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1
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Kamide Y, Sonehara K, Sekiya K, Ueki S, Nakamura Y, Okada Y, Taniguchi M. Bioactive Mediator Profile of Mepolizumab-Treated Eosinophilic Granulomatosis With Polyangiitis. Allergy 2025; 80:882-885. [PMID: 39526755 DOI: 10.1111/all.16395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 10/22/2024] [Accepted: 11/03/2024] [Indexed: 11/16/2024]
Affiliation(s)
- Yosuke Kamide
- Clinical Research Center for Allergy and Rheumatology, NHO Sagamihara National Hospital, Sagamihara, Japan
| | - Kyuto Sonehara
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kiyoshi Sekiya
- Clinical Research Center for Allergy and Rheumatology, NHO Sagamihara National Hospital, Sagamihara, Japan
| | - Shigeharu Ueki
- Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, Akita, Japan
| | - Yuto Nakamura
- Clinical Research Center for Allergy and Rheumatology, NHO Sagamihara National Hospital, Sagamihara, Japan
| | - Yukinori Okada
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan
| | - Masami Taniguchi
- Clinical Research Center for Allergy and Rheumatology, NHO Sagamihara National Hospital, Sagamihara, Japan
- Research Center for Immunology and Allergology, Shonan-Kamakura General Hospital, Kamakura, Japan
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2
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Laidlaw TM. Uncovering new players in IL-5 signaling: Mast cells, mast cell progenitors, and beyond. J Allergy Clin Immunol 2025:S0091-6749(25)00129-0. [PMID: 39924124 DOI: 10.1016/j.jaci.2025.01.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 01/28/2025] [Accepted: 01/30/2025] [Indexed: 02/11/2025]
Affiliation(s)
- Tanya M Laidlaw
- Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women's Hospital, Boston, Mass.
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3
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Chakravarty K, Gaur S, Kumar R, Jha NK, Gupta PK. Exploring the Multifaceted Therapeutic Potential of Probiotics: A Review of Current Insights and Applications. Probiotics Antimicrob Proteins 2025; 17:341-363. [PMID: 39069588 DOI: 10.1007/s12602-024-10328-x] [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] [Accepted: 07/13/2024] [Indexed: 07/30/2024]
Abstract
The interplay between human health and the microbiome has gained extensive attention, with probiotics emerging as pivotal therapeutic agents due to their vast potential in treating various health issues. As significant modulators of the gut microbiota, probiotics are crucial in maintaining intestinal homeostasis and enhancing the synthesis of short-chain fatty acids. Despite extensive research over the past decades, there remains an urgent need for a comprehensive and detailed review that encapsulates probiotics' latest insights and applications. This review focusses on the multifaceted roles of probiotics in promoting health and preventing disease, highlighting the complex mechanisms through which these beneficial bacteria influence both gut flora and the human body at large. This paper also explores probiotics' neurological and gastrointestinal applications, focussing on their significant impact on the gut-brain axis and their therapeutic potential in a broad spectrum of pathological conditions. Current innovations in probiotic formulations, mainly focusing on integrating genomics and biotechnological advancements, have also been comprehensively discussed herein. This paper also critically examines the regulatory landscape that governs probiotic use, ensuring safety and efficacy in clinical and dietary settings. By presenting a comprehensive overview of recent studies and emerging trends, this review aims to illuminate probiotics' extensive therapeutic capabilities, leading to future research and clinical applications. However, besides extensive research, further advanced explorations into probiotic interactions and mechanisms will be essential for developing more targeted and effective therapeutic strategies, potentially revolutionizing health care practices for consumers.
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Affiliation(s)
- Kashyapi Chakravarty
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, 201309, India
| | - Smriti Gaur
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, 201309, India.
| | - Rohit Kumar
- Centre for Development of Biomaterials and Department of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
| | - Niraj Kumar Jha
- Department of Biotechnology, Sharda School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, 602105, India
- School of Bioengineering & Biosciences, Lovely Professional University, Phagwara, Punjab, 144411, India
- Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, 140401, India
| | - Piyush Kumar Gupta
- Centre for Development of Biomaterials and Department of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, 201310, India.
- Department of Biotechnology, Graphic Era (Deemed to be University), Dehradun, Uttarakhand, 248002, India.
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4
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Lefèvre G, Gibier JB, Bongiovanni A, Lhermitte L, Rossignol J, Anglo E, Dendooven A, Dubois R, Terriou L, Launay D, Barete S, Esnault S, Frenzel L, Gourguechon C, Ballul T, Dezoteux F, Staumont-Salle D, Copin MC, Rignault-Bricard R, Maciel TT, Damaj G, Tardivel M, Crinquette-Verhasselt M, Dubreuil P, Maouche-Chrétien L, Bruneau J, Lortholary O, Duployez N, Behal H, Molina TJ, Hermine O. Interactions between eosinophils and IL-5Rα-positive mast cells in nonadvanced systemic mastocytosis. J Allergy Clin Immunol 2024; 154:1523-1533. [PMID: 39151478 DOI: 10.1016/j.jaci.2024.07.025] [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] [Received: 12/18/2023] [Revised: 06/27/2024] [Accepted: 07/10/2024] [Indexed: 08/19/2024]
Abstract
BACKGROUND Bidirectional interactions between eosinophils and mast cells (MCs) have been reported in various allergic diseases. Bone marrow (BM) eosinophilia, and to a lesser extent blood eosinophilia, is common in systemic mastocytosis (SM), but its significance remains unknown. OBJECTIVE We described blood and BM eosinophil characteristics in SM. METHODS A large collection of BM biopsy samples was analyzed using immunohistochemical staining and whole-slide imaging. Eosinophil and extracellular granules were detected by eosinophil peroxidase (EPX) staining and MCs by KIT staining. Complementary analyses were conducted using flow cytometry and immunofluorescence. RESULTS Eosinophil infiltrates and large areas of eosinophil degranulation were observed within or around BM MC infiltrates in SM. EPX staining surface, highlighting intact eosinophils and eosinophil degranulation, was higher in nonadvanced SM (n = 37 BM biopsy samples) compared with both controls (n = 8, P = .0003) and advanced SM (n = 24, P = .014). In nonadvanced SM, positive correlations were observed between serum tryptase levels and percentages of eosinophil counts in BM aspirations (Spearman r coefficient r = 0.38, P = .038), eosinophils count in BM biopsy samples (r = 0.45, P = .007), EPX staining (r = 0.37, P = .035), and eosinophil degranulation (r = 0.39, P = .023). Eosinophil counts in BM biopsy samples also correlated with MC counts (r = 0.47, P = .006) and KIT staining surface (r = 0.49, P = .003). BM MCs expressed IL-5 receptor and other usual eosinophil cytokine/chemokine receptors, and blood eosinophils displayed several increased surface markers compared with controls, suggesting an activated state. CONCLUSION Our data suggest possible cross talk between MCs and eosinophils, supporting MC tryptase release and MC activation-related symptoms. This suggests a rationale for targeting eosinophils in nonadvanced SM not fully controlled by other therapies.
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Affiliation(s)
- Guillaume Lefèvre
- University of Lille, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire (CHU) Lille, and Institute for Translational Research in Inflammation (INFINITE), Lille, France; Institut d'Immunologie, CHU Lille, Lille, France; National Reference Center for Hypereosinophilic Syndromes (CEREO).
| | - Jean-Baptiste Gibier
- University of Lille, Institut de Pathologie, Centre de Biopathologie, CHU Lille, Lille, France
| | - Antonino Bongiovanni
- Centre National de la Recherche Scientifique (CNRS), INSERM, CHU Lille, University of Lille, Institut Pasteur de Lille, Lille, France
| | - Ludovic Lhermitte
- Laboratoire d'Onco-Hématologie, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; University of Paris, Institut Imagine, INSERM, Paris, France; French Reference Center for Mastocytosis (CEREMAST), Hôpital Necker-Enfants Malades, AP-HP, Paris, France
| | - Julien Rossignol
- University of Paris, Institut Imagine, INSERM, Paris, France; French Reference Center for Mastocytosis (CEREMAST), Hôpital Necker-Enfants Malades, AP-HP, Paris, France; Department of Hematology, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
| | - Emilie Anglo
- University of Lille, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire (CHU) Lille, and Institute for Translational Research in Inflammation (INFINITE), Lille, France; Institut d'Immunologie, CHU Lille, Lille, France
| | - Arnaud Dendooven
- University of Lille, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire (CHU) Lille, and Institute for Translational Research in Inflammation (INFINITE), Lille, France; Institut d'Immunologie, CHU Lille, Lille, France
| | - Romain Dubois
- University of Lille, Institut de Pathologie, Centre de Biopathologie, CHU Lille, Lille, France
| | - Louis Terriou
- University of Lille, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire (CHU) Lille, and Institute for Translational Research in Inflammation (INFINITE), Lille, France; National Reference Center for Hypereosinophilic Syndromes (CEREO); Département de Médecine Interne et Immunologie Clinique, CHU Lille, Lille, France
| | - David Launay
- University of Lille, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire (CHU) Lille, and Institute for Translational Research in Inflammation (INFINITE), Lille, France; National Reference Center for Hypereosinophilic Syndromes (CEREO); Département de Médecine Interne et Immunologie Clinique, CHU Lille, Lille, France
| | - Stéphane Barete
- CEREMAST, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Unit de Dermatologie, Sorbonne Université Paris, Paris, France
| | - Stéphane Esnault
- University of Lille, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire (CHU) Lille, and Institute for Translational Research in Inflammation (INFINITE), Lille, France; Institut d'Immunologie, CHU Lille, Lille, France; Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wis
| | - Laurent Frenzel
- University of Paris, Institut Imagine, INSERM, Paris, France; French Reference Center for Mastocytosis (CEREMAST), Hôpital Necker-Enfants Malades, AP-HP, Paris, France; Department of Hematology, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
| | | | - Thomas Ballul
- University of Paris, Institut Imagine, INSERM, Paris, France; French Reference Center for Mastocytosis (CEREMAST), Hôpital Necker-Enfants Malades, AP-HP, Paris, France; Department of Hematology, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
| | - Frédéric Dezoteux
- University of Lille, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire (CHU) Lille, and Institute for Translational Research in Inflammation (INFINITE), Lille, France; National Reference Center for Hypereosinophilic Syndromes (CEREO); Department of Dermatology, CHU Lille, Lille, France
| | - Delphine Staumont-Salle
- University of Lille, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire (CHU) Lille, and Institute for Translational Research in Inflammation (INFINITE), Lille, France; National Reference Center for Hypereosinophilic Syndromes (CEREO); Department of Dermatology, CHU Lille, Lille, France
| | - Marie-Christine Copin
- Department of Pathology, CHU Angers, University of Angers, INSERM, CNRS, CRCI(2)NA, Angers, France
| | | | | | - Gandhi Damaj
- Institut d'Hématologie, University of Caen Normandie, Caen, France
| | - Meryem Tardivel
- Centre National de la Recherche Scientifique (CNRS), INSERM, CHU Lille, University of Lille, Institut Pasteur de Lille, Lille, France
| | | | - Patrice Dubreuil
- Signaling, Hematopoiesis, and Mechanism of Oncogenesis (CRCM), CEREMAST, and Association Française pour les Initiatives de Recherche sur le Mastocyte et les Mastocytose (AFIRMM) studies, INSERM U1068; Institut Paoli-Calmettes; UM105, Aix-Marseille University; and CNRS, UMR7258, Marseille, France
| | | | - Julie Bruneau
- University of Paris, Institut Imagine, INSERM, Paris, France; French Reference Center for Mastocytosis (CEREMAST), Hôpital Necker-Enfants Malades, AP-HP, Paris, France; Department of Pathology, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
| | - Olivier Lortholary
- University of Paris, Institut Imagine, INSERM, Paris, France; French Reference Center for Mastocytosis (CEREMAST), Hôpital Necker-Enfants Malades, AP-HP, Paris, France
| | - Nicolas Duployez
- CNRS, INSERM, CHU Lille, Cancer Heterogeneity, Plasticity, and Resistance to Therapies (CANTHER), University of Lille, Institut d'Hématologie, CHU Lille, Lille, France
| | - Hélène Behal
- University of Lille, CHU Lille, Evaluation des Technologies de Santé et des Pratiques Médicales (METRICS), Lille, France
| | - Thierry Jo Molina
- University of Paris, Institut Imagine, INSERM, Paris, France; Signaling, Hematopoiesis, and Mechanism of Oncogenesis (CRCM), CEREMAST, and Association Française pour les Initiatives de Recherche sur le Mastocyte et les Mastocytose (AFIRMM) studies, INSERM U1068; Institut Paoli-Calmettes; UM105, Aix-Marseille University; and CNRS, UMR7258, Marseille, France
| | - Olivier Hermine
- University of Paris, Institut Imagine, INSERM, Paris, France; French Reference Center for Mastocytosis (CEREMAST), Hôpital Necker-Enfants Malades, AP-HP, Paris, France; Department of Hematology, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
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5
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Alvarado-Vazquez PA, Mendez-Enriquez E, Salomonsson M, Kopac P, Koren A, Bidovec-Stojkovic U, Škrgat S, Simonson OE, Yasinska V, Dahlén SE, Pejler G, Janson C, Korosec P, Malinovschi A, Hallgren J. Targeting of the IL-5 pathway in severe asthma reduces mast cell progenitors. J Allergy Clin Immunol 2024:S0091-6749(24)01169-2. [PMID: 39521285 DOI: 10.1016/j.jaci.2024.10.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 10/18/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Therapies targeting IL-5 or its receptor (IL-5Rα) are currently used to treat patients with severe eosinophilic asthma. OBJECTIVE We sought to investigate the impact of anti-IL-5 and anti-IL-5Rα biological therapies on mast cells (MCs) and their progenitors. METHODS Surface IL-5Rα expression was investigated on MCs and their progenitors in mouse lungs and bone marrow and in human lungs and blood. Isolated human MC progenitors cultured in the presence or absence of IL-5 were analyzed in vitro. Circulating MC progenitors were quantified in patients with severe asthma before and after anti-IL-5 (mepolizumab) or anti-IL-5Rα (benralizumab) therapy. Gene expression analysis of MC progenitors was performed before and after anti-IL-5Rα therapy. RESULTS Approximately 50% of the human primary lung MCs and 30% of the human MC progenitors from individuals with allergic asthma expressed IL-5Rα. In patients with mild to moderate allergic asthma and mice with acute allergic airway inflammation, the fraction of IL-5Rα+ MC progenitors was elevated. In addition, IL-5 promoted the proliferation and/or survival of isolated human MC progenitors. Furthermore, patients with severe asthma from 2 independent cohorts demonstrated a reduction in blood MC progenitors after anti-IL-5 or anti-IL-5Rα treatment. This was associated with improved asthma control as well as a decline in both blood eosinophils and TH2 cells. Finally, the blood MC progenitors remaining after anti-IL-5Rα (benralizumab) treatment exhibited a downregulated expression of genes involved in growth and proliferation. CONCLUSIONS This study introduces the possibility that the clinical effects of targeting IL-5/IL-5Rα in severe asthma may also involve reduction of MC populations.
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Affiliation(s)
| | - Erika Mendez-Enriquez
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Maya Salomonsson
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Peter Kopac
- University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia; Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Ana Koren
- University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia
| | | | - Sabina Škrgat
- University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia; Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Oscar E Simonson
- Department of Surgical Sciences, Uppsala University, Uppsala University Hospital, Uppsala, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Uppsala University Hospital, Uppsala, Sweden
| | - Valentyna Yasinska
- Clinical Lung and Allergy Research Unit, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden; Department of Respiratory Medicine and Allergology, Karolinska University Hospital, Solna, Sweden
| | - Sven-Erik Dahlén
- Clinical Lung and Allergy Research Unit, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden; Department of Respiratory Medicine and Allergology, Karolinska University Hospital, Solna, Sweden; Integrative Metabolomics Unit, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Gunnar Pejler
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Christer Janson
- Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden
| | - Peter Korosec
- University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia; Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Andrei Malinovschi
- Department of Medical Sciences, Clinical Physiology, Uppsala University, Uppsala, Sweden
| | - Jenny Hallgren
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
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6
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Januskevicius A, Vasyle E, Rimkunas A, Malakauskas K. Integrative Cross-Talk in Asthma: Unraveling the Complex Interactions Between Eosinophils, Immune, and Structural Cells in the Airway Microenvironment. Diagnostics (Basel) 2024; 14:2448. [PMID: 39518415 PMCID: PMC11545034 DOI: 10.3390/diagnostics14212448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024] Open
Abstract
Asthma is a chronic inflammatory process that leads to airway narrowing, causing breath loss followed by spasms, wheezing, and shortness of breath. Within the asthmatic lungs, interaction among various immune cells and structural cells plays a significant role in orchestrating an inflammatory response in which eosinophils hold central importance. In these settings, allergens or other environmental exposures commonly drive the immune response to recruit eosinophils to the airways. The appearance of eosinophils in the airways indicates a dynamic interplay of various cell types within lung tissue and does not represent a passive effect of inflammation. The cellular cross-talk causes the persistence of eosinophilic inflammation, and if left untreated, it results in long-term damage to the airway structure and function. Further exacerbation of the condition occurs because of this. We discuss how this complex interplay of eosinophils, immune, and structural cells within the airway microenvironment leads to the distinct pathophysiological features in asthma, the variability in disease severity, and the response to biological treatments.
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Affiliation(s)
- Andrius Januskevicius
- Laboratory of Pulmonology, Department of Pulmonology, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania; (E.V.); (A.R.); (K.M.)
| | - Egle Vasyle
- Laboratory of Pulmonology, Department of Pulmonology, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania; (E.V.); (A.R.); (K.M.)
| | - Airidas Rimkunas
- Laboratory of Pulmonology, Department of Pulmonology, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania; (E.V.); (A.R.); (K.M.)
| | - Kestutis Malakauskas
- Laboratory of Pulmonology, Department of Pulmonology, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania; (E.V.); (A.R.); (K.M.)
- Department of Pulmonology, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania
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7
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Buchheit KM, Shaw D, Chupp G, Lehtimaki L, Heffler E, Finney-Hayward T, Zangrilli J, Kwiatek J, Siddiqui S, Roufosse F, Thamboo A, West N, Vichiendilokkul A, Hellings PW, Peters A, Howarth PH. Interleukin-5 as a pleiotropic cytokine orchestrating airway type 2 inflammation: Effects on and beyond eosinophils. Allergy 2024; 79:2662-2679. [PMID: 39359069 DOI: 10.1111/all.16303] [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: 05/07/2024] [Revised: 08/05/2024] [Accepted: 08/20/2024] [Indexed: 10/04/2024]
Abstract
Interleukin (IL)-5 is the key cytokine in the maturation, activation, proliferation, migration and survival of eosinophils, which are key effector cells in many upper and lower airway diseases. Through its effects on eosinophils, IL-5 indirectly contributes to various pathophysiological processes including tissue damage, repair and remodelling. Understanding the importance of IL-5 in eosinophil-associated diseases led to the development of anti-IL-5 therapies, which provide clinical benefits across a range of conditions. However, recent evidence suggests that eosinophil-depletion alone may not account for all of the therapeutic effects of anti-IL-5 therapy and that IL-5 may also contribute to disease independently of its effects on eosinophils. Indeed, evidence from ex vivo studies and targeted therapy in vivo demonstrates that IL-5 and its inhibition affects a much broader range of cells beyond eosinophils, including epithelial cells, plasma cells, mast cells, basophils, neutrophils, type 2 innate lymphoid cells, T regulatory cells and fibroblasts. This review will provide an update on the evidence supporting the breadth of IL-5 biology relevant to disease pathogenesis beyond eosinophil-associated inflammation, where there is a need for additional insight, and the clinical implications of a more central role of IL-5 in type 2 inflammation.
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Affiliation(s)
- Kathleen M Buchheit
- Division of Allergy and Clinical Immunology, AERD Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Dominick Shaw
- Department of Respiratory Medicine and Thoracic Surgery, Institute for Lung Health, Glenfield Hospital, Leicester, UK
| | - Geoffrey Chupp
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Lauri Lehtimaki
- Faculty of Medicine and Health Technology, Allergy Centre, Tampere University Hospital, Tampere University, Tampere, Finland
| | - Enrico Heffler
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Personalized Medicine, Asthma and Allergy Clinic, IRCCS Humanitas Research Hospital, Milan, Italy
| | | | | | - Justin Kwiatek
- US Medical Affairs, GSK, Collegeville, Pennsylvania, USA
| | - Salman Siddiqui
- National Heart and Lung Institute, NIHR Imperial Biomedical Research Centre, Imperial College London, London, UK
| | - Florence Roufosse
- Department of Internal Medicine, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Andrew Thamboo
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Nicholas West
- School of Pharmacy and Medical Sciences, Griffith University, Southport, Queensland, Australia
| | | | - Peter W Hellings
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium
- Upper Airways Disease Research Unit, University of Ghent, Ghent, Belgium
| | - Anju Peters
- Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Peter H Howarth
- Global Medical Affairs, Respiratory Specialty Care, GSK, London, UK
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8
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Emson C, Han JK, Hopkins C, Asimus S, Cann JA, Chain D, Wu Y, Reddy Y, McCrae C, Cohen D, Kreindler JL, Werkström V, Jison M, Wagenmann M, Bachert C. Pharmacokinetics/pharmacodynamics of benralizumab in chronic rhinosinusitis with nasal polyps: Phase III, randomized, placebo-controlled OSTRO trial. Br J Clin Pharmacol 2024; 90:1952-1963. [PMID: 38715387 DOI: 10.1111/bcp.16087] [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: 07/24/2023] [Revised: 03/27/2024] [Accepted: 04/04/2024] [Indexed: 07/31/2024] Open
Abstract
AIMS Benralizumab, a humanized, afucosylated monoclonal antibody against the interleukin 5 receptor, α subunit, causes rapid depletion of eosinophils by antibody-dependent cellular cytotoxicity. We investigated the pharmacokinetic and pharmacodynamic effects of benralizumab in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) from the phase III OSTRO trial. METHODS Patients received a placebo or 30 mg of benralizumab by subcutaneous injection every 8 weeks (first three doses every 4 weeks) to week 48; a subset of patients continued in an extended follow-up period to assess treatment durability to week 80. Serum benralizumab concentrations and blood eosinophil and basophil counts were assessed to week 80. Biomarker assessments were performed on nasal polyp tissue biopsies at week 56 and nasal lining fluid at weeks 24 and 56 to examine changes in immune cells and inflammatory mediators. RESULTS Among 185 patients in this analysis, 93 received benralizumab. Serum benralizumab concentrations reached a steady state by week 24 (median concentration 385.52 ng mL-1); blood eosinophils were almost fully depleted and blood basophils were reduced between weeks 16 and 56. Nasal polyp tissue eosinophils decreased with benralizumab from 57.6 cells mm-2 at baseline to 0 cells mm-2 at week 56 (P < .001 vs placebo), and tissue mast cells were numerically reduced. In nasal lining fluid, eosinophil-derived neurotoxin was significantly reduced at weeks 24 and 56 (P < .001) and interleukin-17 at week 56 (P < .05) with benralizumab. CONCLUSION Benralizumab treatment led to rapid, sustained, nearly complete depletion of eosinophils from blood and nasal polyp tissue in patients with CRSwNP.
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Affiliation(s)
| | - Joseph K Han
- Eastern Virginia Medical School, Norfolk, Virginia, USA
| | | | | | | | | | - Yuling Wu
- AstraZeneca, Gaithersburg, Maryland, USA
| | - Yasa Reddy
- AstraZeneca, Gaithersburg, Maryland, USA
| | | | | | - James L Kreindler
- Department of Medical Affairs, Vertex Pharmaceuticals, Boston, Massachusetts, USA
| | | | | | - Martin Wagenmann
- Department of Otorhinolaryngology, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Claus Bachert
- University Hospital of Münster, Münster, Germany
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Upper Airways Research Laboratory, Ghent University, Ghent, Belgium
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9
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Berni Canani R, Caminati M, Carucci L, Eguiluz-Gracia I. Skin, gut, and lung barrier: Physiological interface and target of intervention for preventing and treating allergic diseases. Allergy 2024; 79:1485-1500. [PMID: 38439599 DOI: 10.1111/all.16092] [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: 09/05/2023] [Revised: 02/21/2024] [Accepted: 02/23/2024] [Indexed: 03/06/2024]
Abstract
The epithelial barriers of the skin, gut, and respiratory tract are critical interfaces between the environment and the host, and they orchestrate both homeostatic and pathogenic immune responses. The mechanisms underlying epithelial barrier dysfunction in allergic and inflammatory conditions, such as atopic dermatitis, food allergy, eosinophilic oesophagitis, allergic rhinitis, chronic rhinosinusitis, and asthma, are complex and influenced by the exposome, microbiome, individual genetics, and epigenetics. Here, we review the role of the epithelial barriers of the skin, digestive tract, and airways in maintaining homeostasis, how they influence the occurrence and progression of allergic and inflammatory conditions, how current treatments target the epithelium to improve symptoms of these disorders, and what the unmet needs are in the identification and treatment of epithelial disorders.
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Affiliation(s)
- Roberto Berni Canani
- Department of Translational Medical Science, University of Naples Federico II, Naples, Italy
- CEINGE Advanced Biotechnologies, University of Naples Federico II, Naples, Italy
| | - Marco Caminati
- Allergy Unit and Asthma Centre, Verona Integrated University Hospital and Department of Medicine, University of Verona, Verona, Italy
| | - Laura Carucci
- Department of Translational Medical Science, University of Naples Federico II, Naples, Italy
- CEINGE Advanced Biotechnologies, University of Naples Federico II, Naples, Italy
| | - Ibon Eguiluz-Gracia
- Allergy Unit, Hospital Regional Universitario de Malága, Malaga, Spain
- Allergy Group, Biomedical Research Institute of Malaga (IBIMA)-BIONAND Platform, RICORS Inflammatory Diseases, Malaga, Spain
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10
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Furuta EJM, Furuta GT, Shandas R. Minimally Invasive Approaches to Diagnose and Monitor Eosinophilic GI Diseases. Curr Allergy Asthma Rep 2024; 24:269-279. [PMID: 38536531 DOI: 10.1007/s11882-024-01142-0] [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] [Accepted: 03/12/2024] [Indexed: 05/08/2024]
Abstract
PURPOSE OF REVIEW This review seeks to understand novel avenues for eosinophilic GI disease management. Biomarkers offer a unique and non-invasive approach to tracking EoE disease progression. While no biomarkers have definitively met the diagnostic criteria for eosinophilic GI diseases, some biomarkers have been shown to be associated with disease activity. Here, we examine the potential of recently studied biomarkers. RECENT FINDINGS Current research shows advancements in blood, luminal fluid, and breath testing. Particular areas of interest include mRNA analyses, protein fingerprinting, amplicon sequence variants (ASVs), T cells and IgE receptors, eosinophilic cationic proteins, cytokines, and nitric oxide exhalation. Preliminary results showed that mucosal biomarkers, directly captured from the esophagus, may reflect the best representation of biopsy-based results, in contrast to biomarkers obtained from indirect or peripheral (blood, breath) methods. However, this is based on limited clinical studies without sufficient numbers to evaluate true diagnostic accuracy. Large-scale randomized trials are needed to fully ascertain both the optimal sampling technique and the specific biomarkers that reflect diagnostic status of the disease.
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Affiliation(s)
- Ellie J M Furuta
- Department of Public Health, University of Colorado School of Medicine, Aurora, CO, USA
| | - Glenn T Furuta
- Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, USA.
- Gastrointestinal Eosinophilic Diseases Program, University of Colorado School of Medicine, Aurora, CO, USA.
| | - Robin Shandas
- Department of Bioengineering, University of Colorado Denver|Anschutz Medical Campus, Aurora, CO, USA
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11
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Menard-Katcher C, Aceves S. Pathophysiology and Clinical Impact of Esophageal Remodeling and Fibrosis in Eosinophilic Esophagitis. Immunol Allergy Clin North Am 2024; 44:129-143. [PMID: 38575213 DOI: 10.1016/j.iac.2023.12.002] [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: 04/06/2024]
Abstract
Most of the major clinical signs and consequences of eosinophilic esophagitis seem to be related to tissue remodeling. Important data on remodeling activity in patients with eosinophilic esophagitis are provided by a range of current and new biologic markers and diagnostics. To completely clarify the possible advantages and restrictions of therapeutic approaches, clinical studies should take into consideration the existence and reversibility of esophageal remodeling. The degree of mucosal or submucosal disease activity may not be reflected by epithelial eosinophilic inflammation, which is used to define one criterion of disease activity".
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Affiliation(s)
- Calies Menard-Katcher
- Departments of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Digestive Health Institute, Childrens Hospital Colorado, Anschutz Medical Campus, 13123 East 16th Avenue, Aurora, CO 80045, USA.
| | - Seema Aceves
- Division of Pediatric Gastroenterology, Department of Pediatrics, University of California, Biomedical Research Facility 2, 4A17, 3147 Biomedical Sciences Way, La Jolla, CA, USA
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12
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Ding J, Garber JJ, Uchida A, Lefkovith A, Carter GT, Vimalathas P, Canha L, Dougan M, Staller K, Yarze J, Delorey TM, Rozenblatt-Rosen O, Ashenberg O, Graham DB, Deguine J, Regev A, Xavier RJ. An esophagus cell atlas reveals dynamic rewiring during active eosinophilic esophagitis and remission. Nat Commun 2024; 15:3344. [PMID: 38637492 PMCID: PMC11026436 DOI: 10.1038/s41467-024-47647-0] [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: 09/08/2023] [Accepted: 04/09/2024] [Indexed: 04/20/2024] Open
Abstract
Coordinated cell interactions within the esophagus maintain homeostasis, and disruption can lead to eosinophilic esophagitis (EoE), a chronic inflammatory disease with poorly understood pathogenesis. We profile 421,312 individual cells from the esophageal mucosa of 7 healthy and 15 EoE participants, revealing 60 cell subsets and functional alterations in cell states, compositions, and interactions that highlight previously unclear features of EoE. Active disease displays enrichment of ALOX15+ macrophages, PRDM16+ dendritic cells expressing the EoE risk gene ATP10A, and cycling mast cells, with concomitant reduction of TH17 cells. Ligand-receptor expression uncovers eosinophil recruitment programs, increased fibroblast interactions in disease, and IL-9+IL-4+IL-13+ TH2 and endothelial cells as potential mast cell interactors. Resolution of inflammation-associated signatures includes mast and CD4+ TRM cell contraction and cell type-specific downregulation of eosinophil chemoattractant, growth, and survival factors. These cellular alterations in EoE and remission advance our understanding of eosinophilic inflammation and opportunities for therapeutic intervention.
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Affiliation(s)
- Jiarui Ding
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
- Department of Computer Science, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
| | - John J Garber
- Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
- Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
| | - Amiko Uchida
- Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Ariel Lefkovith
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Grace T Carter
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Praveen Vimalathas
- Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
- Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Lauren Canha
- Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Michael Dougan
- Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Kyle Staller
- Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Joseph Yarze
- Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Toni M Delorey
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Orit Rozenblatt-Rosen
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
- Genentech, South San Francisco, CA, 94080, USA
| | - Orr Ashenberg
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Daniel B Graham
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
- Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
- Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Jacques Deguine
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Aviv Regev
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA.
- Genentech, South San Francisco, CA, 94080, USA.
| | - Ramnik J Xavier
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
- Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
- Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
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13
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Chu P, Sheng Y, Shen C, Xia Y, Kong L, Sun J. Structure-based improvement of the binding affinity and recognition specificity of peptide competitors to target pediatric IL-5R/IL-5 interaction by gluing halogen bonds at their complex interface. J Mol Recognit 2024; 37:e3070. [PMID: 37990248 DOI: 10.1002/jmr.3070] [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: 09/06/2023] [Revised: 10/30/2023] [Accepted: 11/10/2023] [Indexed: 11/23/2023]
Abstract
Human interleukin-5 (IL-5) cytokine mediates the development of eosinophils and is involved in a variety of immune inflammatory responses that play a major role in the pathogenesis of childhood asthma, leukemia, and other pediatric allergic diseases. The immunomodulatory cytokine functions by binding to its cognate cell surface receptor IL-5R in a sheet-by-sheet manner, which can be conformationally mimicked and competitively disrupted by a double-stranded cyclic AF18748 peptide. In this study, we systematically examined the co-crystallized complex structure of human IL-5R with AF18748 peptide and rationally designed a halogen bond to glue at the protein-peptide complex interface by substituting the indole moiety of AF18748 Trp13 residue with a halogen atom (X = F, Cl, Br, or I). High-level theoretical calculations imparted presence of the halogen bond between the oxygen atom (O) of IL-5R Glu58 backbone and the halogen atom (X) of AF18748 Trp13 side chain. Experimental assays confirmed that the halogen bond can promote peptide binding moderately or considerably. More importantly, the halogen bond not only enhances peptide affinity to IL-5R, but also improves peptide selectivity for its cognate IL-5R over other noncognate IL-R proteins. As might be expected, the affinity and selectivity conferred by halogen bond increase consistently in the order: H < F < Cl < Br < I. Structural modeling revealed that the halogen bond plus its vicinal π-cation-π stacking co-define a ringed noncovalent system at the complex interface, which involves a synergistic effect to effectively improve the peptide binding potency and recognition specificity.
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Affiliation(s)
- Peipei Chu
- Department of Pediatric Medicine, Children's Hospital of Wujiang District, Soochow University, Suzhou, China
| | - Yeping Sheng
- Department of Pediatric Medicine, Children's Hospital of Wujiang District, Soochow University, Suzhou, China
| | - Chentao Shen
- Department of Pediatric Medicine, Children's Hospital of Wujiang District, Soochow University, Suzhou, China
| | - Yalin Xia
- Department of Pediatric Medicine, Children's Hospital of Wujiang District, Soochow University, Suzhou, China
| | - Lingjun Kong
- Department of Pediatric Medicine, Children's Hospital of Soochow University, Suzhou, China
| | - Jiefan Sun
- Department of Pediatric Medicine, Children's Hospital of Wujiang District, Soochow University, Suzhou, China
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14
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Massironi S, Mulinacci G, Gallo C, Elvevi A, Danese S, Invernizzi P, Vespa E. Mechanistic Insights into Eosinophilic Esophagitis: Therapies Targeting Pathophysiological Mechanisms. Cells 2023; 12:2473. [PMID: 37887317 PMCID: PMC10605530 DOI: 10.3390/cells12202473] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 10/12/2023] [Accepted: 10/16/2023] [Indexed: 10/28/2023] Open
Abstract
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized by eosinophilic infiltration of the esophagus. It arises from a complex interplay of genetic predisposition (susceptibility loci), environmental triggers (allergens and dietary antigens), and a dysregulated immune response, mainly mediated by type 2 T helper cell (Th2)-released cytokines, such as interleukin (IL)-4, IL-5, and IL-13. These cytokines control eosinophil recruitment and activation as well as tissue remodeling, contributing to the characteristic features of EoE. The pathogenesis of EoE includes epithelial barrier dysfunction, mast cell activation, eosinophil degranulation, and fibrosis. Epithelial barrier dysfunction allows allergen penetration and promotes immune cell infiltration, thereby perpetuating the inflammatory response. Mast cells release proinflammatory mediators and promote eosinophil recruitment and the release of cytotoxic proteins and cytokines, causing tissue damage and remodeling. Prolonged inflammation can lead to fibrosis, resulting in long-term complications such as strictures and dysmotility. Current treatment options for EoE are limited and mainly focus on dietary changes, proton-pump inhibitors, and topical corticosteroids. Novel therapies targeting key inflammatory pathways, such as monoclonal antibodies against IL-4, IL-5, and IL-13, are emerging in clinical trials. A deeper understanding of the complex pathogenetic mechanisms behind EoE will contribute to the development of more effective and personalized therapeutic strategies.
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Affiliation(s)
- Sara Massironi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (G.M.); (C.G.); (A.E.)
- School of Medicine and Surgery, University of Milano-Bicocca, 20125 Milan, Italy
| | - Giacomo Mulinacci
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (G.M.); (C.G.); (A.E.)
- School of Medicine and Surgery, University of Milano-Bicocca, 20125 Milan, Italy
| | - Camilla Gallo
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (G.M.); (C.G.); (A.E.)
- School of Medicine and Surgery, University of Milano-Bicocca, 20125 Milan, Italy
| | - Alessandra Elvevi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (G.M.); (C.G.); (A.E.)
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy; (G.M.); (C.G.); (A.E.)
- School of Medicine and Surgery, University of Milano-Bicocca, 20125 Milan, Italy
| | - Edoardo Vespa
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, 20132 Milan, Italy
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15
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Kleuskens MTA, Bek MK, Al Halabi Y, Blokhuis BRJ, Diks MAP, Haasnoot ML, Garssen J, Bredenoord AJ, van Esch BCAM, Redegeld FA. Mast cells disrupt the function of the esophageal epithelial barrier. Mucosal Immunol 2023; 16:567-577. [PMID: 37302713 DOI: 10.1016/j.mucimm.2023.06.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/24/2023] [Accepted: 06/05/2023] [Indexed: 06/13/2023]
Abstract
Mast cells (MCs) accumulate in the epithelium of patients with eosinophilic esophagitis (EoE), an inflammatory disorder characterized by extensive esophageal eosinophilic infiltration. Esophageal barrier dysfunction plays an important role in the pathophysiology of EoE. We hypothesized that MCs contribute to the observed impaired esophageal epithelial barrier. Herein, we demonstrate that coculture of differentiated esophageal epithelial cells with immunoglobulin E-activated MCs significanly decreased epithelial resistance by 30% and increased permeability by 22% compared with non-activated MCs. These changes were associated with decreased messenger RNA expression of barrier proteins filaggrin, desmoglein-1 and involucrin, and antiprotease serine peptidase inhibitor kazal type 7. Using targeted proteomics, we detected various cytokines in coculture supernatants, most notably granulocyte-macrophage colony-stimulating factor and oncostatin M (OSM). OSM expression was increased by 12-fold in active EoE and associated with MC marker genes. Furthermore, OSM receptor-expressing esophageal epithelial cells were found in the esophageal tissue of patients with EoE, suggesting that the epithelial cells may respond to OSM. Stimulation of esophageal epithelial cells with OSM resulted in a dose-dependent decrease in barrier function and expression of filaggrin and desmoglein-1 and an increase in protease calpain-14. Taken together, these data suggest a role for MCs in decreasing esophageal epithelial barrier function in EoE, which may in part be mediated by OSM.
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Affiliation(s)
- Mirelle T A Kleuskens
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Marie K Bek
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Youmna Al Halabi
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Bart R J Blokhuis
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Mara A P Diks
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Maria L Haasnoot
- Department of Gastroenterology & Hepatology, Amsterdam UMC, location AMC, Amsterdam, The Netherlands
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands; Danone Nutricia Research, Utrecht, The Netherlands
| | - Albert J Bredenoord
- Department of Gastroenterology & Hepatology, Amsterdam UMC, location AMC, Amsterdam, The Netherlands
| | - Betty C A M van Esch
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands; Danone Nutricia Research, Utrecht, The Netherlands
| | - Frank A Redegeld
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
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16
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Dellon ES, Peterson KA, Mitlyng BL, Iuga A, Bookhout CE, Cortright LM, Walker KB, Gee TS, McGee SJ, Cameron BA, Galanko JA, Woosley JT, Eluri S, Moist SE, Hirano I. Mepolizumab for treatment of adolescents and adults with eosinophilic oesophagitis: a multicentre, randomised, double-blind, placebo-controlled clinical trial. Gut 2023; 72:1828-1837. [PMID: 37423717 PMCID: PMC11315207 DOI: 10.1136/gutjnl-2023-330337] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 06/28/2023] [Indexed: 07/11/2023]
Abstract
OBJECTIVE We aimed to determine whether mepolizumab, an anti-IL-5 antibody, was more effective than placebo for improving dysphagia symptoms and decreasing oesophageal eosinophil counts in eosinophilic oesophagitis (EoE). METHODS We conducted a multicentre, randomised, double-blind, placebo-controlled, trial. In the first part, patients aged 16-75 with EoE and dysphagia symptoms (per EoE Symptom Activity Index (EEsAI)) were randomised 1:1 to 3 months of mepolizumab 300 mg monthly or placebo. Primary outcome was change in EEsAI from baseline to month 3 (M3). Secondary outcomes included histological, endoscopic and safety metrics. In part 2, patients initially randomised to mepolizumab continued 300 mg monthly for 3 additional months (mepo/mepo), placebo patients started mepolizumab 100 mg monthly (pbo/mepo), and outcomes were reassessed at month 6 (M6). RESULTS Of 66 patients randomised, 64 completed M3, and 56 completed M6. At M3, EEsAI decreased 15.4±18.1 with mepolizumab and 8.3±18.0 with placebo (p=0.14). Peak eosinophil counts decreased more with mepolizumab (113±77 to 36±43) than placebo (146±94 to 160±133) (p<0.001). With mepolizumab, 42% and 34% achieved histological responses of <15 and ≤6 eos/hpf compared with 3% and 3% with placebo (p<0.001 and 0.02). The change in EoE Endoscopic Reference Score at M3 was also larger with mepolizumab. At M6, EEsAI decreased 18.3±18.1 points for mepo/mepo and 18.6±19.2 for pbo/mepo (p=0.85). The most common adverse events were injection-site reactions. CONCLUSIONS Mepolizumab did not achieve the primary endpoint of improving dysphagia symptoms compared with placebo. While eosinophil counts and endoscopic severity improved with mepolizumab at 3 months, longer treatment did not yield additional improvement. TRIAL REGISTRATION NUMBER NCT03656380.
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Affiliation(s)
- Evan S Dellon
- Center for Esophageal Diseases and Swallowing, and Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Kathryn A Peterson
- Department of Internal Medicine, Division of Gastroenterology, University of Utah, Salt Lake City, Utah, USA
| | | | - Alina Iuga
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Christine E Bookhout
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Lindsay M Cortright
- Center for Esophageal Diseases and Swallowing, and Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Kacie B Walker
- Center for Esophageal Diseases and Swallowing, and Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Timothy S Gee
- Center for Esophageal Diseases and Swallowing, and Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Sarah J McGee
- Center for Esophageal Diseases and Swallowing, and Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Brenderia A Cameron
- Center for Esophageal Diseases and Swallowing, and Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Joseph A Galanko
- Center for Esophageal Diseases and Swallowing, and Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - John T Woosley
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Swathi Eluri
- Center for Esophageal Diseases and Swallowing, and Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Susan E Moist
- Center for Esophageal Diseases and Swallowing, and Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Ikuo Hirano
- Division of Gastroenterology and Hepatology, Northwestern University School of Medicine, Chicago, Illinois, USA
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17
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Ptaschinski C, Zhu D, Fonseca W, Lukacs NW. Stem cell factor inhibition reduces Th2 inflammation and cellular infiltration in a mouse model of eosinophilic esophagitis. Mucosal Immunol 2023; 16:727-739. [PMID: 37557983 PMCID: PMC10680063 DOI: 10.1016/j.mucimm.2023.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 07/28/2023] [Accepted: 07/31/2023] [Indexed: 08/11/2023]
Abstract
Eosinophilic esophagitis (EoE) is a T helper (Th)2-mediated inflammatory disorder characterized endoscopically by eosinophilic infiltration leading to fibrosis of the esophagus. Stem cell factor (SCF), a multifunctional cytokine, is upregulated in several allergic diseases, including in patients with EoE. Mast cells and eosinophils express c-kit, the cell surface receptor for SCF, and have been found to play an important role in EoE. Therefore, we investigated whether blocking SCF represents a potential therapeutic approach for EoE. Esophageal inflammation was induced in mice using peanut allergen. In mice with experimental EoE, we found that SCF was upregulated in the esophageal tissue. In EoE mice injected with a polyclonal antibody specific for SCF, we observed a decrease in both mast cells and eosinophils by histological and flow cytometric analysis. Furthermore, Th2 cytokines in the esophagus were decreased in anti-SCF treated mice, as were levels of Th2 cytokines from lung-draining and esophageal lymph nodes. Serum levels of peanut-specific immunoglobulin E were reduced following treatment with anti-SCF. In Kitlf/f-Col1-Cre-ERT mice, which have SCF deleted primarily in myofibroblasts that develop in EoE, we observed similar results as the anti-SCF treated animals for inflammatory cell accumulation, cytokines, and histopathology. These results indicate that therapeutic treatments targeting SCF can reduce allergic inflammation in EoE.
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Affiliation(s)
- Catherine Ptaschinski
- Department of Pathology, University of Michigan, Ann Arbor, USA; Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, USA.
| | - Diana Zhu
- Department of Pathology, University of Michigan, Ann Arbor, USA
| | - Wendy Fonseca
- Department of Pathology, University of Michigan, Ann Arbor, USA
| | - Nicholas W Lukacs
- Department of Pathology, University of Michigan, Ann Arbor, USA; Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, USA
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Franciosi JP, Gordon M, Sinopoulou V, Dellon ES, Gupta SK, Reed CC, Gutiérrez-Junquera C, Venkatesh RD, Erwin EA, Egiz A, Elleithy A, Mougey EB. Medical treatment of eosinophilic esophagitis. Cochrane Database Syst Rev 2023; 7:CD004065. [PMID: 37470293 PMCID: PMC10358040 DOI: 10.1002/14651858.cd004065.pub4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/21/2023]
Abstract
BACKGROUND Eosinophilic esophagitis (EoE) is a chronic antigen-mediated eosinophilic inflammatory disease isolated to the esophagus. As a clinicopathologic disorder, a diagnosis of EoE requires a constellation of clinical symptoms of esophageal dysfunction and histologic findings (at least 15 eosinophils/high-powered microscope field (eos/hpf)). Current guidelines no longer require the failure of response to proton pump inhibitor medications to establish a diagnosis of EoE, but continue to suggest the exclusion of other etiologies of esophageal eosinophilia. The treatment goals for EoE are improvement in clinical symptoms, resolution of esophageal eosinophilia and other histologic abnormalities, endoscopic improvement, improved quality of life, improved esophageal function, minimized adverse effects of treatment, and prevention of disease progression and subsequent complications. Currently, there is no cure for EoE, making long-term treatment necessary. Standard treatment modalities include dietary modifications, esophageal dilation, and pharmacologic therapy. Effective pharmacologic therapies include corticosteroids, rapidly emerging biological therapies, and proton pump inhibitor medications. OBJECTIVES To evaluate the efficacy and safety of medical interventions for people with eosinophilic esophagitis. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and WHO ICTRP to 3 March 2023. SELECTION CRITERIA Randomized controlled trials (RCTs) comparing any medical intervention or food elimination diet for the treatment of eosinophilic esophagitis, either alone or in combination, to any other intervention (including placebo). DATA COLLECTION AND ANALYSIS Pairs of review authors independently selected studies and conducted data extraction and risk of bias assessment. We expressed outcomes as a risk ratio (RR) and as the mean or standardized mean difference (MD/SMD) with 95% confidence interval (CI). We assessed the certainty of the evidence using GRADE. Our primary outcomes were: clinical, histological, and endoscopic improvement, and withdrawals due to adverse events. Secondary outcomes were: serious and total adverse events, and quality of life. MAIN RESULTS We included 41 RCTs with 3253 participants. Eleven studies included pediatric patients while the rest recruited both children and adults. Four studies were in patients with inactive disease while the rest were in patients with active disease. We identified 19 intervention comparisons. In this abstract we present the results of the primary outcomes for the two main comparisons: corticosteroids versus placebo and biologics versus placebo, based on the prespecified outcomes defined of the primary studies. Fourteen studies compared corticosteroids to placebo for induction of remission and the risk of bias for these studies was mostly low. Corticosteroids may lead to slightly better clinical improvement (20% higher), measured dichotomously (risk ratio (RR) 1.74, 95% CI 1.08 to 2.80; 6 studies, 583 participants; number needed to treat for an additional beneficial outcome (NNTB) = 4; low certainty), and may lead to slightly better clinical improvement, measured continuously (standard mean difference (SMD) 0.51, 95% CI 0.17 to 0.85; 5 studies, 475 participants; low certainty). Corticosteroids lead to a large histological improvement (63% higher), measured dichotomously (RR 11.94, 95% CI 6.56 to 21.75; 12 studies, 978 participants; NNTB = 3; high certainty), and may lead to histological improvement, measured continuously (SMD 1.42, 95% CI 1.02 to 1.82; 5 studies, 449 participants; low certainty). Corticosteroids may lead to little to no endoscopic improvement, measured dichotomously (RR 2.60, 95% CI 0.82 to 8.19; 5 studies, 596 participants; low certainty), and may lead to endoscopic improvement, measured continuously (SMD 1.33, 95% CI 0.59 to 2.08; 5 studies, 596 participants; low certainty). Corticosteroids may lead to slightly fewer withdrawals due to adverse events (RR 0.64, 95% CI 0.43 to 0.96; 14 studies, 1032 participants; low certainty). Nine studies compared biologics to placebo for induction of remission. Biologics may result in little to no difference in clinical improvement, measured dichotomously (RR 1.14, 95% CI 0.85 to 1.52; 5 studies, 410 participants; low certainty), and may result in better clinical improvement, measured continuously (SMD 0.50, 95% CI 0.22 to 0.78; 7 studies, 387 participants; moderate certainty). Biologics result in better histological improvement (55% higher), measured dichotomously (RR 6.73, 95% CI 2.58 to 17.52; 8 studies, 925 participants; NNTB = 2; moderate certainty). We could not draw conclusions for this outcome when measured continuously (SMD 1.01, 95% CI 0.36 to 1.66; 6 studies, 370 participants; very low certainty). Biologics may result in little to no difference in endoscopic improvement, measured dichotomously (effect not estimable, low certainty). We cannot draw conclusions for this outcome when measured continuously (SMD 2.79, 95% CI 0.36 to 5.22; 1 study, 11 participants; very low certainty). There may be no difference in withdrawals due to adverse events (RR 1.55, 95% CI 0.88 to 2.74; 8 studies, 792 participants; low certainty). AUTHORS' CONCLUSIONS Corticosteroids (as compared to placebo) may lead to clinical symptom improvement when reported both as dichotomous and continuous outcomes, from the primary study definitions. Corticosteroids lead to a large increase in histological improvement (dichotomous outcome) and may increase histological improvement (continuous outcome) when compared to placebo. Corticosteroids may or may not increase endoscopic improvement (depending on whether the outcome is measured dichotomously or continuously). Withdrawals due to adverse events (dichotomous outcome) may occur less frequently when corticosteroids are compared to placebo. Biologics (as compared to placebo) may not lead to clinical symptom improvement when reported as a dichotomous outcome and may lead to an increase in clinical symptom improvement (as a continuous outcome), from the primary study definitions. Biologics lead to a large increase in histological improvement when reported as a dichotomous outcome, but this is uncertain when reported as a continuous outcome, as compared to placebo. Biologics may not increase endoscopic improvement (dichotomous outcome), but this is uncertain when measured as a continuous outcome. Withdrawals due to adverse events as a dichotomous outcome may occur as frequently when biologics are compared to placebo.
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Affiliation(s)
- James P Franciosi
- Division of Gastroenterology, Hepatology, and Nutrition, Nemours Children's Hospital, Orlando, FL, USA
- College of Medicine, University of Central Florida, Orlando, USA
| | - Morris Gordon
- School of Medicine, University of Central Lancashire, Preston, UK
| | | | - Evan S Dellon
- Department of Medicine, Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Sandeep K Gupta
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Illinois College of Medicine at Peoria and Children's Hospital of Illinois, Peoria, IN, USA
| | - Craig C Reed
- Department of Medicine, Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Carolina Gutiérrez-Junquera
- Pediatric Gastroenterology, University Hospital Puerta de Hierro Majadahonda. Autonomous University of Madrid, Madrid, Spain
| | - Rajitha D Venkatesh
- Pediatrics, Gastroenterology & Hepatology & Nutrition, Nationwide Children's Hospital, Columbus, OH, USA
| | - Elizabeth A Erwin
- Pediatric Allergy, Nationwide Children's Hospital, Columbus, OH, USA
| | - Abdullah Egiz
- School of Medicine, University of Central Lancashire, Preston, UK
| | - Assem Elleithy
- School of Medicine, University of Central Lancashire, Preston, UK
| | - Edward B Mougey
- Clinical Pharmacogenomics and Translational Research, Nemours Children's Health System, Jacksonville, FL, USA
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19
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Yang G, Li J, Liu Y, Wu G, Mo L, Xu Z, Liao Y, Huang Q, Yang P. Targeting the RhoA-GEF-H1 pathway of mast cells attenuates experimental airway allergy. Arch Biochem Biophys 2023; 741:109597. [PMID: 37054768 DOI: 10.1016/j.abb.2023.109597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 04/02/2023] [Accepted: 04/04/2023] [Indexed: 04/15/2023]
Abstract
Mast cells are the major effector cells in allergic diseases. RhoA and its downstream pathway is associated with the pathogenesis of airway allergy. The objective of this study is to test a hypothesis that modulating the RhoA-GEF-H1 axis in mast cells can attenuate airway allergy. An airway allergic disorder (AAD) mouse model was employed. Mast cells were isolated from AAD mouse airway tissues to be analyzed by RNA sequencing. We observed that mast cells isolated from the respiratory tract of AAD mice were resistant to apoptosis. Mast cell mediator levels in nasal lavage fluid were correlated with apoptosis resistance in AAD mice. Activation of RhoA in AAD mast cells was related to resistance to apoptosis. Mast cells isolated from the airway tissues in AAD mouse exhibited strong RhoA-GEF-H1 expression. The RhoA-GEF-H1 axis was associated with the lower FasL expression in AAD mast cells. Activation of the RhoA-GEF-H1 axis promoted the production of mediators in mast cells. Inhibition of GEF-H1 facilitated the SIT-induced mast cell apoptosis and enhanced the therapeutic efficacy of AAD. In conclusion, RhoA-GEF-H1 activities are associated with resistance to apoptosis in mast cells isolated from sites of allergic lesions. The state of apoptosis resistance in mast cells is associated with the state of AAD disease. Inhibition of GEF-H1 restores the sensitivity of mast cells to apoptosis inducers, and alleviates experimental AAD in mice.
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Affiliation(s)
- Gui Yang
- Department of Otolaryngology and Allergy, Longgang Central Hospital, Shenzhen, China
| | - Jianxiang Li
- Department of General Practice Medicine, Third Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Yu Liu
- Department of Otolaryngology, Jinjiang Municipal Hospital, Jinjiang, China
| | - Gaohui Wu
- Department of Otolaryngology, Jinjiang Municipal Hospital, Jinjiang, China
| | - Lihua Mo
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen, China; Institute of Allergy & Immunology of Shenzhen University, State Key Laboratory of Respiratory Disease Allergy Division at Shenzhen University, Shenzhen, China
| | - Ziyi Xu
- Vanke Meisha Academy, Shenzhen, China
| | - Yun Liao
- Department of Otolaryngology and Allergy, Longgang Central Hospital, Shenzhen, China
| | - Qinmiao Huang
- Department of General Practice Medicine, Third Affiliated Hospital of Shenzhen University, Shenzhen, China.
| | - Pingchang Yang
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen, China; Institute of Allergy & Immunology of Shenzhen University, State Key Laboratory of Respiratory Disease Allergy Division at Shenzhen University, Shenzhen, China.
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20
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How an Immune-Factor-Based Formulation of Micro-Immunotherapy Could Interfere with the Physiological Processes Involved in the Atopic March. Int J Mol Sci 2023; 24:ijms24021483. [PMID: 36675006 PMCID: PMC9864899 DOI: 10.3390/ijms24021483] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 01/05/2023] [Accepted: 01/10/2023] [Indexed: 01/14/2023] Open
Abstract
Allergic diseases consist of improper inflammatory reactions to antigens and are currently an important healthcare concern, especially considering their increasing worldwide development in recent decades. The "atopic march" defines the paradigm of allergic diseases occurring in chronological order and displaying specific spatial manifestations, as they usually start as atopic dermatitis (AD) and food allergies during infancy and progressively evolve into allergic asthma (AA) and allergic rhinitis (AR) or rhino-conjunctivitis in childhood. Many immune cell subtypes and inflammatory factors are involved in these hypersensitivity reactions. In particular, the T helpers 2 (Th2) subset, through its cytokine signatures made of interleukins (ILs), such as IL-4, IL-5, IL-10, and IL-13, as well as mast cells and their related histamine pathways, contribute greatly to the perpetuation and evolution of the atopic march. By providing low doses (LD) and ultra-low doses (ULD) of ILs and immune factors to the body, micro-immunotherapy (MI) constitutes an interesting therapeutic strategy for the management of the atopic march and its symptoms. One of the aims of this review is to shed light on the current concept of the atopic march and the underlying immune reactions occurring during the IgE-mediated responses. Moreover, the different classes of traditional and innovative treatments employed in allergic diseases will also be discussed, with a special emphasis on the potential benefits of the MI medicine 2LALERG® formulation in this context.
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21
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Nhu QM, Aceves SS. Current state of biologics in treating eosinophilic esophagitis. Ann Allergy Asthma Immunol 2023; 130:15-20. [PMID: 36243282 DOI: 10.1016/j.anai.2022.10.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/28/2022] [Accepted: 10/03/2022] [Indexed: 11/06/2022]
Abstract
OBJECTIVE Eosinophilic esophagitis (EoE) is a chronic, allergen-mediated, eosinophil-predominant, type 2 inflammatory disease that progresses to fibrostenosis of the esophagus if left untreated. This review focuses on biologics therapy in EoE. DATA SOURCES Manuscripts on EoE treatments are identified on PubMed. STUDY SELECTIONS Original research, randomized controlled trials, retrospective studies, meta-analyses, case series, and case reports of high relevance are selected and reviewed. RESULTS Biologics have been used as investigational therapies for EoE in clinical studies over the years, based on earlier work that identified key cytokines and mediators of eosinophilic inflammation and, more recently, type 2 inflammation that underlie EoE pathogenesis. Dupilumab, a monoclonal antibody that targets the interleukin (IL)-4Rα chain, thereby interfering with IL-4 and IL-13 binding with the receptor, was recently approved by the Food and Drug Administration for EoE. Dupilumab improved clinical symptoms, endoscopic scores, histologic inflammation, and esophageal distensibility. Several clinical trials that target key cytokines such as IL-5, IL-13, and thymic stromal lymphopoietin in EoE are still ongoing. CONCLUSION Topical corticosteroid, proton pump inhibitor therapy, elimination diet, and dilation are widely accepted treatment modalities for EoE. Dupilumab is the first Food and Drug Administration-approved therapy for EoE. Other studies evaluating biologics that target eosinophils, key cytokines, and inflammatory pathways in EoE are ongoing. Treatment algorithms are needed to position EoE therapies as they emerge.
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Affiliation(s)
- Quan M Nhu
- Division of Gastroenterology & Hepatology, Department of Medicine, Scripps Clinic, La Jolla, California; Department of Molecular Medicine, Scripps Research Institute, La Jolla, California
| | - Seema S Aceves
- Division of Allergy & Immunology, Departments of Pediatrics and Medicine, University of California, San Diego, La Jolla, California; Rady Children's Hospital, San Diego, San Diego, California.
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22
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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: 9] [Impact Index Per Article: 4.5] [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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23
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Walter S, Ho J, Alvarado R, Smith G, Croucher DR, Liang S, Grayson JW, Mangussi-Gomes J, Van Es SL, Earls P, Rimmer J, Campbell R, Kalish L, Sacks R, Harvey RJ. Mepolizumab decreases tissue eosinophils while increasing type-2 cytokines in eosinophilic chronic rhinosinusitis. Clin Exp Allergy 2022; 52:1403-1413. [PMID: 35475305 DOI: 10.1111/cea.14152] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 03/14/2022] [Accepted: 04/11/2022] [Indexed: 01/26/2023]
Abstract
BACKGROUND Eosinophilic chronic rhinosinusitis is an often treatment-resistant inflammatory disease mediated by type-2 cytokines, including interleukin (IL)-5. Mepolizumab, a monoclonal antibody drug targeting IL-5, has demonstrated efficacy and safety in inflammatory airway disease, but there is negligible evidence on direct tissue response. The study's aim was to determine the local effect of mepolizumab on inflammatory biomarkers in sinonasal tissue of eosinophilic chronic rhinosinusitis patients. METHODS Adult patients with eosinophilic chronic rhinosinusitis received 100mg mepolizumab subcutaneously at four-weekly intervals for 24 weeks in this prospective phase 2 clinical trial. Tissue eosinophil counts, eosinophil degranulation (assessed as submucosal eosinophil peroxidase deposition by immunohistochemistry) and cytokine levels (measured in homogenates by immunoassay) were evaluated in ethmoid sinus tissue biopsies collected at baseline and at weeks 4, 8, 16 and 24. RESULTS Twenty patients (47.7 ± 11.7 years, 50% female) were included. Sinonasal tissue eosinophil counts decreased after 24 weeks of treatment with mepolizumab (101.64 ± 93.80 vs 41.74 ± 53.76 cells per 0.1 mm2 ; p = .035), eosinophil degranulation remained unchanged (5.79 ± 2.08 vs 6.07 ± 1.20, p = .662), and type-2 cytokine levels increased in sinonasal tissue for IL-5 (10.84 ± 18.65 vs 63.98 ± 50.66, p = .001), IL-4 (4.48 ± 3.77 vs 9.38 ± 7.56, p = .004), IL-13 (4.02 ± 2.57 vs 6.46 ± 3.99, p = .024) and GM-CSF (1.51 ± 1.74 vs 4.50 ± 2.97, p = .001). CONCLUSION Mepolizumab reduced eosinophils in sinonasal tissue, demonstrating that antagonism of IL-5 suppresses eosinophil trafficking. With reduced tissue eosinophils, a local type-2 inflammatory feedback loop may occur. The study exposes mechanistic factors which may explain incomplete treatment response.
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Affiliation(s)
- Sophie Walter
- Rhinology and Skull Base Research Group, St Vincent's Centre for Applied Medical Research, University of New South Wales, Sydney, Australia
| | - Jacqueline Ho
- Rhinology and Skull Base Research Group, St Vincent's Centre for Applied Medical Research, University of New South Wales, Sydney, Australia.,St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Raquel Alvarado
- Rhinology and Skull Base Research Group, St Vincent's Centre for Applied Medical Research, University of New South Wales, Sydney, Australia
| | - Greg Smith
- School of Medical Sciences, University of New South Wales, Sydney, Australia
| | - David R Croucher
- St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia.,Garvan Institute of Medical Research, Sydney, New South Wales, Australia
| | - Sharron Liang
- Department of Anatomical Pathology, St Vincent's Hospital, Sydney, Australia
| | - Jessica W Grayson
- Rhinology and Skull Base Research Group, St Vincent's Centre for Applied Medical Research, University of New South Wales, Sydney, Australia.,Department of Otolaryngology-Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, UK
| | - João Mangussi-Gomes
- Rhinology and Skull Base Research Group, St Vincent's Centre for Applied Medical Research, University of New South Wales, Sydney, Australia
| | - Simone L Van Es
- School of Medical Sciences, University of New South Wales, Sydney, Australia.,New South Wales Health Education and Training Institute, Sydney, Australia
| | - Peter Earls
- Rhinology and Skull Base Research Group, St Vincent's Centre for Applied Medical Research, University of New South Wales, Sydney, Australia.,Department of Anatomical Pathology, St Vincent's Hospital, Sydney, Australia
| | - Janet Rimmer
- Rhinology and Skull Base Research Group, St Vincent's Centre for Applied Medical Research, University of New South Wales, Sydney, Australia.,Woolcock Institute, University of Sydney, Sydney, Australia.,Faculty of Medicine, Notre Dame University, Sydney, Australia
| | - Raewyn Campbell
- Rhinology and Skull Base Research Group, St Vincent's Centre for Applied Medical Research, University of New South Wales, Sydney, Australia.,Department of Otolaryngology Head and Neck Surgery, Royal Prince Alfred Hospital, Sydney, Australia.,Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia
| | - Larry Kalish
- Rhinology and Skull Base Research Group, St Vincent's Centre for Applied Medical Research, University of New South Wales, Sydney, Australia.,Department of Otolaryngology, Head and Neck Surgery, Concord General Hospital, University of Sydney, Sydney, Australia.,Faculty of Medicine, University of Sydney, Sydney, Australia
| | - Raymond Sacks
- Rhinology and Skull Base Research Group, St Vincent's Centre for Applied Medical Research, University of New South Wales, Sydney, Australia.,Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia.,Department of Otolaryngology, Head and Neck Surgery, Concord General Hospital, University of Sydney, Sydney, Australia.,Faculty of Medicine, University of Sydney, Sydney, Australia
| | - Richard J Harvey
- Rhinology and Skull Base Research Group, St Vincent's Centre for Applied Medical Research, University of New South Wales, Sydney, Australia.,Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia
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Inhibition of Complex I of the Respiratory Chain, but Not Complex III, Attenuates Degranulation and Cytokine Secretion in Human Skin Mast Cells. Int J Mol Sci 2022; 23:ijms231911591. [PMID: 36232895 PMCID: PMC9570238 DOI: 10.3390/ijms231911591] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/23/2022] [Accepted: 09/26/2022] [Indexed: 11/07/2022] Open
Abstract
The mechanisms of mast cell (MC) degranulation and MC-driven skin symptoms are well-described. In contrast, data about the role of mitochondrial respiration for immune functions of human skin MCs are lacking. Oxygen consumption rate (OCR) in primary human skin MCs during IgE-mediated activation in the absence of glucose was examined using a metabolic flux analyzer. Effects of the inhibition of mitochondrial complex I (by rotenone A) and III (by myxothiazol) on degranulation and cytokine secretion (IL-4, IL-5, IL-6, IL-13, TNF-α, and GM-CSF) were explored by the β-hexosaminidase release assay and multiplex ELISA. IgE-mediated activation rapidly increased the mitochondrial OCR and extracellular acidification; the contribution of non-mitochondrial oxygen consumption remained unchanged at lower levels. Both myxothiazol and rotenone A reduced OCR, the mitochondrial parameters, and extracellular acidification; however, myxothiazol did not affect degranulation and cytokine secretion. In contrast, degranulation and the secretion of IL-6, IL-13, TNF-α, and GM-CSF were reduced by rotenone A, whereas the secretion of IL-4 and IL-5 was not significantly affected. The inhibitors did not affect cell viability. Our results highlight the important role played by mitochondrial respiration in primary human skin MCs and allow for a conclusion on a hierarchy of their effector functions. Drugs targeting specific pathways in mitochondria may provide future options to control MC-driven skin symptoms.
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Pronio A, Covotta F, Pallotta L, Palma R, Badiali D, Sacchi MC, Lamazza A, Severi C. Eosinophilic Esophagitis: Cytokines Expression and Fibrotic Markers in Comparison to Celiac Disease. Diagnostics (Basel) 2022; 12:diagnostics12092092. [PMID: 36140492 PMCID: PMC9497632 DOI: 10.3390/diagnostics12092092] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 08/24/2022] [Accepted: 08/24/2022] [Indexed: 11/16/2022] Open
Abstract
Introduction: Eosinophilic esophagitis (EoE) is now recognized as the main inflammatory condition that leads to fibrosis, unlike other chronic inflammatory gastrointestinal diseases, such as celiac disease. The aim of our study is to characterize the collagen deposition and cytokine expression involved in the fibrogenic response in patients affected by EoE in comparison to celiac disease. Materials and Methods: Consecutive patients with a clinical suspicion of untreated EoE or active celiac disease were enrolled. In the control group, patients with negative upper endoscopy were included. Total RNA was isolated from biopsy specimens using a commercial kit (SV Total RNA Isolation System, Promega Italia Srl). Quantitative real-time PCR (qRT-PCR) was performed in triplicate using a StepOne™ Real-Time PCR instrument (Thermo Fisher Scientific, Monza, Italy). mRNA encoding for inflammatory molecules: interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 13 (IL-13), and fibrotic markers: transforming growth factor beta 1 (TGF-β), mitogen-activated protein kinase kinase kinase 7 (MAP3K7), serpin family E member 1 (SERPINE1), were quantified using TaqMan Gene Expression Assays (Applied Biosystems). RESULTS. In EoE, the qPCR analysis showed an increase in all the inflammatory cytokines. Both IL-5 and Il-3 mRNA expression resulted in a statistically significant increase in oesophageal mucosa with respect to the celiac duodenum, while no differences were present in IL-4 expression. TGF-β expression was similar to the controls in the mid esophagus but reduced in the distal EoE esophagus (RQ: 0.46 ± 0.1). MAP3K7 expression was reduced in the mid esophagus (RQ: 0.59 ± 0.3) and increased in the distal esophagus (RQ: 1.75 ± 0.6). In turn, the expression of SERPINE1 was increased in both segments and was higher in the mid than in the distal esophagus (RQ: 5.25 ± 3.9, 1.92 ± 0.9, respectively). Collagen deposition was greater in the distal esophagus compared to the mid esophagus [18.1% ± 8 vs. 1.3% ± 1; p = 0.008]. Conclusions: The present study confirms the esophageal fibrotic involution involving the distal esophagus and shows that the inflammatory pathway in EoE is peculiar to this disease and different from other chronic inflammatory gastrointestinal disorders such as celiac disease.
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Affiliation(s)
- Annamaria Pronio
- Department of General Surgery and Surgical Specialties ‘Paride Stefanini’, Sapienza University of Rome, 00185 Rome, Italy
| | - Francesco Covotta
- Department of General Surgery and Surgical Specialties ‘Paride Stefanini’, Sapienza University of Rome, 00185 Rome, Italy
| | - Lucia Pallotta
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Rossella Palma
- Department of General Surgery and Surgical Specialties ‘Paride Stefanini’, Sapienza University of Rome, 00185 Rome, Italy
- Correspondence: ; Tel.: +39-33-4309-1174
| | - Danilo Badiali
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Maria Carlotta Sacchi
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Antonietta Lamazza
- Department of Surgery Pietro Valdoni, Sapienza University of Rome, 00185 Rome, Italy
| | - Carola Severi
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy
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Upparahalli Venkateshaiah S, Yadavalli CS, Kandikattu HK, Kumar S, Oruganti L, Mishra A. Molecules involved in the development of Barrett's esophagus phenotype in chronic eosinophilic esophagitis. Am J Physiol Gastrointest Liver Physiol 2022; 323:G31-G43. [PMID: 35437997 PMCID: PMC9190763 DOI: 10.1152/ajpgi.00321.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 03/15/2022] [Accepted: 04/10/2022] [Indexed: 01/31/2023]
Abstract
This paper aims to investigate the molecules involved in development of Barrett's esophagus (BE) in human eosinophilic esophagitis (EoE). Histopathological, immunohistochemical, real-time PCR Immuno blot, and ELISA analyses are performed to identify the signature genes and proteins involved in the progression of BE in EoE. We detected characteristic features of BE like intermediate columnar-type epithelial cells, induced BE signature genes like ErbB3, CDX1, ErbB2IP in the esophageal mucosa of patients with EoE. In addition, we had observed several BE-associated proteins such as TFF3, p53 and the progression markers like EGFR, p16, MICA, MICB, and MHC molecules in esophageal biopsies of patients with chronic EoE. Interestingly, we also detected mucin-producing columnar cells and MUC-2, MUC-4, and MUC5AC genes and proteins along with induced IL-9 in patients with chronic EoE. A strong correlation of IL-9 with mucin genes is observed that implicated a possible role for IL-9 in the transformation of esophageal squamous epithelial cells to columnar epithelial cells in patients with EoE. These findings indicate that IL-9 may have an important role in BE development in patients with chronic EoE. We also discovered that IL-9 stimulates mucin-producing and barrier cell transcripts and proteins such CK8/18, GATA4, SOX9, TFF1, MUC5AC, and tight junction proteins in primary esophageal epithelial cells when exposed to IL-9. Taken together, these findings provide evidence that indeed IL-9 has a role in the initiation and progression of BE characteristics like development of mucin-producing columnar epithelial cells in patients with chronic EoE.NEW & NOTEWORTHY Intermediate columnar-type epithelial cells are observed in biopsies of patients with EoE. Induced BE signature genes (CK8/18, CDX1 GATA4, SOX9, and Occludin) were observed in patients with chronic EoE. Induction of IL-9 and its correlation with eosinophils mucin-producing genes and proteins was observed in patients with EoE. Induced IL-9 may be responsible for the development of BE in patients with chronic EoE.
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Affiliation(s)
- Sathisha Upparahalli Venkateshaiah
- Section of Pulmonary Diseases, John W. Deming Department of Medicine, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, Louisiana
| | - Chandra Sekhar Yadavalli
- Section of Pulmonary Diseases, John W. Deming Department of Medicine, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, Louisiana
| | - Hemanth Kumar Kandikattu
- Section of Pulmonary Diseases, John W. Deming Department of Medicine, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, Louisiana
| | - Sandeep Kumar
- Section of Pulmonary Diseases, John W. Deming Department of Medicine, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, Louisiana
| | - Lokanatha Oruganti
- Section of Pulmonary Diseases, John W. Deming Department of Medicine, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, Louisiana
| | - Anil Mishra
- Section of Pulmonary Diseases, John W. Deming Department of Medicine, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, Louisiana
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Single-cell RNA sequencing of mast cells in eosinophilic esophagitis reveals heterogeneity, local proliferation, and activation that persists in remission. J Allergy Clin Immunol 2022; 149:2062-2077. [PMID: 35304158 PMCID: PMC9177790 DOI: 10.1016/j.jaci.2022.02.025] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 02/10/2022] [Accepted: 02/11/2022] [Indexed: 11/21/2022]
Abstract
BACKGROUND Mast cells (MCs) are pleiotropic cells that accumulate in the esophagus of patients with eosinophilic esophagitis (EoE) and are thought to contribute to disease pathogenesis, yet their properties and functions in this organ are largely unknown. OBJECTIVES This study aimed to perform a comprehensive molecular and spatial characterization of esophageal MCs in EoE. METHODS Esophageal biopsies obtained from patients with active EoE, patients with EoE in histologic remission, and individuals with histologically normal esophageal biopsies and no history of esophageal disease (ie, control individuals) were subject to single-cell RNA sequencing, flow cytometry, and immunofluorescence analyses. RESULTS This study probed 39,562 single esophageal cells by single-cell RNA sequencing; approximately 5% of these cells were MCs. Dynamic MC expansion was identified across disease states. During homeostasis, TPSAB1highAREGhigh resident MCs were mainly detected in the lamina propria and exhibited a quiescent phenotype. In patients with active EoE, resident MCs assumed an activated phenotype, and 2 additional proinflammatory MC populations emerged in the intraepithelial compartment, each linked to a proliferating MKI67high cluster. One proinflammatory activated MC population, marked as KIThighIL1RL1highFCER1Alow, was not detected in disease remission (termed "transient MC"), whereas the other population, marked as CMA1highCTSGhigh, was detected in disease remission where it maintained an activated state (termed "persistent MC"). MCs were prominent producers of esophageal IL-13 mRNA and protein, a key therapeutic target in EoE. CONCLUSIONS Esophageal MCs comprise heterogeneous populations with transcriptional signatures associated with distinct spatial compartmentalization and EoE disease status. In active EoE, they assume a proinflammatory state and locally proliferate, and they remain activated and poised to reinitiate inflammation even during disease remission.
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Chehade M, Falk GW, Aceves S, Lee JK, Mehta V, Leung J, Shumel B, Jacob-Nara JA, Deniz Y, Rowe PJ, Cunoosamy D, Khodzhayev A. Examining the Role of Type 2 Inflammation in Eosinophilic Esophagitis. GASTRO HEP ADVANCES 2022; 1:720-732. [PMID: 39131849 PMCID: PMC11307682 DOI: 10.1016/j.gastha.2022.05.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 05/06/2022] [Indexed: 08/13/2024]
Abstract
Eosinophilic esophagitis (EoE) is a chronic type 2 inflammatory disease characterized by an eosinophilic inflammatory infiltrate in the esophagus, leading to remodeling, stricture formation, and fibrosis. Triggered by food and aeroallergens, type 2 cytokines interleukin (IL)-4, IL-13, IL-5 produced by CD4+ T helper 2 cells (Th2), eosinophils, mast cells, basophils, and type 2 innate lymphoid cells alter the esophageal epithelial barrier and increase inflammatory cell tissue infiltration. Clustering analysis based on the expression of type 2 inflammatory genes demonstrated the diversity of EoE endotypes. Despite the availability of treatment options for patients with EoE, which include dietary restriction, proton pump inhibitors, swallowed topical steroids, and esophageal dilation, there are still no Food and Drug Administration-approved medications for this disease; as such, there are clear unmet medical needs for these patients. A number of novel biologic therapies currently in clinical trials represent a promising avenue for targeted therapeutic approaches in EoE. This review summarizes our current knowledge on the role of type 2 inflammatory cells and mediators in EoE disease pathogenesis, as well as the future treatment landscape targeting underlying inflammation in EoE.
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Affiliation(s)
- Mirna Chehade
- Deparment of Pediatrics and Medicine, Mount Sinai Center for Eosinophilic Disorders, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Gary W. Falk
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Seema Aceves
- Deparment of Pediatrics and Medicine, University of California, San Diego, California
| | - Jason K. Lee
- Deparment of Clinical Immunology and Allergy and Internal Medicine, Toronto Allergy and Asthma Clinic, Toronto, Ontario, Canada
| | - Vinay Mehta
- Allergy, Asthma & Immunology Associates, P.C., Lincoln, Nebraska
| | - John Leung
- Boston Specialists, Boston, Massachusetts
| | - Brad Shumel
- Regeneron Pharmaceuticals, Inc, Tarrytown, New York
| | | | - Yamo Deniz
- Regeneron Pharmaceuticals, Inc, Tarrytown, New York
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Cascio JA, Walsh M, Hoenig K, Davis B. Treatment of a 4-year-old boy with mepolizumab for lymphocytic hypereosinophilic syndrome. Ann Allergy Asthma Immunol 2022; 129:254-255. [PMID: 35537650 DOI: 10.1016/j.anai.2022.04.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/25/2022] [Accepted: 04/25/2022] [Indexed: 10/18/2022]
Affiliation(s)
- Jason A Cascio
- Division of Immunology, Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa.
| | - Madalyn Walsh
- Division of Immunology, Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa
| | - Kelly Hoenig
- Department of Pharmaceutical Care, University of Iowa Hospitals and Clinics, Iowa City, Iowa
| | - Benjamin Davis
- Division of Immunology, Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa
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Bernardini R, Toschi Vespasiani G, Giannetti A. An Overview of Off-Label Use of Humanized Monoclonal Antibodies in Paediatrics. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:625. [PMID: 35630042 PMCID: PMC9144580 DOI: 10.3390/medicina58050625] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/24/2022] [Accepted: 04/26/2022] [Indexed: 11/28/2022]
Abstract
In recent years, off-label and unlicensed drug use has extensively developed in the paediatric population. For a long time, clinical trials in the paediatric population were considered complicated to perform because of ethical problems, causing frequent off-label use. Off-label drug use remains an important public health issue, especially for children with rare conditions or with diseases not responsive to conventional treatments. The present paper is a narrative review of the literature of off-label drug use in children. The aim of our study is to summarize the main works dealing with the off-label use of biological drugs in paediatrics. Further studies analyzing their efficacy, safety, and cost-benefit ratios are needed to extend the use of biological therapies to the paediatric population.
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Affiliation(s)
- Roberto Bernardini
- Paediatrics and Neonatology Unit, San Giuseppe Hospital, 50053 Empoli, Italy
| | - Gaia Toschi Vespasiani
- Specialty School of Paediatrics, Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy;
| | - Arianna Giannetti
- Paediatrics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
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31
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Bhesania N, Selvakumar PKC, Patel S. Eosinophilic esophagitis: A review of the pediatric population and consideration of upcoming therapies. J Gastroenterol Hepatol 2022; 37:420-427. [PMID: 34655451 DOI: 10.1111/jgh.15706] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 10/04/2021] [Accepted: 10/12/2021] [Indexed: 01/07/2023]
Abstract
Eosinophilic esophagitis (EoE) is a disease entity that has become increasingly recognized in the pediatric population over the last decade and was first recognized as early as 1990. EoE is a clinicopathologic diagnosis with signs and symptoms varying between age groups. The clinical presentation of EoE is variable ranging from milder nonspecific symptoms, such as abdominal pain, vomiting, and dyspepsia, to more severe presentations such as failure to thrive, dysphagia and even food impaction and is dependent on age of diagnosis 2. There is growing body of evidence with regards to the pathophysiology, diagnostic modalities, and treatment options for EoE in the past decade. In this review article, we aim to discuss the disease burden, pathophysiology, diagnostic strategies, and currently available treatment options for EoE based on existing literature.
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Affiliation(s)
- Natalie Bhesania
- Division of Pediatric Gastroenterology and Nutrition, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | | | - Sophia Patel
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Children's Hospital, Cleveland, Ohio, USA
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Racca F, Pellegatta G, Cataldo G, Vespa E, Carlani E, Pelaia C, Paoletti G, Messina MR, Nappi E, Canonica GW, Repici A, Heffler E. Type 2 Inflammation in Eosinophilic Esophagitis: From Pathophysiology to Therapeutic Targets. Front Physiol 2022; 12:815842. [PMID: 35095572 PMCID: PMC8790151 DOI: 10.3389/fphys.2021.815842] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 12/09/2021] [Indexed: 12/11/2022] Open
Abstract
Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease of the esophagus characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation, whose incidence is rising. It significantly affects patients’ quality of life and, if left untreated, results in fibrotic complications. Although broad consensus has been achieved on first-line therapy, a subset of patients remains non-responder to standard therapy. The pathogenesis of EoE is multifactorial and results from the complex, still mostly undefined, interaction between genetics and intrinsic factors, environment, and antigenic stimuli. A deep understanding of the pathophysiology of this disease is pivotal for the development of new therapies. This review provides a comprehensive description of the pathophysiology of EoE, starting from major pathogenic mechanisms (genetics, type 2 inflammation, epithelial barrier dysfunction, gastroesophageal reflux, allergens, infections and microbiota) and subsequently focusing on the single protagonists of type 2 inflammation (involved cells, cytokines, soluble effectors, surface proteins and transcription factors) that could represent present and future therapeutic targets, while summarizing previous therapeutic approaches in literature.
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Affiliation(s)
- Francesca Racca
- Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- *Correspondence: Francesca Racca,
| | - Gaia Pellegatta
- Digestive Endoscopy Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Giuseppe Cataldo
- Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Edoardo Vespa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Digestive Endoscopy Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Elisa Carlani
- Digestive Endoscopy Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Corrado Pelaia
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, Catanzaro, Italy
| | - Giovanni Paoletti
- Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Maria Rita Messina
- Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Emanuele Nappi
- Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Giorgio Walter Canonica
- Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Alessandro Repici
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Digestive Endoscopy Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Enrico Heffler
- Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
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Barrier Impairment and Type 2 Inflammation in Allergic Diseases: The Pediatric Perspective. CHILDREN (BASEL, SWITZERLAND) 2021; 8:children8121165. [PMID: 34943362 PMCID: PMC8700706 DOI: 10.3390/children8121165] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/30/2021] [Accepted: 11/30/2021] [Indexed: 01/02/2023]
Abstract
Allergic diseases represent a global burden. Although the patho-physiological mechanisms are still poorly understood, epithelial barrier dysfunction and Th2 inflammatory response play a pivotal role. Barrier dysfunction, characterized by a loss of differentiation, reduced junctional integrity, and altered innate defence, underpins the pathogenesis of allergic diseases. Epithelial barrier impairment may be a potential therapeutic target for new treatment strategies Up now, monoclonal antibodies and new molecules targeting specific pathways of the immune response have been developed, and others are under investigation, both for adult and paediatric populations, which are affected by atopic dermatitis (AD), asthma, allergic rhinitis (AR), chronic rhinosinusitis with nasal polyps (CRSwNP), or eosinophilic esophagitis (EoE). In children affected by severe asthma biologics targeting IgE, IL-5 and against IL-4 and IL-13 receptors are already available, and they have also been applied in CRSwNP. In severe AD Dupilumab, a biologic which inhibits both IL-4 and IL-13, the most important cytokines involved in inflammation response, has been approved for treatment of patients over 12 years. While a biological approach has already shown great efficacy on the treatment of severe atopic conditions, early intervention to restore epithelial barrier integrity, and function may prevent the inflammatory response and the development of the atopic march.
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Puzzovio PG, Levi-Schaffer F. The allergic effector unit: From basic science to drug-targetable mast cell-eosinophil interactions in patients. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2021; 9:3845-3846. [PMID: 34627540 DOI: 10.1016/j.jaip.2021.07.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 07/02/2021] [Indexed: 12/29/2022]
Affiliation(s)
- Pier Giorgio Puzzovio
- Pharmacology and Experimental Therapeutics Unit, School of Pharmacy, Institute for Drug Research, Faculty of Medicine, the Hebrew University of Jerusalem, Jerusalem, Israel
| | - Francesca Levi-Schaffer
- Pharmacology and Experimental Therapeutics Unit, School of Pharmacy, Institute for Drug Research, Faculty of Medicine, the Hebrew University of Jerusalem, Jerusalem, Israel.
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35
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Reply to "The allergic effector unit: From basic science to drug-targetable mast cell-eosinophil interactions in patients". THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2021; 9:3846-3847. [PMID: 34627542 DOI: 10.1016/j.jaip.2021.07.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 07/02/2021] [Indexed: 11/22/2022]
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He Y, Ning J, Li B, Guo H, Hao N, Wu C. IL-9 contributes to the host immune response against Helicobacter pylori and helps limit infection in a Mouse Model. Helicobacter 2021; 26:e12827. [PMID: 34231938 DOI: 10.1111/hel.12827] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 04/16/2021] [Accepted: 05/09/2021] [Indexed: 12/23/2022]
Abstract
BACKGROUND As an important mediator in lots of diseases, interleukin-9 (IL-9) can be a protector or pro-inflammatory cytokine depending on the complicated inflammatory milieu. Helicobacter pylori (H. pylori) induced a series of immunology cells and cytokines change, and however, the role of IL-9 in H. pylori infection remains unknown. MATERIALS AND METHODS Wild-type and IL-9 deficient mice were infected with H. pylori by means of intragastric administration. The colonization of H. pylori bacteria was measured by detecting specific 16s rDNA, and the intensity of inflammation was observed by H&E stain. The expression level of inflammation cytokines was determined by ELISA and quantitative real-time PCR. RESULTS IL-9 was increased due to the attack of H. pylori, besides deletion of Il9 aggravated the bacterial colonization and inflammation intensity. In addition, treatment of rmIL-9 reduced colonized H. pylori and inflammation level, indicated that IL-9 was a protector for the host against this bacterium. Followed by the H. pylori infection, interferon (IFN)-γ and interleukin (IL)-17A were up-regulated as expected, and nevertheless, the expression of IL-17A shared a positive relationship with IL-9 while IFN-γ negative associated with IL-9. Moreover, we also proved that Treg cells were not involved in the protective effect of IL-9, and meanwhile, CD4+ CD25- T cells secreted more IFN-γ and less IL-17A in vitro due to the deletion of Il9. CONCLUSIONS IL-9 plays a protective role against H. pylori and the protection associated with cytokines change including IFN-γ and IL-17A.
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Affiliation(s)
- Yafei He
- The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Jie Ning
- Department of Critical Care Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Bin Li
- Department of Critical Care Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Hong Guo
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Ningbo Hao
- Department of Gastroenterology, PLA Rocket Force Characteristic Medical Center, Beijing, China
| | - Chao Wu
- Department of Critical Care Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
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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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Bidirectional crosstalk between eosinophils and esophageal epithelial cells regulates inflammatory and remodeling processes. Mucosal Immunol 2021; 14:1133-1143. [PMID: 33972688 PMCID: PMC8380647 DOI: 10.1038/s41385-021-00400-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 03/05/2021] [Accepted: 03/08/2021] [Indexed: 02/04/2023]
Abstract
Eosinophils accumulate adjacent to epithelial cells in the mucosa of patients with eosinophilic esophagitis (EoE), yet the bidirectional communication between these cells is not well understood. Herein, we investigated the crosstalk between human eosinophils and esophageal epithelial cells. We report that blood-derived eosinophils have prolonged survival when cocultured with epithelial cells; 96 ± 1% and 30 ± 6% viability was observed after 7 and 14 days of coculture, respectively, compared with 1 ± 0% and 0 ± 0% of monoculture. In the presence of IL-13 and epithelial cells, eosinophils had greater survival (68 ± 1%) at 14 days compared with cocultures lacking IL-13. Prolonged eosinophil viability did not require cellular contact and was observed when eosinophils were cultured in conditioned media from esophageal epithelial cells; neutralizing GM-CSF attenuated eosinophil survival. The majority of eosinophil transcripts (58%) were dysregulated in cocultured eosinophils compared with freshly isolated cells. Analysis of epithelial cell transcripts indicated that exposure to eosinophils induced differential expression of a subset of genes that were part of the EoE esophageal transcriptome. Collectively, these results uncover a network of crosstalk between eosinophils and esophageal epithelial cells involving epithelial mediated eosinophil survival and reciprocal changes in cellular transcripts, events likely to occur in EoE.
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Chen PH, Anderson L, Zhang K, Weiss GA. Eosinophilic Gastritis/Gastroenteritis. Curr Gastroenterol Rep 2021; 23:13. [PMID: 34331146 DOI: 10.1007/s11894-021-00809-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/10/2021] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW Eosinophilic gastritis/gastroenteritis (EG/EGE) are rare eosinophilic infiltrative disorders in children and adults that fall under the umbrella term eosinophilic gastrointestinal disorders (EGIDs). EGIDs also include eosinophilic esophagitis (EoE) and eosinophilic colitis. In this article, we present the current literature regarding the clinical presentation, diagnostic criteria, and management of EG/EGE. RECENT FINDINGS The underlying complex pathophysiology remains unknown, yet hypersensitivity response is a central component. Unlike EoE, standardized diagnostic criteria are lacking but, promising research employing tissue-based and blood-based methods of diagnosis have been reported. Non-EoE EGIDs are more challenging to treat than EoE. More than a third of patients may achieve spontaneous remission. Still, most will require dietary elimination and/or pharmaceutical interventions, mainly corticosteroids, but also biologics (monoclonal antibodies against IL-4, IL-5, TNFα, integrin α4β7, and IgE), mast-cell stabilizers, leukotriene (LT)-receptor antagonists, and antihistamines. Promising research suggests the role of AK002, an anti-siglec antibody, in clinical and histological improvement. Given the rarity and underdiagnosis of EG/EGE, different natural progression compared to EoE, heterogeneous clinical manifestations, and probable normal endoscopic appearance, it is vital to maintain a high suspicion index in atopic patients, obtain at least 5-6 random biopsies from each site for gastro/duodenal eosinophilic infiltrate with the subsequent exclusion of inflammatory, allergic and infectious differential diagnoses to increase the yield of an accurate diagnosis. Corticosteroids remain the mainstay of treatment, often requiring long-term use. Steroid-sparing agents remain experimental. Goals of therapy move beyond clinical remission but lack evidence to support histological remission.
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Affiliation(s)
- Phillip H Chen
- David Geffen School of Medicine at UCLA, 100 UCLA Medical Plaza, suite 345, Los Angeles, CA, 90095, USA.,Department of Internal Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Lorraine Anderson
- Department of Allergy-Immunology, University of California Los Angeles, Los Angeles, CA, USA
| | - Kuixing Zhang
- Department of Pathology, University of California Los Angeles, Los Angeles, CA, USA
| | - Guy A Weiss
- David Geffen School of Medicine at UCLA, 100 UCLA Medical Plaza, suite 345, Los Angeles, CA, 90095, USA. .,Celiac Disease Program, Vatche and Tamar Manoukian Division of Digestive Diseases, University of California Los Angeles, Los Angeles, CA, USA.
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Sahiner UM, Layhadi JA, Golebski K, István Komlósi Z, Peng Y, Sekerel B, Durham SR, Brough H, Morita H, Akdis M, Turner P, Nadeau K, Spits H, Akdis C, Shamji MH. Innate lymphoid cells: The missing part of a puzzle in food allergy. Allergy 2021; 76:2002-2016. [PMID: 33583026 DOI: 10.1111/all.14776] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 01/29/2021] [Accepted: 02/04/2021] [Indexed: 12/11/2022]
Abstract
Food allergy is an increasingly prevalent disease driven by uncontrolled type 2 immune response. Currently, knowledge about the underlying mechanisms that initiate and promote the immune response to dietary allergens is limited. Patients with food allergy are commonly sensitized through the skin in their early life, later on developing allergy symptoms within the gastrointestinal tract. Food allergy results from a dysregulated type 2 response to food allergens, characterized by enhanced levels of IgE, IL-4, IL-5, and IL-13 with infiltration of mast cells, eosinophils, and basophils. Recent studies raised a possible role for the involvement of innate lymphoid cells (ILCs) in driving food allergy. Unlike lymphocytes, ILCs lack They represent a group of lymphocytes that lack specific antigen receptors. ILCs contribute to immune responses not only by releasing cytokines and other mediators but also by responding to cytokines produced by activated cells in their local microenvironment. Due to their localization at barrier surfaces of the airways, gut, and skin, ILCs form a link between the innate and adaptive immunity. This review summarizes recent evidence on how skin and gastrointestinal mucosal immune system contribute to both homeostasis and the development of food allergy, as well as the involvement of ILCs toward inflammatory processes and regulatory mechanisms.
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Affiliation(s)
- Umit M Sahiner
- Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Inflammation, Repair and Development, Imperial College London, London, UK.,School of Medicine Department of Pediatric Allergy, Hacettepe University, Ankara, Turkey
| | - Janice A Layhadi
- Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Inflammation, Repair and Development, Imperial College London, London, UK
| | - Korneliusz Golebski
- Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.,Department of Respiratory Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | | | - Yaqi Peng
- Swiss Institute of Allergy and Asthma Research, Davos, Switzerland
| | - Bulent Sekerel
- School of Medicine Department of Pediatric Allergy, Hacettepe University, Ankara, Turkey
| | - Stephen R Durham
- Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Inflammation, Repair and Development, Imperial College London, London, UK
| | - Helen Brough
- Children's Allergy Service, Evelina London, Guys and St Thomas, NHS Trust, London, UK.,Paediatric Allergy Group, Department of Women and Children's Heath, School of Life Course Sciences, London, UK.,Paediatric Allergy Group, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Hideaki Morita
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.,Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland.,Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Mübeccel Akdis
- Swiss Institute of Allergy and Asthma Research, Davos, Switzerland
| | - Paul Turner
- Section of Inflammation, Repair and Development, National Heart & Lung Institute, Imperial College London, London, UK
| | - Kari Nadeau
- Sean N. Parker Center for Allergy & Asthma Research, Stanford University, Stanford, CA, USA
| | - Hergen Spits
- Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Cezmi Akdis
- Swiss Institute of Allergy and Asthma Research, Davos, Switzerland
| | - Mohamed H Shamji
- Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Inflammation, Repair and Development, Imperial College London, London, UK
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Harish A, Schwartz SA. Targeted Anti-IL-5 Therapies and Future Therapeutics for Hypereosinophilic Syndrome and Rare Eosinophilic Conditions. Clin Rev Allergy Immunol 2021; 59:231-247. [PMID: 31919743 DOI: 10.1007/s12016-019-08775-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Eosinophilic inflammation is a component of many atopic diseases such as asthma, and biologics targeting eosinophils have been shown to be effective in subsets of these patients. However, there also are conditions in which eosinophils are the key inflammatory cells responsible for driving tissue damage. In these eosinophilic diseases such as hyper-eosinophilic syndrome, eosinophilic esophagitis, and eosinophilic granulomatosis with polyangiitis (EGPA), the development of biologics inhibiting eosinophilic inflammation have offered targeted therapeutic strategies for patients that have not responded well to typical first line drugs, which often have significant adverse side effects with poor disease modification or recurrent relapse with significant morbidity. IL-5 has long been recognized as the key inflammatory cytokine involved in the priming and survival of eosinophils and their proliferation and maturation in eosinophilic disease. There are a number of trials and case series demonstrating the immunomodulatory benefits of anti-IL-5 therapies in these diseases with good clinical responses. Yet, due to the heterogeneity and rarity of these conditions, anti-IL-5 therapies have not resulted in disease remission for all patients. Clearly, further research into the use of anti-IL-5 therapies in various eosinophilic diseases is needed and ongoing investigation into other immune mechanisms underlying chronic eosinophilic diseases may provide alternative therapies for these challenging conditions.
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Affiliation(s)
- Aasha Harish
- Division of Allergy and Immunology, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, 1020 Youngs Road, Williamsville, NY, 14221, USA.
| | - Stanley A Schwartz
- Division of Allergy and Immunology, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, 1020 Youngs Road, Williamsville, NY, 14221, USA
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Abstract
PURPOSE OF REVIEW Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the oesophagus whose incidence is on the rise. Despite maximal use of guideline-based therapies including food elimination diets and steroids, many patients remain symptomatic. This review serves to summarize safety and efficacy of monoclonal antibodies in treatment of EoE. RECENT FINDINGS There has been an increasing number of biologics under consideration for EoE and several that have undergone clinical trials. mAbs that target specific effectors involved in the disease may offer additional clinical and histologic benefit. In addition, they offer a more benign adverse effect profile than traditional therapies. SUMMARY Biologics for treatment of EoE may result in symptom and histologic improvement and has the potential to treat disease with minimal side effects.
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Affiliation(s)
- Simin Zhang
- University of Cincinnati College of Medicine, Department of Internal Medicine, Division of Immunology/Allergy
| | - Amal H Assa'ad
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, Division of Allergy and Immunology, Cincinnati, OH, USA
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43
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Doyle AD, Masuda MY, Kita H, Wright BL. Eosinophils in Eosinophilic Esophagitis: The Road to Fibrostenosis is Paved With Good Intentions. Front Immunol 2020; 11:603295. [PMID: 33335531 PMCID: PMC7736408 DOI: 10.3389/fimmu.2020.603295] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 11/03/2020] [Indexed: 12/15/2022] Open
Abstract
Eosinophilic esophagitis (EoE) is an antigen-driven disease associated with epithelial barrier dysfunction and chronic type 2 inflammation. Eosinophils are the defining feature of EoE histopathology but relatively little is known about their role in disease onset and progression. Classically defined as destructive, end-stage effector cells, eosinophils (a resident leukocyte in most of the GI tract) are increasingly understood to play roles in local immunity, tissue homeostasis, remodeling, and repair. Indeed, asymptomatic esophageal eosinophilia is observed in IgE-mediated food allergy. Interestingly, EoE is a potential complication of oral immunotherapy (OIT) for food allergy. However, we recently found that patients with peanut allergy may have asymptomatic esophageal eosinophilia at baseline and that peanut OIT induces transient esophageal eosinophilia in most subjects. This is seemingly at odds with multiple studies which have shown that EoE disease severity correlates with tissue eosinophilia. Herein, we review the potential role of eosinophils in EoE at different stages of disease pathogenesis. Based on current literature we suggest the following: (1) eosinophils are recruited to the esophagus as a homeostatic response to epithelial barrier disruption; (2) eosinophils mediate barrier-protective activities including local antibody production, mucus production and epithelial turnover; and (3) when type 2 inflammation persists, eosinophils promote fibrosis.
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Affiliation(s)
- Alfred D Doyle
- Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, United States
| | - Mia Y Masuda
- Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, United States
| | - Hirohito Kita
- Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, United States.,Department of Immunology, Mayo Clinic Arizona, Scottsdale, AZ, United States
| | - Benjamin L Wright
- Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, United States.,Division of Pulmonology, Phoenix Children's Hospital, Phoenix, AZ, United States
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Park H, Jung AY, Chang CS, Kim YH. Bacillus clausii, a Foreshore-Derived Probiotic, Attenuates Allergic Airway Inflammation Through Downregulation of Hypoxia Signaling. JOURNAL OF RHINOLOGY 2020. [DOI: 10.18787/jr.2020.00325] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Background and Objectives: The immunomodulatory effects and mechanism of probiotics in allergic airway disease are largely unknown. We studied whether <i>Bacillus clausii</i> (BC), a probiotic derived from mudflats, had anti-allergic effects and compared the results with those of <i>Lactobacillus paracasei</i> (LP). We also examined whether the anti-allergic mechanisms of probiotics are associated with hypoxia signaling.Materials and Method: Forty-two BALB/c mice were randomly assigned to six experimental groups: controls, ovalbumin (OVA)-induced mice for inducing asthma, and OVA-induced mice that were orally administered LP or BC, at 1×10<sup>9</sup> or 5×10<sup>9</sup> CFU/mL each. We performed differential cell count testing on bronchoalveolar lavage fluid (BALF), lung histopathology, serum totals and OVA-specific IgE and IgG1 assessments, Th2 cytokine titers (IL-4, IL-5) in BALF and pulmonary parenchyma, quantitative PCR for <i>heme oxygenase (HO)-1</i> and <i>Hif-1α</i>, and immunohistochemistry.Results: Compared to the OVA group mice, OVA-sensitized mice treated with LP or BC showed significantly reduced numbers of eosinophils and neutrophils in the BALF (p<0.05). Both probiotics also significantly reduced pulmonary inflammation and eosinophil infiltration. Mice in the LP or BC group had a substantially lower titer of IL-4 and IL-5 in BALF, and decreased IL-4 and IL-5 expression in the lung parenchyma. Real-time PCR and immunohistochemistry showed that both LP and BC could significantly suppress <i>HO-1</i> and <i>Hif-1α</i> expression in asthmatic mice (p<0.05).Conclusion: BC can attenuate murine allergic asthma by regulating HIF-1α signaling, and its anti-allergic effect is comparable to that of LP.
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45
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Yamashita M, Miyoshi M, Iwai M, Takeda R, Ono T, Kabuki T. Lactobacillus helveticus SBT2171 Alleviates Perennial Allergic Rhinitis in Japanese Adults by Suppressing Eosinophils: A Randomized, Double-Blind, Placebo-Controlled Study. Nutrients 2020; 12:E3620. [PMID: 33255731 PMCID: PMC7760906 DOI: 10.3390/nu12123620] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 11/17/2020] [Accepted: 11/24/2020] [Indexed: 11/16/2022] Open
Abstract
This article examines the effects of fermented milk (FM) containing Lactobacillus helveticus SBT2171 (LH2171) on the subjective symptoms of individuals with mild and moderate perennial allergy. Two hundred subjects were divided into two groups and consumed FM containing LH2171 or placebo FM once per day for 16 weeks. The primary endpoints were defined as per the degree of nasal and ocular symptoms and difficulty in daily life as determined by the Japanese guidelines for allergy rhinitis and the Japanese allergic rhinitis standard quality of life questionnaire, respectively. The secondary endpoints included parameters related to allergic symptoms in the blood and nasal fluids, as well as the mental status. The severity of allergic rhinitis significantly improved in the LH2171 group compared to that in the placebo group. Additionally, the LH2171 group showed a significantly lower degree of "stuffy nose" (as per the diary survey) than the placebo group. Eosinophil counts in the nasal fluids and in the blood were significantly lower in the LH2171 group compared to the placebo group. Thus, the oral administration of FM containing LH2171 cells alleviated perennial allergic rhinitis in individuals with mild and moderate symptoms, possibly via suppression of eosinophils in both the blood and nasal fluids.
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Affiliation(s)
- Maya Yamashita
- Milk Science Research Institute, MEGMILK SNOW BRAND Co. Ltd., 1-1-2, Minamidai, Kawagoe, Saitama 350-1165, Japan; (M.Y.); (M.M.); (M.I.)
| | - Masaya Miyoshi
- Milk Science Research Institute, MEGMILK SNOW BRAND Co. Ltd., 1-1-2, Minamidai, Kawagoe, Saitama 350-1165, Japan; (M.Y.); (M.M.); (M.I.)
| | - Masayuki Iwai
- Milk Science Research Institute, MEGMILK SNOW BRAND Co. Ltd., 1-1-2, Minamidai, Kawagoe, Saitama 350-1165, Japan; (M.Y.); (M.M.); (M.I.)
| | - Ryuji Takeda
- Department of Nutritional Sciences for Well-Being, Faculty of Health Sciences for Welfare, Kansai University of Welfare Sciences, 3-11-1, Ashigaoka, Kashiwara, Osaka 582-0026, Japan;
| | - Takahiro Ono
- Ueno-Asagao Clinic, 6F Kairaku Building, 2-7-5, Higashiueno, Taito, Tokyo 110-0015, Japan;
| | - Toshihide Kabuki
- Milk Science Research Institute, MEGMILK SNOW BRAND Co. Ltd., 1-1-2, Minamidai, Kawagoe, Saitama 350-1165, Japan; (M.Y.); (M.M.); (M.I.)
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46
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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: 16] [Impact Index Per Article: 3.2] [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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47
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Orsini Delgado ML, Rizzo GP, Fossati CA, Pasquevich KA, Cassataro J, Smaldini PL, Docena GH. Sublingual Omp16-driven redirection of the allergic intestinal response in a pre-clinical model of food allergy. Clin Exp Allergy 2020; 50:954-963. [PMID: 32501552 DOI: 10.1111/cea.13676] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 05/08/2020] [Accepted: 05/29/2020] [Indexed: 01/18/2023]
Abstract
BACKGROUND IgE-mediated food allergy remains a significant and growing worldwide problem. Sublingual immunotherapy (SLIT) shows an excellent safety profile for food allergy, but the clinical efficacy needs to be improved. This study assessed the effects of the Toll-like receptor 4 agonist outer membrane protein (Omp) 16 from Brucella abortus combined with cow´s milk proteins (CMP) through the sublingual route to modulate cow's milk allergy in an experimental model. METHODS Mice sensitized with cholera toxin and CMP were orally challenged with the allergen to elicit hypersensitivity reactions. Then, mice were treated with a very low amount of CMP along with Omp16 as a mucosal adjuvant, and finally, animals were re-exposed to CMP. Systemic and mucosal immune parameters were assessed in vivo and in vitro. RESULTS We found that the sublingual administration of Omp16 + CMP induced a buccal Th1 immune response that modulated the intestinal allergic response with the suppression of symptoms, reduction of IgE and IL-5, and up-regulation of IgG2a and IFN-γ. The adoptive transfer of submandibular IFN-γ-producing α4β7+ CD4+ and CD8+ cells conferred protection against allergic sensitization. The use of Omp16 + CMP promoted enhanced protection compared to CMP alone. CONCLUSION In conclusion, Omp16 represents a promising mucosal adjuvant that can be used to improve the clinical and immune efficacy of SLIT for food allergy.
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Affiliation(s)
- Maria Lucía Orsini Delgado
- Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), UNLP, CONICET, asociado a CIC PBA, Facultad de Ciencias Exactas, Departamento de Ciencias Biológicas, La Plata, Argentina
| | - Gastón Pascual Rizzo
- Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), UNLP, CONICET, asociado a CIC PBA, Facultad de Ciencias Exactas, Departamento de Ciencias Biológicas, La Plata, Argentina
| | - Carlos Alberto Fossati
- Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), UNLP, CONICET, asociado a CIC PBA, Facultad de Ciencias Exactas, Departamento de Ciencias Biológicas, La Plata, Argentina
| | - Karina Alejandra Pasquevich
- Instituto de Investigaciones Biotecnológicas "Dr. Rodolfo A. Ugalde", Universidad Nacional de San Martin y Consejo Nacional de Investigaciones Científicas y Técnicas, San Martín, Argentina
| | - Juliana Cassataro
- Instituto de Investigaciones Biotecnológicas "Dr. Rodolfo A. Ugalde", Universidad Nacional de San Martin y Consejo Nacional de Investigaciones Científicas y Técnicas, San Martín, Argentina
| | - Paola Lorena Smaldini
- Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), UNLP, CONICET, asociado a CIC PBA, Facultad de Ciencias Exactas, Departamento de Ciencias Biológicas, La Plata, Argentina
| | - Guillermo Horacio Docena
- Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), UNLP, CONICET, asociado a CIC PBA, Facultad de Ciencias Exactas, Departamento de Ciencias Biológicas, La Plata, Argentina
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48
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Esophageal type 2 cytokine expression heterogeneity in eosinophilic esophagitis in a multisite cohort. J Allergy Clin Immunol 2020; 145:1629-1640.e4. [PMID: 32197970 DOI: 10.1016/j.jaci.2020.01.051] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 01/07/2020] [Accepted: 01/28/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND There is strong evidence for a role of type 2 cytokines in the pathogenesis of eosinophilic esophagitis (EoE); however, heterogeneity in type 2 gene expression has not been examined. OBJECTIVE We examined type 2 immunity-associated gene expression in esophageal biopsy specimens, aiming to determine the degree of cytokine heterogeneity and its potential clinical significance. METHODS Patients (n = 312) were recruited from 10 sites associated with the Consortium of Eosinophilic Gastrointestinal Disease Researchers. In addition to histologic and endoscopic assessment, esophageal biopsy specimens were examined for expression of 96 genes within the EoE diagnostic panel. RESULTS Five subgroups of patients with active EoE were identified by unsupervised clustering based on expression of IL4, IL5, IL13, C-C motif chemokine ligand 26 (CCL26), thymic stromal lymphopoietin (TSLP), Charcot-Leyden crystal (CLC), C-C motif chemokine receptor 3 (CCR3), and CPA3. These groups differed in age (P < .02) and EoE diagnostic panel score (P < 1.08E-30) but not in eosinophil levels. The group V patients had the highest expression of IL5, TSLP, and CCL26 and genes associated with tissue remodeling, such as COL8A1, actin γ-2 (ACTG2), and tetraspanin 12 (TSPAN12). IL5 and IL13 were highly expressed in group IV; however, groups IV and V differed in age (34 vs 14 years [P < .05]). Groups II and III, which exhibited intermediate expression of IL5 and CPA3, were differentiated by high TSLP and IL13 in group III. CONCLUSION We observed heterogeneous type 2 gene expression among patients with active EoE. Type 2 gene overexpression was not directly proportional to disease features; this was especially true for tissue remodeling events. These findings highlight a clinical opportunity for leveraging molecular endotypes to implement personalized medicine in EoE.
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49
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Gastrointestinal Manifestations of Hypereosinophilic Syndromes and Mast Cell Disorders: a Comprehensive Review. Clin Rev Allergy Immunol 2020; 57:194-212. [PMID: 30003499 DOI: 10.1007/s12016-018-8695-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hypereosinophilic syndrome and mastocytosis are relatively rare proliferative diseases encountered in the general population. However, allergists frequently consider these disorders in the differential of patients presenting with gastrointestinal, pulmonary, cutaneous, and allergic symptoms. Gastrointestinal symptoms are some of the most frequent and/or debilitating aspects of both disease states and in many cases lead to poor quality of life and functional limitation for the patient. They are the third most common clinical manifestation in hypereosinophilic syndrome and have been found to be the most distressful aspect of the disorder in those with systemic mastocytosis. Both eosinophils and mast cells play integral parts in normal gut physiology, but when and how exactly their effector functionality translates into clinically significant disease remains unclear, and the available literature regarding their pathophysiology remains sparse. Eosinophils and mast cells even, in fact, may not necessarily function in isolation from each other but can participate in bidirectional crosstalk. Both are affected by similar mediators and can also influence one another in a paracrine fashion. Their interactions include both production of soluble mediators for specific eosinophil and mast cell receptors (for example, eosinophil recruitment and activation by mast cells releasing histamine and eotaxin) as well as direct physical contact. The mechanistic relationship between clonal forms of hypereosinophilia and systemic mastocytosis has also been explored. The nature of gastrointestinal symptomatology in the setting of both hypereosinophilic syndrome and mast cell disease is frequently manifold, heterogeneous, and the lack of better targeted therapy makes diagnosis and management challenging, especially when faced with a substantial differential. Currently, the management of these gastrointestinal symptoms relies on the treatment of the overall disease process. In hypereosinophilia patients, systemic corticosteroids are mainstay, although steroid-sparing agents such as hydroxyurea, IFN-α, methotrexate, cyclosporine, imatinib, and mepolizumab have been utilized with varying success. In mastocytosis patients, anti-mediator therapy with antihistamines and mast cell stabilization with cromolyn sodium can be considered treatments of choice, followed by other therapies yet to be thoroughly studied, including the role of the low-histamine diet, corticosteroids, and treatment of associated IBS symptoms. Given that both eosinophils and mast cells may have joint pathophysiologic roles, they have the potential to be a combined target for therapeutic intervention in disease states exhibiting eosinophil or mast cell involvement.
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50
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Agache I, Cojanu C, Laculiceanu A, Rogozea L. Critical Points on the Use of Biologicals in Allergic Diseases and Asthma. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2020; 12:24-41. [PMID: 31743962 PMCID: PMC6875478 DOI: 10.4168/aair.2020.12.1.24] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 10/17/2019] [Accepted: 10/18/2019] [Indexed: 12/19/2022]
Abstract
Improved understanding of the contribution of immune-inflammatory mechanisms in allergic diseases and asthma has encouraged development of biologicals and small molecules specifically targeting the innate and adaptive immune response. There are several critical points impacting the efficacy of this stratified approach, from the complexity of disease endotypes to the effectiveness in real-world settings. We discuss here how these barriers can be overcome to facilitate the development of implementation science for allergic diseases and asthma.
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Affiliation(s)
- Ioana Agache
- Department of Allergy and Clinical Immunology, Faculty of Medicine, Transylvania University of Brasov, Brasov, Romania.
| | - Catalina Cojanu
- Department of Allergy and Clinical Immunology, Faculty of Medicine, Transylvania University of Brasov, Brasov, Romania
| | - Alexandru Laculiceanu
- Department of Allergy and Clinical Immunology, Faculty of Medicine, Transylvania University of Brasov, Brasov, Romania
| | - Liliana Rogozea
- Department of Allergy and Clinical Immunology, Faculty of Medicine, Transylvania University of Brasov, Brasov, Romania
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