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Porret R, Alcaraz-Serna A, Peter B, Bernier-Latmani J, Cecchin R, Alfageme-Abello O, Ermellino L, Hafezi M, Pace E, du Pré MF, Lana E, Golshayan D, Velin D, Eyquem J, Tang Q, Petrova TV, Coukos G, Irving M, Pot C, Pantaleo G, Sollid LM, Muller YD. T cell receptor precision editing of regulatory T cells for celiac disease. Sci Transl Med 2025; 17:eadr8941. [PMID: 40106579 DOI: 10.1126/scitranslmed.adr8941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Accepted: 02/11/2025] [Indexed: 03/22/2025]
Abstract
Celiac disease, a gluten-sensitive enteropathy, demonstrates a strong human leukocyte antigen (HLA) association, with more than 90% of patients carrying the HLA-DQ2.5 allotype. No therapy is available for the condition except for a lifelong gluten-free diet. To address this gap, we explored the therapeutic potential of regulatory T cells (Tregs). By orthotopic replacement of T cell receptors (TCRs) through homology-directed repair, we generated gluten-reactive HLA-DQ2.5-restricted CD4+ engineered (e) T effector cells (Teffs) and eTregs and performed in vivo experiments in HLA-DQ2.5 transgenic mice. Of five validated TCRs, TCRs specific for two immunodominant and deamidated gluten epitopes (DQ2.5-glia-α1a and DQ2.5-glia-α2) were selected for further evaluation. CD4+ eTeffs exposed to deamidated gluten through oral gavage colocalized with dendritic and B cells in the Peyer's patches and gut-draining lymph nodes and specifically migrated to the intestine. The suppressive function of human eTregs correlated with high TCR functional activity. eTregs specific for one epitope suppressed the proliferation and gut migration of CD4+ eTeffs specific for the same and the other gluten epitope, demonstrating bystander suppression. The suppression requires an antigen-specific activation of eTregs given that polyclonal Tregs failed to suppress CD4+ eTeffs. These findings highlight the potential of gluten-reactive eTregs as a therapeutic for celiac disease.
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Affiliation(s)
- Raphaël Porret
- Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne CH-1005, Switzerland
| | - Ana Alcaraz-Serna
- Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne CH-1005, Switzerland
| | - Benjamin Peter
- Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne CH-1005, Switzerland
| | - Jeremiah Bernier-Latmani
- Department of Oncology, Lausanne University Hospital and University of Lausanne, 1005 Lausanne, Switzerland
| | - Rebecca Cecchin
- Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne CH-1005, Switzerland
| | - Oscar Alfageme-Abello
- Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne CH-1005, Switzerland
| | - Laura Ermellino
- Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne CH-1005, Switzerland
| | - Morteza Hafezi
- Department of Oncology, Lausanne University Hospital and University of Lausanne, 1005 Lausanne, Switzerland
| | - Eleonora Pace
- Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne CH-1005, Switzerland
| | - M Fleur du Pré
- Norwegian Coeliac Disease Research Centre, Institute of Clinical Medicine, University of Oslo and Department of Immunology, Oslo University Hospital, Oslo NO-0424, Norway
| | - Erica Lana
- Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne CH-1005, Switzerland
| | - Dela Golshayan
- Transplantation Center, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne CH-1005, Switzerland
| | - Dominique Velin
- Service of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, Lausanne CH-1005, Switzerland
| | - Justin Eyquem
- Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA
| | - Qizhi Tang
- Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA
| | - Tatiana V Petrova
- Department of Oncology, Lausanne University Hospital and University of Lausanne, 1005 Lausanne, Switzerland
| | - George Coukos
- Department of Oncology, Lausanne University Hospital and University of Lausanne, 1005 Lausanne, Switzerland
- Ludwig Institute for Cancer Research Lausanne Branch, 1066 Lausanne, Switzerland
| | - Melita Irving
- Department of Oncology, Lausanne University Hospital and University of Lausanne, 1005 Lausanne, Switzerland
- Ludwig Institute for Cancer Research Lausanne Branch, 1066 Lausanne, Switzerland
| | - Caroline Pot
- Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne CH-1005, Switzerland
| | - Giuseppe Pantaleo
- Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne CH-1005, Switzerland
| | - Ludvig M Sollid
- Norwegian Coeliac Disease Research Centre, Institute of Clinical Medicine, University of Oslo and Department of Immunology, Oslo University Hospital, Oslo NO-0424, Norway
| | - Yannick D Muller
- Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne CH-1005, Switzerland
- Centre for Human Immunology Lausanne, Lausanne CH-1005, Switzerland
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Yu T, Xie Y, Wang Z, Li J, Shen Y, Yuan J, Gao J, Fakruddin M, Wu Y, Chen H. Quercetin ameliorates celiac-related intestinal inflammation caused by wheat gluten through modulating oxidative stress, Th1/Th2/Treg balance, and intestinal microflora structure. Food Funct 2024; 15:9343-9356. [PMID: 39188248 DOI: 10.1039/d4fo03025g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/28/2024]
Abstract
Celiac disease is a chronic inflammatory autoimmune disease of the small bowel, and about 1% of the world's population is afflicted with celiac disease. To date, the most efficient treatment option is that the patient is required to strictly follow a gluten-free diet for their entire life, but it's difficult to adhere to and can lead to new nutritional imbalances, making it urgent to find novel nutritional interventions. Our aim was to explore the effects of nutritional intervention with quercetin on the celiac toxic effects of wheat gluten. This study systematically assessed the regulatory roles of quercetin on intestinal oxidative damage, immune response, inflammatory damage, and intestinal microflora dysbiosis in celiac disease by utilizing the established celiac in vitro and in vivo models induced by gluten. We discovered that quercetin could play a crucial role in intervening in celiac pathogenesis, not only owing to its antioxidant properties, but also because it modulates immune cell function and the intestinal microflora structure, particularly the regulation of Th1/Th2/Treg immune cell subpopulations and their functions, inhibition of the abundance of celiac disease marker flora such as Clostridium_celatum and Bacteroides_acidifaciens, and upregulation of the abundance of beneficial flora such as Butyricoccus_pullicaecorum and Bifidobacterium_longum, which ultimately worked together to ameliorate the celiac-related intestinal inflammation triggered by gluten. This study might provide new insights into the regulation of gut immunity and intestinal microflora homeostasis, as well as the potential application of quercetin in celiac disease.
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Affiliation(s)
- Tian Yu
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, Jiangxi, China.
- Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, Jiangxi, China
- School of Food Science and Technology, Nanchang University, Nanchang 330031, Jiangxi, China
| | - Yiting Xie
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, Jiangxi, China.
- Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, Jiangxi, China
- School of Food Science and Technology, Nanchang University, Nanchang 330031, Jiangxi, China
| | - Zhongliang Wang
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, Jiangxi, China.
- Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, Jiangxi, China
- School of Food Science and Technology, Nanchang University, Nanchang 330031, Jiangxi, China
| | - Jingjing Li
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, Jiangxi, China.
- Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, Jiangxi, China
- School of Food Science and Technology, Nanchang University, Nanchang 330031, Jiangxi, China
| | - Yunpeng Shen
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, Jiangxi, China.
- Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, Jiangxi, China
- School of Food Science and Technology, Nanchang University, Nanchang 330031, Jiangxi, China
| | - Juanli Yuan
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, Jiangxi, China.
- School of Pharmaceutical Science, Nanchang University, Nanchang 330006, Jiangxi, China
| | - Jinyan Gao
- School of Food Science and Technology, Nanchang University, Nanchang 330031, Jiangxi, China
| | - Md Fakruddin
- Department of Biochemistry and Microbiology, North South University, Bashundhara, Dhaka 1229, Bangladesh
| | - Yong Wu
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, Jiangxi, China.
- Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, Jiangxi, China
| | - Hongbing Chen
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, Jiangxi, China.
- Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, Jiangxi, China
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3
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Sadighi A, Aghamohammadpour Z, Sadeghpour Heravi F, Somi MH, Masnadi Shirazi Nezhad K, Hosseini S, Bahman Soufiani K, Ebrahimzadeh Leylabadlo H. The protective effects of Helicobacter pylori: A comprehensive review. JOURNAL OF RESEARCH IN CLINICAL MEDICINE 2024; 12:17. [DOI: 10.34172/jrcm.34509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 10/15/2023] [Indexed: 01/03/2025] Open
Abstract
Previous reports have estimated that approximately half of the world’s population is infected with Helicobacter pylori, the most prevalent infectious agent responsible for gastrointestinal illnesses. Due to the life-threatening effects of H. pylori infections, numerous studies have focused on developing medical therapies for H. pylori infections, while the commensal relationship and positive impacts of this bacterium on overall human health have been largely overlooked. The inhibitory efficacy of H. pylori on the progression of several chronic inflammatory disorders and gastrointestinal diseases has recently raised concerns about whether this bacterium should be eradicated in affected individuals or maintained in an appropriate balance depending on the patient’s condition. This review investigates the beneficial effects of H. pylori in preventing various diseases and discusses the potential association of conditions such as inflammatory disorders with the absence of H. pylori.
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Affiliation(s)
- Ali Sadighi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zahra Aghamohammadpour
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mohammad Hossein Somi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Samaneh Hosseini
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Katayoun Bahman Soufiani
- Department of Laboratory Sciences and Microbiology, Faculty of Medical Sciences, Tabriz Medical Sciences, Islamic Azad University, Tabriz, Iran
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Abadie V, Han AS, Jabri B, Sollid LM. New Insights on Genes, Gluten, and Immunopathogenesis of Celiac Disease. Gastroenterology 2024; 167:4-22. [PMID: 38670280 PMCID: PMC11283582 DOI: 10.1053/j.gastro.2024.03.042] [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: 12/12/2023] [Revised: 03/10/2024] [Accepted: 03/11/2024] [Indexed: 04/28/2024]
Abstract
Celiac disease (CeD) is a gluten-induced enteropathy that develops in genetically susceptible individuals upon consumption of cereal gluten proteins. It is a unique and complex immune disorder to study as the driving antigen is known and the tissue targeted by the immune reaction can be interrogated. This review integrates findings gained from genetic, biochemical, and immunologic studies, which together have revealed mechanisms of gluten peptide modification and HLA binding, thereby enabling a maladapted anti-gluten immune response. Observations in human samples combined with experimental mouse models have revealed that the gluten-induced immune response involves CD4+ T cells, cytotoxic CD8+ T cells, and B cells; their cross-talks are critical for the tissue-damaging response. The emergence of high-throughput technologies is increasing our understanding of the phenotype, location, and presumably function of the gluten-specific cells, which are all required to identify novel therapeutic targets and strategies for CeD.
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Affiliation(s)
- Valérie Abadie
- Department of Medicine, University of Chicago, Chicago, Illinois; Section of Gastroenterology, Nutrition and Hepatology, University of Chicago, Chicago, Illinois; Committee on Immunology, University of Chicago, Chicago, Illinois.
| | - Arnold S Han
- Columbia Center for Translational Immunology, Columbia University, New York, New York; Department of Microbiology and Immunology, Columbia University, New York, New York; Department of Medicine, Digestive and Liver Diseases, Columbia University, New York, New York
| | - Bana Jabri
- Department of Medicine, University of Chicago, Chicago, Illinois; Section of Gastroenterology, Nutrition and Hepatology, University of Chicago, Chicago, Illinois; Committee on Immunology, University of Chicago, Chicago, Illinois; Department of Pathology, University of Chicago, Chicago, Illinois; Department of Pediatrics, University of Chicago, Chicago, Illinois
| | - Ludvig M Sollid
- Norwegian Coeliac Disease Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Immunology, Oslo University Hospital-Rikshospitalet, Oslo, Norway
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Noori E, Hashemi N, Rezaee D, Maleki R, Shams F, Kazemi B, Bandepour M, Rahimi F. Potential therapeutic options for celiac Disease: An update on Current evidence from Gluten-Free diet to cell therapy. Int Immunopharmacol 2024; 133:112020. [PMID: 38608449 DOI: 10.1016/j.intimp.2024.112020] [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: 01/23/2024] [Revised: 04/01/2024] [Accepted: 04/03/2024] [Indexed: 04/14/2024]
Abstract
Celiac disease (CD) is a chronic autoimmune enteropathy and multifactorial disease caused by inappropriate immune responses to gluten in the small intestine. Weight loss, anemia, osteoporosis, arthritis, and hepatitis are among the extraintestinal manifestations of active CD. Currently, a strict lifelong gluten-free diet (GFD) is the only safe, effective, and available treatment. Despite the social burden, high expenses, and challenges of following a GFD, 2 to 5 percent of patients do not demonstrate clinical or pathophysiological improvement. Therefore, we need novel and alternative therapeutic approaches for patients. Innovative approaches encompass a broad spectrum of strategies, including enzymatic degradation of gluten, inhibition of intestinal permeability, modulation of the immune response, inhibition of the transglutaminase 2 (TG2) enzyme, blocking antigen presentation by HLA-DQ2/8, and induction of tolerance. Hence, this review is focused on comprehensive therapeutic strategies ranging from dietary approaches to novel methods such as antigen-based immunotherapy, cell and gene therapy, and the usage of nanoparticles for CD treatment.
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Affiliation(s)
- Effat Noori
- Department of Biotechnology, Faculty of Medicine, Shahed University, Tehran, Iran.
| | - Nader Hashemi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Delsuz Rezaee
- School of Allied Medical Sciences, Ilam University of Medical Sciences, Ilam, Iran; Department of Medical Biotechnology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Reza Maleki
- Adelaide Medical School, The University of Adelaide, Adelaide, SA 5005, Australia
| | - Forough Shams
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Bahram Kazemi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mojgan Bandepour
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fardin Rahimi
- Department of Biotechnology, Faculty of Medicine, Shahed University, Tehran, Iran
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Abbasi A, Bazzaz S, A. Ibrahim S, Hekmatdoost A, Hosseini H, Sabahi S, Sheykhsaran E, Rahbar Saadat Y, Asghari Ozma M, Lahouty M. A Critical Review on the Gluten-Induced Enteropathy/Celiac Disease: Gluten-Targeted Dietary and Non-Dietary Therapeutic Approaches. FOOD REVIEWS INTERNATIONAL 2024; 40:883-923. [DOI: 10.1080/87559129.2023.2202405] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Affiliation(s)
- Amin Abbasi
- Student Research Committee, Department of Food Science and Technology, National Nutrition and Food Technology Research Institute, Faculty of Nutrition Science and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sara Bazzaz
- Department of Food Science and Technology, National Nutrition and Food Technology Research Institute, Faculty of Nutrition Science and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Salam A. Ibrahim
- Food Microbiology and Biotechnology Laboratory, Food and Nutritional Sciences Program, College of Agriculture and Environmental Sciences, North Carolina A & T State University, Greensboro, North Carolina, USA
| | - Azita Hekmatdoost
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hedayat Hosseini
- Department of Food Science and Technology, National Nutrition and Food Technology Research Institute, Faculty of Nutrition Science and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sahar Sabahi
- Department of Nutrition, School of Allied Medical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Elham Sheykhsaran
- Department of Medical Bacteriology and Virology, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mahdi Asghari Ozma
- Department of Medical Bacteriology and Virology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Masoud Lahouty
- Department of Microbiology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
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Wang Q, Lu Q, Jia S, Zhao M. Gut immune microenvironment and autoimmunity. Int Immunopharmacol 2023; 124:110842. [PMID: 37643491 DOI: 10.1016/j.intimp.2023.110842] [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: 05/23/2023] [Revised: 08/14/2023] [Accepted: 08/19/2023] [Indexed: 08/31/2023]
Abstract
A variety of immune cells or tissues are present in the gut to form the gut immune microenvironment by interacting with gut microbiota, and to maintain the gut immune homeostasis. Accumulating evidence indicated that gut microbiota dysbiosis might break the homeostasis of the gut immune microenvironment, which was associated with many health problems including autoimmune diseases. Moreover, disturbance of the gut immune microenvironment can also induce extra-intestinal autoimmune disorders through the migration of intestinal pro-inflammatory effector cells from the intestine to peripheral inflamed sites. This review discussed the composition of the gut immune microenvironment and its association with autoimmunity. These findings are expected to provide new insights into the pathogenesis of various autoimmune disorders, as well as novel strategies for the prevention and treatment against related diseases.
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Affiliation(s)
- Qiaolin Wang
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing 210042, China
| | - Qianjin Lu
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing 210042, China
| | - Sujie Jia
- Department of Pharmacy, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China.
| | - Ming Zhao
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing 210042, China.
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8
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Camarca A, Rotondi Aufiero V, Mazzarella G. Role of Regulatory T Cells and Their Potential Therapeutic Applications in Celiac Disease. Int J Mol Sci 2023; 24:14434. [PMID: 37833882 PMCID: PMC10572745 DOI: 10.3390/ijms241914434] [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: 08/03/2023] [Revised: 09/12/2023] [Accepted: 09/14/2023] [Indexed: 10/15/2023] Open
Abstract
Celiac disease (CeD) is a T-cell-mediated immune disease, in which gluten-derived peptides activate lamina propria effector CD4+ T cells. While this effector T cell subset produces proinflammatory cytokines, which cause substantial tissue injury in vivo, additional subsets of T cells exist with regulatory functions (Treg). These subsets include CD4+ type 1 regulatory T cells (Tr1) and CD4+ CD25+ T cells expressing the master transcription factor forkhead box P3 (Foxp3) that may have important implications in disease pathogenesis. In this review, we provide an overview of the current knowledge about the effects of immunomodulating cytokines on CeD inflammatory status. Moreover, we outline the main Treg cell populations found in CeD and how their regulatory activity could be influenced by the intestinal microenvironment. Finally, we discuss the Treg therapeutic potential for the development of alternative strategies to the gluten-free diet (GFD).
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Affiliation(s)
- Alessandra Camarca
- Institute of Food Sciences, National Research Council—CNR, 83100 Avellino, Italy (V.R.A.)
| | - Vera Rotondi Aufiero
- Institute of Food Sciences, National Research Council—CNR, 83100 Avellino, Italy (V.R.A.)
- Department of Medical Translational Sciences and European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, 80138 Naples, Italy
| | - Giuseppe Mazzarella
- Institute of Food Sciences, National Research Council—CNR, 83100 Avellino, Italy (V.R.A.)
- Department of Medical Translational Sciences and European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, 80138 Naples, Italy
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Chauhan SK, Bartolomé Casado R, Landsverk OJB, Johannessen H, Phung D, Nilsen HR, Sætre F, Jahnsen J, Horneland R, Yaqub S, Aandahl EM, Lundin KEA, Bækkevold ES, Jahnsen FL. Human small intestine contains 2 functionally distinct regulatory T-cell subsets. J Allergy Clin Immunol 2023; 152:278-289.e6. [PMID: 36893861 DOI: 10.1016/j.jaci.2023.02.030] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 02/17/2023] [Accepted: 02/23/2023] [Indexed: 03/09/2023]
Abstract
BACKGROUND Regulatory T (Treg) CD4 cells in mouse gut are mainly specific for intestinal antigens and play an important role in the suppression of immune responses against harmless dietary antigens and members of the microbiota. However, information about the phenotype and function of Treg cells in the human gut is limited. OBJECTIVE We performed a detailed characterization of Foxp3+ CD4 Treg cells in human normal small intestine (SI) as well as from transplanted duodenum and celiac disease lesions. METHODS Treg cells and conventional CD4 T cells derived from SI were subjected to extensive immunophenotyping and their suppressive activity and ability to produce cytokines assessed. RESULTS SI Foxp3+ CD4 T cells were CD45RA-CD127-CTLA-4+ and suppressed proliferation of autologous T cells. Approximately 60% of Treg cells expressed the transcription factor Helios. When stimulated, Helios-negative Treg cells produced IL-17, IFN-γ, and IL-10, whereas Helios-positive Treg cells produced very low levels of these cytokines. By sampling mucosal tissue from transplanted human duodenum, we demonstrated that donor Helios-negative Treg cells persisted for at least 1 year after transplantation. In normal SI, Foxp3+ Treg cells constituted only 2% of all CD4 T cells, while in active celiac disease, both Helios-negative and Helios-positive subsets expanded 5- to 10-fold. CONCLUSION The SI contains 2 subsets of Treg cells with different phenotypes and functional capacities. Both subsets are scarce in healthy gut but increase dramatically in active celiac disease.
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Affiliation(s)
- Sudhir Kumar Chauhan
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
| | - Raquel Bartolomé Casado
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Ole J B Landsverk
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Hanna Johannessen
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway; Department of Gastrointestinal and Pediatric Surgery, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Danh Phung
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Hogne Røed Nilsen
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Frank Sætre
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Jørgen Jahnsen
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway
| | - Rune Horneland
- Department of Transplantation Medicine, Section for Transplant Surgery, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Sheraz Yaqub
- Department of Gastrointestinal Surgery, Oslo University Hospital-Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Einar Martin Aandahl
- Department of Transplantation Medicine, Section for Transplant Surgery, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Knut E A Lundin
- Department of Gastroenterology, Oslo University Hospital-Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Espen S Bækkevold
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Frode L Jahnsen
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
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10
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Machado MV. New Developments in Celiac Disease Treatment. Int J Mol Sci 2023; 24:ijms24020945. [PMID: 36674460 PMCID: PMC9862998 DOI: 10.3390/ijms24020945] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/18/2022] [Accepted: 01/01/2023] [Indexed: 01/06/2023] Open
Abstract
Celiac disease (CD) is a common autoimmune disease affecting around 1% of the population. It consists of an immune-mediated enteropathy, triggered by gluten exposure in susceptible patients. All patients with CD, irrespective of the presence of symptoms, must endure a lifelong gluten-free diet (GFD). This is not an easy task due to a lack of awareness of the gluten content in foods and the extensive incorporation of gluten in processed foods. Furthermore, a GFD imposes a sense of limitation and might be associated with decreased quality of life in CD patients. This results in gluten contamination in the diet of four out of five celiac patients adhering to a GFD. Furthermore, one in three adult patients will report persistent symptoms and two in three will not achieve full histological recovery when on a GFD. In recent years, there has been extensive research conducted in the quest to find the holy grail of pharmacological treatment for CD. This review will present a concise description of the current rationale and main clinical trials related to CD drug therapy.
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Affiliation(s)
- Mariana Verdelho Machado
- Gastroenterology Department, Hospital de Vila Franca de Xira, Estrada Carlos Lima Costa, Nª 2, 2600-009 Vila Franca de Xira, Portugal; ; Tel.: +351-263-006-500
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Avenida Prof. Egas Moniz, 1649-028 Lisbon, Portugal
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11
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Kori M, Zamir Y, Yermiyahu SO, Ainbinder I, Daichman S, Pinto GD, Loewenberg Weisband Y, Greenfeld S, Kariv R, Lederman N, Matz E, Shamir R, Dotan I, Turner D. The association of Inflammatory Bowel Disease with Celiac Disease and Celiac Autoimmunity in children and adults: A nationwide study from the epi-IIRN. J Crohns Colitis 2022; 17:700-705. [PMID: 36394548 DOI: 10.1093/ecco-jcc/jjac176] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Indexed: 11/18/2022]
Abstract
BACKGROUND AND AIMS Given the paucity of population-based data on the association between inflammatory bowel diseases (IBD), celiac disease (CeD) and celiac autoimmunity (CeA) we aimed to study the associations in a nationwide study. METHODS Utilizing health administrative data for all four health maintenance organizations in Israel, covering 98% of the population, we explored the prevalence of CeD in children and adults with IBD versus non-IBD matched controls. CeD was defined by three ICD-9 codes and CeA by positivity for tissue transglutaminase antibodies. RESULTS In total, 34,375 IBD patients (56% Crohn's disease [CD] and 44% ulcerative colitis [UC]) were compared with 93,603 non-IBD controls. Among IBD patients, 319 (0.93%) had CeD versus 294 (0.31%) non-IBD controls (odds ratio [OR]=2.97 [95%CI 2.54-3.48]; p<0.001). CeA was identified in 575 (1.67%) IBD patients vs. 158 (0.17%) controls (OR=10.06 [95%CI 8.43-12], p<0.001). The prevalence of CeD was higher in pediatric-onset IBD (87/5,243 [1.66%]) than adult-onset IBD (232/29,132 [0.79%]; p<0.001). CD patients had a higher prevalence of CeD (229/19,264 [1.19%]) than UC patients (90/15,111 [0.56%]; OR=2.01 [95%CI 1.57-2.56]; p<0.001). The diagnosis of CeD preceded the diagnosis of IBD in 241/319 cases (76%). The time to treatment escalation was shorter in patients with both IBD and CeD than in patients with IBD without CeD (p=0.017). CONCLUSION CeD and CeA are more prevalent in IBD patients, especially in pediatric-onset IBD and in CD. The diagnosis of CeD usually precedes that of IBD. Having CeD is associated with more intensified treatment for IBD.
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Affiliation(s)
- Michal Kori
- Pediatric Gastroenterology, Kaplan Medical Center, Rehovot, Israel.,Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Yonatan Zamir
- Dept. of Industrial Engineering & Management, Azrieli College of Engineering Jerusalem (JCE), P.O. Box 3566, Jerusalem 91035, Israel
| | - Sami Or Yermiyahu
- Dept. of Industrial Engineering & Management, Azrieli College of Engineering Jerusalem (JCE), P.O. Box 3566, Jerusalem 91035, Israel
| | - Inessa Ainbinder
- Dept. of Industrial Engineering & Management, Azrieli College of Engineering Jerusalem (JCE), P.O. Box 3566, Jerusalem 91035, Israel
| | | | - Gavriel David Pinto
- Dept. of Industrial Engineering & Management, Azrieli College of Engineering Jerusalem (JCE), P.O. Box 3566, Jerusalem 91035, Israel
| | | | - Shira Greenfeld
- Clalit Health Services, Clalit Research Institute, Tel-Aviv, Israel.,Maccabi Health Services, Tel-Aviv, Israel and the Sackler Faculty of Medicine, Tel Aviv University, Israel
| | | | | | - Eran Matz
- Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel, Sackler Faculty of Medicine, Tel Aviv University, Israel
| | - Raanan Shamir
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petach Tikva, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | | | - Dan Turner
- Juliet Keidan Institute of Pediatric Gastroenterology, the Hebrew university of Jerusalem
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12
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A G, Sun C, Shan Y, Husile H, Bai H. Bidirectional causal link between inflammatory bowel disease and celiac disease: A two-sample mendelian randomization analysis. Front Genet 2022; 13:993492. [PMID: 36204317 PMCID: PMC9530974 DOI: 10.3389/fgene.2022.993492] [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: 07/13/2022] [Accepted: 09/02/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Observational research has shown a correlation between inflammatory bowel disease (IBD) [comprising ulcerative colitis (UC) and Crohn’s disease (CD)] and celiac disease. However, the relationship between these two diseases remains uncertain. Methods: We utilized two-sample Mendelian randomization (MR) to estimate the bidirectional causal relationships between IBD and celiac disease. This study utilized data on single nucleotide polymorphisms (SNPs) from genome-wide association studies (GWASs). Heterogeneity, pleiotropy, and sensitivity analyses were also performed to evaluate the MR results. Results: There was a significant causal relationship between IBD and CD and celiac disease (e.g., IBD and celiac disease, inverse variance weighting (IVW) odds ratio (OR) = 1.0828, 95% CI = 1.0258–1.1428, p = 0.0039; CD and celiac disease, IVW OR = 1.0807, 95% CI = 1.0227–1.1420, p = 0.0058). However, in the reverse direction, we found only suggestive positive causality between celiac disease and CD (e.g., IVW OR = 1.0366, 95% CI = 1.0031–1.0711, p = 0.0319). No evidence of heterogeneity between genetic variants was found (e.g., IBD vs. celiac disease, MR-Egger Q = 47.4391, p = 0.6159). Horizontal pleiotropy hardly influenced causality (e.g., IBD vs. celiac disease, MR-Egger test: p = 0.4340). Leave-one-out analysis showed that individual SNPs did not influence the general results. Conclusion: Our MR analysis revealed a positive causal link between IBD and celiac disease in the European population. In addition, several recommendations for disease prevention and clinical management have been discussed.
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Affiliation(s)
- Gu A
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Caixia Sun
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yuezhan Shan
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Husile Husile
- Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, China
| | - Haihua Bai
- Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, China
- Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
- *Correspondence: Haihua Bai,
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13
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Reduced frequency of circulating regulatory T cells and their related immunosuppressive mediators in treated celiac patients. Mol Biol Rep 2022; 49:8527-8535. [PMID: 35723802 DOI: 10.1007/s11033-022-07674-w] [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: 04/18/2022] [Accepted: 06/01/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Regulatory T cells (Tregs) have an important role in the control of the immune responses. This study aimed to compare the frequency of peripheral blood (PB) CD4+ CD25+ FoxP3+ Treg cells and PB and duodenal expression levels of pro- and anti-inflammatory mediators in treated celiac disease (CD) patients and healthy controls. METHODS AND RESULTS Duodenal biopsy specimens and PB samples were collected from 60 treated CD patients and 60 controls. Flow cytometry analysis was conducted on peripheral blood mononuclear cell (PBMC) specimens and relative PB and duodenal mRNA expression levels of CD25, forkhead box P3 (Foxp3), interleukin (IL)-10 and granzyme B (GrzB) were evaluated using quantitative real-time PCR. The levels of serum IL-10 and IL-6 were tested with sandwich enzyme-linked immunosorbent assay kits. p values < 0.05 were considered significant. Flow cytometry analysis showed a significant decrease in the number of Tregs in CD patients' PBMC specimens (p = 0.012). CD25 and Foxp3 PB mRNA expressions were also lower in CD patients without reaching the significance level (p > 0.05). IL-10 PB mRNA and protein expression did not differ between the groups (p > 0.05), and GrzB PB expression was significantly reduced in CD patients (p = 0.001). In duodenal specimens of CD patients, while significantly increased CD25, Foxp3 mRNA expression (p = 0.01 and 0.001, respectively) and decreased IL-10 mRNA expression (p = 0.02) were observed, GrzB mRNA expression did not differ between groups (p > 0.05). Moreover, a high serum level of IL-6 was observed in CD patients (p = 0.001). CONCLUSIONS Despite following the gluten free diet, there may still be residual inflammation in the intestine of CD patients. Accordingly, finding a therapeutic approach based on strengthening the function of Treg cells in CD might be helpful.
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14
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Klonarakis M, Andrews CN, Raman M, Panaccione R, Ma C. Review article: therapeutic targets for the pharmacologic management of coeliac disease-the future beyond a gluten-free diet. Aliment Pharmacol Ther 2022; 55:1277-1296. [PMID: 35229332 DOI: 10.1111/apt.16846] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/03/2021] [Accepted: 02/13/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Coeliac disease (CeD) is an immune-mediated small bowel enteropathy resulting from dietary gluten exposure. Presently, the only effective treatment is adoption of a gluten-free diet (GFD), although strict adherence is challenging to maintain, and inadvertent gluten exposures are inevitable for most patients. Hence, there is substantial interest in drug development in CeD and multiple novel therapies are under investigation. AIMS To review existing and upcoming clinical trial programmes for pharmacologic agents for CeD. METHODS A narrative review was performed, informed by a search of MEDLINE, Embase, the Cochrane CENTRAL Library and clinicaltrials.gov. RESULTS We summarise the pathophysiology of CeD and the specific steps that are potentially amenable to pharmacologic treatment. We evaluate the evidence supporting existing and future drug targets, including trials of peptidases, gluten sequestrants, tight junction regulators, anti-transglutaminase 2 therapies, immune tolerizing agents, advanced biologics and small molecules, and microbiome-targeted strategies. We highlight unique considerations for conducting CeD trials, including identifying appropriate study populations, assessing results in the context of a gluten challenge, and interpreting CeD-specific clinical and histologic outcomes. Understanding these factors is crucial for accurately appraising the evidence. Finally, we outline what the future of CeD therapy may hold with the introduction of pharmacotherapies. CONCLUSIONS There is a need for pharmacologic options for CeD, either used adjunctively with a GFD for accidental or intentional gluten exposures or for refractory disease. Multiple promising agents are in development, and these trials are likely to lead to approvals for the first generation of pharmacologic agents for CeD within the next 5 years.
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Affiliation(s)
| | - Christopher N Andrews
- Division of Gastroenterology & Hepatology, University of Calgary, Calgary, Alberta, Canada
| | - Maitreyi Raman
- Division of Gastroenterology & Hepatology, University of Calgary, Calgary, Alberta, Canada.,Alberta's Collaboration of Excellence for Nutrition in Digestive Diseases, Calgary, Alberta, Canada
| | - Remo Panaccione
- Division of Gastroenterology & Hepatology, University of Calgary, Calgary, Alberta, Canada
| | - Christopher Ma
- Division of Gastroenterology & Hepatology, University of Calgary, Calgary, Alberta, Canada.,Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
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15
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Kociszewska D, Vlajkovic SM. The Association of Inflammatory Gut Diseases with Neuroinflammatory and Auditory Disorders. Front Biosci (Elite Ed) 2022; 14:8. [PMID: 35730449 DOI: 10.31083/j.fbe1402008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/11/2022] [Accepted: 02/24/2022] [Indexed: 11/06/2022]
Abstract
Disorders such as inflammatory bowel disease (IBD) and celiac disease (CeD) result in intestinal hyperpermeability or 'leaky' gut. The increased permeability of the intestinal barrier allows microbial metabolites, toxins, and pathogens to infiltrate the bloodstream and extraintestinal tissues, causing systemic inflammation. Despite differences in aetiology and pathophysiology, IBD and CeD share several extraintestinal manifestations such as neuroinflammation, neurological and psychiatric manifestations, and sensorineural hearing loss (SNHL). This narrative review focuses on the association between intestinal hyperpermeability with the brain and inner ear diseases. We postulate that the microbial metabolites and pathogens released from the gut increase the permeability of natural barriers, such as the blood-brain barrier (BBB) and blood-labyrinth barrier (BLB). The barrier breakdown allows the spreading of inflammatory processes to the brain and inner ear, leading to disease.
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Affiliation(s)
- Dagmara Kociszewska
- Department of Physiology and The Eisdell Moore Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 1142 Auckland, New Zealand
| | - Srdjan M Vlajkovic
- Department of Physiology and The Eisdell Moore Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 1142 Auckland, New Zealand
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16
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Anderson RP. Emergence of an adaptive immune paradigm to explain celiac disease: a perspective on new evidence and implications for future interventions and diagnosis. Expert Rev Clin Immunol 2021; 18:75-91. [PMID: 34767744 DOI: 10.1080/1744666x.2021.2006636] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Recent patient studies have shown that gluten-free diet is less effective in treating celiac disease than previously believed, and additionally patients remain vulnerable to gluten-induced acute symptoms and systemic cytokine release. Safe and effective pharmacological adjuncts to gluten-free diet are in preclinical and clinical development. Clear understanding of the pathogenesis of celiac disease is critical for drug target identification, establishing efficacy endpoints and to develop non-invasive biomarkers suitable to monitor and potentially diagnose celiac disease. AREAS COVERED The role and clinical effects of CD4+ T cells directed against deamidated gluten in the context of an "adaptive immune paradigm" are reviewed. Alternative hypotheses of gluten toxicity are discussed and contrasted. In the context of recent patient studies, implications of the adaptive immune paradigm for future strategies to prevent, diagnose, and treat celiac disease are outlined. EXPERT OPINION Effective therapeutics for celiac disease are likely to be approved and necessitate a variety of new clinical instruments and tests to stratify patient need, monitor remission, and confirm diagnosis in uncertain cases. Sensitive assessments of CD4+ T cells specific for deamidated gluten are likely to play a central role in clinical management, and to facilitate research and pharmaceutical development.
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17
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Verdu EF, Schuppan D. Co-factors, Microbes, and Immunogenetics in Celiac Disease to Guide Novel Approaches for Diagnosis and Treatment. Gastroenterology 2021; 161:1395-1411.e4. [PMID: 34416277 DOI: 10.1053/j.gastro.2021.08.016] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 08/10/2021] [Accepted: 08/10/2021] [Indexed: 12/14/2022]
Abstract
Celiac disease (CeD) is a frequent immune-mediated disease that affects not only the small intestine but also many extraintestinal sites. The role of gluten proteins as dietary triggers, HLA-DQ2 or -DQ8 as major necessary genetic predisposition, and tissue transglutaminase (TG2) as mechanistically involved autoantigen, are unique features of CeD. Recent research implicates many cofactors working in synergism with these key triggers, including the intestinal microbiota and their metabolites, nongluten dietary triggers, intestinal barrier defects, novel immune cell phenotypes, and mediators and cytokines. In addition, apart from HLA-DQ2 and -DQ8, multiple and complex predisposing genetic factors and interactions have been defined, most of which overlap with predispositions in other, usually autoimmune, diseases that are linked to CeD. The resultant better understanding of CeD pathogenesis, and its manifold manifestations has already paved the way for novel therapeutic approaches beyond the lifelong strict gluten-free diet, which poses a burden to patients and often does not lead to complete mucosal healing. Thus, supported by improved mouse models for CeD and in vitro organoid cultures, several targeted therapies are in phase 2-3 clinical studies, such as highly effective gluten-degrading oral enzymes, inhibition of TG2, cytokine therapies, induction of tolerance to gluten ingestion, along with adjunctive and preventive approaches using beneficial probiotics and micronutrients. These developments are supported by novel noninvasive markers of CeD severity and activity that may be used as companion diagnostics, allow easy-to perform and reliable monitoring of patients, and finally support personalized therapy for CeD.
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Affiliation(s)
- Elena F Verdu
- Division of Gastroenterology, Department of Internal Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada
| | - Detlef Schuppan
- Institute of Translational Immunology,Research Center for Immune Therapy and Celiac Center, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
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18
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Voisine J, Abadie V. Interplay Between Gluten, HLA, Innate and Adaptive Immunity Orchestrates the Development of Coeliac Disease. Front Immunol 2021; 12:674313. [PMID: 34149709 PMCID: PMC8206552 DOI: 10.3389/fimmu.2021.674313] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 05/18/2021] [Indexed: 12/26/2022] Open
Abstract
Several environmental, genetic, and immune factors create a "perfect storm" for the development of coeliac disease: the antigen gluten, the strong association of coeliac disease with HLA, the deamidation of gluten peptides by the enzyme transglutaminase 2 (TG2) generating peptides that bind strongly to the predisposing HLA-DQ2 or HLA-DQ8 molecules, and the ensuing unrestrained T cell response. T cell immunity is at the center of the disease contributing to the inflammatory process through the loss of tolerance to gluten and the differentiation of HLA-DQ2 or HLA-DQ8-restricted anti-gluten inflammatory CD4+ T cells secreting pro-inflammatory cytokines and to the killing of intestinal epithelial cells by cytotoxic intraepithelial CD8+ lymphocytes. However, recent studies emphasize that the individual contribution of each of these cell subsets is not sufficient and that interactions between these different populations of T cells and the simultaneous activation of innate and adaptive immune pathways in distinct gut compartments are required to promote disease immunopathology. In this review, we will discuss how tissue destruction in the context of coeliac disease results from the complex interactions between gluten, HLA molecules, TG2, and multiple innate and adaptive immune components.
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Affiliation(s)
- Jordan Voisine
- Department of Medicine, The University of Chicago, Chicago, IL, United States.,Committee on Immunology, The University of Chicago, Chicago, IL, United States
| | - Valérie Abadie
- Department of Medicine, The University of Chicago, Chicago, IL, United States.,Section of Gastroenterology, Nutrition and Hepatology, The University of Chicago, Chicago, IL, United States
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19
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Kemppainen E, Salmi T, Lindfors K. Missing Insight Into T and B Cell Responses in Dermatitis Herpetiformis. Front Immunol 2021; 12:657280. [PMID: 33854513 PMCID: PMC8039136 DOI: 10.3389/fimmu.2021.657280] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 03/12/2021] [Indexed: 12/18/2022] Open
Abstract
Dermatitis herpetiformis is a cutaneous form of celiac disease manifesting as an itching rash typically on the elbows, knees and buttocks. It is driven by the ingestion of gluten-containing cereals and characterized by granular deposits of immunoglobulin A in the papillary dermis. These antibodies target transglutaminase (TG) 3 and in the majority of patients they are also found in circulation. The circulating antibodies disappear and skin symptoms resolve as a result of gluten-free diet but the cutaneous anti-TG3 IgA deposits may persist for several years. In dermatitis herpetiformis, plasma cells secreting antibodies against TG3 are located in the intestinal mucosa similarly to those producing TG2 antibodies characteristic for celiac disease. In fact, both TG2- and TG3-specific plasma cells and gluten responsive T cells are found in dermatitis herpetiformis patients but the interplay between these cell populations is unknown. The small bowel mucosal damage in celiac disease is believed to be mediated by co-operation of cytotoxic intraepithelial T cells and the inflammatory milieu contributed by gluten-reactive CD4+ T cells, whereas the skin lesions in dermatitis herpetiformis appear to be devoid of gluten reactive T cells. Thus, how celiac disease-type intestinal T and B cell responses develop into an autoimmune condition affecting the skin is still incompletely understood. Finally, the skin and small bowel lesions may reappear upon reintroduction of gluten in patients treated with gluten-free diet but virtually nothing is known about the long-lived B cell and memory T cell populations activating in response to dietary gluten in dermatitis herpetiformis.
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Affiliation(s)
- Esko Kemppainen
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Teea Salmi
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.,Department of Dermatology, Tampere University Hospital, Tampere, Finland
| | - Katri Lindfors
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
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20
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Cellular and molecular bases of refractory celiac disease. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 358:207-240. [PMID: 33707055 DOI: 10.1016/bs.ircmb.2020.12.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Refractory celiac disease (RCD) encompasses biologically heterogeneous disorders that develop in a small proportion (0.3%) of individuals with celiac disease that are associated with high morbidity. Two broad categories are currently recognized, type I (RCD I) and type II (RCD II), based on immunophenotypic and molecular features of the intraepithelial lymphocytes (IELs). RCD I is characterized by a polyclonal expansion of IELs displaying a normal immunophenotype, while RCD II represents a clonal proliferation of immunophenotypically "aberrant" IELs, and is considered a low-grade lymphoproliferative disorder. The pathogenesis of RCD I has not been clarified, but limited studies suggest multifactorial etiology. On the other hand, recent immunologic, molecular and immunophenotypic analyses have proposed lineage-negative innate IELs to be the cell of origin of a proportion of RCD II cases. Furthermore, sequencing studies have identified frequent, recurrent, activating mutations in members of the JAK-STAT pathway in RCD II. This finding, in conjunction with prior in vitro experimental observations, suggests roles of deregulated cytokine signaling in disease pathogenesis. In this review, we describe current understanding of environmental, immune and genetic factors associated with the development of RCD and briefly discuss diagnostic and therapeutic considerations.
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21
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Pinto-Sanchez MI, Seiler CL, Santesso N, Alaedini A, Semrad C, Lee AR, Bercik P, Lebwohl B, Leffler DA, Kelly CP, Moayyedi P, Green PH, Verdu EF. Association Between Inflammatory Bowel Diseases and Celiac Disease: A Systematic Review and Meta-Analysis. Gastroenterology 2020; 159:884-903.e31. [PMID: 32416141 DOI: 10.1053/j.gastro.2020.05.016] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 04/23/2020] [Accepted: 05/02/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS There is controversy over the association between celiac disease (CeD) and inflammatory bowel diseases (IBD). We performed a systematic review and meta-analysis to assess evidence for an association between CeD and IBD. METHODS We searched databases including MEDLINE, EMBASE, CENTRAL, Web of Science, CINAHL, DARE, and SIGLE through June 25, 2019 for studies assessing the risk of CeD in patients with IBD, and IBD in patients with CeD, compared with controls of any type. We used the Newcastle-Ottawa Scale to evaluate the risk of bias and GRADE to assess the certainty of the evidence. RESULTS We identified 9791 studies and included 65 studies in our analysis. Moderate certainty evidence found an increased risk of CeD in patients with IBD vs controls (risk ratio [RR] 3.96; 95% confidence interval [CI] 2.23-7.02) and increased risk of IBD in patients with CeD vs controls (RR 9.88; 95% CI 4.03-24.21). There was low-certainty evidence for the risk of anti-Saccharomyces antibodies, a serologic marker of IBD, in patients with CeD vs controls (RR 6.22; 95% CI 2.44-15.84). There was low-certainty evidence for no difference in risk of HLA-DQ2 or DQ8 in patients with IBD vs controls (RR 1.04; 95% CI 0.42-2.56), and very low-certainty evidence for an increased risk of anti-tissue transglutaminase in patients with IBD vs controls (RR 1.52; 95% CI 0.52-4.40). Patients with IBD had a slight decrease in risk of anti-endomysial antibodies vs controls (RR 0.70; 95% CI 0.18-2.74), but these results are uncertain. CONCLUSIONS In a systematic review and meta-analysis, we found an increased risk of IBD in patients with CeD and increased risk of CeD in patients with IBD, compared with other patient populations. High-quality prospective cohort studies are needed to assess the risk of CeD-specific and IBD-specific biomarkers in patients with IBD and CeD.
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Affiliation(s)
- Maria Ines Pinto-Sanchez
- Department of Medicine, Farncombe Family Digestive Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Caroline L Seiler
- Department of Medicine, Farncombe Family Digestive Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Nancy Santesso
- Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada
| | - Armin Alaedini
- Celiac Disease Center at Columbia University, New York, New York
| | - Carol Semrad
- Celiac Disease Center at University of Chicago Medicine, Chicago, Illinois
| | - Anne R Lee
- Celiac Disease Center at Columbia University, New York, New York
| | - Premysl Bercik
- Department of Medicine, Farncombe Family Digestive Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Benjamin Lebwohl
- Celiac Disease Center at Columbia University, New York, New York
| | - Daniel A Leffler
- Department of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Ciaran P Kelly
- Department of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Paul Moayyedi
- Department of Medicine, Farncombe Family Digestive Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Peter H Green
- Celiac Disease Center at Columbia University, New York, New York
| | - Elena F Verdu
- Department of Medicine, Farncombe Family Digestive Research Institute, McMaster University, Hamilton, Ontario, Canada.
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Aghamohamadi E, Kokhaei P, Rostami-Nejad M, Pak F, Rostami K, Moradi A, Pourhoseingholi MA, Chaleshi V, Masotti A, Zali MR. Serum Level and Gene Expression of Interleukin-15 Do Not Correlate with Villous Atrophy in Celiac Disease Patients. Genet Test Mol Biomarkers 2020; 24:502-507. [PMID: 32700980 DOI: 10.1089/gtmb.2019.0265] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Background and Aims: Interleukin-15 (IL-15) is a key player in the pathogenesis of celiac disease (CD). We investigated the functional role of IL-15 in the process of epithelial cell phenotypic modification at different stages of CD. Materials and Methods: In this study, we looked for correlations between the IL-15 mRNA levels in duodenal tissue and serum protein levels in a cohort of Iranian patients affected by CD based on the degree of histopathology. Ninety-five formalin-fixed, paraffin-embedded duodenal tissue specimens were collected: 23 with a Marsh I value; 30 with a Marsh II value; 32 with a Marsh III value; and 10 normal controls. The expression levels of the IL-15 gene in these biopsy specimens were determined by real-time quantitative polymerase chain reaction (qPCR), and IL-15 serum protein concentrations were determined by enzyme-linked immunosorbent assay and compared to tissue expression. Results: The IL-15 mRNA levels were higher in patients with Marsh II compared with the control group, and the Marsh I, and Marsh III groups. The differences between the Marsh II and Marsh I patients were statistically significant (p = 0.03). Similarly, the serum concentration of IL-15 was higher in Marsh II patients compared to those with Marsh I and Marsh III lesions, although the differences were not statistically significant (p = 0.221). Conclusions: Our results demonstrate that IL-15 gene expression might be elevated only in the early stages of CD onset (and histological damage) and that IL-15 serum levels do not significantly correlate with its tissue expression whatever the degree of histopathology.
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Affiliation(s)
- Elham Aghamohamadi
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Parviz Kokhaei
- Cancer Research Center, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Mohammad Rostami-Nejad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Pak
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Kamran Rostami
- Department of Gastroenterology, Mid Central DHB, Palmerston Hospital, Palmerston North, New Zealand
| | - Afshin Moradi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohamad Amin Pourhoseingholi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Chaleshi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Andrea Masotti
- Research Laboratories, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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23
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Marsilio I, Maddalo G, Ghisa M, Savarino EV, Farinati F, Zingone F. The coeliac stomach: A review of the literature. Dig Liver Dis 2020; 52:615-624. [PMID: 32295740 DOI: 10.1016/j.dld.2020.03.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 02/02/2020] [Accepted: 03/10/2020] [Indexed: 12/11/2022]
Abstract
Beyond the small intestine, coeliac disease (CeD) may affect other gastrointestinal tracts, including the stomach. However, various studies have reported conflicting results regarding the association between CeD and gastric manifestations. The aim of this study was to analyze the existing literature on gastric involvement in CeD. A literature search was conducted in bibliographic databases of Embase, PubMed, Scopus, and Web of Science. Studies reporting the association between CeD and gastric disorders were examined in detail and are fully described in the review. Both in children and adults, a strong correlation between lymphocytic gastritis and CeD was found at CeD diagnosis, and lymphocytic gastritis seemed to improve on a gluten-free diet. Most of the literature described a lower risk of gastritis related to Helicobacter pylori infection in CeD subjects compared to controls. However, due to the discordance among studies in terms of study design and population, a clear association could not be determined. Finally, the relationship between CeD and reflux or dyspepsia has yet to be defined, as well as the association between CeD and autoimmune gastritis. CeD appears to be a multiform entity associated with different gastric disorders with a different degree of relationship. Thus, gastric biopsies should be routinely taken during upper endoscopy in CeD patients.
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Affiliation(s)
- Ilaria Marsilio
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padua, Padua 35128, Italy
| | - Gemma Maddalo
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padua, Padua 35128, Italy
| | - Matteo Ghisa
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padua, Padua 35128, Italy
| | - Edoardo Vincenzo Savarino
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padua, Padua 35128, Italy
| | - Fabio Farinati
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padua, Padua 35128, Italy
| | - Fabiana Zingone
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padua, Padua 35128, Italy.
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24
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Inoue H, Rai S, Tanaka H, Espinoza JL, Watatani Y, Kumode T, Serizawa K, Nakayama S, Taniguchi Y, Morita Y, Tatsumi Y, Ashida T, Matsumura I. Tumour-immune microenvironment in duodenal-type follicular lymphoma. Br J Haematol 2020; 191:243-252. [PMID: 32383789 DOI: 10.1111/bjh.16715] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 04/04/2020] [Accepted: 04/12/2020] [Indexed: 01/29/2023]
Abstract
Despite duodenal-type follicular lymphoma (DTFL) being morphologically, immunophenotypically and genetically indistinguishable from nodal FL (nFL), this entity typically shows a significantly better prognosis. Here, we analysed the tumour immune microenvironments of diagnostic specimens from patients with DTFL (n = 30), limited-stage FL (LSFL; n = 19) and advanced-stage FL (ASFL; n = 31). The mean number of CD8+ tumour-infiltrating lymphocytes (TILs) in the neoplastic follicles was higher in DTFL (1,827/mm2 ) than in LSFL (1,150/mm2 ) and ASFL (1,188/mm2 ) (P = 0·002, P = 0·002, respectively). In addition, CD8+ PD1- T cells with non-exhausting phenotype were more abundant in the peripheral blood (PB) of DTFL than in LSFL and ASFL, indicating that DTFL may exhibit a better and longer-lasting T cell-mediated immune response. Moreover, whereas FOXP3+ CTLA-4+ effector regulatory T cells (eTregs) were rarely observed in the neoplastic follicles of DTFL (mean: 12/mm2 ), they were more abundant in LSFL (78/mm2 ) and ASFL (109/mm2 ) (P = 2·80 × 10-5 , P = 4·74 × 10-8 , respectively), and the numbers of eTregs correlated inversely with those of CD8+ TILs (r = -0267; P = 0·018). Furthermore, DTFL showed significantly fewer circulating FOXP3hi CD45RA- CD25hi eTregs (0·146%) than ASFL (0·497%) and healthy controls (0·639%) (P = 0·0003, P = 6·79 × 10-7 , respectively). These results suggest that the augmented anti-tumour immune reactions may contribute to a better prognosis on DTFL.
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Affiliation(s)
- Hiroaki Inoue
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Osakasayama, Japan
| | - Shinya Rai
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Osakasayama, Japan
| | - Hirokazu Tanaka
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Osakasayama, Japan
| | - J Luis Espinoza
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Osakasayama, Japan
| | - Yosaku Watatani
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Osakasayama, Japan
| | - Takahiro Kumode
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Osakasayama, Japan
| | - Kentaro Serizawa
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Osakasayama, Japan
| | - Shoko Nakayama
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Osakasayama, Japan
| | - Yasuhiro Taniguchi
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Osakasayama, Japan
| | - Yasuyoshi Morita
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Osakasayama, Japan
| | - Yoichi Tatsumi
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Osakasayama, Japan
| | - Takashi Ashida
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Osakasayama, Japan
| | - Itaru Matsumura
- Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Osakasayama, Japan
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25
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Caio G, Ciccocioppo R, Zoli G, De Giorgio R, Volta U. Therapeutic options for coeliac disease: What else beyond gluten-free diet? Dig Liver Dis 2020; 52:130-137. [PMID: 31831308 DOI: 10.1016/j.dld.2019.11.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 11/12/2019] [Accepted: 11/17/2019] [Indexed: 12/11/2022]
Abstract
Coeliac disease is a chronic and systemic autoimmune condition triggered by gluten ingestion in genetically predisposed subjects. Currently, the only effective treatment available is a strict, lifelong gluten-free diet. However, patients perceive gluten withdrawal as an unsustainable burden in their life and some of them can exhibit persistent symptoms despite a strict diet. Thus, gluten-free diet represents a challenge, leading scientists to look for alternative or complementary treatments. This review will focus on non-dietary therapies for coeliac disease highlighting six therapeutic strategies: (1) decreasing gluten immunogenic content before it reaches the intestine; (2) sequestering gluten in the gut lumen before absorption; (3) blocking the passage of gluten through a leaky intestinal barrier; (4) preventing the enhancement of immune response against gliadin; (5) dampening the downstream immune activation; (6) inducing immune tolerance to gluten. Most developing therapies are only in the pre-clinical phase with only a few being tested in phase 2b or 3 trials. Although new approaches raise the hope for coeliacs giving them a chance to come back to gluten, for the time being a cautionary appraisal of new therapies suggests that they may have a complementary role to gluten withdrawal, mainly to prevent inadvertent gluten contamination.
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Affiliation(s)
- Giacomo Caio
- Department of Medical Sciences, University of Ferrara, Italy
| | - Rachele Ciccocioppo
- Gastroenterology Unit, Department of Medicine, A.O.U.I. Policlinico G. B. Rossi and University of Verona, Italy
| | - Giorgio Zoli
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Italy
| | | | - Umberto Volta
- Department of Medical and Surgical Scieces, University of Bologna, Italy
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26
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Luongo D, Maurano F, Bergamo P, Rossi M. Microbial transglutaminase: A biotechnological tool to manage gluten intolerance. Anal Biochem 2020; 592:113584. [PMID: 31953047 DOI: 10.1016/j.ab.2020.113584] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Revised: 01/09/2020] [Accepted: 01/13/2020] [Indexed: 02/07/2023]
Abstract
Celiac disease (CD) is a chronic immune-mediated disease in which gluten ingestion leads to damage of the small intestinal mucosa in genetically susceptible individuals. The enteropathy is mainly induced by the production of IFN-γ from intestinal CD4+T cells that recognise gliadin peptides following deamidation by tissue transglutaminase. The only available therapy is a strict, lifelong gluten-free diet (GFD). This diet is strongly demanding for patients, which justifies the search for alternative strategies. The enzyme approach is one promising strategy to address this issue. In particular, transamidation of wheat gliadin by microbial transglutaminase (mTG) was fully effective at inhibiting gliadin-specific IFN-γ secretion in intestinal T cells from CD patients. Furthermore, transamidated gliadin induced higher levels of the anti-inflammatory IL-10 than native gliadin in different in vitro models. These data suggest that a more balanced immune response could be induced by mTG-treated gliadin in the small intestine of celiac patients. Furthermore, the highlighted biological property of mTG-treated gliadin could be exploited to induce tolerance to native gliadin in at-risk individuals.
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Affiliation(s)
- Diomira Luongo
- Institute of Food Sciences, National Research Council, Avellino, Italy
| | - Francesco Maurano
- Institute of Food Sciences, National Research Council, Avellino, Italy
| | - Paolo Bergamo
- Institute of Food Sciences, National Research Council, Avellino, Italy
| | - Mauro Rossi
- Institute of Food Sciences, National Research Council, Avellino, Italy.
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27
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Renga G, Bellet MM, Stincardini C, Pariano M, Oikonomou V, Villella VR, Brancorsini S, Clerici C, Romani L, Costantini C. To Be or Not to Be a Pathogen: Candida albicans and Celiac Disease. Front Immunol 2019; 10:2844. [PMID: 31867008 PMCID: PMC6906151 DOI: 10.3389/fimmu.2019.02844] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 11/19/2019] [Indexed: 12/20/2022] Open
Abstract
Celiac disease (CD) is an immune-mediated disorder triggered by the ingestion of gluten and characterized by reversible small-bowel mucosal atrophy in genetically predisposed subjects. Although the prevalence of CD has increased, many aspects of this pathology are still unrecognized. Candida albicans, a commensal of the human gastrointestinal tract, has been linked to CD for a long time based, among others, upon the observation of similarity between the fungal wall component, hyphal wall protein 1, and CD-related gliadin T-cell epitopes. We have recently demonstrated that Candida may switch from commensal to pathogen contingent upon several players, including mast cells, key sentinels of the immune system at the interface between the environment and the host, and the pleiotropic cytokine IL-9. However, other factors are likely to play a role by altering the balance between inflammation and tolerance. In this regard, tryptophan and its metabolites are increasingly being recognized in promoting mucosal homeostasis by balancing the immune response to external cues. Based on these premises, we will discuss how the output of Candida colonization in the gut is highly contextual, being determined at the intersection of many immunological (IL-9/mast cells) and metabolic (tryptophan) pathways that ultimately dictate the Candida commensalism vs. pathogenicity in CD, thus paving the way for novel therapeutic opportunities in CD.
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Affiliation(s)
- Giorgia Renga
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - Marina M Bellet
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | | | - Marilena Pariano
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - Vasilis Oikonomou
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - Valeria R Villella
- Division of Genetics and Cell Biology, European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Milan, Italy
| | | | - Carlo Clerici
- Gastroenterology Unit, Santa Maria della Misericordia Hospital of Perugia, Perugia, Italy
| | - Luigina Romani
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - Claudio Costantini
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
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28
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Shariati A, Aslani HR, Shayesteh MR, Taghipour A, Nasser A, Safari H, Alizade-Sani M, Dehghan A, Azimi T. Are Viruses and Parasites Linked to Celiac Disease? A Question that Still has no Definite Answer. Curr Pharm Biotechnol 2019; 20:1181-1193. [PMID: 31456516 DOI: 10.2174/1389201020666190828124924] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 07/01/2019] [Accepted: 08/07/2019] [Indexed: 12/17/2022]
Abstract
Celiac Disease (CD) is a complex autoimmune enteropathy of the small intestine that commonly
occurs in genetically predisposed individuals due to intake of gluten and related proteins. Gluten
consumption, duration of breast-feeding, various infections, especially frequent intestinal infections,
vaccinations and use of antibiotics can be linked to CD. It is predicted that it affects 1% of the
global population and its incidence rate is increasing. Most of the people with the HLA-DQ2 or HLADQ8
are at a higher risk of developing this disease. The link between infections and autoimmune diseases
has been very much considered in recent years. In several studies, we explained that pathogenic
and non-pathogenic microorganisms might have multiple roles in initiation, exacerbation, and development
of Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Disease (IBD). In various studies,
the relationship between infections caused by viruses, such as Epstein-Barr Virus (EBV), Rotavirus,
Hepatitis C (HCV), Hepatitis B virus (HBV), Cytomegalovirus (CMV), and Influenza virus, and parasites
including Giardia spp. and Toxoplasma gondii with CD has been raised. However, increasing evidence
proposes that some of these microorganisms, especially helminths, can also have protective and
even therapeutic roles in the CD process. Therefore, in order to determine the role of microorganisms
in the process of this disease, we attempted to summarize the evidence suggesting the role of viral and
parasitic agents in pathogenesis of CD.
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Affiliation(s)
- Aref Shariati
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hamid R. Aslani
- Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad R.H. Shayesteh
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Taghipour
- Department of Parasitology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ahmad Nasser
- Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Safari
- Health Promotion Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mahmood Alizade-Sani
- Food Safety and Hygiene Division, Environmental Health Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Amin Dehghan
- Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Taher Azimi
- Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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29
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Vorobjova T, Tagoma A, Oras A, Alnek K, Kisand K, Talja I, Uibo O, Uibo R. Celiac Disease in Children, Particularly with Accompanying Type 1 Diabetes, Is Characterized by Substantial Changes in the Blood Cytokine Balance, Which May Reflect Inflammatory Processes in the Small Intestinal Mucosa. J Immunol Res 2019; 2019:6179243. [PMID: 31214623 PMCID: PMC6535873 DOI: 10.1155/2019/6179243] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 04/08/2019] [Accepted: 04/24/2019] [Indexed: 02/08/2023] Open
Abstract
Cytokines play a pivotal role in the maintenance of intestinal homeostasis inducing pro- or anti-inflammatory response and mucosal barrier function in celiac disease (CD) and type 1 diabetes (T1D). We aimed to compare the levels of pro- and anti-inflammatory cytokines in CD patients without and with coexisting T1D, as well as to evaluate its association with the presence of enteroviruses (EV), regulatory T cells (Tregs), and dendritic cells (DCs) in small bowel mucosa. Altogether, 72 patients (median age 10.1 years) who had undergone small bowel biopsy were studied. The study group consisted of 24 patients with CD (median age 6.5 years), 9 patients with CD and concomitant T1D (median age 7.0 years), two patients with T1D (median age 8.5 years), and 37 patients (median age 14.0 years) with functional gastrointestinal disorders (FGD) and a normal small bowel mucosa as controls. The levels of 33 cytokines in serum were measured by multiple analysis using the Milliplex® MAP Magnetic Bead assay. The densities of FOXP3+ Tregs, CD11c+ DC, indoleamine 2,3-dioxygenase+ (IDO+) DC, langerin+ (CD207+) DCs, and EV were evaluated by immunohistochemistry as described in our previous studies. Circulating anti-EV IgA and IgG were evaluated using ELISA. The most important finding of the study is the significant increase of the serum levels of IL-5, IL-8, IL-13, IL-15, IL-17F, IL-22, IL-27, IP-10, MIP-1β, sIL-2Rα, sTNFRII, and TNFα in CD patients compared to controls and its correlation with the degree of small bowel mucosa damage graded according to the Marsh classification. The leptin level was higher in females in all study groups. The levels of IL-2, IL-6, IL-12 (P70), IL-15, IP-10, and IFNγ correlated significantly with the density of FOXP3+ Tregs in lamina propria of the small bowel mucosa, which supports the evidence about the signaling role of these cytokines in the peripheral maintenance of FOXP3+ Tregs. At the same time, a significant negative correlation occurred between the level of IL-4 and density of FOXP3+ Tregs in controls. Another important finding of our study was the correlation of IL-17F, IP-10, sTNFRII, MCP-1, and GM-CSF with the density of EV-positive cells in the lamina propria of the small bowel mucosa. Correlation of MIP-1 (CCL-4) with CD103+ DC and langerin+ DC densities may point to their significance in the recruitment of immune cells into the lamina propria and in driving the inflammatory response in CD patients. Our results suggest the predominance of Th1 and Th17 immune responses over EV VP1 protein in CD and T1D patients. The significant elevation of Th2 cytokines, like IL-5 and IL-13, but not IL-4, in CD patients and its correlation with the degree of small bowel mucosa damage could reflect the role of these cytokines in gut defense and inflammation.
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Affiliation(s)
- Tamara Vorobjova
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Aili Tagoma
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Astrid Oras
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Kristi Alnek
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Kalle Kisand
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Ija Talja
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Oivi Uibo
- Department of Pediatrics, Institute of Clinical Medicine, University of Tartu, Estonia
- Children's Clinic, Tartu University Hospital, Tartu, Estonia
| | - Raivo Uibo
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
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30
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Di Sabatino A, Lenti MV, Corazza GR, Gianfrani C. Vaccine Immunotherapy for Celiac Disease. Front Med (Lausanne) 2018; 5:187. [PMID: 29998106 PMCID: PMC6028606 DOI: 10.3389/fmed.2018.00187] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 06/08/2018] [Indexed: 12/29/2022] Open
Abstract
Autoimmune and allergic disorders are highly prevalent conditions in which an altered or abnormal immune response is mounted against self- or environmental antigens, respectively. Antigen-based immunotherapy is a therapeutic option aimed at restoring the specific immune tolerance toward pathogenic antigens while leaving the rest of the immune system unaffected. This strategy proved efficacy especially in allergic diseases, including asthma, allergic rhinitis, and food allergies, but still has shortcomings for the treatment of autoimmune diseases. However, there are no available therapies, currently, in clinical practice for restoring the physiological tolerance that is typically lost in autoimmune diseases. In celiac disease, which is a common immune-mediated enteropathy triggered by the ingestion of gluten in genetically susceptible individuals, antigen-based immunotherapy could be a feasible option thanks to our deep understanding of the pathogenic mechanisms underpinning this condition. In fact, the immunodominant gluten epitopes are well-characterized and are recognized by pathogenic CD4+ T-cells that could be desensitized with immunotherapy. Moreover, the intestinal damage occurring in celiac disease (i.e., villous atrophy) is reversible upon gluten withdrawal. Only recently the results of a phase I trial of an intradermal, adjuvant-free, formulation of three specific gluten peptides (Nexvax2) showed a good safety profile, albeit its efficacy still needs to be demonstrated. More results are awaited, as they may radically change patients' quality of life that is constrained by the lifelong gluten-free diet and by the potential onset of life-threatening complications.
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Affiliation(s)
- Antonio Di Sabatino
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Marco V. Lenti
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Gino R. Corazza
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Carmen Gianfrani
- Institute of Protein Biochemistry-National Research Council, Naples, Italy
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31
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Otašević V, Jovanović I. Histopathological changes of gastric mucosa in celiac disease. MEDICINSKI PODMLADAK 2018. [DOI: 10.5937/mp69-13383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
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32
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Tye-Din JA, Galipeau HJ, Agardh D. Celiac Disease: A Review of Current Concepts in Pathogenesis, Prevention, and Novel Therapies. Front Pediatr 2018; 6:350. [PMID: 30519552 PMCID: PMC6258800 DOI: 10.3389/fped.2018.00350] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 10/29/2018] [Indexed: 12/14/2022] Open
Abstract
Our understanding of celiac disease and how it develops has evolved significantly over the last half century. Although traditionally viewed as a pediatric illness characterized by malabsorption, it is now better seen as an immune illness with systemic manifestations affecting all ages. Population studies reveal this global disease is common and, in many countries, increasing in prevalence. These studies underscore the importance of specific HLA susceptibility genes and gluten consumption in disease development and suggest that other genetic and environmental factors could also play a role. The emerging data on viral and bacterial microbe-host interactions and their alterations in celiac disease provides a plausible mechanism linking environmental risk and disease development. Although the inflammatory lesion of celiac disease is complex, the strong HLA association highlights a central role for pathogenic T cells responding to select gluten peptides that have now been defined for the most common genetic form of celiac disease. What remains less understood is how loss of tolerance to gluten occurs. New insights into celiac disease are now providing opportunities to intervene in its development, course, diagnosis, and treatment.
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Affiliation(s)
- Jason A Tye-Din
- Immunology Division, The Walter and Eliza Hall Institute, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.,Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, VIC, Australia.,Centre for Food & Allergy Research, Murdoch Children's Research Institute, Parkville, VIC, Australia
| | - Heather J Galipeau
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Daniel Agardh
- The Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.,Unit of Endocrinology and Gastroenterology, Department of Pediatrics, Skåne University Hospital, Malmö, Sweden
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Lucero Y, Oyarzún A, O'Ryan M, Quera R, Espinosa N, Valenzuela R, Simian D, Alcalde E, Arce C, Farfán MJ, Vergara AF, Gajardo I, Mendez J, Carrasco J, Errázuriz G, Gonzalez M, Ossa JC, Maiza E, Perez-Bravo F, Castro M, Araya M. Helicobacter pylori cagA+ Is Associated with Milder Duodenal Histological Changes in Chilean Celiac Patients. Front Cell Infect Microbiol 2017; 7:376. [PMID: 28879170 PMCID: PMC5572207 DOI: 10.3389/fcimb.2017.00376] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 08/08/2017] [Indexed: 12/14/2022] Open
Abstract
HIGHLIGHTS
What is already known about this subject? Celiac disease (CD) has a high clinical and histological diversity and the mechanisms underlying this phenomenon remain elusive. H. pylori is a bacterium that chronically infect gastric and duodenal mucosa activating both a Th1/Th17 and T-reg pathways. The role of H. pylori (and the effect of their virulence factors) in CD have not yet completely elucidated. What are the new findings? cagA+ H. pylori strains are associated to milder histological damage in infected CD patients. In active-CD patients the presence of cagA+ H. pylori is associated to an increase in T-reg markers, contrasting with a downregulation in cagA+ infected potential-CD individuals. How might it impact on clinical practice in the foreseeable future? The identification of microbiological factors that could modulate inflammation and clinical expression of CD may be used in the future as preventive strategies or as supplementary treatment in patients that cannot achieve complete remission, contributing to the better care of these patients. Background: Mechanisms underlying the high clinical and histological diversity of celiac disease (CD) remain elusive. Helicobacter pylori (Hp) chronically infects gastric and duodenal mucosa and has been associated with protection against some immune-mediated conditions, but its role (specifically of cagA+ strains) in CD is unclear. Objective: To assess the relationship between gastric Hp infection (cagA+ strains) and duodenal histological damage in patients with CD. Design: Case-control study including patients with active-CD, potential-CD and non-celiac individuals. Clinical presentation, HLA genotype, Hp/cagA gene detection in gastric mucosa, duodenal histology, Foxp3 positive cells and TGF-β expression in duodenal lamina propria were analyzed. Results: We recruited 116 patients, 29 active-CD, 37 potential-CD, and 50 non-CD controls. Hp detection was similar in the three groups (~30–40%), but cagA+ strains were more common in infected potential-CD than in active-CD (10/11 vs. 4/10; p = 0.020) and non-CD (10/20; p = 0.025). Among active-CD patients, Foxp3 positivity was significantly higher in subjects with cagA+ Hp+ compared to cagA- Hp+ (p < 0.01) and Hp- (p < 0.01). In cagA+ Hp+ individuals, Foxp3 positivity was also higher comparing active- to potential-CD (p < 0.01). TGF-β expression in duodenum was similar in active-CD with cagA+ Hp+ compared to Hp- and was significantly downregulated in cagA+ potential-CD subjects compared to other groups. Conclusion: Hp infection rates were similar among individuals with/without CD, but infection with cagA+ strains was associated with milder histological damage in celiac patients infected by Hp, and in active-CD cases with higher expression of T-reg markers. Results suggest that infection by cagA+ Hp may be protective for CD progression, or conversely, that these strains are prone to colonize intestinal mucosa with less severe damage.
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Affiliation(s)
- Yalda Lucero
- Hospital Dr. Luis Calvo MackennaSantiago, Chile.,Department of Pediatrics and Pediatric Surgery, Faculty of Medicine, University of ChileSantiago, Chile.,Microbiology and Micology Program, Faculty of Medicine, University of ChileSantiago, Chile
| | - Amaya Oyarzún
- Laboratory of Immunegenetics, Institute of Nutrition and Food Technology, University of ChileSantiago, Chile
| | - Miguel O'Ryan
- Microbiology and Micology Program, Faculty of Medicine, University of ChileSantiago, Chile.,Millenium Institute of Immunology and Immunotherapy, Faculty of Medicine, University of ChileSantiago, Chile
| | - Rodrigo Quera
- Department of Gastroenterology, Clínica Las CondesSantiago, Chile
| | | | - Romina Valenzuela
- Department of Pediatrics and Pediatric Surgery, Faculty of Medicine, University of ChileSantiago, Chile
| | - Daniela Simian
- Department of Gastroenterology, Clínica Las CondesSantiago, Chile
| | | | | | - Mauricio J Farfán
- Hospital Dr. Luis Calvo MackennaSantiago, Chile.,Department of Pediatrics and Pediatric Surgery, Faculty of Medicine, University of ChileSantiago, Chile
| | | | - Iván Gajardo
- Department of Pediatrics and Pediatric Surgery, Faculty of Medicine, University of ChileSantiago, Chile
| | | | | | - Germán Errázuriz
- Department of Gastroenterology, Clínica Las CondesSantiago, Chile
| | | | - Juan C Ossa
- Hospital Dr. Luis Calvo MackennaSantiago, Chile.,Department of Pediatrics and Pediatric Surgery, Faculty of Medicine, University of ChileSantiago, Chile
| | | | | | - Magdalena Castro
- Millenium Institute of Immunology and Immunotherapy, Faculty of Medicine, University of ChileSantiago, Chile
| | - Magdalena Araya
- Microbiology and Micology Program, Faculty of Medicine, University of ChileSantiago, Chile
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Zundler S, Neurath MF. Pathogenic T cell subsets in allergic and chronic inflammatory bowel disorders. Immunol Rev 2017; 278:263-276. [DOI: 10.1111/imr.12544] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Sebastian Zundler
- Department of Medicine 1; University of Erlangen-Nuremberg; Kussmaul Campus for Medical Research & Translational Research Center; Erlangen Germany
| | - Markus F. Neurath
- Department of Medicine 1; University of Erlangen-Nuremberg; Kussmaul Campus for Medical Research & Translational Research Center; Erlangen Germany
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Narang M, Puri AS, Sachdeva S, Singh J, Kumar A, Saran RK. Celiac disease and Helicobacter pylori infection in children: Is there any Association? J Gastroenterol Hepatol 2017; 32:1178-1182. [PMID: 27862319 DOI: 10.1111/jgh.13654] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 10/21/2016] [Accepted: 11/09/2016] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIM Helicobacter pylori (HP) infection can influence the inflammatory and immune responses in the gut and may therefore play a role in the development of gluten-related enteropathy in genetically susceptible individuals. Our objective was to assess the relationship between celiac disease and HP infection in children. METHODS Children (1-18 years) diagnosed as celiac disease (CD) (n = 324) with submission of gastric and duodenal biopsies and duodenal histology having Marsh grade III features were eligible for the study. Non-celiac patients referred for endoscopy were selected as controls. We studied proportion of HP prevalence in children with confirmed CD as compared with HP prevalence in reference group comprising non-celiac children referred for endoscopy. We also evaluated predictors of HP infection in children with celiac disease. RESULTS Of the 324 participants with CD, gastric HP was seen in 37 (11.4%) patients. The prevalence of HP in patients without CD (50%, P < 0.001) was significantly higher. Among patients with CD, HP infection was most frequent in patients with Marsh IIIa. In the stepwise regression analysis for risk factors of HP infection in CD patients: presence of gastritis, hemoglobin, and absence of scalloping were found to be independent predictors in a multivariate setup. CONCLUSION Celiac disease and gastric HP infection have inverse relationship that raises the question whether development of HP infection confers protection against CD.
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Affiliation(s)
- Manish Narang
- Department of Gastroenterology, GB Pant Institute of Post Graduate Medical Education and Research, Delhi, India
| | - Amarender Singh Puri
- Department of Gastroenterology, GB Pant Institute of Post Graduate Medical Education and Research, Delhi, India
| | - Sanjeev Sachdeva
- Department of Gastroenterology, GB Pant Institute of Post Graduate Medical Education and Research, Delhi, India
| | - Jatinderpal Singh
- Department of Gastroenterology, GB Pant Institute of Post Graduate Medical Education and Research, Delhi, India
| | - Ajay Kumar
- Department of Gastroenterology, GB Pant Institute of Post Graduate Medical Education and Research, Delhi, India
| | - Ravindra K Saran
- Department of Pathology, GB Pant Institute of Post Graduate Medical Education and Research, Delhi, India
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Kessel A, Lin C, Vadasz Z, Peri R, Eiza N, Berkowitz D. The association between semaphorin 3A levels and gluten-free diet in patients with celiac disease. Clin Immunol 2017; 184:73-76. [PMID: 28502679 DOI: 10.1016/j.clim.2017.05.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2016] [Revised: 04/10/2017] [Accepted: 05/10/2017] [Indexed: 12/20/2022]
Abstract
Celiac disease (CD) is an inflammatory disease affecting the small intestine. We aim to assess serum level and expression of semaphorin 3A (Sema3A) on T regulatory (Treg) cells in CD patients. Twenty-six newly diagnosed celiac patients, 13 celiac patients on a gluten-free diet and 16 healthy controls included in the study. Sema3A protein level in the serum of celiac patients was significantly higher compared to healthy group (7.17±1.8ng/ml vs. 5.67±1.5ng/ml, p=0.012). Sema3A expression on Treg cells was statistically lower in celiac patients compared to healthy subjects (p=0.009) and significantly lower in celiac patients compared to celiac patients on gluten free diet (p=0.04). Negative correlation was found between Sema3A on Teg cells and the level of IgA anti-tTG antibodies (r=-0.346, p<0.01) and anti-DGP (r=-0.448, p<0.01). This study suggests involvement of the Sema3A in the pathogenesis of CD.
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Affiliation(s)
- Aharon Kessel
- Division of Allergy and Clinical Immunology, Bnai Zion Medical Center, Technion Faculty of Medicine, Haifa, Israel.
| | - Chen Lin
- Division of Allergy and Clinical Immunology, Bnai Zion Medical Center, Technion Faculty of Medicine, Haifa, Israel
| | - Zahava Vadasz
- Division of Allergy and Clinical Immunology, Bnai Zion Medical Center, Technion Faculty of Medicine, Haifa, Israel
| | - Regina Peri
- Division of Allergy and Clinical Immunology, Bnai Zion Medical Center, Technion Faculty of Medicine, Haifa, Israel
| | - Nasren Eiza
- Division of Allergy and Clinical Immunology, Bnai Zion Medical Center, Technion Faculty of Medicine, Haifa, Israel
| | - Drora Berkowitz
- Division of Pediatric Gastroenterology, Bnai Zion Medical Center, Faculty of Medicine, Technion, Haifa, Israel
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Hill LJ, Williams AC. Meat Intake and the Dose of Vitamin B 3 - Nicotinamide: Cause of the Causes of Disease Transitions, Health Divides, and Health Futures? Int J Tryptophan Res 2017; 10:1178646917704662. [PMID: 28579801 PMCID: PMC5419340 DOI: 10.1177/1178646917704662] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 03/15/2017] [Indexed: 12/26/2022] Open
Abstract
Meat and vitamin B3 - nicotinamide - intake was high during hunter-gatherer times. Intake then fell and variances increased during and after the Neolithic agricultural revolution. Health, height, and IQ deteriorated. Low dietary doses are buffered by 'welcoming' gut symbionts and tuberculosis that can supply nicotinamide, but this co-evolved homeostatic metagenomic strategy risks dysbioses and impaired resistance to pathogens. Vitamin B3 deficiency may now be common among the poor billions on a low-meat diet. Disease transitions to non-communicable inflammatory disorders (but longer lives) may be driven by positive 'meat transitions'. High doses of nicotinamide lead to reduced regulatory T cells and immune intolerance. Loss of no longer needed symbiotic 'old friends' compounds immunological over-reactivity to cause allergic and auto-immune diseases. Inhibition of nicotinamide adenine dinucleotide consumers and loss of methyl groups or production of toxins may cause cancers, metabolic toxicity, or neurodegeneration. An optimal dosage of vitamin B3 could lead to better health, but such a preventive approach needs more equitable meat distribution. Some people may require personalised doses depending on genetic make-up or, temporarily, when under stress.
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Affiliation(s)
- Lisa J Hill
- Neuroscience and Ophthalmology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Adrian C Williams
- Department of Neurology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
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38
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van Leeuwen MA, Costes LMM, van Berkel LA, Simons-Oosterhuis Y, du Pré MF, Kozijn AE, Raatgeep HC, Lindenbergh-Kortleve DJ, van Rooijen N, Koning F, Samsom JN. Macrophage-mediated gliadin degradation and concomitant IL-27 production drive IL-10- and IFN-γ-secreting Tr1-like-cell differentiation in a murine model for gluten tolerance. Mucosal Immunol 2017; 10:635-649. [PMID: 27579860 DOI: 10.1038/mi.2016.76] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 07/12/2016] [Indexed: 02/04/2023]
Abstract
Celiac disease is caused by inflammatory T-cell responses against the insoluble dietary protein gliadin. We have shown that, in humanized mice, oral tolerance to deamidated chymotrypsin-digested gliadin (CT-TG2-gliadin) is driven by tolerogenic interferon (IFN)-γ- and interleukin (IL)-10-secreting type 1 regulatory T-like cells (Tr1-like cells) generated in the spleen but not in the mesenteric lymph nodes. We aimed to uncover the mechanisms underlying gliadin-specific Tr1-like-cell differentiation and hypothesized that proteolytic gliadin degradation by splenic macrophages is a decisive step in this process. In vivo depletion of macrophages caused reduced differentiation of splenic IFN-γ- and IL-10-producing Tr1-like cells after CT-TG2-gliadin but not gliadin peptide feed. Splenic macrophages, rather than dendritic cells, constitutively expressed increased mRNA levels of the endopeptidase Cathepsin D; macrophage depletion significantly reduced splenic Cathepsin D expression in vivo and Cathepsin D efficiently degraded recombinant γ-gliadin in vitro. In response to CT-TG2-gliadin uptake, macrophages enhanced the expression of Il27p28, a cytokine that favored differentiation of gliadin-specific Tr1-like cells in vitro, and was previously reported to increase Cathepsin D activity. Conversely, IL-27 neutralization in vivo inhibited splenic IFN-γ- and IL-10-secreting Tr1-like-cell differentiation after CT-TG2-gliadin feed. Our data infer that endopeptidase mediated gliadin degradation by macrophages and concomitant IL-27 production drive differentiation of splenic gliadin-specific Tr1-like cells.
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Affiliation(s)
- M A van Leeuwen
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - L M M Costes
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - L A van Berkel
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Y Simons-Oosterhuis
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - M F du Pré
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.,Center for Immune Regulation, Institute of Immunology, University of Oslo and Oslo University Hospital -Rikshospitalet, Oslo, Norway
| | - A E Kozijn
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - H C Raatgeep
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - D J Lindenbergh-Kortleve
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - N van Rooijen
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - F Koning
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - J N Samsom
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands
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Cook L, Munier CML, Seddiki N, van Bockel D, Ontiveros N, Hardy MY, Gillies JK, Levings MK, Reid HH, Petersen J, Rossjohn J, Anderson RP, Zaunders JJ, Tye-Din JA, Kelleher AD. Circulating gluten-specific FOXP3 +CD39 + regulatory T cells have impaired suppressive function in patients with celiac disease. J Allergy Clin Immunol 2017; 140:1592-1603.e8. [PMID: 28283419 DOI: 10.1016/j.jaci.2017.02.015] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 02/03/2017] [Accepted: 02/16/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Celiac disease is a chronic immune-mediated inflammatory disorder of the gut triggered by dietary gluten. Although the effector T-cell response in patients with celiac disease has been well characterized, the role of regulatory T (Treg) cells in the loss of tolerance to gluten remains poorly understood. OBJECTIVE We sought to define whether patients with celiac disease have a dysfunction or lack of gluten-specific forkhead box protein 3 (FOXP3)+ Treg cells. METHODS Treated patients with celiac disease underwent oral wheat challenge to stimulate recirculation of gluten-specific T cells. Peripheral blood was collected before and after challenge. To comprehensively measure the gluten-specific CD4+ T-cell response, we paired traditional IFN-γ ELISpot with an assay to detect antigen-specific CD4+ T cells that does not rely on tetramers, antigen-stimulated cytokine production, or proliferation but rather on antigen-induced coexpression of CD25 and OX40 (CD134). RESULTS Numbers of circulating gluten-specific Treg cells and effector T cells both increased significantly after oral wheat challenge, peaking at day 6. Surprisingly, we found that approximately 80% of the ex vivo circulating gluten-specific CD4+ T cells were FOXP3+CD39+ Treg cells, which reside within the pool of memory CD4+CD25+CD127lowCD45RO+ Treg cells. Although we observed normal suppressive function in peripheral polyclonal Treg cells from patients with celiac disease, after a short in vitro expansion, the gluten-specific FOXP3+CD39+ Treg cells exhibited significantly reduced suppressive function compared with polyclonal Treg cells. CONCLUSION This study provides the first estimation of FOXP3+CD39+ Treg cell frequency within circulating gluten-specific CD4+ T cells after oral gluten challenge of patients with celiac disease. FOXP3+CD39+ Treg cells comprised a major proportion of all circulating gluten-specific CD4+ T cells but had impaired suppressive function, indicating that Treg cell dysfunction might be a key contributor to disease pathogenesis.
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Affiliation(s)
- Laura Cook
- Immunovirology and Pathogenesis Program, The Kirby Institute, UNSW Sydney, Sydney, Australia; St Vincent's Centre for Applied Medical Research, St Vincent's Hospital, Sydney, Australia.
| | - C Mee Ling Munier
- Immunovirology and Pathogenesis Program, The Kirby Institute, UNSW Sydney, Sydney, Australia
| | - Nabila Seddiki
- Immunovirology and Pathogenesis Program, The Kirby Institute, UNSW Sydney, Sydney, Australia; St Vincent's Centre for Applied Medical Research, St Vincent's Hospital, Sydney, Australia
| | - David van Bockel
- Immunovirology and Pathogenesis Program, The Kirby Institute, UNSW Sydney, Sydney, Australia
| | - Noé Ontiveros
- Immunology Division, Walter and Eliza Hall Institute, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
| | - Melinda Y Hardy
- Immunology Division, Walter and Eliza Hall Institute, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
| | - Jana K Gillies
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Megan K Levings
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Hugh H Reid
- Infection and Immunity Program, The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Australia
| | - Jan Petersen
- Infection and Immunity Program, The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Australia
| | - Jamie Rossjohn
- Infection and Immunity Program, The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Australia; Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom
| | - Robert P Anderson
- Immunology Division, Walter and Eliza Hall Institute, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia; ImmusanT, Cambridge, Mass
| | - John J Zaunders
- Immunovirology and Pathogenesis Program, The Kirby Institute, UNSW Sydney, Sydney, Australia; St Vincent's Centre for Applied Medical Research, St Vincent's Hospital, Sydney, Australia
| | - Jason A Tye-Din
- Immunology Division, Walter and Eliza Hall Institute, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia; Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Australia
| | - Anthony D Kelleher
- Immunovirology and Pathogenesis Program, The Kirby Institute, UNSW Sydney, Sydney, Australia; St Vincent's Centre for Applied Medical Research, St Vincent's Hospital, Sydney, Australia
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Kumar J, Kumar M, Pandey R, Chauhan NS. Physiopathology and Management of Gluten-Induced Celiac Disease. J Food Sci 2017; 82:270-277. [PMID: 28140462 DOI: 10.1111/1750-3841.13612] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Revised: 11/21/2016] [Accepted: 12/09/2016] [Indexed: 12/13/2022]
Abstract
Proline- and glutamine-rich gluten proteins are one of the major constituents of cereal dietary proteins, which are largely resistant to complete cleavage by the human gastrointestinal (GI) digestive enzymes. Partial digestion of gluten generates approximately 35 amino acids (aa) immunomodulatory peptides which activate T-cell-mediated immune system, followed by immunological inflammation of mucosa leading to the onset of celiac disease (CD). CD is an autoimmune disease associated with HLA-DQ2/DQ8 polymorphism and dysbiosis of gut microbiota. CD is either diagnosed using duodenal mucosal biopsis or serological testing for transglutaminase 2 (TG2) specific antibodies (IgA and IgG). Current therapy for CD management is gluten-free diet, while other therapies like glutenase, probiotics, immunomodulation, jamming of HLA-DQ2, inhibition of TG2, and gluten tolerance aided by gluten tolerizing vaccines are being developed.
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Affiliation(s)
- Jitendra Kumar
- Dept. of Biochemistry, M.D. Univ., Rohtak, 124001, Haryana, India
| | - Manoj Kumar
- Dept. of Biochemistry, M.D. Univ., Rohtak, 124001, Haryana, India
| | - Rajesh Pandey
- Ayurgenomics Unit-TRISUTRA, Inst. of Genomics and Integrative Biology, Council of Scientific and Industrial Research, New Delhi, 110020, India
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Serena G, Yan S, Camhi S, Patel S, Lima RS, Sapone A, Leonard MM, Mukherjee R, Nath BJ, Lammers KM, Fasano A. Proinflammatory cytokine interferon-γ and microbiome-derived metabolites dictate epigenetic switch between forkhead box protein 3 isoforms in coeliac disease. Clin Exp Immunol 2017; 187:490-506. [PMID: 27936497 DOI: 10.1111/cei.12911] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Revised: 11/16/2016] [Accepted: 11/17/2016] [Indexed: 12/21/2022] Open
Abstract
Coeliac disease (CD) is an autoimmune enteropathy triggered by gluten and characterized by a strong T helper type 1 (Th1)/Th17 immune response in the small intestine. Regulatory T cells (Treg ) are CD4+ CD25++ forkhead box protein 3 (FoxP3+ ) cells that regulate the immune response. Conversely to its counterpart, FoxP3 full length (FL), the alternatively spliced isoform FoxP3 Δ2, cannot properly down-regulate the Th17-driven immune response. As the active state of CD has been associated with impairments in Treg cell function, we aimed at determining whether imbalances between FoxP3 isoforms may be associated with the disease. Intestinal biopsies from patients with active CD showed increased expression of FOXP3 Δ2 isoform over FL, while both isoforms were expressed similarly in non-coeliac control subjects (HC). Conversely to what we saw in the intestine, peripheral blood mononuclear cells (PBMC) from HC subjects did not show the same balance between isoforms. We therefore hypothesized that the intestinal microenvironment may play a role in modulating alternative splicing. The proinflammatory intestinal microenvironment of active patients has been reported to be enriched in butyrate-producing bacteria, while high concentrations of lactate have been shown to characterize the preclinical stage of the disease. We show that the combination of interferon (IFN)-γ and butyrate triggers the balance between FoxP3 isoforms in HC subjects, while the same does not occur in CD patients. Furthermore, we report that lactate increases both isoforms in CD patients. Collectively, these findings highlight the importance of the ratio between FoxP3 isoforms in CD and, for the first time, associate the alternative splicing process mechanistically with microbial-derived metabolites.
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Affiliation(s)
- G Serena
- Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA.,Graduate Program in Life Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - S Yan
- Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA
| | - S Camhi
- Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA
| | - S Patel
- Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA
| | - R S Lima
- Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA
| | - A Sapone
- Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA.,Celiac Center, Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - M M Leonard
- Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA
| | - R Mukherjee
- Celiac Center, Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - B J Nath
- Department of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
| | - K M Lammers
- Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA
| | - A Fasano
- Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA.,European Biomedical Research Institute of Salerno (EBRIS), Salerno, Italy
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Hardy MY, Tye-Din JA. Coeliac disease: a unique model for investigating broken tolerance in autoimmunity. Clin Transl Immunology 2016; 5:e112. [PMID: 27990287 PMCID: PMC5133362 DOI: 10.1038/cti.2016.58] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 09/12/2016] [Accepted: 09/12/2016] [Indexed: 01/06/2023] Open
Abstract
Coeliac disease, a prevalent immune-mediated enteropathy driven by dietary gluten, provides an exceptional human model to dissect the genetic, environmental and immunologic factors operating in autoimmunity. Despite the causative antigen being an exogenous food protein, coeliac disease has many features in common with autoimmune disease including a strong HLA class II association and the presence of pathogenic CD4+ T cells and autoantibodies. CD8+ intraepithelial lymphocytes specifically target and destroy intestinal epithelium in response to stress signals and not a specific antigen. A unique feature of coeliac disease is the ability to remove gluten to induce disease remission and reintroduce it to trigger a memory response. This provides an unparalleled opportunity to study disease-relevant CD4+ T cells that have been expanded in vivo. As a result, the causative peptides have been characterised at a level unprecedented for any autoimmune disease. Despite the complexity of the gluten proteome, resistance to gastrointestinal proteolysis and susceptibility to post-translational modification by transglutaminase help shape a restricted repertoire of immunogenic gluten peptides that have high affinity for disease-associated HLA. The critical steps in coeliac disease pathogenesis have been broadly elucidated and provide the basis for experimental therapies in pre-clinical or clinical development. However, little is known about how and why tolerance to gluten sometimes breaks or fails to develop. Understanding the interactions between genes, the environment, gluten immunity and the microbiome may provide novel approaches for the prevention and treatment of disease.
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Affiliation(s)
- Melinda Y Hardy
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Jason A Tye-Din
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia; Centre of Food and Allergy Research, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, Victoria, Australia
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Lammi A, Arikoski P, Hakulinen A, Schwab U, Uusitupa M, Heinonen S, Savilahti E, Kinnunen T, Ilonen J. Development of gliadin-specific immune responses in children with HLA-associated genetic risk for celiac disease. Scand J Gastroenterol 2016; 51:168-77. [PMID: 26161465 DOI: 10.3109/00365521.2015.1067328] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The development of gliadin-specific antibody and T-cell responses were longitudinally monitored in young children with genetic risk for celiac disease (CD). MATERIAL AND METHODS 291 newborn children positive for HLA-DQB1*02 and -DQA1*05 alleles were followed until 3-4 years of age by screening for tissue transglutaminase autoantibodies (tTGA) by using a commercial ELISA-based kit and antibodies to deamidated gliadin peptide (anti-DGP) by an immunofluorometric assay. Eighty-five of the children were also followed for peripheral blood gliadin-specific CD4(+) T-cell responses by using a carboxyfluorescein diacetate succinimidyl ester-based in vitro proliferation assay. RESULTS The cumulative incidence of tTGA seropositivity during the follow-up was 6.5%. CD was diagnosed in nine of the tTGA-positive children (3.1%) by duodenal biopsy at a median 3.5 years of age. All of the children with confirmed CD were both IgA and IgG anti-DGP positive at the time of tTGA seroconversion and in over half of the cases IgG anti-DGP positivity even preceded tTGA seroconversion. Peripheral blood T-cell responses to deamidated and native gliadin were detected in 40.5% and 22.2% of the children at the age of 9 months and these frequencies decreased during the follow-up to the levels of 22.2% and 8.9%, respectively. CONCLUSIONS Anti-DGP antibodies may precede tTGA seroconversion and thus frequent monitoring of both tTGA and anti-DGP antibodies may allow earlier detection of CD in genetically susceptible children. Peripheral blood gliadin-specific T-cell responses are relatively common in HLA-DQ2-positive children and are not directly associated with the development of CD.
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Affiliation(s)
- Anne Lammi
- a 1 Department of Clinical Microbiology, University of Eastern Finland , Kuopio, Finland
| | - Pekka Arikoski
- b 2 Department of Pediatrics, Kuopio University Hospital and University of Eastern Finland , Kuopio, Finland
| | - Arja Hakulinen
- c 3 Children's Hospital, University of Helsinki , Helsinki, Finland
| | - Ursula Schwab
- d 4 Institute of Public Health and Clinical Nutrition, University of Eastern Finland , Kuopio, Finland.,e 5 Institute of Clinical Medicine, Internal Medicine, Kuopio University Hospital , Kuopio, Finland
| | - Matti Uusitupa
- d 4 Institute of Public Health and Clinical Nutrition, University of Eastern Finland , Kuopio, Finland
| | - Seppo Heinonen
- f 6 Department of Obstetrics and Gynecology, Helsinki University Hospital and University of Helsinki , Helsinki, Finland
| | - Erkki Savilahti
- c 3 Children's Hospital, University of Helsinki , Helsinki, Finland
| | - Tuure Kinnunen
- a 1 Department of Clinical Microbiology, University of Eastern Finland , Kuopio, Finland
| | - Jorma Ilonen
- a 1 Department of Clinical Microbiology, University of Eastern Finland , Kuopio, Finland.,g 7 Immunogenetics Laboratory, University of Turku , Turku, Finland
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Kuhn C, Besançon A, Lemoine S, You S, Marquet C, Candon S, Chatenoud L. Regulatory mechanisms of immune tolerance in type 1 diabetes and their failures. J Autoimmun 2016; 71:69-77. [DOI: 10.1016/j.jaut.2016.05.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 05/07/2016] [Indexed: 12/11/2022]
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Hoeppli RE, MacDonald KG, Levings MK, Cook L. How antigen specificity directs regulatory T-cell function: self, foreign and engineered specificity. HLA 2016; 88:3-13. [PMID: 27256587 DOI: 10.1111/tan.12822] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 04/29/2016] [Indexed: 02/06/2023]
Abstract
Regulatory T cells (Tregs) are a suppressive subset of T cells that have important roles in maintaining self-tolerance and preventing immunopathology. The T-cell receptor (TCR) and its antigen specificity play a dominant role in the differentiation of cells to a Treg fate, either in the thymus or in the periphery. This review focuses on the effects of the TCR and its antigen specificity on Treg biology. The role of Tregs with specificity for self-antigen has primarily been studied in the context of autoimmune disease, although recent studies have focused on their role in steady-state conditions. The role of Tregs that are specific for pathogens, dietary antigens and allergens is much less studied, although recent data suggest a significant and previously underappreciated role for Tregs during memory responses to a wide range of foreign antigens. The development of TCR- or chimeric antigen receptor (CAR)-transduced T cells means we are now able to engineer Tregs with disease-relevant antigen specificities, paving the way for ensuring specificity with Treg-based therapies. Understanding the role that antigens play in driving the generation and function of Tregs is critical for defining the pathophysiology of many immune-mediated diseases, and developing new therapeutic interventions.
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Affiliation(s)
- R E Hoeppli
- Department of Surgery, University of British Columbia and Child & Family Research Institute, Vancouver, Canada
| | - K G MacDonald
- Department of Surgery, University of British Columbia and Child & Family Research Institute, Vancouver, Canada
| | - M K Levings
- Department of Surgery, University of British Columbia and Child & Family Research Institute, Vancouver, Canada
| | - L Cook
- Department of Surgery, University of British Columbia and Child & Family Research Institute, Vancouver, Canada
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Mercadante ER, Lorenz UM. Breaking Free of Control: How Conventional T Cells Overcome Regulatory T Cell Suppression. Front Immunol 2016; 7:193. [PMID: 27242798 PMCID: PMC4870238 DOI: 10.3389/fimmu.2016.00193] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 05/02/2016] [Indexed: 01/10/2023] Open
Abstract
Conventional T (Tcon) cells are crucial in shaping the immune response, whether it is protection against a pathogen, a cytotoxic attack on tumor cells, or an unwanted response to self-antigens in the context of autoimmunity. In each of these immune settings, regulatory T cells (Tregs) can potentially exert control over the Tcon cell response, resulting in either suppression or activation of the Tcon cells. Under physiological conditions, Tcon cells are able to transiently overcome Treg-imposed restraints to mount a protective response against an infectious threat, achieving clonal expansion, differentiation, and effector function. However, evidence has accumulated in recent years to suggest that Tcon cell resistance to Treg-mediated suppression centrally contributes to the pathogenesis of autoimmune disease. Tipping the balance too far in the other direction, cancerous tumors utilize Tregs to establish an overly suppressive microenvironment, preventing antitumor Tcon cell responses. Given the wide-ranging clinical importance of the Tcon/Treg interaction, this review aims to provide a better understanding of what determines whether a Tcon cell is susceptible to Treg-mediated suppression and how perturbations to this finely tuned balance play a role in pathological conditions. Here, we focus in detail on the complex array of factors that confer Tcon cells with resistance to Treg suppression, which we have divided into two categories: (1) extracellular factor-mediated signaling and (2) intracellular signaling molecules. Further, we explore the therapeutic implications of manipulating the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway, which is proposed to be the convergence point of signaling pathways that mediate Tcon resistance to suppression. Finally, we address important unresolved questions on the timing and location of acquisition of resistance, and the stability of the “Treg-resistant” phenotype.
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Affiliation(s)
- Emily R Mercadante
- Department of Microbiology Immunology and Cancer Biology, Beirne Carter Center for Immunology Research, University of Virginia , Charlottesville, VA , USA
| | - Ulrike M Lorenz
- Department of Microbiology Immunology and Cancer Biology, Beirne Carter Center for Immunology Research, University of Virginia , Charlottesville, VA , USA
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Ciccocioppo R, Cangemi GC, Kruzliak P, Corazza GR. Concise Review: Cellular Therapies: The Potential to Regenerate and Restore Tolerance in Immune-Mediated Intestinal Diseases. Stem Cells 2016; 34:1474-86. [PMID: 27016400 DOI: 10.1002/stem.2367] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Revised: 03/01/2016] [Accepted: 03/10/2016] [Indexed: 12/18/2022]
Abstract
Chronic inflammatory enteropathies, including celiac disease, Crohn's disease, and ulcerative colitis, are lifelong disabling conditions whose cure is still an unmet need, despite the great strides made in understanding their complex pathogenesis. The advent of cellular therapies, mainly based on the use of stem cells, represents a great step forward thanks to their multitarget strategy. Both hematopoietic stem cells (HSC) and mesenchymal stem/stromal cells (MSC) have been employed in the treatment of refractory cases with promising results. The lack of immunogenicity makes MSC more suitable for therapeutic purposes as their infusion may be performed across histocompatibility locus antigen barriers without risk of rejection. The best outcome has been obtained when treating fistulizing Crohn's disease with local injections of MSC. In addition, both HSC and MSC proved successful in promoting regeneration of intestinal mucosa, and favoring the expansion of a T-cell regulatory subset. By virtue of the ability to favor mucosal homeostasis, this last cell population has been exploited in clinical trials, with inconsistent results. Finally, the recent identification of the epithelial stem cell marker has opened up the possibility of tissue engineering, with an array of potential applications for intestinal diseases. However, the underlying mechanisms of action of these interconnected therapeutic strategies are still poorly understood. It is conceivable that over the next few years their role will become clearer as the biological interactions with injured tissues and the hierarchy by which they deliver their action are unraveled through a continuous moving from bench to bedside and vice versa. Stem Cells 2016;34:1474-1486.
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Affiliation(s)
- Rachele Ciccocioppo
- Clinica Medica I, Department of Internal Medicine Fondazione IRCCS Policlinico San Matteo, Università degli Studi di Pavia, Italy
| | - Giuseppina Cristina Cangemi
- Clinica Medica I, Department of Internal Medicine Fondazione IRCCS Policlinico San Matteo, Università degli Studi di Pavia, Italy
| | - Peter Kruzliak
- Laboratory of Structural Biology and Proteomics, Central Laboratories, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic
| | - Gino Roberto Corazza
- Clinica Medica I, Department of Internal Medicine Fondazione IRCCS Policlinico San Matteo, Università degli Studi di Pavia, Italy
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Hisamatsu T, Erben U, Kühl AA. The Role of T-Cell Subsets in Chronic Inflammation in Celiac Disease and Inflammatory Bowel Disease Patients: More Common Mechanisms or More Differences? Inflamm Intest Dis 2016; 1:52-62. [PMID: 29922658 DOI: 10.1159/000445133] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 03/02/2016] [Indexed: 12/13/2022] Open
Abstract
Background Chronic intestinal inflammation due to noninfectious causes represents a growing health issue all over the world. Celiac disease as well as inflammatory bowel diseases (IBD) like Crohn's disease and ulcerative and microscopic colitis involve uncontrolled T-cell activation and T-cell-mediated damage as common denominators. Therefore, diagnosis and treatment decisions clearly benefit from the knowledge of the intricacies of the systemic and the local T-cell activity. Summary Depending on the cytokine milieu, CD4+ T cells can differentiate into proinflammatory T helper 1 (Th1), anti-inflammatory Th2, antimicrobial Th17, pleiotropic Th9, tissue-instructing Th22 cells, and in the regulatory compartment forkhead box protein 3+ Treg, suppressive Tr1 or Th3 cells. Additionally, follicular Th cells provide B-cell help in antibody class switching; cytotoxic CD8+ T cells target virus-infected or tumor cells. This review discusses our current knowledge on the contribution of defined T-cell subpopulations to establishing and maintaining chronic intestinal inflammation in either of the above entities. It also puts emphasis on the differences in the prevalence of these diseases between Eastern and Western countries. Key Messages In celiac disease, the driving role of T cells in the lamina propria and in the epithelium mainly specific for two defined antigens is well established. Differences in genetics and lifestyle between Western and Eastern countries were instrumental in understanding underlying mechanisms. In IBD, the vast amount of potential antigens and the corresponding antigen-specific T cells makes it unlikely to find universal triggers. Increased mucosal CD4+ regulatory T cells in all four entities fail to control or abrogate local inflammatory processes. Thus, prevailing differences in the functional T-cell subtypes driving chronic intestinal inflammation in celiac disease and IBD at best allow some overlap in the treatment options for either disease.
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Affiliation(s)
- Tadakazu Hisamatsu
- The Third Department of Internal Medicine, Kyorin University School of Medicine, Mitaka, Tokyo, Japan
| | - Ulrike Erben
- Medical Department (Gastroenterology/Infectious Diseases/Rheumatology), Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Research Center ImmunoSciences, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Anja A Kühl
- Medical Department (Gastroenterology/Infectious Diseases/Rheumatology), Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Research Center ImmunoSciences, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Berlin, Germany
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Christophersen A, Risnes LF, Bergseng E, Lundin KEA, Sollid LM, Qiao SW. Healthy HLA-DQ2.5+ Subjects Lack Regulatory and Memory T Cells Specific for Immunodominant Gluten Epitopes of Celiac Disease. THE JOURNAL OF IMMUNOLOGY 2016; 196:2819-26. [DOI: 10.4049/jimmunol.1501152] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 01/13/2016] [Indexed: 11/19/2022]
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New insights into immune mechanisms underlying autoimmune diseases of the gastrointestinal tract. Autoimmun Rev 2015; 14:1161-9. [PMID: 26275585 DOI: 10.1016/j.autrev.2015.08.004] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2015] [Accepted: 08/05/2015] [Indexed: 02/07/2023]
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