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Xu X, Zhou Y, Tan Z, Huang Y, Dong K, Gu Y, Chen J, Yu Z. Risk factors for stoma and incision complications of enterostomy in children with very early-onset inflammatory bowel disease: a prospective cohort study. Eur J Pediatr 2025; 184:146. [PMID: 39828783 DOI: 10.1007/s00431-024-05952-2] [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: 10/19/2024] [Revised: 12/13/2024] [Accepted: 12/21/2024] [Indexed: 01/22/2025]
Abstract
Enterostomy is utilized to mitigate severe clinical symptoms in children with very early-onset inflammatory bowel disease (VEO-IBD) and to provide a window for stem cell transplantation. Nevertheless, the incidence of postoperative complications is significant, and there is currently a lack of research exploring the risk factors associated with complications related to the stoma and incision following the procedure. The objective of this study is to investigate the risk factors for stoma and incision complications after enterostomy in patients with VEO-IBD. From January 2015 to December 2023, 49 children with VEO-IBD who underwent enterostomy were enrolled in the study. Demographic characteristics, blood biochemical indices, weighted Pediatric Crohn's Disease Activity Index (wPCDAI), and enterostomy-related information were prospectively collected. Multivariate logistic regression was employed to identify the risk factors for ostomy and incision-related complications. All 49 included VEO-IBD children had interleukin-10 (IL-10) signaling defects, with 27 (55.1%) having stomal-related complications and 10 (20.4%) had incision complications after enterostomy. Univariate analysis revealed that wPCDAI (OR, 1.03; 95% CI, 1.00-1.07; P = 0.05) showed a tendency towards statistical significance in the occurrence of ostomy complications. Weight-for-age Z-score (WAZ) (OR, 0.57; 95% CI, 0.39-0.84; P = 0.004), height-for-age Z-score (HAZ) (OR, 0.57; 95% CI, 0.37-0.88; P = 0.01), type of surgery (OR, 0.12; 95% CI, 0.03-0.56, P = 0.007), C-reactive protein (CRP) (OR, 1.02; 95% CI, 1.01-1.04; P = 0.007), and wPCDAI (OR, 1.08; 95% CI, 1.01-1.14; P = 0.009) demonstrated statistical significance in the occurrence of incision complications. However, multivariate binary logistic regression did not reveal any statistically significant factors. CONCLUSION Although emergency surgery is unavoidable, our study suggests that improving nutritional status, reducing CRP levels, and increasing preoperative wPCDAI scores may help reduce post-enterostomy stoma and incision complications in VEO-IBD children with interleukin-10 (IL-10) signaling defects. Further large-scale studies are needed to confirm these findings. WHAT IS KNOWN • Enterostomy is commonly used to manage severe symptoms in children with VEO-IBD and to provide a window for stem cell transplantation. • The incidence of postoperative complications, including stoma and incision-related issues, is significant in these patients. WHAT IS NEW • This study identifies potential risk factors for stoma and incision complications following enterostomy in children with VEO-IBD, particularly those with IL-10 signaling defects. • Factors such as nutritional status (WAZ and HAZ), CRP levels, type of surgery, and the wPCDAI were found to be associated with stoma and incision complications in univariate analysis, although multivariate analysis did not show statistical significance for these factors.
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Affiliation(s)
- Xiaofeng Xu
- Department of Gastroenterology, Children's Hospital of Fudan University, No. 399, Wanyuan Rd., Minhang District, Shanghai, China.
| | - Yiwen Zhou
- Department of Gastroenterology, Children's Hospital of Fudan University, No. 399, Wanyuan Rd., Minhang District, Shanghai, China
| | - Zhixin Tan
- School of Nursing, Fudan University, Shanghai, China
| | - Ying Huang
- Department of Gastroenterology, Children's Hospital of Fudan University, No. 399, Wanyuan Rd., Minhang District, Shanghai, China
| | - Kuiran Dong
- Surgical Department, Children's Hospital of Fudan University, Shanghai, China
| | - Ying Gu
- Nursing Department, Children's Hospital of Fudan University, Shanghai, China
| | - Jie Chen
- Surgical Department/Stoma Wound Care Clinic, Children's Hospital of Fudan University, Shanghai, China
| | - Zhuowen Yu
- Department of Gastroenterology, Children's Hospital of Fudan University, No. 399, Wanyuan Rd., Minhang District, Shanghai, China.
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Khavkin AI, Permyakova AA, Tsepilova MO, Kaplina AV, Sitkin SI, Surkov AN, Getmanov SD. Modern View on Very Early Onset and Early Onset Inflammatory Bowel Diseases in Children. CURRENT PEDIATRICS 2024; 23:145-151. [DOI: 10.15690/vsp.v23i3.2768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Nowadays, an urgent problem of pediatric gastroenterology is the study of inflammatory bowel diseases with very early onset (VEO-IBD), which have unique genetic, clinical, immunological, morphological, and laboratory sings. Early VEO-IBD is usually considered as monogenic disease, especially in combination with congenital immune defects, which leads to difficulties in diagnosis and management this pathology. Despite this, systematization of information about this group of nosological forms of IBD is practically not carried out. This article presents a review of the available information on etiological factors, course variants, and therapeutic options for VEO-IBD.
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Affiliation(s)
| | | | | | | | - Stanislav I. Sitkin
- Almazov National Medical Research Centre; North-Western State Medical University named after I.I. Mechnikov
| | - Andrey N. Surkov
- Research Institute of Pediatrics and Children’s Health in Petrovsky National Research Centre of Surgery; Pirogov Russian National Research Medical University
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Tang Z, Sun S, Ji M, Shi P, Wang Y, Huang Z, Huang Y. Long-term outcomes after enterostomy for very early-onset inflammatory bowel disease with interleukin-10 signaling deficiency. BMC Gastroenterol 2023; 23:404. [PMID: 37986047 PMCID: PMC10661559 DOI: 10.1186/s12876-023-03051-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 11/10/2023] [Indexed: 11/22/2023] Open
Abstract
BACKGROUND Very early-onset inflammatory bowel disease (VEOIBD) with interleukin-10 (IL10R) signaling deficiency usually requires enterostomy in patients who are refractory to traditional treatment. This study aimed to evaluate long-term outcomes after enterostomy for VEOIBD patients with IL10R signaling deficiency. METHODS The medical records of all patients undergoing enterostomy for signaling deficiency were retrospectively assessed during 2012.1-2022.7 in a tertiary teaching hospital, Children's Hospital of Fudan University, Shanghai, China. Data on disease history, diagnosis and details of enterostomy and stoma closure and follow-up were collected. Univariate and multivariate logistic regression analyses were used to evaluate the risk factors associated with the long-term outcome of delayed stoma closure. RESULTS A total of 46 patients underwent an enterostomy, 19 who required emergency enterostomy and 27 with selective enterostomy. After ten years of follow-up, 35 patients underwent hematopoietic stem cell transplantation (HSCT), and 25 patients were alive after HSCT. The median timeframe between HSCT and stoma closure was 19.6 [15.9,26.2] months. Nineteen patients underwent stoma closure and had an average age of 3.9 ± 1.5 years; 6 patients were waiting for stoma closure. Based on a univariate logistic model, risk factors significantly associated with late stoma closure were age at enterostomy and age at HSCT. However, multivariate logistic regression showed no statistically significant factor associated with late stoma closure. There was no significant difference between the stoma closure group and delay closure group in the z scores of weight for age at follow up. CONCLUSIONS This study determined the long-term outcomes after enterostomy for VEOIBD with interleukin-10 signaling deficiency. The appropriate time point of enterostomy and HSCT may improve quality of life in the long term.
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Affiliation(s)
- Zifei Tang
- Department of Gastroenterology, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, Minhang District, 201102, China
| | - Song Sun
- Department of Surgery, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Min Ji
- Department of Radiology, Children's Hospital of Fudan University, 201102, Shanghai, China
| | - Peng Shi
- Pediatric Clinical Research Unit, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Yuhuan Wang
- Department of Gastroenterology, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, Minhang District, 201102, China
| | - Zhiheng Huang
- Department of Gastroenterology, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, Minhang District, 201102, China.
| | - Ying Huang
- Department of Gastroenterology, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, Minhang District, 201102, China.
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Bucciol G, Moens L, Ogishi M, Rinchai D, Matuozzo D, Momenilandi M, Kerrouche N, Cale CM, Treffeisen ER, Al Salamah M, Al-Saud BK, Lachaux A, Duclaux-Loras R, Meignien M, Bousfiha A, Benhsaien I, Shcherbina A, Roppelt A, COVID Human Genetic Effort, Gothe F, Houhou-Fidouh N, Hackett SJ, Bartnikas LM, Maciag MC, Alosaimi MF, Chou J, Mohammed RW, Freij BJ, Jouanguy E, Zhang SY, Boisson-Dupuis S, Béziat V, Zhang Q, Duncan CJ, Hambleton S, Casanova JL, Meyts I. Human inherited complete STAT2 deficiency underlies inflammatory viral diseases. J Clin Invest 2023; 133:e168321. [PMID: 36976641 PMCID: PMC10266780 DOI: 10.1172/jci168321] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 03/24/2023] [Indexed: 03/29/2023] Open
Abstract
STAT2 is a transcription factor activated by type I and III IFNs. We report 23 patients with loss-of-function variants causing autosomal recessive (AR) complete STAT2 deficiency. Both cells transfected with mutant STAT2 alleles and the patients' cells displayed impaired expression of IFN-stimulated genes and impaired control of in vitro viral infections. Clinical manifestations from early childhood onward included severe adverse reaction to live attenuated viral vaccines (LAV) and severe viral infections, particularly critical influenza pneumonia, critical COVID-19 pneumonia, and herpes simplex virus type 1 (HSV-1) encephalitis. The patients displayed various types of hyperinflammation, often triggered by viral infection or after LAV administration, which probably attested to unresolved viral infection in the absence of STAT2-dependent types I and III IFN immunity. Transcriptomic analysis revealed that circulating monocytes, neutrophils, and CD8+ memory T cells contributed to this inflammation. Several patients died from viral infection or heart failure during a febrile illness with no identified etiology. Notably, the highest mortality occurred during early childhood. These findings show that AR complete STAT2 deficiency underlay severe viral diseases and substantially impacts survival.
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Affiliation(s)
- Giorgia Bucciol
- Laboratory of Inborn Errors of Immunity, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Pediatrics, Leuven University Hospitals, Leuven, Belgium
| | - Leen Moens
- Laboratory of Inborn Errors of Immunity, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Masato Ogishi
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA
| | - Darawan Rinchai
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA
| | - Daniela Matuozzo
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris Cité, Imagine Institute, Paris, France
| | - Mana Momenilandi
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris Cité, Imagine Institute, Paris, France
| | - Nacim Kerrouche
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA
| | - Catherine M. Cale
- Department of Immunology, Great Ormond Street Hospital, London, United Kingdom
| | - Elsa R. Treffeisen
- Division of Immunology, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Mohammad Al Salamah
- King Abdullah Specialist Children’s Hospital and International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- Ministry of the National Guard–Health Affairs, Riyadh, Saudi Arabia
| | - Bandar K. Al-Saud
- Pediatric Department, Section of Immunology and Allergy, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Alain Lachaux
- Gastroenterology, Hepatology and Nutrition Unit, University and Pediatric Hospital of Lyon, and Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, Autophagy, Infection and Immunity, Lyon, France
| | - Remi Duclaux-Loras
- Gastroenterology, Hepatology and Nutrition Unit, University and Pediatric Hospital of Lyon, and Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, Autophagy, Infection and Immunity, Lyon, France
| | - Marie Meignien
- Internal Medicine and Vascular Pathology Service, University Hospital of Lyon, Lyon, France
| | - Aziz Bousfiha
- Clinical Immunology, Inflammation and Allergy Laboratory (LICIA), Faculty of Medicine and Pharmacy, King Hassan II University, Casablanca, Morocco
- Clinical Immunology Unit, Pediatric Infectious Disease Department Children’s Hospital, Ibn Rochd University Hospital, Casablanca, Morocco
| | - Ibtihal Benhsaien
- Clinical Immunology, Inflammation and Allergy Laboratory (LICIA), Faculty of Medicine and Pharmacy, King Hassan II University, Casablanca, Morocco
- Clinical Immunology Unit, Pediatric Infectious Disease Department Children’s Hospital, Ibn Rochd University Hospital, Casablanca, Morocco
| | - Anna Shcherbina
- Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - Anna Roppelt
- Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | | | - Florian Gothe
- Translational and Clinical Research Institute, Immunity and Inflammation Theme, Newcastle University, Newcastle upon Tyne, United Kingdom
- Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Nadhira Houhou-Fidouh
- Department of Virology, INSERM, Infection, Antimicrobiens, Modélisation, Evolution, UMR 1137, Bichat–Claude Bernard Hospital, University of Paris, Assistance Publique–Hôpitaux de Paris, Paris, France
| | - Scott J. Hackett
- Department of Paediatrics, Birmingham Chest Clinic and Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Lisa M. Bartnikas
- Division of Immunology, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Michelle C. Maciag
- Division of Immunology, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Mohammed F. Alosaimi
- Immunology Research Laboratory, Department of Pediatrics, King Saud University, Riyadh, Saudi Arabia
| | - Janet Chou
- Division of Immunology, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Reem W. Mohammed
- Pediatric Department, Section of Immunology and Allergy, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Bishara J. Freij
- Pediatric Infectious Diseases Section, Beaumont Children’s Hospital, Royal Oak, Michigan, USA
- Oakland University William Beaumont School of Medicine, Rochester, Michigan, USA
| | - Emmanuelle Jouanguy
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris Cité, Imagine Institute, Paris, France
| | - Shen-Ying Zhang
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris Cité, Imagine Institute, Paris, France
| | - Stephanie Boisson-Dupuis
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris Cité, Imagine Institute, Paris, France
| | - Vivien Béziat
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris Cité, Imagine Institute, Paris, France
| | - Qian Zhang
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris Cité, Imagine Institute, Paris, France
| | - Christopher J.A. Duncan
- The COVID Human Genetic Effort is detailed in Supplemental Acknowledgments
- Department of Infectious Disease and Tropical Medicine, The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom, and
| | - Sophie Hambleton
- Translational and Clinical Research Institute, Immunity and Inflammation Theme, Newcastle University, Newcastle upon Tyne, United Kingdom
- Great North Children’s Hospital, The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris Cité, Imagine Institute, Paris, France
- Department of Pediatrics, Necker Hospital for Sick Children, Assistance Publique–Hôpitaux de Paris, Paris, France
- Howard Hughes Medical Institute, New York, New York, USA
| | - Isabelle Meyts
- Laboratory of Inborn Errors of Immunity, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Pediatrics, Leuven University Hospitals, Leuven, Belgium
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Fadeeva N, Khatkov I, Bodunova N, Knyazev O, Bordin D, Parfenov A, Nikolskaya K, Nikolaev S, Rumyantsev K, Polyakova V, Yanova T. Personalized Medicine for IBD Patients. BIONANOSCIENCE 2023; 13:330-337. [DOI: 10.1007/s12668-023-01067-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/17/2023] [Indexed: 01/27/2023]
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Drabent P, Berrebi D. [Pediatric very early onset inflammatory bowel disease: Role of pathology]. Ann Pathol 2023. [PMID: 36863899 DOI: 10.1016/j.annpat.2023.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2023]
Abstract
Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are a heterogeneous group of multifactorial pathologies, often polygenic, due to a dysregulated immune response in a genetically susceptible host. In children under 6 years of age, a significant proportion of IBD, named "very early onset inflammatory bowel diseases" (VEO-IBD), are monogenic disorders in more than one third of cases. Over 80 genes have been linked to VEO-IBD and pathological descriptions are sparce. In this clarification, we describe the clinical aspects of monogenic VEO-IBD and the main causative genes, as well as the various histological patterns observed in intestinal biopsies. The management of a patient with VEO-IBD should be a coordinated effort by a multidisciplinary team including pediatric gastroenterologists, immunologists, geneticists, and of course pediatric pathologists.
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Affiliation(s)
- Philippe Drabent
- Service d'anatomie et cytologie pathologiques, hôpitaux universitaires Necker-Enfants malades et Robert Debré, AP-HP, université de Paris, 149, rue de Sèvres, 75015 Paris, France
| | - Dominique Berrebi
- Service d'anatomie et cytologie pathologiques, hôpitaux universitaires Necker-Enfants malades et Robert Debré, AP-HP, université de Paris, 149, rue de Sèvres, 75015 Paris, France.
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Korol CB, Belkaya S, Alsohime F, Lorenzo L, Boisson-Dupuis S, Brancale J, Neehus AL, Vilarinho S, Zobaida A, Halwani R, Al-Muhsen S, Casanova JL, Jouanguy E. Fulminant Viral Hepatitis in Two Siblings with Inherited IL-10RB Deficiency. J Clin Immunol 2023; 43:406-420. [PMID: 36308662 PMCID: PMC9892130 DOI: 10.1007/s10875-022-01376-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 09/28/2022] [Indexed: 02/05/2023]
Abstract
Fulminant viral hepatitis (FVH) caused by hepatitis A virus (HAV) is a life-threatening disease that typically strikes otherwise healthy individuals. The only known genetic etiology of FVH is inherited IL-18BP deficiency, which unleashes IL-18-dependent lymphocyte cytotoxicity and IFN-γ production. We studied two siblings who died from a combination of early-onset inflammatory bowel disease (EOIBD) and FVH due to HAV. The sibling tested was homozygous for the W100G variant of IL10RB previously described in an unrelated patient with EOIBD. We show here that the out-of-frame IL10RB variants seen in other EOIBD patients disrupt cellular responses to IL-10, IL-22, IL-26, and IFN-λs in overexpression conditions and in homozygous cells. By contrast, the impact of in-frame disease-causing variants varies between cases. When overexpressed, the W100G variant impairs cellular responses to IL-10, but not to IL-22, IL-26, or IFN-λ1, whereas cells homozygous for W100G do not respond to IL-10, IL-22, IL-26, or IFN-λ1. As IL-10 is a potent antagonist of IFN-γ in phagocytes, these findings suggest that the molecular basis of FVH in patients with IL-18BP or IL-10RB deficiency may involve excessive IFN-γ activity during HAV infections of the liver. Inherited IL-10RB deficiency, and possibly inherited IL-10 and IL-10RA deficiencies, confer a predisposition to FVH, and patients with these deficiencies should be vaccinated against HAV and other liver-tropic viruses.
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Affiliation(s)
- Cecilia B Korol
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
| | - Serkan Belkaya
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
- Department of Molecular Biology and Genetics, Ihan Dogramaci Bilkent University, Ankara, Turkey
| | - Fahad Alsohime
- Immunology Research Laboratory, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Lazaro Lorenzo
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
| | - Stéphanie Boisson-Dupuis
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
| | - Joseph Brancale
- Department of Internal Medicine, Section of Digestive Diseases, and Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Anna-Lena Neehus
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
| | - Silvia Vilarinho
- Department of Internal Medicine, Section of Digestive Diseases, and Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Alsum Zobaida
- Department of Pediatrics, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Rabih Halwani
- Department of Clinical Sciences, College of Medicine, Sharjah Institute for Medical Research (SIMR), University of Sharjah, Sharjah, United Arab Emirates
| | - Saleh Al-Muhsen
- Immunology Research Laboratory, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Department of Pediatrics, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Jean-Laurent Casanova
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
- Howard Hughes Medical Institute, New York City, NY, USA
- Department of Pediatrics, Necker Hospital for Sick Children, Paris, France
| | - Emmanuelle Jouanguy
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
- Imagine Institute, Paris Cité University, Paris, France.
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
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Monteleone G, Stolfi C. Smad7 Antisense Oligonucleotide in Crohn's Disease: A Re-Evaluation and Explanation for the Discordant Results of Clinical Trials. Pharmaceutics 2022; 15:pharmaceutics15010095. [PMID: 36678723 PMCID: PMC9864707 DOI: 10.3390/pharmaceutics15010095] [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: 11/08/2022] [Revised: 12/22/2022] [Accepted: 12/23/2022] [Indexed: 12/29/2022] Open
Abstract
In Crohn's disease (CD) and ulcerative colitis (UC), the major inflammatory bowel diseases (IBD) in human beings, the tissue-damaging inflammatory response is characterized by elevated levels of Suppressor of Mothers Against Decapentaplegic (Smad)7, an inhibitor of the immunosuppressive cytokine Transforming Growth Factor (TGF)-β1. Consistently, preclinical work in mouse models of IBD-like colitis showed that the knockdown of Smad7 with an antisense oligonucleotide (AS) attenuated the mucosal inflammation, thus paving the way for the development of an AS-containing pharmaceutical compound, named mongersen, for clinical use. The initial phase 1 and phase 2 studies showed that oral administration of mongersen was safe and effective in inducing clinical remission in active CD patients. However, subsequently, a large multicentered, randomized, double-blind, placebo-controlled, phase 3 trial was prematurely discontinued because of an interim analysis showing no effect of mongersen on the activity of CD. In this study we will discuss recent data showing that the majority of the batches of mongersen used in the phase 3 study were chemically different from those used in the previous clinical trials, with some of them being unable to knockdown Smad7 in cultured cells. The accumulating evidence highlights the need to maintain consistent manufacturing requirements for clinical AS, as well as the potential benefits of in vitro bioassays as a part of quality control. New clinical trials evaluating mongersen's impact on IBD using chemically homogenous batches will be needed to ascertain the therapeutic efficacy of such a drug.
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Genetic and Epigenetic Etiology of Inflammatory Bowel Disease: An Update. Genes (Basel) 2022; 13:genes13122388. [PMID: 36553655 PMCID: PMC9778199 DOI: 10.3390/genes13122388] [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: 11/17/2022] [Revised: 12/06/2022] [Accepted: 12/09/2022] [Indexed: 12/23/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic disease with periods of exacerbation and remission of the disease. The etiology of IBD is not fully understood. Many studies point to the presence of genetic, immunological, environmental, and microbiological factors and the interactions between them in the occurrence of IBD. The review looks at genetic factors in the context of both IBD predisposition and pharmacogenetics.
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Sharifinejad N, Zaki-Dizaji M, Sepahvandi R, Fayyaz F, Dos Santos Vilela MM, ElGhazali G, Abolhassani H, Ochs HD, Azizi G. The clinical, molecular, and therapeutic features of patients with IL10/IL10R deficiency: a systematic review. Clin Exp Immunol 2022; 208:281-291. [PMID: 35481870 PMCID: PMC9226142 DOI: 10.1093/cei/uxac040] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 04/19/2022] [Accepted: 04/25/2022] [Indexed: 01/19/2023] Open
Abstract
Interleukin10 (IL10) and IL10 receptor (IL10R) deficiencies are monogenic inborn errors of immunity (IEI) causing early-onset inflammatory bowel diseases (IBD). In this report, we systematically reviewed articles that included related keywords using PubMed, Web of Science, and Scopus databases. The articles were screened for eligibility criteria before data extraction. We assessed 286 patients (44.5% female) with IL10 and/or IL10R deficiencies who were predominantly from China (40.7%), Italy (13.9%), and South Korea (8.5%). The median age of onset was 1.0 (0.3-4.0) months with a median age of genetic diagnosis at 16.0 (7.4-81.0) months. Consanguinity was reported in all evaluable patients with IL10 deficiency and in 38.2% of patients with IL10R deficiency (22.9% of patients with IL10RA, and 79.4% of patients with IL10RB deficiency). The most prevalent mutations in IL10RA were c.301C>T (p.R101W) and c.537G>A (p.T179T), those in IL10RB were c.139A>G (p.K47E) and c.611G>A (p.W204X). Auto-inflammation and enteropathy were present in all cases. The first presentation of both groups was protracted diarrhea (45.7%), bloody diarrhea (17.8%), and colitis (15.5%). Patients with IL10R deficiency had a high frequency of dermatologic manifestations (50.5%) and failure to thrive (60.5%), while IL10-deficient patients lacked those complications. In the majority of patients, the basic immunologic parameters were in normal ranges. Of the entire publications, 30.7% underwent hemopoietic stem cell transplantation, 57.5% surgery, and 86.6% immunosuppressive treatment. The 10-year survival rate was higher in patients with IL10 deficiency than in patients with IL10R deficiency. In conclusion, IL10/IL10R deficiency predominantly presents with treatment-resistant, early-onset IBD within the first months of life. We detected no clear correlation between the phenotype of patients carrying the same variant. The high prevalence of distinct clinical manifestations reported in IL10RA- and IL10RB-deficient patients might be attributable to the interactions between the target tissue and cytokines other than IL10 capable of binding to IL10RB. These results gain translational significance by contributing to earlier diagnosis, adequate therapy, and avoiding delay in the diagnosis and unfavorable outcomes.
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Affiliation(s)
- Niusha Sharifinejad
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Majid Zaki-Dizaji
- Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran
| | - Roya Sepahvandi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Farimah Fayyaz
- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran.,Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Maria Marluce Dos Santos Vilela
- Center for Investigation in Pediatrics, Pediatrics Department, Faculty of Medical Sciences, State University of Campinas (UNICAMP). Campinas, SP, Brazil
| | - Gehad ElGhazali
- Department of Clinical Microbiology and Immunology, Sheikh Khalifa Medical City, Abu Dhabi, UAE
| | - Hassan Abolhassani
- Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hans D Ochs
- Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.,Seattle Children's Research Institute, Seattle, WA, USA
| | - Gholamreza Azizi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
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11
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Flinn AM, Gennery AR. Primary immune regulatory disorders: Undiagnosed needles in the haystack? Orphanet J Rare Dis 2022; 17:99. [PMID: 35241125 PMCID: PMC8895571 DOI: 10.1186/s13023-022-02249-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 02/13/2022] [Indexed: 12/16/2022] Open
Abstract
Primary Immune Regulatory Disorders (PIRD) describe a group of conditions characterized by loss of normal inflammatory control and immune tolerance mechanisms, with autoimmunity as a predominant clinical feature. PIRD can arise due to defects in the number or function of regulatory T-lymphocytes, defects in the immune mechanisms required to ‘turn off’ inflammation such as in perforin-dependent cytotoxicity or alterations in cytokine signalling pathways. Diagnosis of PIRD is a significant challenge to physicians due to their rarity, complexity, and diversity in clinical manifestations. Many of these individual conditions lack a genotype–phenotype correlation and display incomplete penetrance. However, establishing a diagnosis is integral in optimizing patient management, including the use of individualized treatment approaches. Increasing awareness among physicians is necessary as patients are likely to present to different subspecialties. Due to the rarity of these conditions, worldwide collaboration and data-sharing is essential to improve our knowledge of the clinical spectrum and disease course in PIRD, and to optimize therapeutic strategies including identification of which patients can benefit from hematopoietic stem cell transplant.
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Affiliation(s)
- Aisling M Flinn
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Andrew R Gennery
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
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12
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Sandy NS, Marega LF, Bechara GD, Riccetto AGL, Bonfim C, Vilela MMDS, Ribeiro AF, Servidoni MDF, Lomazi EA. Elevated IgA and IL-10 levels in very-early-onset inflammatory bowel disease secondary to IL-10 receptor deficiency. REVISTA PAULISTA DE PEDIATRIA 2021; 40:e2020434. [PMID: 34730757 PMCID: PMC8565602 DOI: 10.1590/1984-0462/2022/40/2020434] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 03/21/2021] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To report two patients with very-early-onset inflammatory bowel disease (VEOIBD) secondary to interleukin-10 receptor (IL-10R) mutations, explore immunophenotyping data and plasma cytokine profile on these cases compared to healthy controls, and describe the phenotype of IL-10/IL-10R mutations based on a literature review. CASE DESCRIPTION We report on two female infants referred to our tertiary center at the age of ten months, with severe colonic and perianal disease, as well as significant malnutrition, who had shown limited response to usual inflammatory bowel disease (IBD) therapy agents. In the first case, whole-exome sequencing (WES) revealed a homozygous (c.537G>A/p.T179T) mutation in exon 4 of the IL-10RA gene, while in the second patient, compound heterozygosity was identified, also in the IL-10RA gene (chr11:117.859.199 variant A>G/p.Tyr57Cys and chr11: 117.860.335 variant G>T/p.Val123Leu). Both patients underwent hematopoietic cell transplantation (HCT). Immunological work-up of these patients revealed increased IL-10 plasma levels and increased IgA. COMMENTS Our case reports disclose novel findings on plasma cytokine profile in IL-10R deficiency, and we describe the severe phenotype of IL-10/IL-10R deficiency that should be recognized by physicians.
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13
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Mas-Orea X, Sebert M, Benamar M, Petitfils C, Blanpied C, Saoudi A, Deraison C, Barreau F, Cenac N, Dietrich G. Peripheral Opioid Receptor Blockade Enhances Epithelial Damage in Piroxicam-Accelerated Colitis in IL-10-Deficient Mice. Int J Mol Sci 2021; 22:7387. [PMID: 34299013 PMCID: PMC8304158 DOI: 10.3390/ijms22147387] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 07/05/2021] [Accepted: 07/07/2021] [Indexed: 01/02/2023] Open
Abstract
Mucosal CD4+ T lymphocytes display a potent opioid-mediated analgesic activity in interleukin (IL)-10 knockout mouse model of inflammatory bowel diseases (IBD). Considering that endogenous opioids may also exhibit anti-inflammatory activities in the periphery, we examined the consequences of a peripheral opioid receptor blockade by naloxone-methiodide, a general opioid receptor antagonist unable to cross the blood-brain barrier, on the development of piroxicam-accelerated colitis in IL-10-deficient (IL-10-/-) mice. Here, we show that IL-10-deficient mice treated with piroxicam exhibited significant alterations of the intestinal barrier function, including permeability, inflammation-related bioactive lipid mediators, and mucosal CD4+ T lymphocyte subsets. Opioid receptor antagonization in the periphery had virtually no effect on colitis severity but significantly worsened epithelial cell apoptosis and intestinal permeability. Thus, although the endogenous opioid tone is not sufficient to reduce the severity of colitis significantly, it substantially contributes to the protection of the physical integrity of the epithelial barrier.
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Affiliation(s)
- Xavier Mas-Orea
- IRSD, Université de Toulouse—Paul Sabatier, INSERM, INRAe, ENVT, UPS, 31000 Toulouse, France; (X.M.-O.); (M.S.); (C.P.); (C.B.); (C.D.); (F.B.); (N.C.)
| | - Morgane Sebert
- IRSD, Université de Toulouse—Paul Sabatier, INSERM, INRAe, ENVT, UPS, 31000 Toulouse, France; (X.M.-O.); (M.S.); (C.P.); (C.B.); (C.D.); (F.B.); (N.C.)
| | - Mehdi Benamar
- INFINITY, Université de Toulouse—Paul Sabatier, INSERM, CNRS, UPS, 31000 Toulouse, France; (M.B.); (A.S.)
| | - Camille Petitfils
- IRSD, Université de Toulouse—Paul Sabatier, INSERM, INRAe, ENVT, UPS, 31000 Toulouse, France; (X.M.-O.); (M.S.); (C.P.); (C.B.); (C.D.); (F.B.); (N.C.)
| | - Catherine Blanpied
- IRSD, Université de Toulouse—Paul Sabatier, INSERM, INRAe, ENVT, UPS, 31000 Toulouse, France; (X.M.-O.); (M.S.); (C.P.); (C.B.); (C.D.); (F.B.); (N.C.)
| | - Abdelhadi Saoudi
- INFINITY, Université de Toulouse—Paul Sabatier, INSERM, CNRS, UPS, 31000 Toulouse, France; (M.B.); (A.S.)
| | - Céline Deraison
- IRSD, Université de Toulouse—Paul Sabatier, INSERM, INRAe, ENVT, UPS, 31000 Toulouse, France; (X.M.-O.); (M.S.); (C.P.); (C.B.); (C.D.); (F.B.); (N.C.)
| | - Frederick Barreau
- IRSD, Université de Toulouse—Paul Sabatier, INSERM, INRAe, ENVT, UPS, 31000 Toulouse, France; (X.M.-O.); (M.S.); (C.P.); (C.B.); (C.D.); (F.B.); (N.C.)
| | - Nicolas Cenac
- IRSD, Université de Toulouse—Paul Sabatier, INSERM, INRAe, ENVT, UPS, 31000 Toulouse, France; (X.M.-O.); (M.S.); (C.P.); (C.B.); (C.D.); (F.B.); (N.C.)
| | - Gilles Dietrich
- IRSD, Université de Toulouse—Paul Sabatier, INSERM, INRAe, ENVT, UPS, 31000 Toulouse, France; (X.M.-O.); (M.S.); (C.P.); (C.B.); (C.D.); (F.B.); (N.C.)
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14
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Tang Z, Zhang P, Ji M, Yin C, Zhao R, Huang Z, Huang Y. Characterization of novel and large fragment deletions in exon 1 of the IL10RA gene in Chinese children with very early onset inflammatory bowel diseases. BMC Gastroenterol 2021; 21:167. [PMID: 33849446 PMCID: PMC8045347 DOI: 10.1186/s12876-021-01756-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 04/08/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Defects in interleukin 10 (IL10) and its receptors are particularly involved in very early onset inflammatory bowel disease (VEOIBD). However, large fragment deletions of IL10 receptor A (IL10RA) are rare. METHODS VEOIBD patients with confirmed mutations in the IL10RA gene were enrolled from January 1, 2019 to June 30, 2020. The clinical features and endoscopic-radiological findings of the patients with large fragment deletions of the IL10RA gene were determined and followed up. RESULTS Thirty-five patients with IL10RA gene mutations, namely, 28 compound heterozygous mutations and 7 homozygote mutations, were enrolled in this study. Six patients carried the reported point mutation c.301C > T (p. R101RW) or c.537 G > A (p. T179T) in one locus and a large fragment deletion in exon 1 in another locus, which were novel mutations in this gene. A 333-bp deletion of exon 1 (117857034-11857366 del) was the main mutation in this locus in 85.7% of the patients with large fragment deletions. The time of disease onset ranged from birth to 4 years, and diarrhea was the main initial symptom. In total, 6/7 patients had perianal complications, including perianal abscess, fistula and skin tags. Six patients accepted thalidomide treatment, 5/7 accepted mesalamine, 3/7 accepted hematopoietic stem cell transplantation (HSCT), and 3/7 were waiting for HSCT. CONCLUSIONS We identified a novel large deletion of exon 1 involving the IL10RA gene for the first time and showed the characteristics of VEOIBD patients. This study expands the spectrum of Chinese VEOIBD patients with IL0RA gene mutations.
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Affiliation(s)
- Zifei Tang
- Department of Gastroenterology, Children’s Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102 China
| | - Ping Zhang
- Center for Molecular Medicine, Pediatrics Research Institute, Children’s Hospital of Fudan University, Shanghai, 201102 China
| | - Min Ji
- Department of Radiology, Children’s Hospital of Fudan University, Shanghai, 201102 China
| | - Chunlan Yin
- Department of Gastroenterology, Children’s Hospital of Hebei Province, Shijiazhuang, 050030 China
| | - Ruiqin Zhao
- Department of Gastroenterology, Children’s Hospital of Hebei Province, Shijiazhuang, 050030 China
| | - Zhiheng Huang
- Department of Gastroenterology, Children’s Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102 China
| | - Ying Huang
- Department of Gastroenterology, Children’s Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102 China
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15
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Krawiec P, Pawłowska-Kamieniak A, Pac-Kożuchowska E. Interleukin 10 and interleukin 10 receptor in paediatric inflammatory bowel disease: from bench to bedside lesson. J Inflamm (Lond) 2021; 18:13. [PMID: 33691712 PMCID: PMC7948370 DOI: 10.1186/s12950-021-00279-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Accepted: 03/04/2021] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND The differences between adults and children in inflammatory bowel disease (IBD) phenotype, severity, complications, co-morbidities, and response to the therapy resulted in the extraction of paediatric IBD. It has been revealed that the substantial role in the development of IBD in children under 6 years of age plays a single genetic mutation (monogenic IBD). On the other hand, in older children and adolescents IBD is usually associated with number of interactions between susceptibility loci (polygenic IBD). MAIN BODY Until now there have been described about 60 monogenic defects which affect the variety of immune mechanisms in IBD pathogenesis including epithelial barrier, function of neutrophil granulocytes and phagocytes, T- and B-cell selection and activation, immune inhibitory mechanisms, or apoptosis. Il-10 is an anti-inflammatory cytokine which modulates innate and adaptive immunity affecting expression of pro-inflammatory molecules and function of the variety of immune cells. Patients with identified defects in Il-10 pathway manifest with life-threating colitis with perianal lesions which occurs within first months of life. Allogenic hematopoietic stem cell transplantation is curative therapy in children with Il-10 signalling defects. CONCLUSION Clinical awareness of Il-10 signalling defects enables early recognition and prompt management of the disease.
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Affiliation(s)
- Paulina Krawiec
- Department of Paediatrics and Gastroenterology, Medical University of Lublin, Racławickie 1, 20-059 Lublin, Poland
| | | | - Elżbieta Pac-Kożuchowska
- Department of Paediatrics and Gastroenterology, Medical University of Lublin, Racławickie 1, 20-059 Lublin, Poland
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16
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Ye Z, Hu W, Wu B, Zhang Y, Lei C, Williams I, Shouval DS, Kanegane H, Kim KM, de Ridder L, Shah N, Ling G, Yerushalmi B, Kotlarz D, Snapper S, Horn R, Klein C, Muise AM, Huang Y, Uhlig HH. Predictive Prenatal Diagnosis for Infantile-onset Inflammatory Bowel Disease Because of Interleukin-10 Signalling Defects. J Pediatr Gastroenterol Nutr 2021; 72:276-281. [PMID: 32925557 PMCID: PMC8191811 DOI: 10.1097/mpg.0000000000002937] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVES Advances in genetic technologies provide opportunities for patient care and ethical challenges. Clinical care of patients with rare Mendelian disorders is often at the forefront of those developments. Whereas in classical polygenic inflammatory bowel disease (IBD), the predictive value of genetic variants is very low, predictive prenatal genetic diagnosis can inform families at high risk of severe genetic disorders. Patients with IL-10 signalling defects because of pathogenic variants in IL10RA, Il10RB, and IL10 develop severe infantile onset inflammatory bowel disease that is completely penetrant and has a high morbidity and substantial mortality despite treatment. METHODS We performed a survey among tertiary specialist paediatric centers of 10 countries on the utilization of predictive prenatal genetic diagnosis in IL-10 signalling defects. We retrospectively report prenatal genetics in a series of 8 families. RESULTS International variation in legislation, guidelines, expert opinion, as well as cultural and religious background of families and clinicians results in variable utilization of preimplantation and prenatal genetic testing for IL-10 signalling defects. Eleven referrals for prenatal diagnosis for IL-10 signalling defects were identified across 4 countries. We report on 8 families who underwent prenatal preimplantation monogenic testing after in vitro fertilization (n = 2) and/or by amniocentesis/chorion villus sampling (n = 6). A genetic diagnosis was established in 1 foetus and excluded in 7 foetuses (all IL10RA variants). CONCLUSIONS Prenatal genetic testing for IL10R-defects is feasible, yet the legal and ethical considerations are complex and controversial. In some countries, predictive genetics for IL-10-related signalling defects is entering clinical practice.
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Affiliation(s)
- Ziqing Ye
- Department of Gastroenterology, Children’s Hospital of Fudan University, Shanghai, China
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Wenhui Hu
- Department of Gastroenterology, Children’s Hospital of Fudan University, Shanghai, China
| | - Bingbing Wu
- Key Lab of Birth Defects, Children’s Hospital of Fudan University, Shanghai, China
| | - Yueping Zhang
- Shanghai Ji Ai Genetics & IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Caixia Lei
- Shanghai Ji Ai Genetics & IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Isabelle Williams
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Dror S. Shouval
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Ramag Gan, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Hirokazu Kanegane
- Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Kyung Mo Kim
- Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children’s Hospital 88, Olympic-Ro 43 Gil, Songpa-Gu, Seoul, Korea
| | - Lissy de Ridder
- Department of Paediatric Gastroenterology, Erasmus University Medical Center Sophia Children’s Hospital, Rotterdam, The Netherlands
| | - Neil Shah
- Department of Paediatric Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Galina Ling
- Pediatric Gastroenterology Unit, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Baruch Yerushalmi
- Pediatric Gastroenterology Unit, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Daniel Kotlarz
- Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, Ludwig-Maximilians-Universität, Munich, Germany
| | - Scott Snapper
- Boston Children’s Hospital and Harvard Medical School, Boston, MA
| | - Ruth Horn
- Wellcome Centre for Ethics and Humanities and the Ethox Centre, University of Oxford, UK
| | - Christoph Klein
- Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, Ludwig-Maximilians-Universität, Munich, Germany
| | - Aleixo M. Muise
- SickKids Inflammatory Bowel Disease Centre and Cell Biology Program, Research Institute
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Ying Huang
- Department of Gastroenterology, Children’s Hospital of Fudan University, Shanghai, China
| | - Holm H. Uhlig
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
- Department of Pediatrics, University of Oxford, Oxford, United Kingdom
- Biomedical Research Center, University of Oxford, Oxford, United Kingdom
- Translational Gastroenterology Unit
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17
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TNF Receptor 1 Promotes Early-Life Immunity and Protects against Colitis in Mice. Cell Rep 2020; 33:108275. [PMID: 33086075 PMCID: PMC7682618 DOI: 10.1016/j.celrep.2020.108275] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 08/05/2020] [Accepted: 09/23/2020] [Indexed: 02/08/2023] Open
Abstract
Neutralization of tumor necrosis factor (TNF) represents a widely used therapeutic strategy for autoimmune diseases including inflammatory bowel disease (IBD). However, the fact that many patients with IBD are non-responsive to anti-TNF therapies suggests the need for a better understanding of TNF signaling in IBD. Here, we show that co-deletion of TNF receptor 1 (TNFR1, Tnfrsf1a) in the Il10-/- spontaneous colitis model exacerbates disease, resulting in very-early-onset inflammation after weaning. The disease can be interrupted by treatment with antibiotics. The single deletion of TNFR1 induces subclinical colonic epithelial dysfunction and mucosal immune abnormalities, including accumulation of neutrophils and depletion of B cells. During the pre-disease period (before weaning), both Tnfr1-/- and Il10-/-Tnfr1-/- animals exhibit impaired expression of pro-inflammatory cytokines compared with wild-type and Il10-/- controls, respectively. Collectively, these results demonstrate the net anti-inflammatory functions of TNF/TNFR1 signaling through the regulation of colonic immune homeostasis in early life.
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18
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Posovszky C, Barth TFE. [The gut: center of immunity : Rare inflammatory bowel diseases caused by immunodeficiencies]. DER PATHOLOGE 2020; 41:211-223. [PMID: 32253499 DOI: 10.1007/s00292-020-00775-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The gut is the largest immune organ of the human body with an enormous mucosal interface. By acting as a physical barrier and by hosting many of the body's immune cells and tissues, the gut is the first line of defense against potentially harmful substances. Therefore, diseases leading to impaired immune response or disruption of the epithelial barrier result in autoimmune, infectious, or inflammatory bowel disease, frequently associated with diarrhea, malabsorption, melena, and growth failure. The differential diagnosis represents an interdisciplinary challenge in this group of rare diseases. The diseases are characterized by clinical, immunological, and histopathological features caused by mutations in single genes. In the following, we will focus on histological findings within the various entities of immunodeficiencies.
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Affiliation(s)
- Carsten Posovszky
- Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Ulm, Eythstr. 24, 89075, Ulm, Deutschland.
| | - Thomas F E Barth
- Institut für Pathologie, Universitätsklinikum Ulm, Albert-Einstein-Allee 8, 89081, Ulm, Deutschland
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19
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Vajravelu RK, Copelovitch L, Osterman MT, Scott FI, Mamtani R, Lewis JD, Denburg MR. Inflammatory Bowel Diseases Are Associated With an Increased Risk for Chronic Kidney Disease, Which Decreases With Age. Clin Gastroenterol Hepatol 2020; 18:2262-2268. [PMID: 31683056 PMCID: PMC7569504 DOI: 10.1016/j.cgh.2019.10.043] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 10/09/2019] [Accepted: 10/21/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS It is not clear what factors affect risk of chronic kidney disease (CKD) in patients with inflammatory bowel disease (IBD); increased risk has been inconsistently associated with use of 5-aminosalicylates (5-ASAs). We aimed to calculate the relative hazard of CKD among patients with IBD, adjusted for CKD risk factors, and to determine whether IBD medications are associated with change in estimated glomerular filtration rate (eGFR). METHODS We performed a retrospective cohort study of data from The Health Improvement Network. Patients with IBD (n = 17,807) were matched for age, sex, and practice to individuals without IBD (n = 63,466). The relative hazard of CKD, stages 3 through 5D, in patients with IBD was calculated using a Cox proportional hazards model adjusted for common CKD risk factors. We also evaluated the association of 5-ASAs, azathioprine, and methotrexate with change in eGFR using a longitudinal model. RESULTS After we controlled for risk factors associated with CKD, we found IBD to be associated with development of CKD in patients 16-77 years old. As patient age increased, the adjusted hazard ratio for CKD decreased monotonically, from 7.88 (95% CI, 2.56-24.19) at age 16 to 1.13 (95% CI, 1.01-1.25) at age 77. In the longitudinal analysis, exposure to 5-ASAs or methotrexate was not associated with change in eGFR, whereas azathioprine was associated with a slightly higher eGFR (0.32 mL/min/1.73 m2; 95% CI, 0.16-0.48). CONCLUSIONS In a retrospective study of more than 80,000 persons, we found that IBD is associated with increased risk of CKD, and the hazard ratio is highest among younger patients. Commonly used non-biologic therapeutic agents were not associated with lower eGFR.
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Affiliation(s)
- Ravy K Vajravelu
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
| | - Lawrence Copelovitch
- Division of Nephrology, Department of Pediatrics, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Mark T Osterman
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Frank I Scott
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Division of Gastroenterology, Department of Medicine, University of Colorado Denver School of Medicine, Aurora, Colorado
| | - Ronac Mamtani
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - James D Lewis
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Michelle R Denburg
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Division of Nephrology, Department of Pediatrics, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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20
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Durant L, Stentz R, Noble A, Brooks J, Gicheva N, Reddi D, O’Connor MJ, Hoyles L, McCartney AL, Man R, Pring ET, Dilke S, Hendy P, Segal JP, Lim DNF, Misra R, Hart AL, Arebi N, Carding SR, Knight SC. Bacteroides thetaiotaomicron-derived outer membrane vesicles promote regulatory dendritic cell responses in health but not in inflammatory bowel disease. MICROBIOME 2020; 8:88. [PMID: 32513301 PMCID: PMC7282036 DOI: 10.1186/s40168-020-00868-z] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 05/13/2020] [Indexed: 06/09/2023]
Abstract
BACKGROUND Bacteroides thetaiotaomicron (Bt) is a prominent member of the human intestinal microbiota that, like all gram-negative bacteria, naturally generates nanosized outer membrane vesicles (OMVs) which bud off from the cell surface. Importantly, OMVs can cross the intestinal epithelial barrier to mediate microbe-host cell crosstalk involving both epithelial and immune cells to help maintain intestinal homeostasis. Here, we have examined the interaction between Bt OMVs and blood or colonic mucosa-derived dendritic cells (DC) from healthy individuals and patients with Crohn's disease (CD) or ulcerative colitis (UC). RESULTS In healthy individuals, Bt OMVs stimulated significant (p < 0.05) IL-10 expression by colonic DC, whereas in peripheral blood-derived DC they also stimulated significant (p < 0.001 and p < 0.01, respectively) expression of IL-6 and the activation marker CD80. Conversely, in UC Bt OMVs were unable to elicit IL-10 expression by colonic DC. There were also reduced numbers of CD103+ DC in the colon of both UC and CD patients compared to controls, supporting a loss of regulatory DC in both diseases. Furthermore, in CD and UC, Bt OMVs elicited a significantly lower proportion of DC which expressed IL-10 (p < 0.01 and p < 0.001, respectively) in blood compared to controls. These alterations in DC responses to Bt OMVs were seen in patients with inactive disease, and thus are indicative of intrinsic defects in immune responses to this commensal in inflammatory bowel disease (IBD). CONCLUSIONS Overall, our findings suggest a key role for OMVs generated by the commensal gut bacterium Bt in directing a balanced immune response to constituents of the microbiota locally and systemically during health which is altered in IBD patients. Video Abstract.
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Affiliation(s)
- Lydia Durant
- Antigen Presentation Research Group, Imperial College London, Northwick Park & St. Mark’s Hospital Campus, Watford Rd, Harrow, Greater London HA1 3UJ UK
| | - Régis Stentz
- Gut Microbes and Health Research Programme, Quadram Institute Bioscience, Norwich, NR4 7UQ UK
| | - Alistair Noble
- Antigen Presentation Research Group, Imperial College London, Northwick Park & St. Mark’s Hospital Campus, Watford Rd, Harrow, Greater London HA1 3UJ UK
| | - Johanne Brooks
- Gut Microbes and Health Research Programme, Quadram Institute Bioscience, Norwich, NR4 7UQ UK
- Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ UK
| | - Nadezhda Gicheva
- Gut Microbes and Health Research Programme, Quadram Institute Bioscience, Norwich, NR4 7UQ UK
| | - Durga Reddi
- Antigen Presentation Research Group, Imperial College London, Northwick Park & St. Mark’s Hospital Campus, Watford Rd, Harrow, Greater London HA1 3UJ UK
| | - Matthew J. O’Connor
- Antigen Presentation Research Group, Imperial College London, Northwick Park & St. Mark’s Hospital Campus, Watford Rd, Harrow, Greater London HA1 3UJ UK
| | - Lesley Hoyles
- Department of Biosciences, Nottingham Trent University, Clifton Campus, Nottingham, NG11 8NS UK
| | - Anne L. McCartney
- Food Microbial Sciences Unit, University of Reading, Whiteknights, Reading, RG6 6UR UK
| | - Ripple Man
- St Mark’s Hospital, London North West University Healthcare NHS Trust, Harrow, Greater London HA1 3UJ UK
| | - E. Tobias Pring
- Antigen Presentation Research Group, Imperial College London, Northwick Park & St. Mark’s Hospital Campus, Watford Rd, Harrow, Greater London HA1 3UJ UK
- St Mark’s Hospital, London North West University Healthcare NHS Trust, Harrow, Greater London HA1 3UJ UK
| | - Stella Dilke
- Antigen Presentation Research Group, Imperial College London, Northwick Park & St. Mark’s Hospital Campus, Watford Rd, Harrow, Greater London HA1 3UJ UK
- St Mark’s Hospital, London North West University Healthcare NHS Trust, Harrow, Greater London HA1 3UJ UK
| | - Philip Hendy
- Antigen Presentation Research Group, Imperial College London, Northwick Park & St. Mark’s Hospital Campus, Watford Rd, Harrow, Greater London HA1 3UJ UK
- St Mark’s Hospital, London North West University Healthcare NHS Trust, Harrow, Greater London HA1 3UJ UK
| | - Jonathan P. Segal
- St Mark’s Hospital, London North West University Healthcare NHS Trust, Harrow, Greater London HA1 3UJ UK
| | - Dennis N. F. Lim
- St Mark’s Hospital, London North West University Healthcare NHS Trust, Harrow, Greater London HA1 3UJ UK
| | - Ravi Misra
- St Mark’s Hospital, London North West University Healthcare NHS Trust, Harrow, Greater London HA1 3UJ UK
| | - Ailsa L. Hart
- St Mark’s Hospital, London North West University Healthcare NHS Trust, Harrow, Greater London HA1 3UJ UK
| | - Naila Arebi
- St Mark’s Hospital, London North West University Healthcare NHS Trust, Harrow, Greater London HA1 3UJ UK
| | - Simon R. Carding
- Gut Microbes and Health Research Programme, Quadram Institute Bioscience, Norwich, NR4 7UQ UK
- Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ UK
| | - Stella C. Knight
- Antigen Presentation Research Group, Imperial College London, Northwick Park & St. Mark’s Hospital Campus, Watford Rd, Harrow, Greater London HA1 3UJ UK
- St Mark’s Hospital, London North West University Healthcare NHS Trust, Harrow, Greater London HA1 3UJ UK
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21
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Abstract
Influenza viruses infect millions of people around the globe annually, usually causing self-limited upper respiratory tract infections. However, a small but non-negligible proportion of patients suffer from life-threatening pulmonary disease. Those affected include otherwise healthy individuals, and children with primary infections in particular. Much effort has been devoted to virological studies of influenza and vaccine development. By contrast, the enormous interindividual variability in susceptibility to influenza has received very little attention. One interesting hypothesis is that interindividual variability is driven largely by the genetic makeup of the infected patients. Unbiased genomic approaches have been used to search for genetic lesions in children with life-threatening pulmonary influenza. Four monogenic causes of severe influenza pneumonitis—deficiencies of GATA2, IRF7, IRF9, and TLR3—have provided evidence that severe influenza pneumonitis can be genetic and often in patients with no other severe infections. These deficiencies highlight the importance of human type I and III IFN-mediated immunity for host defense against influenza. Clinical penetrance is incomplete, and the underlying mechanisms are not yet understood. However, human genetic studies have clearly revealed that seemingly sporadic and isolated life-threatening influenza pneumonitis in otherwise healthy individuals can be genetic.
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22
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Basso L, Benamar M, Mas-Orea X, Deraison C, Blanpied C, Cenac N, Saoudi A, Dietrich G. Endogenous control of inflammatory visceral pain by T cell-derived opioids in IL-10-deficient mice. Neurogastroenterol Motil 2020; 32:e13743. [PMID: 31588671 DOI: 10.1111/nmo.13743] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 09/17/2019] [Accepted: 09/18/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND The opioid-mediated analgesic activity of mucosal CD4+ T lymphocytes in colitis has been reported in immunocompetent mice so far. Here, we investigated whether CD4+ T lymphocytes alleviate from inflammation-induced abdominal pain in mice with defective immune regulation. METHODS Endogenous control of visceral pain by opioids locally produced in inflamed mucosa was assessed in IL-10-deficient mice. KEY RESULTS CD4+ T lymphocytes but not F4/80+ macrophages isolated from the lamina propria of IL-10-deficient mice with colitis express enkephalin-containing opioid peptides as assessed by cytofluorometry. Colitis in IL-10-/- mice was not associated with abdominal pain. Intraperitoneal injection of naloxone-methiodide, a peripheral opioid receptor antagonist, induced abdominal hypersensitivity in IL-10-/- mice with colitis. CONCLUSION AND INFERENCES Opioid-mediated analgesic activity of mucosal T lymphocytes remains operating in IL-10-/- mice with impaired immune regulation. The data suggest that endogenous T cell-derived opioids might reduce inflammation-induced abdominal pain in inflammatory bowel diseases associated with homozygous "loss of function mutations" in interleukin-10.
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Affiliation(s)
- Lilian Basso
- IRSD, INSERM, INRA, ENVT, UPS, Université de Toulouse, Toulouse, France
| | - Mehdi Benamar
- Centre de Physiopathologie de Toulouse Purpan (CPTP), UPS, INSERM, CNRS, Université de Toulouse, Toulouse, France
| | - Xavier Mas-Orea
- IRSD, INSERM, INRA, ENVT, UPS, Université de Toulouse, Toulouse, France
| | - Céline Deraison
- IRSD, INSERM, INRA, ENVT, UPS, Université de Toulouse, Toulouse, France
| | | | - Nicolas Cenac
- IRSD, INSERM, INRA, ENVT, UPS, Université de Toulouse, Toulouse, France
| | - Abdelhadi Saoudi
- Centre de Physiopathologie de Toulouse Purpan (CPTP), UPS, INSERM, CNRS, Université de Toulouse, Toulouse, France
| | - Gilles Dietrich
- IRSD, INSERM, INRA, ENVT, UPS, Université de Toulouse, Toulouse, France
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23
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Tang Z, Huang Z, Yan W, Zhang Y, Shi P, Dong K, Gong Y, Ji M, Wang Y, Yu Z, Huang Y. Complications of enterostomy and related risk factor analysis of very early onset inflammatory bowel disease with interleukin-10 signalling deficiency: a single-centre retrospective analysis. BMC Gastroenterol 2020; 20:8. [PMID: 31931724 PMCID: PMC6958732 DOI: 10.1186/s12876-020-1160-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Accepted: 01/01/2020] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Interleukin-10 (IL10) signalling pathway deficiency results in severe very early onset inflammatory bowel disease (VEOIBD), and enterostomy is often inevitable. However, studies in these surgical populations are lacking. This study aims to determine the enterostomy characteristics, postoperative complications and related risk factors in enterostomy patients. METHODS From March 1, 2015, to December 31, 2018, patients with IL10R-mutation who underwent enterostomy were recruited for analysis. We collected data on the patients' clinical characteristics, enterostomy characteristics, postoperative complications and related risk factors. RESULTS Twelve patients required emergency enterostomy, and 10 patients underwent elective enterostomy. Twelve patients experienced postoperative complications, including wound infection (27.3%), wound dehiscence (18.2%), reoperation (18.2%), etc. Compared with the pre-enterostomy values, there was a decrease in C-reactive protein (CRP) (P = 0.001), an increase in albumin (P = 0.001) and an improvement in the weight-for-age (P = 0.029) and body mass index (BMI) Z-scores (P = 0.004) after enterostomy. There was a significant difference between the pre-operation and postoperation medicine expenses (P = 0.002). Univariate binary logistic regression analysis revealed a statistically significant influence of CRP (OR: 1.43, 95% CI: 1.07-1.91, P = 0.016) and a tendency towards a significant influence of intestinal perforation, albumin level, BMI Z-score and weighted paediatric Crohn's disease activity index (wPCDAI). Multivariate logistic regression analysis showed that CRP (OR: 1.40), wPCDAI (OR: 2.88) and perforation (OR: 1.72) showed a tendency to behave as independent risk factors for postoperative complications, but the results were not significant (all P > 0.05). CONCLUSIONS Surgery and enterostomy showed benefits for VEOIBD with IL-10 signalling deficiency. The timing of intervention, potential postoperative complications, economic burden and other related problems should be considered.
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Affiliation(s)
- Zifei Tang
- Department of Gastroenterology, Children’s Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102 People’s Republic of China
| | - Zhiheng Huang
- Department of Gastroenterology, Children’s Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102 People’s Republic of China
| | - Weili Yan
- Department of Clinical Epidemiology, Children’s Hospital of Fudan University, Shanghai, 201102 China
| | - Yi Zhang
- Department of Clinical Epidemiology, Children’s Hospital of Fudan University, Shanghai, 201102 China
| | - Peng Shi
- Department of Information, Children’s Hospital of Fudan University, Shanghai, 201102 China
| | - Kuiran Dong
- Department of Surgery, Children’s Hospital of Fudan University, Shanghai, 201102 China
| | - Ying Gong
- Department of Radiology, Children’s Hospital of Fudan University, Shanghai, 201102 China
| | - Min Ji
- Department of Radiology, Children’s Hospital of Fudan University, Shanghai, 201102 China
| | - Yuhuan Wang
- Department of Gastroenterology, Children’s Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102 People’s Republic of China
| | - Zhuowe Yu
- Department of Gastroenterology, Children’s Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102 People’s Republic of China
| | - Ying Huang
- Department of Gastroenterology, Children’s Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102 People’s Republic of China
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24
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Sun S, Ye Z, Zheng S, Chen G, Qian X, Dong K, Huang Y. Surgical treatment of monogenic inflammatory bowel disease: A single clinical center experience. J Pediatr Surg 2019; 54:2155-2161. [PMID: 31027905 DOI: 10.1016/j.jpedsurg.2019.02.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 02/17/2019] [Accepted: 02/18/2019] [Indexed: 02/07/2023]
Abstract
PURPOSE With the wide application of immunologic reconstitution treatment, such as hematopoietic stem-cell transplantation (HSCT), most patients of inflammatory bowel disease (IBD) with immunodeficiency owing to monogenic abnormalities need surgical intervention during the course of treatment, which is quite different from traditional IBD surgery. The aim of this study was to generalize the surgical strategies as a part of comprehensive therapy for these rare diseases. METHODS A retrospective study was conducted based on the clinical data of children with immunodeficiency-derived IBD who underwent surgical treatment in Children's Hospital of Fudan University between January 2015 and December 2017. RESULTS A total of 18 patients with monogenic abnormalities were enrolled. The major surgical indications included 11 cases of acute or chronic intestinal obstructions, 4 refractory intestinal infections, and 3 pneumoperitoneum, while 12 cases had perforations noted during intraoperative exploration. All of the patients underwent varieties of enterostomies to divert the affected or obstructed intestine during the primary surgery. Wound infections or dehiscence occurred in 7 patients, and 2 patients underwent reoperations for adhesive intestinal obstruction and prolapse. Postoperatively, 15 patients survived, 13 of which achieved immune reconstitution through subsequent HSCT or immunoglobulin supplementation. In the second-stage surgery, a posterior sagittal approach rectal resection was performed in 5 patients with complex anorectal complications. Twelve patients had undergone stoma closure procedures. CONCLUSION Surgical intervention should be performed earlier because the perforations are usually insidious in monogenic IBD. Preventative enterostomies are suggested in preparation for HSCT among patients with severe anorectal complications. Wound infections are the most common complication after the primary operation. Posterior sagittal rectal resection is a good option for patients with complex anorectal complications. TYPE OF STUDY Clinical research paper. LEVEL OF EVIDENCE Level IV.
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Affiliation(s)
- Song Sun
- Surgical department, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Ziqing Ye
- Gastroenterology department, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Shan Zheng
- Surgical department, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Gong Chen
- Surgical department, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Xiaowen Qian
- Hematology department, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Kuiran Dong
- Surgical department, Children's Hospital of Fudan University, Shanghai, 201102, China.
| | - Ying Huang
- Gastroenterology department, Children's Hospital of Fudan University, Shanghai, 201102, China.
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25
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Veenbergen S, Li P, Raatgeep HC, Lindenbergh-Kortleve DJ, Simons-Oosterhuis Y, Farrel A, Costes LMM, Joosse ME, van Berkel LA, de Ruiter LF, van Leeuwen MA, Winter D, Holland SM, Freeman AF, Wakabayashi Y, Zhu J, de Ridder L, Driessen GJ, Escher JC, Leonard WJ, Samsom JN. IL-10 signaling in dendritic cells controls IL-1β-mediated IFNγ secretion by human CD4 + T cells: relevance to inflammatory bowel disease. Mucosal Immunol 2019; 12:1201-1211. [PMID: 31417161 PMCID: PMC6752724 DOI: 10.1038/s41385-019-0194-9] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 07/24/2019] [Indexed: 02/04/2023]
Abstract
Uncontrolled interferon γ (IFNγ)-mediated T-cell responses to commensal microbiota are a driver of inflammatory bowel disease (IBD). Interleukin-10 (IL-10) is crucial for controlling these T-cell responses, but the precise mechanism of inhibition remains unclear. A better understanding of how IL-10 exerts its suppressive function may allow identification of individuals with suboptimal IL-10 function among the heterogeneous population of IBD patients. Using cells from patients with an IL10RA deficiency or STAT3 mutations, we demonstrate that IL-10 signaling in monocyte-derived dendritic cells (moDCs), but not T cells, is essential for controlling IFNγ-secreting CD4+ T cells. Deficiency in IL-10 signaling dramatically increased IL-1β release by moDCs. IL-1β boosted IFNγ secretion by CD4+ T cells either directly or indirectly by stimulating moDCs to secrete IL-12. As predicted a signature of IL-10 dysfunction was observed in a subgroup of pediatric IBD patients having higher IL-1β expression in activated immune cells and macroscopically affected intestinal tissue. In agreement, reduced IL10RA expression was detected in peripheral blood mononuclear cells and a subgroup of pediatric IBD patients exhibited diminished IL-10 responsiveness. Our data unveil an important mechanism by which IL-10 controls IFNγ-secreting CD4+ T cells in humans and identifies IL-1β as a potential classifier for a subgroup of IBD patients.
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Affiliation(s)
- S Veenbergen
- Laboratory of Pediatrics, division Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, the Netherlands.,Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, USA.,To whom correspondence should be addressed: , Dr. Janneke N. Samsom, PhD; Erasmus University Medical Center-Sophia Children’s Hospital, Laboratory of Pediatrics, division Gastroenterology and Nutrition, Room Ee1567A, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands; Tel: +31-(0)10-7043444; Fax: +31-(0)10-7044761; Sharon Veenbergen:
| | - P Li
- Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, USA
| | - HC Raatgeep
- Laboratory of Pediatrics, division Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - DJ Lindenbergh-Kortleve
- Laboratory of Pediatrics, division Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Y Simons-Oosterhuis
- Laboratory of Pediatrics, division Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - A Farrel
- Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, USA
| | - LMM Costes
- Laboratory of Pediatrics, division Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - ME Joosse
- Laboratory of Pediatrics, division Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - LA van Berkel
- Laboratory of Pediatrics, division Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - LF de Ruiter
- Laboratory of Pediatrics, division Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - MA van Leeuwen
- Laboratory of Pediatrics, division Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - D Winter
- Department of Pediatric Gastroenterology, Sophia Children’s Hospital-Erasmus University Medical Center, Rotterdam, the Netherlands
| | - SM Holland
- Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA
| | - AF Freeman
- Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA
| | - Y Wakabayashi
- DNA Sequencing and Genomics Core, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, USA
| | - J Zhu
- DNA Sequencing and Genomics Core, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, USA
| | - L de Ridder
- Department of Pediatric Gastroenterology, Sophia Children’s Hospital-Erasmus University Medical Center, Rotterdam, the Netherlands
| | - GJ Driessen
- Department of Pediatric Infectious Disease and Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands.,Haga Teaching Hospital, Juliana Children’s Hospital, The Hague, the Netherlands
| | - JC Escher
- Department of Pediatric Gastroenterology, Sophia Children’s Hospital-Erasmus University Medical Center, Rotterdam, the Netherlands
| | - WJ Leonard
- Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, USA
| | - JN Samsom
- Laboratory of Pediatrics, division Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, the Netherlands.,To whom correspondence should be addressed: , Dr. Janneke N. Samsom, PhD; Erasmus University Medical Center-Sophia Children’s Hospital, Laboratory of Pediatrics, division Gastroenterology and Nutrition, Room Ee1567A, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands; Tel: +31-(0)10-7043444; Fax: +31-(0)10-7044761; Sharon Veenbergen:
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26
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Zhao M, Burisch J. Impact of Genes and the Environment on the Pathogenesis and Disease Course of Inflammatory Bowel Disease. Dig Dis Sci 2019; 64:1759-1769. [PMID: 31073736 DOI: 10.1007/s10620-019-05648-w] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Crohn's disease and ulcerative colitis constitute two major subgroups of inflammatory bowel diseases (IBD), a group of complex polygenic diseases characterized by chronic and progressive inflammation in the gastrointestinal tract. In recent years, methodological advances in genetic analysis have greatly expanded our understanding of the genetic background of IBD. So far, more than 240 genetic risk loci have been identified for IBD. However, these risk alleles explain less than 30% of the susceptibility to disease development, suggesting that environmental factors contribute considerably. The increasing occurrence of IBD in Eastern countries following their 'westernization', as well as the increased risk of disease among those who migrate to high-incidence regions, also suggest that the environment is key in the pathogenesis of IBD. In this review, we summarize the current evidence on the role of genetic and environmental factors in the susceptibility to, and disease course of, IBD, and we suggest how these findings might be applied to clinical practice.
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Affiliation(s)
- Mirabella Zhao
- Gastro Unit, Hvidovre University Hospital, Kettegaard Alle 30, 2650, Hvidovre, Denmark
| | - Johan Burisch
- Gastro Unit, Hvidovre University Hospital, Kettegaard Alle 30, 2650, Hvidovre, Denmark.
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27
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Ince MN, Elliott DE. Effective Use of the Laboratory in the Management of Patients with Inflammatory Bowel Diseases. Gastroenterol Clin North Am 2019; 48:237-258. [PMID: 31046973 DOI: 10.1016/j.gtc.2019.02.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Inflammatory bowel disease (IBD) comprises a group of chronic, intestinal inflammatory disorders, including ulcerative colitis and Crohn's disease. IBD is characterized by periods of relapse and remission. Long-term progressive intestinal inflammation can result in severe and devastating complications, such as intestinal strictures and/or fistulae. Immune suppressive medications with potent side effects are often used to control inflammation and limit disease activity. Laboratory tests guide various decisions in clinical management of IBD. We discuss tests used to diagnose IBD, assess for relapse or remission, monitor the effectiveness of therapeutic regimen, screen for the maintenance of health, and diagnose or prevent complications.
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Affiliation(s)
- M Nedim Ince
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Iowa, Carver College of Medicine, University of Iowa Hospitals and Clinics, 4546 JCP, 200 Hawkins Drive, Iowa City, IA 52242, USA.
| | - David E Elliott
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Iowa, Carver College of Medicine, University of Iowa Hospitals and Clinics, 4607 JCP, 200 Hawkins Drive, Iowa City, IA 52242, USA
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28
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Yazdani R, Moazzami B, Madani SP, Behniafard N, Azizi G, Aflatoonian M, Abolhassani H, Aghamohammadi A. Candidiasis associated with very early onset inflammatory bowel disease: First IL10RB deficient case from the National Iranian Registry and review of the literature. Clin Immunol 2019; 205:35-42. [PMID: 31096038 DOI: 10.1016/j.clim.2019.05.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Revised: 03/02/2019] [Accepted: 05/11/2019] [Indexed: 02/07/2023]
Abstract
Defects in interleukin-10 (IL10) and interleukin-10 receptors (IL10R) are closely related to very early onset (infantile) inflammatory bowel disease (VEO-IBD). In the present study, we report a novel homozygous null mutation within interleukin-10 receptor B (IL10RB) gene in a child presenting with severe VEO-IBD. In accordance with previous reports, our patient manifested with chronic diarrhea, failure to thrive, intermittent fever and multiple anal ulcers associated with Candidiasis. Homozygous null mutation within IL10RB gene (c.92C > T, p.S31P) affecting the extracellular domain of protein was discovered in this patient. In conclusion, the diagnosis of IL-10R gene mutations should always be considered as a possible cause of refractory diarrhea and failure to thrive. Mutation analysis could help detect the genetic defects associated with these clinical manifestations and to determine the most appropriate treatment option for patients affected by this disease.
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Affiliation(s)
- Reza Yazdani
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran and the University of Medical Science, Tehran, Iran
| | - Bobak Moazzami
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran and the University of Medical Science, Tehran, Iran
| | - Seyedeh Panid Madani
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran and the University of Medical Science, Tehran, Iran
| | - Nasrin Behniafard
- Department of Allergy and Clinical Immunology, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
| | - Gholamreza Azizi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Majid Aflatoonian
- Pediatric Department, Growth Disorders of Children Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Hassan Abolhassani
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran and the University of Medical Science, Tehran, Iran; Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Asghar Aghamohammadi
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran and the University of Medical Science, Tehran, Iran.
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Conrad M, Carreon C, Dawany N, Russo P, Kelsen J. Distinct Histopathological Features at Diagnosis of Very Early Onset Inflammatory Bowel Disease. J Crohns Colitis 2019; 13:615-625. [PMID: 30551128 PMCID: PMC6486490 DOI: 10.1093/ecco-jcc/jjy212] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Children with very early onset inflammatory bowel disease [VEO-IBD] represent a unique cohort, often with a severe phenotype that is refractory to conventional medications, and some cases have underlying primary immunodeficiencies. Previous work has identified distinct histopathological patterns in the gastrointestinal tract in patients with primary immunodeficiencies. The aim of this study is to characterise the diagnostic histological findings in patients with VEO-IBD as compared with older onset paediatric IBD, and determine if there are unique pathological changes that can shed light on the driving forces of the disease, particularly immunodeficiencies. METHODS Clinical retrospective chart review, including disease characteristics and endoscopic findings, was performed on all included subjects. Two paediatric pathologists reviewed biopsies from diagnostic upper endoscopies and colonoscopies of subjects with very early onset inflammatory bowel disease and older onset inflammatory bowel disease, to evaluate for the presence of 11 histological features previously associated with inflammatory bowel disease and primary immunodeficiencies. RESULTS The diagnostic gastrointestinal biopsies of subjects with very early onset inflammatory bowel disease differed from those in older onset paediatric IBD, demonstrated by increased frequency of apoptosis, severe chronic architectural changes, small intestine villous blunting, and eosinophils in the crypts, lamina propria, and surface epithelium. CONCLUSIONS The diagnostic biopsies of children with very early onset inflammatory bowel disease can identify characteristic features that may be important in guiding the diagnostic work-up in this population.
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Affiliation(s)
- Máire A Conrad
- Children’s Hospital of Philadelphia, Department of Pediatrics, Philadelphia, PA, USA
- Perelman School of Medicine at the University of Pennsylvania, Department of Pediatrics, Philadelphia, PA, USA
- Corresponding author: Máire A. Conrad, MD, MS, Children’s Hospital of Philadelphia, Division of Gastroenterology, Hepatology, and Nutrition, Wood Bldg Rm 3393, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA. Tel.: [267] 426–1495; fax: [215] 590–3606;
| | - Chrystalle Katte Carreon
- Children’s Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, Philadelpha, PA, USA
- Perelman School of Medicine at the University of Pennsylvania, Department of Pathology and Laboratory Medicine, Philadelphia, PA, USA
| | - Noor Dawany
- Children’s Hospital of Philadelphia, Department of Biomedical and Health Informatics, Philadelphia, PA, USA
| | - Pierre Russo
- Children’s Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, Philadelpha, PA, USA
- Perelman School of Medicine at the University of Pennsylvania, Department of Pathology and Laboratory Medicine, Philadelphia, PA, USA
| | - Judith R Kelsen
- Children’s Hospital of Philadelphia, Department of Pediatrics, Philadelphia, PA, USA
- Perelman School of Medicine at the University of Pennsylvania, Department of Pediatrics, Philadelphia, PA, USA
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Zheng C, Huang Y, Hu W, Shi J, Ye Z, Qian X, Huang Z, Xue A, Wang Y, Lu J, Tang Z, Wu J, Wang L, Peng K, Zhou Y, Miao S, Sun H. Phenotypic Characterization of Very Early-Onset Inflammatory Bowel Disease with Interleukin-10 Signaling Deficiency: Based on a Large Cohort Study. Inflamm Bowel Dis 2019; 25:756-766. [PMID: 30212871 DOI: 10.1093/ibd/izy289] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Interleukin-10 (IL10)/interleukin-10 receptor (IL10R) deficiency is a rare disease with life-threatening infantile-onset colitis. We sought to accurately phenotype this disorder based on a large cohort of patients with a proven defect of IL10 signaling and to clarify the effects of allogeneic hematopoietic stem cell transplantation (HSCT). METHODS We analyzed the phenotypes of our 61 patients and reviewed 78 other previously reported cases with identified mutations in the genes encoding IL10 or IL10R. We also compared the clinical features of patients with interleukin-10 receptor B (IL10RB), interleukin-10 receptor A (IL10RA), and IL10 mutations. The therapeutic effects of allogeneic HSCT were evaluated. RESULTS We found that the disease onset time was extremely early: 70.3% within 30 days postnatal and 94.9% within the first 6 months of life. In addition, 94.2% of patients typically presented with perianal lesions. Oral ulcers and skin rash were common extra-intestinal manifestations (33.8% and 51.8%, respectively). There was no statistically significant difference in disease onset time, perianal lesion involvement, or mortality rate among patients with IL10RB, IL10RA, or IL10 deficiency. However, the surgery rate was higher in patients with IL10RB mutations than in those with IL10 or IL10RA mutations (P < 0.05). Compared with those with IL10RA deficiency, a higher percentage (32%, 9 of 28) of patients with IL10RB mutations developed B-cell lymphoma (P < 0.01). Compared with other regions, a higher percentage (98.7%) of IL10RA mutations was detected among patients in East Asia countries (P < 0.01), with hot-spot mutation sites of c.C301T and c.G537A. Allogeneic HSCT is efficacious but has a high mortality rate (17.5%, 7 of 40). CONCLUSIONS Our study expands the current knowledge on the genotype-correlated phenotypes with a defect of IL10 signaling. B-cell lymphoma was more frequent than would be expected in patients with IL10RB mutations. There may be a unique genetic architecture among Eastern Asia compared with other populations. Although allogeneic HSCT represents a causal therapeutic approach for IL10-and IL10R-deficient patients, a word of caution is warranted.
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Affiliation(s)
- Cuifang Zheng
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China
| | - Ying Huang
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China
| | - Wenhui Hu
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China
| | - Jieru Shi
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China
| | - Ziqing Ye
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China
| | - Xiaowen Qian
- Department of Hematology & Oncology, Children's Hospital of Fudan University, Shanghai, China
| | - Zhiheng Huang
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China
| | - Aijuan Xue
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China
| | - Yuhuan Wang
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China
| | - Junping Lu
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China
| | - Zifei Tang
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China
| | - Jie Wu
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China
| | - Lin Wang
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China
| | - Kaiyue Peng
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China
| | - Ying Zhou
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China
| | - Shijian Miao
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China
| | - Hua Sun
- Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China
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Oh SH, Sung YH, Kim I, Sim CK, Lee JH, Baek M, Pack CG, Seok C, Seo EJ, Lee MS, Kim KM. Novel Compound Heterozygote Mutation in IL10RA in a Patient With Very Early-Onset Inflammatory Bowel Disease. Inflamm Bowel Dis 2019; 25:498-509. [PMID: 30462267 DOI: 10.1093/ibd/izy353] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Indexed: 12/25/2022]
Abstract
BACKGROUND Very early-onset inflammatory bowel disease (VEO-IBD) is often associated with monogenetic disorders. IL-10RA deficiency is one of the major causal mutations in VEO-IBD. Here, we aimed to identify the causal mutation associated with severe IBD in a 1-year-old patient, validate the pathogenicity of the mutation, and characterize the mutant protein. METHODS To identify the causal mutation, targeted exome sequencing (ES) was performed using the genomic DNA from the patient. To validate the pathogenicity, IL-10RA functional tests were performed using the patient's peripheral blood mononuclear cells (PBMCs). Additionally, flow cytometry analysis, confocal microscopy on overexpressed green fluorescent protein-fused mutants, and computational analysis on the structures of IL-10RA proteins were performed. RESULTS We identified a novel compound heterozygote mutation p.[Tyr91Cys];[Pro146Alafs*40] in the IL10RA gene of the patient. The missense variant p.Tyr91Cys was previously identified but not functionally tested, and a frameshift variant, p.Pro146Alafs*40, is novel and nonfunctional. PBMCs from the patient showed defective signal transducer and activator of transcription 3 activation. The p.Tyr91Cys mutant protein failed to properly localize on the plasma membrane. The p.Tyr91Cys mutation seems to disrupt the hydrophobic core structure surrounding the tyrosine 91 residue, causing structural instability. CONCLUSIONS Targeted ES and linkage analysis identified novel compound heterozygous mutations p.[Tyr91Cys];[Pro146Alafs*40] in the IL10RA gene of a child with severe VEO-IBD. p.Tyr91Cys proteins were functionally defective in IL-10RA signaling and failed to properly localize on the plasma membrane, probably due to its structural instability.
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Affiliation(s)
- Seak Hee Oh
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Young Hoon Sung
- Department of Convergence Medicine, Asan Institutes for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Inki Kim
- Department of Convergence Medicine, Asan Institutes for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chan Kyu Sim
- Lab of Molecular Immunology and Medicine, Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Korea
| | - Jung Hoon Lee
- Lab of Molecular Immunology and Medicine, Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Korea
| | - Minkyung Baek
- Department of Chemistry, Seoul National University, Seoul, Korea
| | - Chan-Gi Pack
- Department of Convergence Medicine, Asan Institutes for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chaok Seok
- Department of Chemistry, Seoul National University, Seoul, Korea
| | - Eul Ju Seo
- Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Myeong Sup Lee
- Lab of Molecular Immunology and Medicine, Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyung Mo Kim
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
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Teng X, Xu L, Sun M, Guo J. Phenotypic characteristics and clinical manifestations of inflammatory bowel disease in infants and children under 2 years of age in Liaoning Province, China: five of six infants with IL-10R mutations. Paediatr Int Child Health 2019; 39:59-64. [PMID: 30900524 DOI: 10.1080/20469047.2018.1560700] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Accepted: 12/11/2018] [Indexed: 10/27/2022]
Abstract
A retrospective analysis of the phenotypic characteristics, clinical manifestations, investigations and interleukin-10 receptor (IL-10R) status of inflammatory bowel disease (IBD) in infants and children under 2 years of age in Liaoning Province, China between January 2015 and October 2016 is described. Six patients without a family history of IBD were diagnosed with Crohn disease, and IL-10R mutations were detected in five of them. Compound heterozygous patients with IL-10R mutations had severe clinical manifestations, were resistant to standard medication for IBD and had a poor prognosis as haematopoietic stem cell transplantation (HSCT) was not undertaken. Two of these patients died of suspected septicaemia. IBD in infants and children under 2 years of age is life-threatening when patients with IL-10R mutations do not receive allogeneic HSCT.
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Affiliation(s)
- Xu Teng
- a Department of Pediatric Gastroenterology , Shengjing Hospital of China Medical University , Shenyang , China
| | - Lingfen Xu
- a Department of Pediatric Gastroenterology , Shengjing Hospital of China Medical University , Shenyang , China
| | - Mei Sun
- a Department of Pediatric Gastroenterology , Shengjing Hospital of China Medical University , Shenyang , China
| | - Jing Guo
- a Department of Pediatric Gastroenterology , Shengjing Hospital of China Medical University , Shenyang , China
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Wei H, Li B, Sun A, Guo F. Interleukin-10 Family Cytokines Immunobiology and Structure. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1172:79-96. [PMID: 31628652 DOI: 10.1007/978-981-13-9367-9_4] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The Interleukin (IL)-10 cytokine family includes IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26, which are considered as Class 2α-helical cytokines. IL-10 is the most important cytokine in suppressing pro-inflammatory responses in all kinds of autoimmune diseases and limiting excessive immune responses. Due to protein structure homology and shared usage of receptor complexes as well as downstream signaling pathway, other IL-10 family cytokines also show indispensable functions in immune regulation, tissue homeostasis, and host defense. In this review, we focus on immune functions and structures of different cytokines in this family and try to better understand how their molecular mechanisms connect to their biological functions. The molecular details regarding their actions also provide useful information in developing candidate immune therapy reagents for a variety of diseases.
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Affiliation(s)
- Huaxing Wei
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, People's Republic of China
| | - Bofeng Li
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, People's Republic of China.
| | - Anyuan Sun
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, People's Republic of China
| | - Feng Guo
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, People's Republic of China
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Compound heterozygous mutations in IL10RA combined with a complement factor properdin mutation in infantile-onset inflammatory bowel disease. Eur J Gastroenterol Hepatol 2018; 30:1491-1496. [PMID: 30199474 DOI: 10.1097/meg.0000000000001247] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVES Inflammatory bowel diseases (IBDs) are chronic and multifactorial diseases resulting from a complex interaction of host genetic factors and environmental stimuli. Although many genome-wide association studies have identified host genetic factors associated with IBD, rare Mendelian forms of IBD have been reported in patients with very early onset forms. Therefore, this study aimed to identify genetic variants associated with infantile-onset IBD. PARTICIPANTS AND METHODS We obtained genomic DNA from whole blood samples of a male patient with infantile-onset IBD and nonconsanguineous Korean parents. Whole-exome sequencing was performed using trio samples. Then, we analyzed the data using susceptibility genes for monogenic forms of IBD and various immunodeficiencies and protein structural analysis. RESULTS The patient who presented with oral aphthous ulcers at the age of 14 days suffered from severe colitis and was refractory to medical treatment. Compound heterozygous mutations in IL10RA (p.R101W; p.T179T) were found in the patient. In addition, a hemizygous mutation in complement factor properdin (CFP) (p.L456V) located on the X-chromosome was detected, inherited from the patient's mother. Protein structural modeling suggested impaired properdin subunit interactions by p.L456V that may hamper protein oligomerization required for complement activation. CONCLUSION This study identified compound heterozygous mutations in IL10RA combined with a hemizygous CFP mutation in infantile-onset IBD by using whole-exome sequencing. CFP p.L456V may exacerbate symptoms of infantile-onset IBD by disturbing oligomerization of properdin.
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Charbit-Henrion F, Bègue B, Sierra A, Hanein S, Stolzenberg MC, Li Z, Pellegrini S, Garcelon N, Jeanpierre M, Neven B, Loge I, Picard C, Rosain J, Bustamante J, Le Lorc’h M, Pigneur B, Fernandes A, GENIUS Group, Rieux-Laucat F, Amil Dias J, Ruemmele FM, Cerf-Bensussan N. Copy number variations and founder effect underlying complete IL-10Rβ deficiency in Portuguese kindreds. PLoS One 2018; 13:e0205826. [PMID: 30365510 PMCID: PMC6203366 DOI: 10.1371/journal.pone.0205826] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 10/02/2018] [Indexed: 12/19/2022] Open
Abstract
Mutations in interleukin-10 receptor (IL-10R) genes are one cause of very early-onset inflammatory bowel disease with perianal lesions, which can be cured by hematopoietic stem cell transplantation. Using a functional test, which assesses responsiveness of peripheral monocytes to IL-10, we identified three unrelated Portuguese patients carrying two novel IL-10RB mutations. In the three patients, sequencing of genomic DNA identified the same large deletion of exon 3 which precluded protein expression. This mutation was homozygous in two patients born from consanguineous families and heterozygous in the third patient born from unrelated parents. Microsatellite analysis of the IL10RB genomic region revealed a common haplotype in the three Portuguese families pointing to a founder deletion inherited from a common ancestor 400 years ago. In the third patient, surface expression of IL-10R was normal but signaling in response to IL-10 was impaired. Complementary DNA sequencing and next-generation sequencing of IL10RB locus with custom-made probes revealed a ≈ 6 Kb duplication encompassing the exon 6 which leads to a frameshift mutation and a loss of the TYK2-interacting Box 2 motif. Altogether, we describe two novel copy number variations in IL10RB, one with founder effect and one preserving cell surface expression but abolishing signaling.
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Affiliation(s)
- Fabienne Charbit-Henrion
- INSERM, UMR1163 and Institut Imagine, Laboratory of Intestinal Immunity, Paris, France
- Paris Descartes University-Sorbonne Paris Cité, Paris, France
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Necker-Enfants Malades Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France
- GENIUS group, Paris, France
| | - Bernadette Bègue
- INSERM, UMR1163 and Institut Imagine, Laboratory of Intestinal Immunity, Paris, France
- Paris Descartes University-Sorbonne Paris Cité, Paris, France
- GENIUS group, Paris, France
| | - Anaïs Sierra
- INSERM, UMR1163 and Institut Imagine, Laboratory of Intestinal Immunity, Paris, France
- Paris Descartes University-Sorbonne Paris Cité, Paris, France
- GENIUS group, Paris, France
| | - Sylvain Hanein
- Paris Descartes University-Sorbonne Paris Cité, Paris, France
- INSERM UMR1163 and Institut Imagine, Translational Genetic, Paris, France
| | - Marie-Claude Stolzenberg
- Paris Descartes University-Sorbonne Paris Cité, Paris, France
- INSERM UMR1163 and Institut Imagine, Immunogenetics of Paediatric Autoimmunity, Paris, France
| | - Zhi Li
- Cytokine Signaling Unit, Institut Pasteur, INSERM 1221, Paris, France
| | - Sandra Pellegrini
- Cytokine Signaling Unit, Institut Pasteur, INSERM 1221, Paris, France
| | - Nicolas Garcelon
- Paris Descartes University-Sorbonne Paris Cité, Paris, France
- INSERM, Centre de Recherche des Cordeliers, UMR 1138 Equipe 22, Institut Imagine, Paris France
| | - Marc Jeanpierre
- Paris Descartes University-Sorbonne Paris Cité, Paris, France
- Genetic Unit, Cochin Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France
| | - Bénédicte Neven
- Paris Descartes University-Sorbonne Paris Cité, Paris, France
- INSERM UMR1163 and Institut Imagine, Immunogenetics of Paediatric Autoimmunity, Paris, France
- Paediatric Haematology-Immunology and Rheumatology Unit, Necker-Enfants Malades Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France
| | - Isabelle Loge
- Department of Paediatrics, Hôpital Charles-Nicolle, CHU Rouen, Rouen, France
| | - Capucine Picard
- Paris Descartes University-Sorbonne Paris Cité, Paris, France
- Study Centre for Primary Immunodeficiency, Necker-Enfants Malades Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France
| | - Jérémie Rosain
- Paris Descartes University-Sorbonne Paris Cité, Paris, France
- Study Centre for Primary Immunodeficiency, Necker-Enfants Malades Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163 and Institut Imagine, Necker Hospital for Sick Children, Paris, France
| | - Jacinta Bustamante
- Paris Descartes University-Sorbonne Paris Cité, Paris, France
- Study Centre for Primary Immunodeficiency, Necker-Enfants Malades Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163 and Institut Imagine, Necker Hospital for Sick Children, Paris, France
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, New York, United States of America
| | - Marc Le Lorc’h
- Histology, Embryology and Cytogenetics Unit, Necker-Enfants Malades Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France
| | - Bénédicte Pigneur
- INSERM, UMR1163 and Institut Imagine, Laboratory of Intestinal Immunity, Paris, France
- Paris Descartes University-Sorbonne Paris Cité, Paris, France
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Necker-Enfants Malades Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France
- GENIUS group, Paris, France
| | - Alicia Fernandes
- Centre of Biological Resources, Structure Fédérative de Recherche Necker, INSERM US24, CNRS UMS3633, Assistance Publique des Hôpitaux de Paris (AP-HP), and Institut Imagine, Paris, France
| | | | - Frédéric Rieux-Laucat
- Paris Descartes University-Sorbonne Paris Cité, Paris, France
- INSERM UMR1163 and Institut Imagine, Immunogenetics of Paediatric Autoimmunity, Paris, France
| | - Jorge Amil Dias
- GENIUS group, Paris, France
- Department of Paediatrics, Centro Hospitalar S. João, Porto, Portugal
| | - Frank M. Ruemmele
- INSERM, UMR1163 and Institut Imagine, Laboratory of Intestinal Immunity, Paris, France
- Paris Descartes University-Sorbonne Paris Cité, Paris, France
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Necker-Enfants Malades Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France
- GENIUS group, Paris, France
| | - Nadine Cerf-Bensussan
- INSERM, UMR1163 and Institut Imagine, Laboratory of Intestinal Immunity, Paris, France
- Paris Descartes University-Sorbonne Paris Cité, Paris, France
- GENIUS group, Paris, France
- * E-mail:
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Zadka Ł, Kulus MJ, Kurnol K, Piotrowska A, Glatzel-Plucińska N, Jurek T, Czuba M, Nowak A, Chabowski M, Janczak D, Dzięgiel P. The expression of IL10RA in colorectal cancer and its correlation with the proliferation index and the clinical stage of the disease. Cytokine 2018; 110:116-125. [DOI: 10.1016/j.cyto.2018.04.030] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 04/24/2018] [Accepted: 04/25/2018] [Indexed: 12/16/2022]
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Charbit-Henrion F, Parlato M, Hanein S, Duclaux-Loras R, Nowak J, Begue B, Rakotobe S, Bruneau J, Fourrage C, Alibeu O, Rieux-Laucat F, Lévy E, Stolzenberg MC, Mazerolles F, Latour S, Lenoir C, Fischer A, Picard C, Aloi M, Dias JA, Hariz MB, Bourrier A, Breuer C, Breton A, Bronsky J, Buderus S, Cananzi M, Coopman S, Crémilleux C, Dabadie A, Dumant-Forest C, Gurkan OE, Fabre A, Fischer A, Diaz MG, Gonzalez-Lama Y, Goulet O, Guariso G, Gurcan N, Homan M, Hugot JP, Jeziorski E, Karanika E, Lachaux A, Lewindon P, Lima R, Magro F, Major J, Malamut G, Mas E, Mattyus I, Mearin LM, Melek J, Navas-Lopez VM, Paerregaard A, Pelatan C, Pigneur B, Pais IP, Rebeuh J, Romano C, Siala N, Strisciuglio C, Tempia-Caliera M, Tounian P, Turner D, Urbonas V, Willot S, Ruemmele FM, Cerf-Bensussan N. Diagnostic Yield of Next-generation Sequencing in Very Early-onset Inflammatory Bowel Diseases: A Multicentre Study. J Crohns Colitis 2018; 12:1104-1112. [PMID: 29788237 PMCID: PMC6113703 DOI: 10.1093/ecco-jcc/jjy068] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 03/14/2018] [Accepted: 05/16/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment. METHODS A total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally. RESULTS Molecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES. CONCLUSIONS Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.
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Affiliation(s)
- Fabienne Charbit-Henrion
- INSERM, UMR1163, Laboratory of Intestinal Immunity, and Imagine Institute, Paris, France
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- Paediatric Gastroenterology, Hepatology and Nutrition Unit, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
| | - Marianna Parlato
- INSERM, UMR1163, Laboratory of Intestinal Immunity, and Imagine Institute, Paris, France
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
| | - Sylvain Hanein
- INSERM, UMR 1163 Translational Genetic, and Imagine Institute, Paris, France
| | - Rémi Duclaux-Loras
- INSERM, UMR1163, Laboratory of Intestinal Immunity, and Imagine Institute, Paris, France
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
| | - Jan Nowak
- INSERM, UMR1163, Laboratory of Intestinal Immunity, and Imagine Institute, Paris, France
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Bernadette Begue
- INSERM, UMR1163, Laboratory of Intestinal Immunity, and Imagine Institute, Paris, France
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
| | - Sabine Rakotobe
- INSERM, UMR1163, Laboratory of Intestinal Immunity, and Imagine Institute, Paris, France
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
| | - Julie Bruneau
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- Pathology Department, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Cécile Fourrage
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- Bioinformatics Platform, Imagine Institute Paris, France
| | - Olivier Alibeu
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- Genomic Platform, Imagine Institute, Paris, France
| | - Frédéric Rieux-Laucat
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- INSERM, UMR1163, Immunogenetics of Paediatric Autoimmunity, and Imagine Institute, Paris, France
| | - Eva Lévy
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- INSERM, UMR1163, Immunogenetics of Paediatric Autoimmunity, and Imagine Institute, Paris, France
| | - Marie-Claude Stolzenberg
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- INSERM, UMR1163, Immunogenetics of Paediatric Autoimmunity, and Imagine Institute, Paris, France
| | - Fabienne Mazerolles
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- INSERM, UMR1163, Immunogenetics of Paediatric Autoimmunity, and Imagine Institute, Paris, France
| | - Sylvain Latour
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- INSERM, UMR1163, Lymphocyte activation and EBV susceptibility, and Imagine Institute, Paris, France
| | - Christelle Lenoir
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- INSERM, UMR1163, Lymphocyte activation and EBV susceptibility, and Imagine Institute, Paris, France
| | - Alain Fischer
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- Collège de France, Médecine expérimentale, Paris, France
- INSERM UMR 1163 and Imagine Institute, Paris, France
| | - Capucine Picard
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- INSERM, UMR1163, Lymphocyte activation and EBV susceptibility, and Imagine Institute, Paris, France
- Investigation Centre for Immunodeficiency, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris and Imagine Institute, Paris, France
| | - Marina Aloi
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Sapienza University of Rome, Paediatric Gastroenterology and Liver Unit, Department of Pediatrics, Rome, Italy
| | - Jorge Amil Dias
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Centro Hospitalar São João, Porto, Portugal
| | - Mongi Ben Hariz
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Hopital La Marsa, Tunisia
| | - Anne Bourrier
- Department of Gastroenterology, Hôpital St Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Christian Breuer
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Universitätsklinikum Hamburg, Hamburg, Germany
| | - Anne Breton
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Gastroenterology, Hepatology, Nutrition, and Diabetes, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | - Jiri Bronsky
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- University Hospital Motol, Prague, Czech Republic
| | - Stephan Buderus
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- St. Marien Hospital, Bonn, Germany
| | - Mara Cananzi
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Unit of Paediatric Hepatology, Department of Woman and Child Health, University Hospital of Padova, Padova, Italy
| | - Stéphanie Coopman
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, Jeanne De Flandre Children’s Hospital, Lille University Faculty of Medicine, Lille, France
| | - Clara Crémilleux
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Centre Hospitalo-Universitaire de St-Etienne, St-Etienne, France
| | - Alain Dabadie
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Service de médecine de l’enfant et de l’adolescent, Hôpital Sud – Centre Hospitalo-Universitaire de Rennes, Rennes, France
| | - Clémentine Dumant-Forest
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Centre Hospitalo-Universitaire Charles Nicolle, Rouen, France
| | - Odul Egritas Gurkan
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Paediatric Gastroenterology, Hepatology and Nutrition, Gazi University, Ankara, Turkey
| | - Alexandre Fabre
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Assistance publique Hôpitaux de Marseille, Hôpital de la Timone, Marseille, France
| | - Aude Fischer
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Centre Hospitalo-Universitaire Sud Réunion, St Pierre, France
| | - Marta German Diaz
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Unit of Paediatric Nutrition, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Yago Gonzalez-Lama
- Inflammatory Bowel Disease Unit, Hospital Universitario Puerta de Hierro–Majadahonda, Madrid, Spain
| | - Olivier Goulet
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- Paediatric Gastroenterology, Hepatology and Nutrition Unit, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
| | - Graziella Guariso
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- University of Padua, Italy
| | - Neslihan Gurcan
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Paediatric Gastroenterology, Hepatology and Nutrition, Gazi University, Ankara, Turkey
| | - Matjaz Homan
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Gastroenterology, Hepatology and Nutrition, University Children’s Hospital, Ljubljana, Slovenia
| | - Jean-Pierre Hugot
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Departments of Paediatric Digestive and Respiratory Diseases, Hôpital Robert-Debré, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Eric Jeziorski
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Infectious diseases and Immunology, Centre Hospitalo-Universitaire de Montpellier, Montpellier, France
| | - Evi Karanika
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, University General Hospital of Thessaloniki, Thessaloniki, Greece
| | - Alain Lachaux
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Centre de Nutrition parentérale à domicile, Hôpital Femme–Mère–Enfant CHU de Lyon HCL - GH Est, Bron, France
| | - Peter Lewindon
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Gastroenterology and Hepatology, Lady Cilento Children’s Hospital and the Faculty of Medicine and Biomedical Sciences, TUniversity of Queensland, Brisbane, Australia
| | - Rosa Lima
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Centro Hospitalar São João, Porto, Portugal
| | - Fernando Magro
- Gastroenterology Department, Hospital de São João, Institute of Pharmacology and Therapeutics Faculty of Medicine and MedInUP - Centre for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal
| | - Janos Major
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- MRE Bethesda Gyermekkórháza; Department of Pediatrics, Budapest, Hungary
| | - Georgia Malamut
- INSERM, UMR1163, Laboratory of Intestinal Immunity, and Imagine Institute, Paris, France
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- Department of Gastroenterology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Emmanuel Mas
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Gastroenterology, Hepatology, Nutrition, and Diabetes, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | - Istvan Mattyus
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Semmelweis University; Department of Paediatrics, Budapest, Hungary
| | - Luisa M Mearin
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Leiden University Medical Centre, Department of Paediatrics, Leiden, The Netherlands
| | - Jan Melek
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- University Hospital, Hradec Kralove, Czech Republic
| | - Victor Manuel Navas-Lopez
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Hospital Regional Universitario de Málaga, Departamento de Pediatría, Malaga, Spain
| | - Anders Paerregaard
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Hvidovre University Hospital, Department of Paediatrics, Copenhagen, Denmark
| | - Cecile Pelatan
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Centre Hospitalier du Mans, Le Mans, France
| | - Bénédicte Pigneur
- INSERM, UMR1163, Laboratory of Intestinal Immunity, and Imagine Institute, Paris, France
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- Paediatric Gastroenterology, Hepatology and Nutrition Unit, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
| | - Isabel Pinto Pais
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Centro Hospitalar Gaia Espinho, Department of Paediatrics, Vila Nova de Gaia, Portugal
| | - Julie Rebeuh
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Centre Hospitalo-Universitaire de Strasbourg, Strasbourg, France
| | - Claudio Romano
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Hospital of Messina, University of Messina, Messina, Italy
| | - Nadia Siala
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Hôpital Mongi Slim, La Marsa, Tunisia
| | - Caterina Strisciuglio
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Woman, Child and General and Specialized Surgery, Second University of Naples, Naples, Italy
| | - Michela Tempia-Caliera
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, FMH Pédiatrie et FA Gastroentérologie et hépatologie, Clinique des Grangettes, Geneva, Switzerland
| | - Patrick Tounian
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatric Nutrition and Gastroenterology, Hôpital Armand Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Dan Turner
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Shaare Zedek Medical Centre, Jerusalem, Israel
| | - Vaidotas Urbonas
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatric Gastroenterology, Vilnius University Clinic for Children’s Diseases, Vilnius, Lithuania
| | - Stéphanie Willot
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Centre hospitalier régional universitaire, Hôpital Clocheville, Tours, France
| | - Frank M Ruemmele
- INSERM, UMR1163, Laboratory of Intestinal Immunity, and Imagine Institute, Paris, France
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- Paediatric Gastroenterology, Hepatology and Nutrition Unit, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
| | - Nadine Cerf-Bensussan
- INSERM, UMR1163, Laboratory of Intestinal Immunity, and Imagine Institute, Paris, France
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
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Azizi G, Yazdani R, Rae W, Abolhassani H, Rojas M, Aghamohammadi A, Anaya JM. Monogenic polyautoimmunity in primary immunodeficiency diseases. Autoimmun Rev 2018; 17:1028-1039. [PMID: 30107266 DOI: 10.1016/j.autrev.2018.05.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 05/02/2018] [Indexed: 02/08/2023]
Abstract
Primary immunodeficiency diseases (PIDs) consist of a large group of genetic disorders that affect distinct components of the immune system. PID patients are susceptible to infection and non-infectious complications, particularly autoimmunity. A specific group of monogenic PIDs are due to mutations in genes that are critical for the regulation of immunological tolerance and immune responses. This group of monogenic PIDs is at high risk of developing polyautoimmunity (i.e., the presence of more than one autoimmune disease in a single patient) because of their impaired immunity. In this review, we discuss the mechanisms of autoimmunity in PIDs and the characteristics of polyautoimmunity in the following PIDs: IPEX; monogenic IPEX-like syndrome; LRBA deficiency; CTLA4 deficiency; APECED; ALPS; and PKCδ deficiency.
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Affiliation(s)
- Gholamreza Azizi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Reza Yazdani
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Wiliam Rae
- Department of Immunology, MP8, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, Hampshire SO16 6YD, UK
| | - Hassan Abolhassani
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Manuel Rojas
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia
| | - Asghar Aghamohammadi
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Juan-Manuel Anaya
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia.
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Wang XQ, Xiao Y, Xu X, Yu Y, Shan CY, Guo Y, Gong L, Zhou T, Gao SS, Yuan YZ, Wang XJ, Xu CD. Study of disease phenotype and its association with prognosis of paediatric inflammatory bowel disease in China. BMC Pediatr 2018; 18:229. [PMID: 30001197 PMCID: PMC6044010 DOI: 10.1186/s12887-018-1212-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Accepted: 07/06/2018] [Indexed: 02/08/2023] Open
Abstract
Background To investigate the unique features of inflammatory bowel disease (IBD) in children, we wanted to identify whether there might be a strong correlation between the disease phenotype and its prognosis at various ages in paediatric patients. Methods We collected data from patients diagnosed with IBD (ulcerative colitis (UC) or Crohn’s disease (CD)) from 2002 to 2016. The diagnosis was made according to the Porto criteria and Paris Classification. Patient characteristics, clinical manifestations and treatments were collected. Risk factors for surgery, mortality and relapse were analysed by Cox proportional hazard models. Results Of the 143 patients, 113 had CD, and 30 had UC; there were 89 males and 54 females with a median age of 9 years (y). Thirteen patients in the 0–2 y group were identified as having mutations in IL-10 receptor A, and this mutation was significantly more common in this age group than in 3–9 and 10–16 y patients. The risk factor for surgery was the B3 phenotype; risk factors for death were age 0–2 y and B3 phenotype; 0–2 y, B3 phenotype and steroid dependency were risk factors for early relapse. Conclusions Clinical manifestations of the onset of IBD in infants and toddlers were extensive and aggressive and were closely associated with early relapse and death. It is of particular interest that some of these patients developed IBD due to monogenic disorders; thus, introduction of genetic testing is essential for these patients.
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Affiliation(s)
- Xin-Qiong Wang
- Department of Paediatrics, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, No. 197, Rui Jin Er Road, Shanghai, 200025, China
| | - Yuan Xiao
- Department of Paediatrics, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, No. 197, Rui Jin Er Road, Shanghai, 200025, China
| | - Xu Xu
- Department of Paediatrics, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, No. 197, Rui Jin Er Road, Shanghai, 200025, China
| | - Yi Yu
- Department of Paediatrics, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, No. 197, Rui Jin Er Road, Shanghai, 200025, China
| | - Cheng-Yan Shan
- Department of Paediatrics, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, No. 197, Rui Jin Er Road, Shanghai, 200025, China
| | - Yan Guo
- Department of Paediatrics, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, No. 197, Rui Jin Er Road, Shanghai, 200025, China
| | - Ling Gong
- Department of Paediatrics, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, No. 197, Rui Jin Er Road, Shanghai, 200025, China
| | - Tong Zhou
- Department of Paediatrics, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, No. 197, Rui Jin Er Road, Shanghai, 200025, China
| | - Shen-Shen Gao
- Department of Paediatrics, Ruijin Hospital North, Shanghai Jiao Tong University, School of Medicine, Shanghai, 201821, China
| | - Yao-Zong Yuan
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200025, China
| | - Xiao-Jin Wang
- Department of Biostatistics, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200025, China
| | - Chun-Di Xu
- Department of Paediatrics, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, No. 197, Rui Jin Er Road, Shanghai, 200025, China. .,Department of Paediatrics, Ruijin Hospital North, Shanghai Jiao Tong University, School of Medicine, Shanghai, 201821, China.
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40
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The Treatment of Inflammatory Bowel Disease in Patients with Selected Primary Immunodeficiencies. J Clin Immunol 2018; 38:579-588. [DOI: 10.1007/s10875-018-0524-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 06/06/2018] [Indexed: 12/25/2022]
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41
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Peng K, Qian X, Huang Z, Lu J, Wang Y, Zhou Y, Wang H, Wu B, Wang Y, Chen L, Zhai X, Huang Y. Umbilical Cord Blood Transplantation Corrects Very Early-Onset Inflammatory Bowel Disease in Chinese Patients With IL10RA-Associated Immune Deficiency. Inflamm Bowel Dis 2018; 24:1416-1427. [PMID: 29788474 DOI: 10.1093/ibd/izy028] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hematopoietic stem cell transplantation is considered the only curative therapy for very early-onset inflammatory bowel disease with specific immune defects, such as interleukin-10 receptor deficiency. We performed reduced-intensity conditioning before umbilical cord blood transplantation in patients with interleukin-10 receptor-A deficiency. METHODS We enrolled 9 very early-onset inflammatory bowel disease patients with typical manifestations. We diagnosed the patients with interleukin-10 receptor-A deficiency by whole-exome sequencing. Umbilical cord blood transplantation was performed in all 9 patients. Eight patients received the reduced-intensity conditioning regimen, and 1 patient received the myeloablative conditioning regimen. RESULTS All 9 patients received transplantation between the ages of 6 months to 43 months (average, 16.8 months) with body weights ranging from 3 to 10.4 kg (average, 6.6 kg). The patients displayed complete chimerism at 2-8 weeks after transplantation; 6 patients achieved complete remission without evidence of graft-vs-host disease or infections; 1 patient died of chronic lung graft-vs-host disease at 6 months post-transplantation; and the other 2 patients died of sepsis post-transplantation because of unsuccessful engraftments. Severe malnutrition and growth retardation associated with interleukin-10 receptor-A deficiency were significantly improved post-transplantation. CONCLUSIONS We recommend umbilical cord blood transplantation as a potential treatment for very early-onset inflammatory bowel disease with a defined monogenic immunodeficiency, and we suggest that reduced-intensity conditioning chemotherapy is more suitable than myeloablative conditioning for patients with severe malnutrition and bowel disease. We have demonstrated success with reduced-intensity conditioning for interleukin-10 receptor-A deficiency in pediatric patients with severe clinical conditions. 10.1093/ibd/izy028_video1izy028.video15786489183001.
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Affiliation(s)
- Kaiyue Peng
- Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China
| | - Xiaowen Qian
- Department of Hematology and Oncology, Children's Hospital of Fudan University, Shanghai, China
| | - Zhiheng Huang
- Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China
| | - Junping Lu
- Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China
| | - Yuhuan Wang
- Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China
| | - Ying Zhou
- Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China
| | - Huijun Wang
- Molecular Genetic Diagnosis Center, Shanghai Key Lab Birth Defects, Pediatric Research Institute, Children' s Hospital of Fudan University, Shanghai, China
| | - Bingbing Wu
- Molecular Genetic Diagnosis Center, Shanghai Key Lab Birth Defects, Pediatric Research Institute, Children' s Hospital of Fudan University, Shanghai, China
| | - Ying Wang
- Molecular Genetic Diagnosis Center, Shanghai Key Lab Birth Defects, Pediatric Research Institute, Children' s Hospital of Fudan University, Shanghai, China
| | - Lingli Chen
- Department of Pathology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Xiaowen Zhai
- Department of Hematology and Oncology, Children's Hospital of Fudan University, Shanghai, China
| | - Ying Huang
- Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China
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Impaired IL-10 Receptor-mediated Suppression in Monocyte From Patients With Crohn Disease. J Pediatr Gastroenterol Nutr 2018; 66:779-784. [PMID: 29045353 DOI: 10.1097/mpg.0000000000001795] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVES Interleukin-10 (IL-10) is an immunoregulatory cytokine that has a central role in suppressing proinflammatory responses. Patients with deleterious mutations in interleukin (IL)-10 or IL-10 receptor (IL-10R) genes develop severe colitis and perianal disease in the first months of life. Whether IL-10R expression and signaling in pediatric- or adult-onset Crohn disease (CD) are altered is unknown. The objective of this study was to characterize IL-10R expression and IL-10R-mediated suppression in patients with CD. METHODS Monocytes were sorted from peripheral blood mononuclear cells of patients with CD and control subjects. IL-10R expression was determined by flow cytometry. Monocytes were stimulated with lipopolysaccharide (LPS) for 3 hours in the presence of different concentrations of IL-10 to determine IL-10-mediated suppression of tumor necrosis factor α production. Signaling through the IL-10R was evaluated by quantifying STAT3 phosphorylation in response to IL-10 stimulation. RESULTS Forty-two subjects were enrolled in this study: 19 with CD and 23 controls. Stimulation of monocytes with LPS markedly increased IL-10R expression in both groups but to a much lower extent in patients with CD. In addition, IL-10-mediated suppression of TNFα production upon LPS stimulation and IL-10-induced STAT3 phosphorylation were attenuated in patients with CD versus controls. Finally, LPS-stimulated monocytes from patients with CD secreted significantly lower quantities of IL-10, compared with control monocytes. CONCLUSIONS IL-10R expression and signaling are decreased in monocytes from patients with CD. Additional studies are required to assess whether similar patterns occur in other innate immune cells, especially in the gut, and whether disease activity, medical therapy, and genetic factors modulate these findings.
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Azizi G, Abolhassani H, Zaki-Dizaji M, Habibi S, Mohammadi H, Shaghaghi M, Yazdani R, Anaya JM, Rezaei N, Hammarström L, Aghamohammadi A. Polyautoimmunity in Patients with LPS-Responsive Beige-Like Anchor (LRBA) Deficiency. Immunol Invest 2018. [PMID: 29528757 DOI: 10.1080/08820139.2018.1446978] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND Polyautoimmunity is defined as the presence of more than one autoimmune disorder in a single patient. Lipopolysaccharide (LPS)-responsive beige-like anchor (LRBA) deficiency is one of the monogenic causes of polyautoimmunity. The aim of this study was to report the characteristics of polyautoimmunity in patients with LRBA deficiency. METHODS A total of 14 LRBA deficiency patients with confirmed autoimmunity were enrolled in this study. For those patients with polyautoimmunity, demographic information, clinical records, laboratory, and molecular data were collected. We also compared our results with the currently reported patients with LRBA deficiency associated with polyautoimmunity. RESULTS In 64.2% (9 out of 14) of patients, autoimmunity presented as polyautoimmunity. In these patients, autoimmune cytopenias were the most frequent complication, observed in seven patients. Three patients presented with four different types of autoimmune conditions. The review of the literature showed that 41 of 72 reported LRBA deficient patients (74.5%) had also polyautoimmunity, with a wide spectrum of autoimmune diseases described. Hematopoietic stem cell transplantation is increasingly used as the treatment for patients with severe polyautoimmunity associated to LRBA deficiency. CONCLUSIONS Mutation in LRBA gene is one of the causes of monogenic polyautoimmunity. Awareness of this association is important in order to make an early diagnosis and prompt treatment.
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Affiliation(s)
- Gholamreza Azizi
- a Non-Communicable Diseases Research Center , Alborz University of Medical Sciences , Karaj , Iran.,b Research Center for Immunodeficiencies, Children's Medical Center , Tehran University of Medical Sciences , Tehran , Iran
| | - Hassan Abolhassani
- b Research Center for Immunodeficiencies, Children's Medical Center , Tehran University of Medical Sciences , Tehran , Iran.,c Primary Immunodeficiency Diseases Network (PIDNet) , Universal Scientific Education and Research Network (USERN) , Tehran , Iran.,d Division of Clinical Immunology, Department of Laboratory Medicine , Karolinska Institute at Karolinska University Hospital Huddinge , Stockholm , Sweden
| | - Majid Zaki-Dizaji
- e Department of Medical Genetics, School of Medicine , Tehran University of Medical Sciences , Tehran , Iran
| | - Sima Habibi
- b Research Center for Immunodeficiencies, Children's Medical Center , Tehran University of Medical Sciences , Tehran , Iran.,c Primary Immunodeficiency Diseases Network (PIDNet) , Universal Scientific Education and Research Network (USERN) , Tehran , Iran
| | - Hamed Mohammadi
- f Department of Immunology, School of Medicine , Tabriz University of Medical Sciences , Tabriz , Iran
| | - Mohammadreza Shaghaghi
- b Research Center for Immunodeficiencies, Children's Medical Center , Tehran University of Medical Sciences , Tehran , Iran.,g Network of Immunology in Infections, Malignancy and Autoimmunity (NIIMA) , Universal Scientific Education and Research Network (USERN) , Tehran , Iran
| | - Reza Yazdani
- b Research Center for Immunodeficiencies, Children's Medical Center , Tehran University of Medical Sciences , Tehran , Iran
| | - Juan-Manuel Anaya
- h Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences , Universidad del Rosario , Bogotá , Colombia
| | - Nima Rezaei
- b Research Center for Immunodeficiencies, Children's Medical Center , Tehran University of Medical Sciences , Tehran , Iran.,g Network of Immunology in Infections, Malignancy and Autoimmunity (NIIMA) , Universal Scientific Education and Research Network (USERN) , Tehran , Iran
| | - Lennart Hammarström
- d Division of Clinical Immunology, Department of Laboratory Medicine , Karolinska Institute at Karolinska University Hospital Huddinge , Stockholm , Sweden
| | - Asghar Aghamohammadi
- b Research Center for Immunodeficiencies, Children's Medical Center , Tehran University of Medical Sciences , Tehran , Iran.,c Primary Immunodeficiency Diseases Network (PIDNet) , Universal Scientific Education and Research Network (USERN) , Tehran , Iran
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Abstract
Very early onset inflammatory bowel disease (VEO-IBD) represents a unique and growing subset of patients with inflammatory bowel disease (IBD). Some VEO-IBD patients present with immunodeficiency and possess loss of function genetic mutations involving immune pathways that cause their IBD. A search for Mendelian causes of IBD is likely most beneficial when the presentation involves extra-intestinal autoimmunity or involves intestinal histopathology that is atypical for IBD. While a subset of these young patients will have highly aggressive courses (and likely present with immunodeficiency), the majority of patients with VEO-IBD appear to have disease courses similar to that of their older counterparts. Most notably, many of these young children will require long courses of immunosuppression simply as a result of the profoundly early presentation-thus increasing their long-term risks of cancer and opportunistic infections.
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Affiliation(s)
- Christopher J Moran
- Harvard Medical School, Department of Pediatrics, 175 Cambridge St, Suite 567, Boston, MA 02114.
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Phenotype and Management of Infantile-onset Inflammatory Bowel Disease: Experience from a Tertiary Care Center in China. Inflamm Bowel Dis 2017; 23:2154-2164. [PMID: 29140941 DOI: 10.1097/mib.0000000000001269] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Infantile-onset inflammatory bowel disease (IBD) comprises rare and clinically severe disorders. We examined the phenotypes and genetic causes of patients with infantile-onset IBD from a tertiary medical center. METHODS We enrolled 38 patients with infantile-onset IBD and applied standardized treatment with medical, surgical, and supportive care. Targeted sequencing and whole-exome sequencing were performed. Clinical data were retrieved from medical records. RESULTS Median age of onset of disease was 12.5 (interquartile range: 7.0-30.0) days. All patients had diarrhea, whereas 18 (47.4%) patients reported hematochezia. Thirteen (34.2%) patients had oral ulcers, 15 (39.5%) patients had perianal abscess, and 9 (52.9%) female patients had rectovaginal fistula. Six (18.8%) patients had intestinal strictures and 4 (12.1%) patients had perforation. Twelve (31.6%) patients underwent surgical procedures. Median age of surgery was 272.5 days, and cumulative probability for surgery during first year was 32.1%. One-year mortality of patients was 25.9%. Sequencing showed 24 (63.2%) patients had causative IL10RA mutations, 1 patient had EPCAM mutation, 1 patient had TNFAIP3 mutation, and 1 patient had LRBA mutation, whereas causative mutations cannot be identified in the other 11 (28.9%) patients. Umbilical cord blood stem cell transplantation has been applied to 8 cases with IL10RA mutations, of whom 5 (71.4%) patients have achieved clinical remission. CONCLUSIONS Patients with infantile-onset IBD had severe phenotype and early onset. Medical, surgical interventions with supportive care are essential. High-throughput sequencing ensures appropriate treatment. Hematopoietic stem cell transplantation can be performed in selected patients with IL10RA mutations (see Video Abstract, Supplemental Digital Content 1, http://links.lww.com/IBD/B657).
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Shouval DS, Konnikova L, Griffith AE, Wall SM, Biswas A, Werner L, Nunberg M, Kammermeier J, Goettel JA, Anand R, Chen H, Weiss B, Li J, Loizides A, Yerushalmi B, Yanagi T, Beier R, Conklin LS, Ebens CL, Santos FGMS, Sherlock M, Goldsmith JD, Kotlarz D, Glover SC, Shah N, Bousvaros A, Uhlig HH, Muise AM, Klein C, Snapper SB. Enhanced TH17 Responses in Patients with IL10 Receptor Deficiency and Infantile-onset IBD. Inflamm Bowel Dis 2017; 23:1950-1961. [PMID: 29023267 DOI: 10.1097/mib.0000000000001270] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND IL10 receptor (IL10R) deficiency causes severe infantile-onset inflammatory bowel disease. Intact IL10R-dependent signals have been shown to be important for innate and adaptive immune cell functions in mice. We have previously reported a key role of IL10 in the generation and function of human anti-inflammatory macrophages. Independent of innate immune cell defects, the aim of the current study was to determine the role of IL10R signaling in regulating human CD4 T-cell function. METHODS Peripheral blood mononuclear cells and intestinal biopsies cells were collected from IL10/IL10R-deficient patients and controls. Frequencies of CD4 T-cell subsets, naive T-cell proliferation, regulatory T cell (Treg)-mediated suppression, and Treg and TH17 generation were determined by flow cytometry. Transcriptional profiling was performed by NanoString and quantitative real-time polymerase chain reaction. RNA in situ hybridization was used to determine the quantities of various transcripts in intestinal mucosa. RESULTS Analysis of 16 IL10- and IL10R-deficient patients demonstrated similar frequencies of peripheral blood and intestinal Tregs, compared with control subjects. In addition, in vitro Treg suppression of CD4 T-cell proliferation and generation of Treg were not dependent on IL10R signaling. However, IL10R-deficient T naive cells exhibited higher proliferative capacity, a strong TH17 signature, and an increase in polarization toward TH17 cells, compared with controls. Moreover, the frequency of TH17 cells was increased in the colon and ileum of IL10R-deficient patients. Finally, we show that stimulation of IL10R-deficient Tregs in the presence of IL1β leads to enhanced production of IL17A. CONCLUSIONS IL10R signaling regulates TH17 polarization and T-cell proliferation in humans but is not required for the generation and in vitro suppression of Tregs. Therapies targeting the TH17 axis might be beneficial for IL10- and IL10R-deficient patients as a bridge to allogeneic hematopoietic stem cell transplantation.
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Affiliation(s)
- Dror S Shouval
- 1Division of Pediatric Gastroenterology and Nutrition, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Ramat-Gan, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts; 4VEO-IBD Consortium; 5Department of Pediatrics and Newborn Medicine, Brigham and Women's Hospital, Boston, Massachusetts; 6Harvard Medical School, Boston, Massachusetts; 7Great Ormond Street Hospital London, London, England; 8Translational Gastroenterology Unit, University of Oxford, Oxford, England; 9Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Florida, Gainesville, Florida; 10Division of Gastroenterology and Nutrition, The Children's Hospital at Montefiore, Bronx, New York; 11Pediatric Gastroenterology Unit, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; 12Department of Pediatrics, Kurume University School of Medicine, Kurume, Japan; 13Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany; 14Department of Gastroenterology, Children's National Medical Center, Washington, DC; 15Division of Pediatric Hematology and Oncology, University of Michigan, Ann Arbor, Michigan; 16Hospital das Clınicas, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; 17Division of Gastroenterology, McMaster Children's Hospital, West Hamilton, Ontario, Canada; 18Dr von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany; 19Division of Pathology, Boston Children's Hospital, Boston, Massachusetts; 20Department of Pediatrics, University of Oxford, Oxford, England; 21Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; 22Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada; 23Department of Biochemistry, Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; and 24Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts
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Abstract
Inflammatory bowel disease (IBD), including Crohn disease and ulcerative colitis, is characterized by chronic intestinal inflammation due to a complex interaction of genetic determinants, disruption of mucosal barriers, aberrant inflammatory signals, loss of tolerance, and environmental triggers. Importantly, the incidence of pediatric IBD is rising, particularly in children younger than 10 years. In this review, we discuss the clinical presentation of these patients and highlight environmental exposures that may affect disease risk, particularly among people with a background genetic risk. With regard to both children and adults, we review advancements in understanding the intestinal epithelium, the mucosal immune system, and the resident microbiota, describing how dysfunction at any level can lead to diseases like IBD. We conclude with future directions for applying advances in IBD genetics to better understand pathogenesis and develop therapeutics targeting key pathogenic nodes.
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Affiliation(s)
- Joanna M Peloquin
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease and.,Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02114.,Harvard Medical School, Boston, Massachusetts 02115; , , ,
| | - Gautam Goel
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02114.,Harvard Medical School, Boston, Massachusetts 02115; , , ,
| | - Eduardo J Villablanca
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease and.,Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02114.,Harvard Medical School, Boston, Massachusetts 02115; , , ,
| | - Ramnik J Xavier
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease and.,Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02114.,Harvard Medical School, Boston, Massachusetts 02115; , , , .,Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142.,Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
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Zheng Y, Ge W, Ma Y, Xie G, Wang W, Han L, Bian B, Li L, Shen L. miR-155 Regulates IL-10-Producing CD24 hiCD27 + B Cells and Impairs Their Function in Patients with Crohn's Disease. Front Immunol 2017; 8:914. [PMID: 28824639 PMCID: PMC5540954 DOI: 10.3389/fimmu.2017.00914] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 07/18/2017] [Indexed: 12/20/2022] Open
Abstract
Regulatory interleukin-10 (IL-10)-producing B cells (B10 cells) play a critical role in preventing and curing autoimmune diseases in experimental mouse models. However, the precise cellular and molecular mechanisms of action of B10 cells in humans, especially in patients with Crohn's disease (CD), remain to be determined. miR-155 regulates many physiological and pathological conditions, including inflammation such as that in CD. In this study, we aimed to explore the effect of miRNA-155 on IL-10 production by B cells in healthy controls (HCs) and CD patients. Interestingly, we found that CD24hiCD27+ B cells express high levels of miRNA-155 and IL-10, which are positively correlated. Additionally, CD24hiCD27+ B cells express higher levels of Toll-like receptor 9 than those found in other B cell subsets. Overexpression of miRNA-155 promotes IL-10 production, while inhibition of miRNA-155 decreases IL-10 production. We determined that miR-155 directly inhibits the expression of Jarid2, which reduces H3K27me3 binding to the IL10 promoter and increases IL-10 gene expression. In coculture systems, the CD24hiCD27+ B cells from HCs suppressed the secretion of TNFα and IFNγ by monocytes and T cells, respectively. However, the number and function of CD24hiCD27+ B cells from CD patients were decreased. Moreover, we found that miR-155 induces CD24hiCD27+ B cells to produce higher levels of TNFα instead of IL-10 in CD patients than in the controls and that the increased number of IL-10+TNFα+ B cells reduces the induction of Foxp3 expression and the inhibition of IFNγ production by CD4+CD25- T cells, as well as TNFα production by monocytes. Our study demonstrates the critical role of miRNA-155 in the regulation of IL-10 production by B cells and reveals the novel molecular mechanism underlying the functional impairment of B10 cells in CD patients. Our study has the potential to drive the development of B10 cell-based strategies to ameliorate disease progression in CD patients.
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Affiliation(s)
- Yingxia Zheng
- Department of Laboratory Medicine, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wensong Ge
- Department of Gastroenterology, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanhui Ma
- Department of Laboratory Medicine, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guohua Xie
- Department of Laboratory Medicine, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiwei Wang
- Department of Laboratory Medicine, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Han
- Department of Laboratory Medicine, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bingxian Bian
- Department of Laboratory Medicine, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Li
- Department of Laboratory Medicine, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lisong Shen
- Department of Laboratory Medicine, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Development and Function of Immune Cells in an Adolescent Patient With a Deficiency in the Interleukin-10 Receptor. J Pediatr Gastroenterol Nutr 2017. [PMID: 28644354 DOI: 10.1097/mpg.0000000000001559] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVE Monogenic defects in the interleukin-10 (IL-10) pathway are extremely rare and cause infantile-onset inflammatory bowel disease (IBD)-like pathology. Understanding how immune responses are dysregulated in monogenic IBD-like diseases can provide valuable insight in "classical" IBD pathogenesis. Here, we studied long-term immune cell development and function in an adolescent IL-10 receptor (IL10RA)-deficient patient who presented in infancy with severe colitis and fistulizing perianal disease and is currently treated with immune suppressants. METHODS Biomaterial was collected from the IL10RA-deficient patient, pediatric patients with IBD, and healthy controls. The frequency and phenotype of immune cells were determined in peripheral blood and intestinal biopsies by flow cytometry and immunohistochemistry. Functional changes in monocyte-derived dendritic cells and T cells were assessed by in vitro activation assays. RESULTS The IL10RA-deficient immune system developed normally with respect to numbers and phenotype of circulating immune cells. Despite normal co-stimulatory molecule expression, bacterial lipopolysaccharide-stimulated monocyte-derived dendritic cells from the IL10RA-deficient patient released increased amounts of tumor necrosis factor α compared to healthy controls. Upon T-cell receptor ligation, IL10RA-deficient peripheral blood mononuclear cells released increased amounts of T-cell cytokines interferon γ and IL-17 agreeing with high numbers of T-bet and IL-17 cells in intestinal biopsies taken at disease onset. In vitro, the immunosuppressive drug thalidomide used to treat the patient's decreased peripheral blood mononuclear cell-derived tumor necrosis factor production. CONCLUSIONS With time and during immunosuppressive treatment the IL10RA-deficient immune system develops relatively normally. Upon activation, IL-10 is crucial for controlling excessive inflammatory cytokine release by dendritic cells and preventing interferon γ and IL-17-mediated T-cell responses.
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Mutations in Interleukin-10 Receptor and Clinical Phenotypes in Patients with Very Early Onset Inflammatory Bowel Disease: A Chinese VEO-IBD Collaboration Group Survey. Inflamm Bowel Dis 2017; 23:578-590. [PMID: 28267044 DOI: 10.1097/mib.0000000000001058] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Interleukin-10 (IL10) signaling plays an important role in the pathogenesis of very early onset inflammatory bowel disease (VEO-IBD) in children. However, little is known about the role of the IL10 axis in children with VEO-IBD in China. METHODS The Chinese VEO-IBD Collaboration Group was created to collect clinical and genetic data from patients deficient in IL10 and the IL10 receptor. High-throughput sequencing was performed to identify mutations in these genes. RESULTS We identified 32 compound heterozygous mutations and 9 homozygous mutations in IL10 receptor subunit alpha and 1 homozygous mutation in IL10 receptor subunit beta. Among these mutations, 10 novel mutations were identified, and 6 pathogenic mutations had been previously described. In patients with IL10 receptor subunit alpha mutations, c.301C>T (p.R101RW) and c.537 G>A (p.T179T) were the most common mutations. For 88.1% of the patients, the initial symptom was diarrhea, with a time of onset of 10.4 ± 8.0 days. Oral ulcers were the first symptom in 23.8% of the patients, with a time of onset of 9.7 ± 2.8 days. Extraintestinal manifestations included perianal abscesses (22/42), perianal fistulas (23/42), oral ulcers (20/42), and recurrent eczema (15/42). Twelve patients underwent enterostomy. These patients also had lower average Z scores in height-for-age and weight-for-age. Various treatment strategies were used, including fecal microbiota transplantation; however, only hematopoietic stem cell transplantation was efficacious. CONCLUSIONS This study identified genotypes and phenotypes of Chinese VEO-IBD infants with IL10 receptor mutations. Our study expands the current knowledge on the involvement of the IL10 axis in patients with VEO-IBD.
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