Bénédicte Pigneur1, Johanna Escher, Mamoun Elawad, Rosa Lima, Stephan Buderus, Jaroslaw Kierkus, Graziella Guariso, Danielle Canioni, Karen Lambot, Cécile Talbotec, Neil Shah, Bernadette Begue, Frédéric Rieux-Laucat, Olivier Goulet, Nadine Cerf-Bensussan, Bénédicte Neven, Frank M Ruemmele. 1. *Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France; †Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Service de Gastroentérologie pédiatrique, Paris, France; ‡Department of Pediatric Gastroenterology, ErasmusMC-Sophia Children's Hospital, Rotterdam, the Netherlands; §Department of Gastroenterology, Great Ormond Street Hospital for Sick Children and Institute of Child Health, London, United Kingdom; ‖Pediatric Gastroenterology Unit, Centro Hospitalar do Porto, Porto, Portugal; ¶Marienhospital, Bonn, Germany; **Department of Gastroenterology, Hepatology and Feeding Disorders, The Children's Memorial Health Institute, Warsaw, Poland; ††Gastroenterologia, Endoscopia Digestiva, Epatologia e Cura del Bambino con Trapianto di Fegato, Dipartimento Salute della Donna e del Bambino, Padova, Italy; ‡‡Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Service d'anatomopathologie, Paris, France; §§Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Service de radiologie, Paris, France; ‖‖INSERM U989, Paris, France; and ¶¶INSERM U768, Paris, France.
Abstract
OBJECTIVE: Early-onset inflammatory bowel disease starting within the first months of life could be due to a particular genetic defect. We set up the GENetically determined ImmUne-mediated enteropathieS (GENIUS) network and collected infants with a proven defect of the IL10 axis for accurate phenotyping of disease presentation and evolution. DESIGN: Ten patients with early-onset inflammatory bowel disease with confirmed mutations in IL10, IL10RA, or IL10RB genes were characterized on clinical, endoscopic-histological, immunobiological, and radiological findings. Functional assays to confirm defective responses to IL10 were performed on peripheral blood mononuclear cells. RESULTS: A functional defect in IL10 signaling was confirmed in all IL10R patients tested. Disease started with severe diarrhea within the first 12 weeks in all patients. All infants showed Crohn's disease-like ulcerations limited to the colon with marked perianal inflammation (fissures, abscess, and fistula); disease progression to the small bowel occurred in only 1 patient. Four of the 10 patients had granulomata on histology, and all patients showed Crohn's disease-like mesenteric infiltration on imaging. Disease pattern was indistinguishable between IL10R alpha or beta chain or IL10 defects; autoimmunity was not observed. Mutations in IL10 were more frequently associated with bacterial and viral infections. Patients responded partially to treatment with steroids or anti-tumor necrosis factor drugs, whereas hematopoietic stem cell transplantation proved efficacious. CONCLUSION: The importance of the IL10 pathway within the colonic mucosa is highlighted by the development of severe colitis within a few weeks in infants with mutations in IL10, IL10RA, or IL10RB. Immunosuppression failed to correct the defect in this pathway, which seems to be a key to controlling inflammation in the colon.
OBJECTIVE: Early-onset inflammatory bowel disease starting within the first months of life could be due to a particular genetic defect. We set up the GENetically determined ImmUne-mediated enteropathieS (GENIUS) network and collected infants with a proven defect of the IL10 axis for accurate phenotyping of disease presentation and evolution. DESIGN: Ten patients with early-onset inflammatory bowel disease with confirmed mutations in IL10, IL10RA, or IL10RB genes were characterized on clinical, endoscopic-histological, immunobiological, and radiological findings. Functional assays to confirm defective responses to IL10 were performed on peripheral blood mononuclear cells. RESULTS: A functional defect in IL10 signaling was confirmed in all IL10Rpatients tested. Disease started with severe diarrhea within the first 12 weeks in all patients. All infants showed Crohn's disease-like ulcerations limited to the colon with marked perianal inflammation (fissures, abscess, and fistula); disease progression to the small bowel occurred in only 1 patient. Four of the 10 patients had granulomata on histology, and all patients showed Crohn's disease-like mesenteric infiltration on imaging. Disease pattern was indistinguishable between IL10R alpha or beta chain or IL10 defects; autoimmunity was not observed. Mutations in IL10 were more frequently associated with bacterial and viral infections. Patients responded partially to treatment with steroids or anti-tumor necrosis factor drugs, whereas hematopoietic stem cell transplantation proved efficacious. CONCLUSION: The importance of the IL10 pathway within the colonic mucosa is highlighted by the development of severe colitis within a few weeks in infants with mutations in IL10, IL10RA, or IL10RB. Immunosuppression failed to correct the defect in this pathway, which seems to be a key to controlling inflammation in the colon.
Authors: Kaida Ning; Kyle Gettler; Wei Zhang; Sok Meng Ng; B Monica Bowen; Jeffrey Hyams; Michael C Stephens; Subra Kugathasan; Lee A Denson; Eric E Schadt; Gabriel E Hoffman; Judy H Cho Journal: Hum Mol Genet Date: 2015-05-01 Impact factor: 6.150
Authors: Ravy K Vajravelu; Lawrence Copelovitch; Mark T Osterman; Frank I Scott; Ronac Mamtani; James D Lewis; Michelle R Denburg Journal: Clin Gastroenterol Hepatol Date: 2019-11-01 Impact factor: 11.382
Authors: Dror S Shouval; Christen L Ebens; Ryan Murchie; Katelyn McCann; Raja Rabah; Christoph Klein; Aleixo M Muise; Scott B Snapper Journal: J Pediatr Gastroenterol Nutr Date: 2016-07 Impact factor: 2.839