lisovsky
- Department of Pathology, Dartmouth-Hitchcock Medical Center and Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
| | - Maria Westerhoff
- Department of Anatomic Pathology, University of Washington School of Medicine, Seattle, Washington
| | - Xuchen Zhang
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
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Characterizing the inflammatory response in esophageal mucosal biopsies in children with eosinophilic esophagitis. Clin Transl Immunology 2016; 5:e88. [PMID: 27525061 PMCID: PMC4973319 DOI: 10.1038/cti.2016.30] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 03/18/2016] [Accepted: 03/18/2016] [Indexed: 12/28/2022] Open
Abstract
Eosinophilic esophagitis (EoE) is an emerging allergic, IgE- and non-IgE (Th2 cell)-mediated disease. There are major gaps in the understanding of the basic mechanisms that drive the persistence of EoE. We investigated whether esophageal biopsies from children with EoE demonstrate an inflammatory response that is distinct from normal controls. We prospectively enrolled 84 patients, of whom 77 were included in our analysis, aged 4-17 years (12.8±3.8 years; 81% males). Five esophageal biopsies were collected from each patient at the time of endoscopy. Intramucosal lymphocytes were isolated, phenotyped and stimulated with phorbol 12-myristate 13-acetate/ionomycin to measure their potential to produce cytokines via flow cytometry. We also performed cytokine arrays on 72-h biopsy culture supernatants. CD8(+) T cells, compared with CD4(+) T cells, synthesized more TNF-α and interferon (IFN)-γ after mitogen stimulation in the EoE-New/Active vs EoE-Remission group (P=0.0098; P=0.02) and controls (P=0.0008; P=0.03). Culture supernatants taken from explant esophageal tissue contained 13 analytes that distinguished EoE-New/Active from EoE-Remission and Controls. Principal component analysis and cluster analysis based on these analytes distinctly separated EoE-New/Active from EoE-Remission and Controls. In summary, we have identified a previously unappreciated role for CD8(+) T lymphocytes with potential to produce TNF-α and IFN-γ in EoE. Our results suggest that CD8(+) T cells have a role in the persistence or progression of EoE. We have also identified a panel of analytes produced by intact esophageal biopsies that differentiates EoE-New/Active from EoE-Remission and controls. Our results suggest that esophageal epithelial cells may have specific immune effector functions in EoE that control the type and amplitude of inflammation.
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Dellon ES, Yellore V, Andreatta M, Stover J. A single biopsy is valid for genetic diagnosis of eosinophilic esophagitis regardless of tissue preservation or location in the esophagus. JOURNAL OF GASTROINTESTINAL AND LIVER DISEASES : JGLD 2016; 24:151-7. [PMID: 26114173 DOI: 10.15403/jgld.2014.1121.242.bsy] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND & AIMS A new gene expression profile test may distinguish eosinophilic esophagitis (EoE) and gastroesophageal reflux disease (GERD), but the optimal tissue preparation and biopsy location are unknown. We aimed to determine if formalin-fixed paraffin-embedded (FFPE) and RNA-later (RNAL) preserved specimens from newly diagnosed EoE patients have equivalent gene expression scores and whether scores vary by esophageal biopsy location. METHODS We analyzed prospectively collected and banked esophageal biopsies from EoE patients and GERD controls. Paired FFPE and RNAL samples from the distal, mid, and proximal esophagus were used. RNA was extracted, and gene expression for a previously constructed 96 gene panel was quantified with a summary expression score. Scores were compared between EoE and GERD patients, between FFPE and RNAL samples, and between the different esophageal locations. RESULTS A total of 72 samples, representing paired FFPE and RNAL specimens from 9 EoE cases and 3 GERD controls, were analyzed. Overall median gene expression scores were similar between FFPE and RNAL (238 vs 227; p=0.64), correlation was excellent between FFPE and RNAL (Spearman's rho=0.90; p<0.001), and there were no differences by biopsy level. Median gene scores distinguished EoE from controls (134 vs 402; p=0.02), and overall agreement between preservation methods and EoE case status was perfect (kappa=1.0; p<0.001). CONCLUSIONS Gene expression scores were equivalent in FFPE and RNAL, and were also similar across three esophageal locations. This implies that a single biopsy in either FFPE or RNAL from anywhere in the esophagus may have the potential for genetic diagnosis of EoE.
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Affiliation(s)
- Evan S Dellon
- Center for Esophageal Diseases and Swallowing; Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
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Davis BP, Rothenberg ME. Mechanisms of Disease of Eosinophilic Esophagitis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2016; 11:365-93. [PMID: 26925500 DOI: 10.1146/annurev-pathol-012615-044241] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Eosinophilic esophagitis (EoE) is a recently recognized inflammatory disease of the esophagus with clinical symptoms derived from esophageal dysfunction. The etiology of EoE is now being elucidated, and food hypersensitivity is emerging as the central cornerstone of disease pathogenesis. Herein, we present a thorough picture of the current clinical, pathologic, and molecular understanding of the disease with a focus on disease mechanisms.
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Affiliation(s)
- Benjamin P Davis
- Division of Immunology, Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242;
| | - Marc E Rothenberg
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229;
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46
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Goyal A, Cheng E. Recent discoveries and emerging therapeutics in eosinophilic esophagitis. World J Gastrointest Pharmacol Ther 2016; 7:21-32. [PMID: 26855809 PMCID: PMC4734951 DOI: 10.4292/wjgpt.v7.i1.21] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2015] [Revised: 10/13/2015] [Accepted: 12/11/2015] [Indexed: 02/06/2023] Open
Abstract
Eosinophilic esophagitis (EoE) is an allergy-mediated disease culminating in severe eosinophilic inflammation and dysfunction of the esophagus. This chronic disorder of the esophagus causes significant morbidity, poor quality of life, and complications involving fibrosis and esophageal remodeling. Overlapping features between EoE and gastroesophageal reflux disease (GERD) pose great challenges to differentiating the two conditions, although the two disorders are not mutually exclusive. Recent findings suggest that the confounding condition proton pump inhibitor - responsive esophageal eosinophilia (PPI-REE) is likely a subset of EoE. Since PPIs have therapeutic properties that can benefit EoE, PPIs should be considered as a therapeutic option for EoE rather than a diagnostic screen to differentiate GERD, PPI-REE, and EoE. Other current treatments include dietary therapy, corticosteroids, and dilation. Immunomodulators and biologic agents might have therapeutic value, and larger trials are needed to assess efficacy and safety. Understanding the pathophysiology of EoE is critical to the development of novel therapeutics.
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Lymphocytic Esophagitis With CD4 T-cell-predominant Intraepithelial Lymphocytes and Primary Esophageal Motility Abnormalities: A Potential Novel Clinicopathologic Entity. Am J Surg Pathol 2016; 39:1558-67. [PMID: 26379147 DOI: 10.1097/pas.0000000000000493] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Lymphocytic esophagitis (LE) is an uncommon poorly defined histologic pattern. Its significance is largely unknown. The goal of our study was to characterize LE clinically, histologically, and immunophenotypically. Biopsies of 45 patients with LE and no intraepithelial granulocytes were selected throughout a 36-month period during routine diagnostic work. After reevaluation, complete absence of intraepithelial granulocytes was confirmed in 21 patients (LE-NG group), and few granulocytes were found in 24 patients (LE-FG). The control group consisted of 28 patients with active esophagitis consistent with reflux and overtly increased intraepithelial lymphocytes (REIL). The ratio of CD4:CD8 intraepithelial lymphocytes (IEL)>1 indicated predominance of CD4 IEL; the ratio ≤1 indicated predominance of CD8 IEL. Dysphagia was the primary complaint in 71%, 54%, and 39% of the patients with LE-NG, LE-FG, and REIL, respectively (P=0.04, LE-NG vs. REIL). Importantly, primary esophageal motility abnormalities were found in 10/11 (91%) tested LE-NG patients, 6/10 (60%) LE-FG patients, and 6/11 (54%) REIL patients. CD4 IELs were predominant in 81%, 50%, and 39% of LE-NG, LE-FG, and REIL cases, respectively (P=0.004, LE-NG vs. REIL), and in 90%, 83%, and 88% of the cases with primary motility abnormalities from the same groups. The prevalence of primary motility abnormalities was significantly higher in patients with CD4-predominant esophagitis than in patients with CD8-predominant esophagitis from all groups (21/24 [83%] vs. 2/8 [25%], P=0.005). A distinctive type of LE with predominance of CD4 IEL is associated with primary motility abnormalities suggesting a diagnostic utility of evaluating CD4 and CD8 subpopulations of T cells in LE.
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Leung J, Beukema KR, Shen AH. Allergic mechanisms of Eosinophilic oesophagitis. Best Pract Res Clin Gastroenterol 2015; 29:709-720. [PMID: 26552770 PMCID: PMC4919901 DOI: 10.1016/j.bpg.2015.09.012] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Revised: 06/25/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023]
Abstract
Eosinophilic oesophagitis (EoE) is characterized by oesophageal dysfunction and oesophageal eosinophilia refractory to proton-pump-inhibitor treatment. EoE is a food allergy, as elimination of food trigger(s) abrogates the disease, while trigger reintroduction causes recurrence. The allergic mechanism of EoE involves both IgE and non-IgE processes. There is a break in oral tolerance, the immune mechanism allowing enteric exposure to food and micro-organisms without causing deleterious immune responses. Changes in life-style, alterations in gut flora and use of antibiotics may be increasing disease prevalence. Mouse models of EoE and human studies revealed the role of regulatory T-cells and iNKT-cells in the pathogenesis. Th2-cytokines like IL-4, IL-5 and IL-13, and other cytokines like TGFβ and TSLP are involved, but perhaps no one cytokine is critically important for driving the disease. Control of EoE may require a pharmaceutical approach that blocks more than one target in the Th2-inflammatory pathway.
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A Clinical Prediction Tool Identifies Cases of Eosinophilic Esophagitis Without Endoscopic Biopsy: A Prospective Study. Am J Gastroenterol 2015; 110:1347-54. [PMID: 26303128 PMCID: PMC4586067 DOI: 10.1038/ajg.2015.239] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Accepted: 07/02/2015] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Eosinophilic esophagitis (EoE) is difficult to distinguish from gastroesophageal reflux (GERD) and other causes of dysphagia. We assessed the utility of a set of clinical and endoscopic features for predicting EoE without obtaining esophageal biopsies. METHODS We prospectively enrolled consecutive adults undergoing outpatient upper endoscopy at the University of North Carolina from July 2011 through December 2013. Incident cases of EoE were diagnosed per consensus guidelines. Non-EoE controls had either GERD- or dysphagia-predominant symptoms. A predictive model containing clinical and endoscopic, but no histological, data was assessed. Receiver operator characteristic curves were constructed and the area under the curve (AUC) was calculated. RESULTS A total of 81 EoE cases (mean age 38 years; 60% male; 93% white; 141 eosinophils per high-power field (eos/hpf)) and 144 controls (mean age 52, 38% male; 82% white; 3 eos/hpf) were enrolled. A combination of clinical (age, sex, dysphagia, food allergy) and endoscopic (rings, furrows, plaques, hiatal hernia) features was highly predictive of EoE. The AUC was 0.944, with sensitivity, specificity, and accuracy of 84, 97, and 92%. Similar values were seen after limiting controls to those with only reflux or dysphagia or to those with esophageal eosinophilia not due to EoE. CONCLUSIONS We validated a set of clinical and endoscopic features to predict EoE with a high degree of accuracy and allow identification of those at very low risk of disease. Use of these predictors at the point-of-care will avoid the effort and expense of low-yield histological examinations for EoE.
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Abstract
The mechanisms underlying eosinophilic esophagitis (EoE) have been intensely investigated, and significant advances have been made in understanding the pathogenesis of EoE. EoE is defined as a chronic immune/antigen-mediated disease, characterized clinically by symptoms of esophageal dysfunction and histologically by an esophageal eosinophilic infiltrate. In this paper, we will review the current knowledge of EoE pathophysiology based on both animal and human data and discuss possible etiologic mechanisms from the genetic and environmental perspectives. EoE is a Th2-predominant inflammatory process triggered by allergens. Proinflammatory cytokines and chemokines recruit eosinophils and other effector cells, such as mast cells, into the esophageal epithelium, where they cause direct damage and promote esophageal remodeling. The genetic expression profile of EoE has been described, and several single nucleotide polymorphisms have been identified and associated with EoE. While this genetic contribution is important, it is difficult to postulate that EoE is primarily a genetic disease. Given the rapid epidemiologic changes in the incidence and prevalence of EoE over the past two decades, environmental factors may be the driving force. While it is not known what causes EoE in an individual patient at a specific time, the current hypothesis is that there is a complex interaction between genetic factors and environmental exposures that remains to be elucidated.
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Affiliation(s)
- Thomas M. Runge
- Center for Esophageal Diseases and Swallowing, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC
| | - Evan S. Dellon
- Center for Esophageal Diseases and Swallowing, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC
- Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC
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