Journal ArticleDOI
Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease
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TLDR
Understanding of prototypic monogenic ‘orphan’ diseases cannot only provide treatment options for the affected patients but also inform on immunological mechanisms and complement the functional understanding of the pathogenesis of IBD.Abstract:
Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, has multifactorial aetiology with complex interactions between genetic and environmental factors. Over 150 genetic loci are associated with IBD. The genetic contribution of the majority of those loci towards explained heritability is low. Recent studies have reported an increasing spectrum of human monogenic diseases that can present with IBD-like intestinal inflammation. A substantial proportion of patients with those genetic defects present with very early onset of intestinal inflammation. The 40 monogenic defects with IBD-like pathology selected in this review can be grouped into defects in intestinal epithelial barrier and stress response, immunodeficiencies affecting granulocyte and phagocyte activity, hyper- and autoinflammatory disorders as well as defects with disturbed T and B lymphocyte selection and activation. In addition, there are defects in immune regulation affecting regulatory T cell activity and interleukin (IL)-10 signalling. Related to the variable penetrance of the IBD-like phenotype, there is a likely role for modifier genes and gene-environment interactions. Treatment options in this heterogeneous group of disorders range from anti-inflammatory and immunosuppressive therapy to blockade of tumour necrosis factor α and IL-1β, surgery, haematopoietic stem cell transplantation or gene therapy. Understanding of prototypic monogenic 'orphan' diseases cannot only provide treatment options for the affected patients but also inform on immunological mechanisms and complement the functional understanding of the pathogenesis of IBD.read more
Citations
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Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 1: Definitions, Diagnosis, Extra-intestinal Manifestations, Pregnancy, Cancer Surveillance, Surgery, and Ileo-anal Pouch Disorders.
Fernando Magro,Paolo Gionchetti,Rami Eliakim,Sandro Ardizzone,Alessandro Armuzzi,Manuel Barreiro-de Acosta,Johan Burisch,Krisztina Gecse,Ailsa Hart,Pieter Hindryckx,Cord Langner,Jimmy K. Limdi,Gianluca Pellino,Edyta Zagórowicz,Tim Raine,Marcus Harbord,Florian Rieder +16 more
TL;DR: This research presents a meta-analyses of Gastroenterology and Hepatology at the cellular and molecular level, which shows clear trends in the development of immune-oncology-metabolical pathways towards “clinically checkpoints”.
Journal ArticleDOI
The diagnostic approach to monogenic very early onset inflammatory bowel disease.
Holm H. Uhlig,Tobias Schwerd,Sibylle Koletzko,Neil Shah,Neil Shah,Jochen Kammermeier,Abdul Elkadri,Jodie Ouahed,Jodie Ouahed,David C. Wilson,David C. Wilson,Simon Travis,Dan Turner,Christoph Klein,Scott B. Snapper,Scott B. Snapper,Aleixo M. Muise +16 more
TL;DR: Key intestinal, extraintestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation are described and approaches for identifying patients likely to have these disorders are provided.
Journal ArticleDOI
Mechanisms of Disease: Inflammatory Bowel Diseases
TL;DR: IBD pathogenesis is a result of the interplay of genetic susceptibility and environmental impact on the microbiome that through a weakened intestinal barrier will lead to inappropriate intestinal immune activation, and mechanisms proposed to cause IBD are reviewed from the genetic, environmental, intestinal barrier, and immunologic perspectives.
Journal ArticleDOI
Inflammatory Bowel Disease: Genetics, Epigenetics, and Pathogenesis
Italia Loddo,Claudio Romano +1 more
TL;DR: The evidence that genetic factors contribute in small part to disease pathogenesis confirms the important role of microbial and environmental factors in the pathogenesis of IBD.
Journal ArticleDOI
Genetics of Inflammatory Bowel Diseases
TL;DR: The rapidly evolving area of direct-to-consumer genetic testing and the current utility of clinical exome sequencing is discussed, especially in very early onset, severe IBD cases.
References
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Journal ArticleDOI
Interleukin-10-deficient mice develop chronic enterocolitis
TL;DR: The results indicate that the bowel inflammation in the mutants originates from uncontrolled immune responses stimulated by enteric antigens and that IL-10 is an essential immunoregulator in the intestinal tract.
Journal ArticleDOI
Increasing Incidence and Prevalence of the Inflammatory Bowel Diseases With Time, Based on Systematic Review
Natalie A. Molodecky,Ing Shian Soon,Doreen M. Rabi,William A. Ghali,Mollie Ferris,Greg W. Chernoff,Eric I Benchimol,Eric I Benchimol,Remo Panaccione,Subrata Ghosh,Herman W. Barkema,Gilaad G. Kaplan +11 more
TL;DR: Although there are few epidemiologic data from developing countries, the incidence and prevalence of IBD are increasing with time and in different regions around the world, indicating its emergence as a global disease.
Journal ArticleDOI
Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease
Luke Jostins,Stephan Ripke,Rinse K. Weersma,Richard H. Duerr,Dermot P.B. McGovern,Ken Y. Hui,James Lee,L. Philip Schumm,Yashoda Sharma,Carl A. Anderson,Jonah Essers,Mitja Mitrovic,Kaida Ning,Isabelle Cleynen,Emilie Theatre,Sarah L. Spain,Soumya Raychaudhuri,Philippe Goyette,Zhi Wei,Clara Abraham,Jean-Paul Achkar,Tariq Ahmad,Leila Amininejad,Ashwin N. Ananthakrishnan,Vibeke Andersen,Jane M. Andrews,Leonard Baidoo,Tobias Balschun,Peter A. Bampton,Alain Bitton,Gabrielle Boucher,Stephan Brand,Carsten Büning,Ariella Cohain,Sven Cichon,Mauro D'Amato,Dirk De Jong,Kathy L Devaney,Marla Dubinsky,Cathryn Edwards,David Ellinghaus,Lynnette R. Ferguson,Denis Franchimont,Karin Fransen,Richard B. Gearry,Michel Georges,Christian Gieger,Jürgen Glas,Talin Haritunians,Ailsa Hart,Christopher J. Hawkey,Matija Hedl,Xinli Hu,Tom H. Karlsen,Limas Kupčinskas,Subra Kugathasan,Anna Latiano,Debby Laukens,Ian C. Lawrance,Charlie W. Lees,Edouard Louis,Gillian Mahy,John C. Mansfield,Angharad R. Morgan,Craig Mowat,William G. Newman,Orazio Palmieri,Cyriel Y. Ponsioen,Uroš Potočnik,Natalie J. Prescott,Miguel Regueiro,Jerome I. Rotter,Richard K Russell,Jeremy D. Sanderson,Miquel Sans,Jack Satsangi,Stefan Schreiber,Lisa A. Simms,Jurgita Sventoraityte,Stephan R. Targan,Kent D. Taylor,Mark Tremelling,Hein W. Verspaget,Martine De Vos,Cisca Wijmenga,David C. Wilson,Juliane Winkelmann,Ramnik J. Xavier,Sebastian Zeissig,Bin Zhang,Clarence K. Zhang,Hongyu Zhao,Mark S. Silverberg,Vito Annese,Hakon Hakonarson,Steven R. Brant,Graham L. Radford-Smith,Christopher G. Mathew,John D. Rioux,Eric E. Schadt,Mark J. Daly,Andre Franke,Miles Parkes,Severine Vermeire,Jeffrey C. Barrett,Judy H. Cho +105 more
TL;DR: A meta-analysis of Crohn’s disease and ulcerative colitis genome-wide association scans is undertaken, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls.
Journal ArticleDOI
The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3.
Craig L. Bennett,Jacinda R. Christie,Fred Ramsdell,Mary E. Brunkow,Polly J. Ferguson,Luke Whitesell,Thaddeus E. Kelly,Frank T. Saulsbury,Phillip F. Chance,Hans D. Ochs +9 more
TL;DR: Genetic evidence is presented that different mutations of the human gene FOXP3, the ortholog of the gene mutated in scurfy mice (Foxp3), causes IPEX syndrome.
Journal ArticleDOI
Genetics and pathogenesis of inflammatory bowel disease
TL;DR: Recent advances have provided substantial insight into the maintenance of mucosal immunity and the pathogenesis of inflammatory bowel disease, and the role of genetic predispositions and how they affect interactions with microbial and environmental factors is emphasized.
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