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51. Intestinal expression of the anti-inflammatory interleukin-1 homologue IL-37 in pediatric inflammatory bowel disease

Author

Ana Maria Bulau, Roland Kappler, Philip Bufler, Johanna Althans, Doris Mayr, Simon Weidlich, Tobias Schwerd, and Sibylle Koletzko

Subjects
Male, Pathology, medicine.medical_specialty, Adolescent, Colon, Inflammation, Inflammatory bowel disease, Crohn Disease, Medicine, Humans, RNA, Messenger, Colitis, Intestinal Mucosa, Child, Messenger RNA, business.industry, Interleukin-17, Gastroenterology, Interleukin-18, Interleukin, medicine.disease, Ulcerative colitis, Up-Regulation, Pediatrics, Perinatology and Child Health, Immunohistochemistry, Colitis, Ulcerative, Female, medicine.symptom, Inflammation Mediators, business, Immunostaining, Interleukin-1
Abstract

Objectives The function of interleukin (IL)-37 has not been resolved. We recently showed that IL-37 suppresses colonic inflammation in mice. To gain more insight into its relevance in human disease, we investigated the expression of IL-37 in the intestine of pediatric patients with chronic inflammatory bowel disease (IBD). Methods Intestinal biopsies were obtained from children with IBD (18 Crohn disease [CD], 14 ulcerative colitis [UC] and 11 controls) during endoscopy and analyzed for IL-37 expression by immunohistochemistry and real-time polymerase chain reaction. Results were correlated with immunostaining for IL-18 and IL-17, messenger RNA (mRNA) levels of pro- and anti-inflammatory cytokines, and clinical parameters. Results IL-37 protein was detected in epithelial cells and submucosal lymphoid cells of patients with CD and UC as well as healthy controls. IL-37 protein expression tended to be higher with submucosal lymphoid cell infiltration of patients with CD and UC and correlated with histological severity score of inflammation. IL-18 showed a staining pattern similar to that of IL-37, whereas staining for IL-17 revealed distinct positive cells scattered in the submucosal layer. mRNA expression of IL-8, IL-17, and IL-10 was upregulated in patients with CD and UC. mRNA levels of IL-18 and IL-37 were not significantly elevated compared with controls. Levels of IL-37 and IL-18 mRNA showed a positive correlation in the CD group. Conclusions IL-37 protein is expressed in healthy and diseased bowel tissue. IL-37 and IL-18 show a similar expression pattern and correlate at mRNA levels. Future studies are warranted to delineate the specific contribution of IL-37 to modulate chronic bowel inflammation in humans.

Published
2014

52. The diagnostic approach to monogenic very early onset inflammatory bowel disease

Author

Holm H. Uhlig, Jochen Kammermeier, Neil Shah, Dan Turner, Scott B. Snapper, Abdul Elkadri, Christoph Klein, David C. Wilson, Sibylle Koletzko, Aleixo M. Muise, Tobias Schwerd, Simon Travis, and Jodie Ouahed

Subjects
Next-Generation Sequencing, Candidate gene, Genetic counseling, Disease, Pediatrics, Inflammatory bowel disease, Article, Indeterminate Colitis, IBD Unclassified, Whole Exome Sequencing, Crohn Disease, Predictive Value of Tests, Risk Factors, Genetics, Humans, Ulcerative Colitis, Immunodeficiency, Medicine, Genetic Predisposition to Disease, Genetic Testing, Age of Onset, Genetic testing, Crohn's disease, Hepatology, medicine.diagnostic_test, business.industry, Inflammatory Bowel Disease, Gastroenterology, Prognosis, medicine.disease, Penetrance, 3. Good health, Phenotype, Immunology, Primary immunodeficiency, Colitis, Ulcerative, Unclassified Colitis, business, Crohn’s Disease
Abstract

Patients with a diverse spectrum of rare genetic disorders can present with inflammatory bowel disease (monogenic IBD). Patients with these disorders often develop symptoms during infancy or early childhood, along with endoscopic or histological features of Crohn's disease, ulcerative colitis, or IBD unclassified. Defects in interleukin-10 signaling have a Mendelian inheritance pattern with complete penetrance of intestinal inflammation. Several genetic defects that disturb intestinal epithelial barrier function or affect innate and adaptive immune function have incomplete penetrance of the IBD-like phenotype. Several of these monogenic conditions do not respond to conventional therapy and are associated with high morbidity and mortality. Due to the broad spectrum of these extremely rare diseases, a correct diagnosis is frequently a challenge and often delayed. In many cases, these diseases cannot be categorized based on standard histological and immunologic features of IBD. Genetic analysis is required to identify the cause of the disorder and offer the patient appropriate treatment options, which include medical therapy, surgery, or allogeneic hematopoietic stem cell transplantation. In addition, diagnosis based on genetic analysis can lead to genetic counseling for family members of patients. We describe key intestinal, extraintestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation. In addition, we provide approaches for identifying patients likely to have these disorders. We also discuss classic approaches to identify these variants in patients, starting with phenotypic and functional assessments that lead to analysis of candidate genes. As a complementary approach, we discuss parallel genetic screening using next-generation sequencing followed by functional confirmation of genetic defects.

Published
2014

53. Repeated exclusive enteral nutrition in the treatment of paediatric Crohn's disease: predictors of efficacy and outcome

Author

A. Schwarzer, Stephanie B. Schatz, Philip Bufler, Tobias Schwerd, Klara Frivolt, Sibylle Koletzko, and Katharina J. Werkstetter

Subjects
Male, medicine.medical_specialty, Adolescent, Genotype, Nod2 Signaling Adaptor Protein, Azathioprine, Disease, Enteral Nutrition, Crohn Disease, Recurrence, NOD2, Internal medicine, medicine, Humans, Pharmacology (medical), Child, Retrospective Studies, Crohn's disease, Hepatology, business.industry, Remission Induction, Gastroenterology, Retrospective cohort study, Mean age, Anthropometry, medicine.disease, Surgery, Parenteral nutrition, Treatment Outcome, Female, business, Immunosuppressive Agents, medicine.drug
Abstract

Exclusive enteral nutrition (EEN) induces remission and mucosal healing in children with active Crohn's disease (CD).To compare short- and long-term outcomes of the first vs. second courses of EEN, and to identify predictors of sustained remission.Retrospective single centre analysis of all patients with CD (6-18 years) treated with EEN over 7.5 years. Patients were excluded if exposed to anti-TNFα or corticosteroids 3 months prior to EEN. Data included disease phenotype, activity, NOD2 genotype, laboratory indices and anthropometrics. Remission and relapse were defined by mathematically weighted Paediatric Crohn's Disease Activity Index (wPCDAI) with 1-year follow-up.Of 94 patients treated with EEN, 52 fulfilled inclusion criteria (31 male, mean age 13.2 years). Azathioprine was started within the first month in 33/52 patients; 26/52 received a second EEN course. First compared to second EEN revealed higher wPCDAI at start (59 vs. 40, P0.0001), tended to higher remission rates after 3 months (92% vs. 77%, n.s.), but showed comparable 1-year relapse rates (67% vs. 70%, median time 231 vs. 145 days, n.s.). Disease activity, weight gain and inflammatory markers showed better improvement with first EEN. Faecal calprotectin200 μg/g during EEN was associated with shorter remission (median time 157 vs. 287 days, n.s.). Certain NOD2 genotypes were related to higher relapse rates (92% R702W or G908R vs. 50% 1007fs vs. 60% wild-type, P0.01).Exclusive enteral nutrition induces remission in active Crohn's disease, but efficacy tends to decrease with the second course. Despite early azathioprine use, 1-year relapse rates are high, but may be related to NOD2 genotype.

Published
2013

54. Immunostimulatory RNA blocks suppression by regulatory T cells

Author

Raffael Thaler, Gunther Hartmann, Veit Hornung, Carole Bourquin, Tim Sparwasser, Stefan Moder, David Anz, Hendrik Poeck, Stefan Endres, Tobias Schwerd, Viktor H. Koelzer, Robert Besch, Katharina Lahl, and Simon Rothenfusser

Subjects
Interferon-Induced Helicase, IFIH1, viruses, Immunology, Oligonucleotides, Antigen-Presenting Cells, chemical and pharmacologic phenomena, T-Lymphocytes, Regulatory, Virus, DEAD-box RNA Helicases, Mice, Immune system, Immunology and Allergy, Animals, RNA Viruses, Antigen-presenting cell, DEAD Box Protein 58, Mice, Inbred BALB C, Membrane Glycoproteins, biology, Base Sequence, Effector, Interleukin-6, RNA, TLR7, biology.organism_classification, Sendai virus, Cell biology, Mice, Inbred C57BL, Toll-Like Receptor 7, RNA, Viral
Abstract

The role of immune suppression by regulatory T (Treg) cells in the maintenance of immune homeostasis is well established. However, little is known about how Treg cell function is inhibited on viral infection to allow the development of a protective immune response. As viral RNA is a crucial mediator for activation of antiviral immunity, we examined the effects of immunostimulatory RNA and infection with RNA viruses on Treg cell function. We show that synthetic RNA oligonucleotides potently inhibit Treg cell-induced suppression in a sequence-dependent manner. This effect is entirely dependent on TLR7 activation of APCs and subsequent IL-6 production. In addition, stimulation with the RNA viruses encephalomyocarditis virus and Sendai virus that specifically activate the RNA-sensing helicases melanoma differentiation-associated gene 5 (MDA-5) and retinoic acid-inducible gene I (RIG-I) also blocks Treg cell function. Interestingly, this effect is seen even in the absence of APCs. Consistent with this, both Treg and T effector cells express RIG-I and MDA-5. Using MDA-5–deficient mice, we demonstrate that the loss of Treg cell function on infection with encephalomyocarditis virus is strictly dependent on MDA-5 expression by Treg cells. Thus, we show in this study for the first time that activation of a RIG-I–like helicase on Treg cells blocks their suppressive function.

Published
2009

55. Isolated Crohn's Colitis: Is Localization Crucial? Characteristics of Pediatric Patients From the CEDATA–GPGE Registry

Author

Lotta Elonen, Lena Wölfle, Jan de Laffolie, Carsten Posovszky, the CEDATA–GPGE-Study-Group, Tobias Schwerdt, Rainer Ganschow, Stefan Trenkel, Burkhard Rodeck, Stefan Wirth, Marlen Zurek, Matthias Heiduk, Michael Paulussen, Gunter Flemming, Ekkehard Sturm, Axel Enninger, Söhnke Dammann, Henning Böhme, Michael Melter, Thomas Lang, Philip Bufler, Thomas Lücke, Markus Knuf, Norbert Wagner, Thomas Kaiser, Ralf Pallacks, Andre Hörning, Jens Klinge, Steffen Reinsch, Rüdiger Adam, Stefan Buderus, Markus Richter, Antje Ballauf, Ilse Broekaert, Lars Heerdts, Carolin Blüml, Sabine Peitzsch, Andreas Krahl, Simone Jedwilayties, Maik Heine, Marko Reitmann, Kai Nils Pargac, Jutta Kringel, Anke Dick, Patrick Gerner, Michael Friedt, Enno Iven, Gunter Burmester, Anke Esser, Olaf Raecke, Kerstin Ehrentraut, Esther Schmidt, Jan Däbritz, Stefan Sgoll, Ahlke Willenborg, Sebastian Horn, Ralph Melchior, Rüdiger Kardoff, Martina Kohl-Sobania, Benedikt Pircher, Christoph Ehrsam, Daniela Nolkemper, Adrian Lieb, Almuth Hauer, Markus Prenninger, Martin Laaß, and Dieter Furthner

Subjects
IBD, pediatric, Crohn's disease, ulcerative colitis, Crohn's colitis, isolated colonic Crohn's, Pediatrics, RJ1-570
Abstract

IntroductionPediatric patients with inflammatory bowel disease (IBD) are classified into Crohn's disease (CD), ulcerative colitis (UC), and unclassifiable (IBD-U). However, data provide evidence that ileal CD (L1) is distinct from colonic CD (L2). The aim of this study was to investigate the clinical features of isolated Crohn's colitis in a pediatric population.Material and MethodsChildren who were prospectively included in the CEDATA–GPGE registry on diagnosis were compared according to the diagnosis of CD with L2 vs. L1 and ileocolonic (L3) involvement pattern as well as IBD-U and UC. The clinical significance of L2 was investigated with regard to extraintestinal manifestations, treatment, surgery, and disease activity.ResultsFifty-two patients with L2 CD at a median age of 13.4 years (±3.8 SD) were compared with 182 L1 (13.8 ± 2.9 SD), 782 with L3 (12.8 ± 3.3 SD), 653 with UC (12.7 ± 3.8 SD), and 111 patients with IBD-U (11.9 ± 4.7 SD). Bloody stools at diagnosis were more common in L2 (44%) than in L1 (19.7%) and L3 (28.8%), but not as common as in UC (66.5%) and IBD-U (61.3%). Fewer CD patients with L2 (10.2%) received exclusive enteral nutrition therapy (EEN) as induction than patients with L1 (34.3%) and L3 (33.3%). After induction therapy, 42.3% of patients with L2 received immunosuppressants and 21% biologicals during follow-up (L1 56.5/10.5%; L3 59/21%; CU 43.5/11.9%; IBD-U 26.1/12.6%). Extraintestinal manifestations were more frequent in L2 (23.1%) vs. L1 (18.7%), L3 (20.2%), CU (15.8%), and IBD-U (11.7%). The number of patients requiring surgery did not differ within the CD subgroups and was significantly lower in UC and IBD-U. Perianal fistula surgery was significantly more common in L2 (44%) than in L1 (4.8%) or L3 (21.7%). In addition, the frequency of surgery for perianal abscesses was also more frequent in L2 (55.6%) than in L1 (12.7%) or L3 (38.4%).ConclusionsThe consideration of pediatric Crohn's colitis as a distinct disease seems necessary as it is characterized by extraintestinal manifestations (EIMs) with mainly joint involvement and perianal fistulas or abscesses requiring surgery and biologic therapy. Thus, colonic Crohn's disease may have an influence on the therapeutic stratification and should be addressed in further studies.

Published
2022
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56. P-052: Accumulation of intra-abdominal adipose tissue in pediatric Crohn’s disease

Author

Philip Bufler, M.S. Hajji, Eva Coppenrath, Sibylle Koletzko, Klara Frivolt, Tobias Schwerd, and H. Hetterich

Subjects
medicine.medical_specialty, Intra-Abdominal Fat, Pediatric Crohn's disease, business.industry, Internal medicine, Gastroenterology, Medicine, Adipose tissue, General Medicine, business, Biomedical sciences
Abstract

P-051 Changes in selective lipids during treatment-induced remission of active pediatric IBD V. Brahmbhatt1 *, F.P. Martin2, N. Bosco1, I. Montoliu1, M. Oliveira1, P. Guy1, S. Schatz3, K. Werkstetter3, E. Schiffrin1, B. Koletzko3, J. Benyacoub1, S. Koletzko3. 1Nestle Research Center, Lausanne, Switzerland, 2Nestle Institute of Health Sciences, Lausanne, Switzerland, 3Dr. von Hauner Children’s Hospital, Munich, Germany

Published
2014

57. P002 The antiinflammatory function and ATP dependent externalization of Interleukin-37 is dependent on caspase-1 processing

Author

V. Klingl, Michaela Fink, Philip Bufler, Ana-Maria Bulau, Soohyun Kim, and Tobias Schwerd

Subjects
Innate immune system, medicine.medical_treatment, Immunology, Mutant, Caspase 1, Interleukin, Inflammasome, Hematology, Transfection, Biology, Biochemistry, Molecular biology, Cytokine, medicine, Extracellular, Immunology and Allergy, Molecular Biology, medicine.drug
Abstract

Introduction Interleukin (IL-) 37, the newly described member of the IL-1 family, is a fundamental inhibitor of innate immunity. IL-37, like IL-1 β , IL-18 and IL-33, is processed by caspase-1 to generate the mature cytokine. We have reported that only the postcleavage mature form of the IL-37 precursor but not the N-terminal propiece specifically translocates to the nucleus upon LPS stimulation to downregulate innate immune responses. Intracellularly, IL-37 associates with Smad3, which is an important TGF- β signalling molecule. It is not yet known whether processing of IL-37 is mandatory for its immunomodulatory activity and its release into the extracellular space. Methods A caspase-1 cleavage site encoded by exon 1 of the IL-37 gene has been predicted between residues D20 and E21. We generated a mutant form of IL-37 by site directed mutagenesis and isolated single clones of transfected RAW 264.7 cells expressing IL-37D20A. Results Processing of mutant IL-37D20A is significantly reduced compared to wildtype (wt) IL-37 in transfected RAW264.7 cells. However, processing of IL-37D20A is not fully abrogated indicating that additional proteases are involved. Next, we challenged RAW 264.7 macrophages expressing IL-37D20A or wtIL-37 with LPS. Levels of secreted IL-6 were substantially increased (250%) in IL-37D20A compared to wtIL-37 expressing cells which were comparable to the Mock-transfected cells. These results indicate that caspase-1 processing of IL-37 is important for its antiinflammatory function. Finally, we investigated whether IL-37 is secreted from cells. We challenged IL-37 transfected RAW264.7 cells with LPS and subsequently added ATP to activate the NLRP3 inflammasome and caspase-1. Our results show that precursor IL-37 is constitutively released from stimulated cells but mature IL-37 is only secreted upon the addition of ATP. Pretreatment of the cells with a pancaspase inhibitor significantly reduced the amount of secreted mature IL-37 after ATP treatment. Interestingly, mature IL-37 is not detected in the lysate of transfected RAW264.7 cells indicating a complete ATP-induced release of mature IL-37 from cytoplasm into the extracellular space. Conclusion In summary, our present data indicate that the processing of IL-37 by caspase-1 is a prerequisite for its antiinflammatory function and that IL-37 is actively secreted into the extracellular space.

Published
2012

58. Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

Author

Serra, Eva Gonçalves, Schwerd, Tobias, Moutsianas, Loukas, Cavounidis, Athena, Fachal, Laura, Pandey, Sumeet, Kammermeier, Jochen, Croft, Nicholas M, Posovszky, Carsten, Rodrigues, Astor, Russell, Richard K, Barakat, Farah, Auth, Marcus K H, Heuschkel, Robert, Zilbauer, Matthias, Fyderek, Krzysztof, Braegger, Christian, Travis, Simon P, Satsangi, Jack, Parkes, Miles, Thapar, Nikhil, Ferry, Helen, Matte, Julie C, Gilmour, Kimberly C, Wedrychowicz, Andrzej, Sullivan, Peter, Moore, Carmel, Sambrook, Jennifer, Ouwehand, Willem, Roberts, David, Danesh, John, Baeumler, Toni A, Fulga, Tudor A, Karaminejadranjbar, Mohammad, Ahmed, Ahmed, Wilson, Rachel, Barrett, Jeffrey C, Elkadri, Abdul, Griffiths, Anne M, Snapper, Scott B, Shah, Neil, Muise, Aleixo M, Wilson, David C, Uhlig, Holm H, Anderson, Carl A, Marlen, Zurek, Caterina, Strisciuglio, Mamoun, Elawad, Bernice, Lo, Carolina, Arancibia-Carcamo, Adam, Bailey, Ellie, Barnes, Elizabeth Louise, Bird-Lieberman, Oliver, Brain, Barbara, Braden, Jane, Collier, James, East, Lucy, Howarth, Satish, Keshav, Paul, Klenerman, Simon, Leedham, Rebecca, Palmer, Fiona, Powrie, Alison, Simmons, Matthew, Walker, Zoe, Tolkien, Stephen, Kaptoge, David, Allen, Susan, Mehenny, Jonathan, Mant, Emanuele, Di Angelantonio, Simon G, Thompson, Bahtiyar, Yilmaz, Pascal, Juillerat, Markus, Geuking, Reiner, Wiest, Andrew J, Macpherson, Francisco Damian, Bravo, Lukas, Brügger, Ove, Carstens, Ulrike Graf, Bigler, Benjamin, Heimgartner, Monica, Rusticeanu, Sybille, Schmid-Uebelhart, Bruno, Strebel, Aurora, Tatu, Radu, Tutuian, Ove, Øyås, Charlotte, Ramon, Jörg, Stelling, Yannick, Franc, Nicolas, Fournier, Valerie E H, Pittet, Bernard, Burnand, Mara, Egger, Delphine, Golay, Astrid, Marot, Leilla, Musso, Valérie, Pittet, Jean-Benoît, Rossel, Vivianne, Seematter, Joachim, Sommer, Rachel, Vulliamy, Pierre, Michetti, Michel H, Maillard, Céline, Keller, Andreas, Nydegger, Alain, Schoepfe, Eva, Archanioti, Jessica, Ezri, Montserrat, Fraga, Alain, Schoepfer, Christoph, Müller, Gerhard, Rogler, Luc, Biedermann, Mirjam, Blattmann, Sabine, Burk, Barbara, Dora, Michael, Fried, Benjamin, Misselwitz, Beat, Müllhaupt, Nicole, Obialo, Daniel, Pohl, Nadia, Raschle, Michael, Scharl, Stephan, Vavricka, Roland, Von Känel, Jonas, Zeitz, Karim, Abdelrahman, Gentiana, Ademi, Jan, Borovicka, Stephan, Brand, Remus, Frei, Johannes, Haarer, Christina, Knellwolf-Grieger, Claudia, Krieger-Grübel, Patrizia, Künzler, Christa, Meyenberger, Pamela, Meyer, Nina, Röhrich, Mikael, Sawatzki, Martin, Schelling, Gian-Marco, Semadeni, Michael, Sulz, Dorothee, Zimmermann, Patrick, Aepli, Dominique H, Criblez, Cyrill, Hess, Jean-Pierre, Richterich, Johannes, Spalinger, Dominic, Staudenmann, Andreas, Stulz, Stefanie, Wöhrle, Amman, Thomas, Claudia, Anderegg, Henrik, Köhler, Rachel, Kusche, Anca-Teodora, Antonino, Eviano, Arrigoni, José M, Bengoa, Sophie, Cunningham, Philippe, de Saussure, Laurent, Girard, Diana Bakker, de Jong, Polat, Bastürk, Simon, Brunner, Lukas, Degen, Petr, Hruz, Carolina, Khalid-de Bakker, Jan, Niess, Bruno, Balsiger, Janine, Haldemann, Gaby, Saner, Frank, Seibold, Peter, Bauerfeind, Andrea, Becocci, Dominique, Belli, Janek, Binek, Peter, Hengstler, Stephan, Boehm, Tujana, Boldanov, Patrick, Bühr, Rebekka, Koller, Vanessa, Rueger, Arne, Senning, Emanuel, Burri, Sophie, Buyse, Dahlia-Thao, Cao, Fabrizia, D'Angelo, Joakim, Delarive, Christopher, Doerig, Roxane, Hessler, Claudia, Preissler, Ronald, Rentsch, Branislav, Risti, Marc Alain, Ritz, Michael, Steuerwald, Jürg, Vögtlin, Markus, Sagmeister, Bernhard, Sauter, Susanne, Schibli, Christiane, Sokollik, Hugo, Schlauri, Jean-François, Schnegg, Mariam, Seirafi, Holger, Spangenberger, Philippe, Stadler, Peter, Staub, Volker, Stenz, Michela, Tempia-Caliera, Joël, Thorens, Kaspar, Truninger, Patrick, Urfer, Francesco, Viani, Dominique, Vouillamoz, Silvan, Zander, Tina, Wyli, L, Jostins, N A, Kennedy, T, Ahmad, C A, Lamb, C, Edwards, A, Hart, C, Hawkey, J C, Mansfield, C, Mowat, W G, Newman, A, Simmons, M, Tremelling, J C, Lee, N J, Prescott, C G, Mathew, C W, Lees, D P B, McGovern, S R, Targan, G, Botwin, E, Mengesha, P, Fleshner, C, Landers, D, Li, J D, Rioux, A, Bitton, J, Côté-Daigneault, M J, Daly, R, Xavier, K, Morris, G, Boucher, J H, Cho, C, Abraham, M, Merad, B, Sands, I, Peter, K, Hao, Y, Itan, R H, Duerr, L, Konnikova, M B, Schwartz, S, Proksell, E, Johnston, V, Miladinova, W, Chen, S R, Brant, L, Datta, M S, Silverberg, L P, Schumm, S, Birch, M, Giri, K, Gettler, Y, Sharma, C, Stevens, M, Lazarev, T, Haritunians, Fachal, Laura [0000-0002-7256-9752], Croft, Nicholas M [0000-0002-1519-6435], Posovszky, Carsten [0000-0002-9487-8812], Russell, Richard K [0000-0001-7398-4926], Zilbauer, Matthias [0000-0002-7272-0547], Travis, Simon P [0000-0002-2690-4361], Matte, Julie C [0000-0001-5642-648X], Wedrychowicz, Andrzej [0000-0003-1448-167X], Fulga, Tudor A [0000-0002-1056-0082], Karaminejadranjbar, Mohammad [0000-0002-7770-2065], Ahmed, Ahmed [0000-0001-6509-2581], Muise, Aleixo M [0000-0001-9624-3346], Wilson, David C [0000-0003-0879-1129], Apollo - University of Cambridge Repository, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de gastro-entérologie, Croft, Nicholas M. [0000-0002-1519-6435], Russell, Richard K. [0000-0001-7398-4926], Travis, Simon P. [0000-0002-2690-4361], Matte, Julie C. [0000-0001-5642-648X], Fulga, Tudor A. [0000-0002-1056-0082], Muise, Aleixo M. [0000-0001-9624-3346], Wilson, David C. [0000-0003-0879-1129], Eva Gonçalves, Serra, Tobias, Schwerd, Loukas, Moutsiana, Athena, Cavounidi, Laura, Fachal, Sumeet, Pandey, Jochen, Kammermeier, Nicholas M, Croft, Carsten, Posovszky, Astor, Rodrigue, Richard K, Russell, Farah, Barakat, Marcus K H, Auth, Robert, Heuschkel, Matthias, Zilbauer, Krzysztof, Fyderek, Christian, Braegger, Simon P, Travi, Jack, Satsangi, Miles, Parke, Nikhil, Thapar, Helen, Ferry, Julie C, Matte, Kimberly C, Gilmour, Andrzej, Wedrychowicz, Peter, Sullivan, Carmel, Moore, Jennifer, Sambrook, Willem, Ouwehand, David, Robert, John, Danesh, Toni A, Baeumler, Tudor A, Fulga, Mohammad, Karaminejadranjbar, Ahmed, Ahmed, Rachel, Wilson, Jeffrey C, Barrett, Abdul, Elkadri, Anne M, Griffith, Scott B, Snapper, Neil, Shah, Aleixo M, Muise, David C, Wilson, Holm H, Uhlig, Carl A, Anderson, Zurek, Marlen, Strisciuglio, Caterina, Elawad, Mamoun, Lo, Bernice, Arancibia-Carcamo, Carolina, Bailey, Adam, Barnes, Ellie, Bird-Lieberman, Elizabeth Louise, Brain, Oliver, Braden, Barbara, Collier, Jane, East, Jame, Howarth, Lucy, Keshav, Satish, Klenerman, Paul, Leedham, Simon, Palmer, Rebecca, Powrie, Fiona, Simmons, Alison, Walker, Matthew, Tolkien, Zoe, Kaptoge, Stephen, Allen, David, Mehenny, Susan, Mant, Jonathan, Di Angelantonio, Emanuele, Thompson, Simon G, Yilmaz, Bahtiyar, Juillerat, Pascal, Geuking, Marku, Wiest, Reiner, Macpherson, Andrew J, Bravo, Francisco Damian, Brügger, Luka, Carstens, Ove, Bigler, Ulrike Graf, Heimgartner, Benjamin, Rusticeanu, Monica, Schmid-Uebelhart, Sybille, Strebel, Bruno, Tatu, Aurora, Tutuian, Radu, Øyås, Ove, Ramon, Charlotte, Stelling, Jörg, Franc, Yannick, Fournier, Nicola, Pittet, Valerie E H, Burnand, Bernard, Egger, Mara, Golay, Delphine, Marot, Astrid, Musso, Leilla, Pittet, Valérie, Rossel, Jean-Benoît, Seematter, Vivianne, Sommer, Joachim, Vulliamy, Rachel, Michetti, Pierre, Maillard, Michel H, Keller, Céline, Nydegger, Andrea, Schoepfe, Alain, Archanioti, Eva, Ezri, Jessica, Fraga, Montserrat, Schoepfer, Alain, Müller, Christoph, Rogler, Gerhard, Biedermann, Luc, Blattmann, Mirjam, Burk, Sabine, Dora, Barbara, Fried, Michael, Misselwitz, Benjamin, Müllhaupt, Beat, Obialo, Nicole, Pohl, Daniel, Raschle, Nadia, Scharl, Michael, Vavricka, Stephan, Von Känel, Roland, Zeitz, Jona, Abdelrahman, Karim, Ademi, Gentiana, Borovicka, Jan, Brand, Stephan, Frei, Remu, Haarer, Johanne, Knellwolf-Grieger, Christina, Krieger-Grübel, Claudia, Künzler, Patrizia, Meyenberger, Christa, Meyer, Pamela, Röhrich, Nina, Sawatzki, Mikael, Schelling, Martin, Semadeni, Gian-Marco, Sulz, Michael, Zimmermann, Dorothee, Aepli, Patrick, Criblez, Dominique H, Hess, Cyrill, Richterich, Jean-Pierre, Spalinger, Johanne, Staudenmann, Dominic, Stulz, Andrea, Wöhrle, Stefanie, Thomas, Amman, Anderegg, Claudia, Köhler, Henrik, Kusche, Rachel, Antonino, Anca-Teodora, Arrigoni, Eviano, Bengoa, José M, Cunningham, Sophie, de Saussure, Philippe, Girard, Laurent, de Jong, Diana Bakker, Bastürk, Polat, Brunner, Simon, Degen, Luka, Hruz, Petr, Khalid-de Bakker, Carolina, Niess, Jan, Balsiger, Bruno, Haldemann, Janine, Saner, Gaby, Seibold, Frank, Bauerfeind, Peter, Becocci, Andrea, Belli, Dominique, Binek, Janek, Hengstler, Peter, Boehm, Stephan, Boldanov, Tujana, Bühr, Patrick, Koller, Rebekka, Rueger, Vanessa, Senning, Arne, Burri, Emanuel, Buyse, Sophie, Cao, Dahlia-Thao, D'Angelo, Fabrizia, Delarive, Joakim, Doerig, Christopher, Hessler, Roxane, Preissler, Claudia, Rentsch, Ronald, Risti, Branislav, Ritz, Marc Alain, Steuerwald, Michael, Vögtlin, Jürg, Sagmeister, Marku, Sauter, Bernhard, Schibli, Susanne, Sokollik, Christiane, Schlauri, Hugo, Schnegg, Jean-Françoi, Seirafi, Mariam, Spangenberger, Holger, Stadler, Philippe, Staub, Peter, Stenz, Volker, Tempia-Caliera, Michela, Thorens, Joël, Truninger, Kaspar, Urfer, Patrick, Viani, Francesco, Vouillamoz, Dominique, Zander, Silvan, Wyli, Tina, Jostins, L, Kennedy, N A, Ahmad, T, Lamb, C A, Edwards, C, Hart, A, Hawkey, C, Mansfield, J C, Mowat, C, 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Subjects
0301 basic medicine, Male, Multifactorial Inheritance, General Physics and Astronomy, 631/208/1516, 13, Inflammatory bowel disease, Whole Exome Sequencing, Adult, Age of Onset, Case-Control Studies, Child, Child, Preschool, Cohort Studies, Female, Genes, Recessive, Genetic Predisposition to Disease, Genetic Variation, Humans, Infant, Infant, Newborn, Inflammatory Bowel Diseases/etiology, Inflammatory Bowel Diseases/genetics, Loss of Function Mutation, Mosaicism, Mutation, NADPH Oxidase 2/genetics, Pedigree, Primary Immunodeficiency Diseases/complications, Primary Immunodeficiency Diseases/genetics, Risk Factors, 0302 clinical medicine, Primary Immunodeficiency Disease, Medicine, lcsh:Science, Exome sequencing, 49/31, education.field_of_study, Multidisciplinary, Medical genetics, article, 692/699/249/1570, 631/250/249/2510/257, 631/208/248, 3. Good health, NADPH Oxidase 2, 030211 gastroenterology & hepatology, Case-Control Studie, Human, medicine.medical_specialty, Science, Primary Immunodeficiency Diseases, Population, 45/22, 45/23, digestive system, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immunological deficiency syndromes, Exome Sequencing, Immunogenetics, Allele, education, 45, business.industry, Risk Factor, Inflammatory Bowel Disease, Case-control study, General Chemistry, medicine.disease, Inflammatory Bowel Diseases, digestive system diseases, 49, 030104 developmental biology, Immunology, Primary immunodeficiency, lcsh:Q, Age of onset, Cohort Studie, business
Abstract

Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P, Adult forms of inflammatory bowel disease (IBD) are of a polygenic nature, but paediatric and very early onset (VEO) IBD also occur as monogenic forms. Here, using whole exome sequencing, the authors explore both the monogenic and polygenic contribution to VEO-IBD and characterize a rare somatic mosaic VEO-IBD patient.

Published
2020

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