Synergistic effect of interleukin-10-receptor variants in a case of early-onset ulcerative colitis (original) (raw)
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Inflammatory Bowel Disease and Mutations Affecting the Interleukin-10 Receptor
New England Journal of Medicine, 2009
METHODS-We performed genetic-linkage analysis and candidate-gene sequencing on samples from two unrelated consanguineous families with children who were affected by early-onset inflammatory bowel disease. We screened six additional patients with early-onset colitis for mutations in two candidate genes and carried out functional assays in patients' peripheral-blood mononuclear cells. We performed an allogeneic hematopoietic stem-cell transplantation in one patient.
Genes & Immunity, 2000
The influence of biallelic polymorphisms in the tumour necrosis factor-alpha (TNF␣), lymphotoxin-alpha (LT␣) and interleukin-10 (IL-10) genes on stimulated TNF␣ and IL-10 production was studied in ulcerative colitis (UC) patients, Crohn's disease (CD) patients and in healthy controls. A polymerase chain reaction sequence-specific primer (PCR-SSP) system was developed to type nine biallelic polymorphisms, three in each of the TNF␣, LT␣ and IL-10 genes. Production of the TNF␣ and IL-10 was measured by ELISA in lipopolysaccharide (LPS) stimulated whole blood. Four haplotypes of the TNF␣ gene, three haplotypes of LT␣ and three haplotypes of IL-10 were identified. No significant differences in haplotype frequencies were found between patients and controls overall. On subgroup analysis however, haplotype TNF-2 was more frequent in women with extensive colitis compared to distal colitis (31% vs 12%; P = 0.028). This difference was even greater for the combined TNF-2-LT␣-2 haplotype (56% vs 21%; P = 0.0007). The TNF-2 and LT␣-2 haplotypes were associated with higher TNF␣ production in CD patients, and the TNF-4 haplotype was associated with lower TNF␣ production in UC patients. The A allele in the IL-10 promoter region at position −1082 was associated with decreased IL-10 production in CD patients and controls (P = 0.005, P = 0.015 respectively). These data provide evidence that the effect of TNF␣, LT␣ and IL-10 gene polymorphisms on cytokine production differ in CD, UC patients and controls. Genes and Immunity (2000) 1, 185-190.
Digestive diseases and sciences, 2001
Interleukin-10 (IL-10) has a key role in regulating mucosal inflammation. The role of functional polymorphisms at positions -627 and -1117 in the IL-10 gene as candidate susceptibility loci in inflammatory bowel disease and their importance in determining disease extent were evaluated in 159 patients with ulcerative colitis (83 left-sided; 76 extensive), 90 patients with Crohn's disease (22 small bowel; 29 large bowel; 39 both), and 227 controls. Genotyping was performed either by PCR-RFLP assays (-627 site) or SSCP analysis (-1117 site). An excess of -627A allele was observed in patients with left-sided colitis (52%) compared with controls (33%; P = 0.004) suggesting that IL-10 may influence the extent of the disease. These results were not replicated in a newly recruited group (N = 100) of patients with UC. We conclude that polymorphisms at -627 and -1117 sites in the IL-10 gene do not contribute to the susceptibility to IBD or determining the extent of the disease in our popu...
Revista Española de Enfermedades Digestivas, 2006
Background and objectives: interleukin-10 (IL-10) has a key role in regulating mucosal inflammation in inflammatory bowel disease. In our population of Spanish ulcerative colitis (UC) patients, we have previously demostrated that two polymorphisms (IL-10.G14 microsatellite allele and homozygous for the-1082G alelle (guanine at position-1082)) in the IL-10 gene were susceptibility markers for disease. No data exist regarding the relationship of these IL-10 polymorphims with phenotypic subpopulations in UC. Therefore, this study sought to examine the contribution of IL-10 polymorphims to phenotypical variability in UC. Material and methods: a cohort of 215 Spanish unrelated patients with UC recruited in a single center was studied. All patients were rigorously phenotyped and followed for at least 3 years (mean time: 11.8 years). The clinical phenotype was established before genotyping. Genotyping was performed using polymerase chain reaction (PCR) assays. Results: patiens with UC included 129 (60%) men and 89 (40%) women. Mean age at diagnosis was 38 years, with a range of 8-83. Disease extent included 127 (59.1%) left-side patients and 88 (40.9%) extensive patients. Neither UC phenotype variable was associated with the presence of susceptibility polymorphims (10G14 microsatellite and-1082G alelle). Conclusions: in Madrid's Spanish population of UC patients, the carrying of the ILG14 microsatellite or-1082G polymorphism in the IL-10 gene was not associated with phenotype of disease.
Over-expression of interleukin 10 in mucosal T cells of patients with active ulcerative colitis
Clinical and Experimental Immunology, 2003
Ulcerative colitis (UC), a chronic inflammatory bowel disease, exhibits pronounced increase of T lymphocytes in the inflamed mucosa. To understand the role of intestinal T lymphocytes in the pathogenesis of UC their cytokine production in the mucosa was analysed. Intestinal T lymphocytes of UC, Crohn's disease and control patients were analysed for cytokine mRNA levels by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) directly after isolation without in vitro stimulation. Frequencies of cytokine positive cells were determined in UC and control colon by immunomorphometry. T lymphocytes in normal colon expressed interleukin (IL)-2, interferon (IFN)-g , tumour necrosis factor (TNF)-a and transforming growth factor (TGF)-b 1, but not IL-4, IL-5 or IL-10. In UC, a highly significant increase in IL-10 mRNA levels in T lymphocytes and an increased frequency of IL-10 positive cells was seen in colon. IL-10 mRNA levels were also elevated in T lymphocytes of the noninflamed ileum and correlated with disease activity at both locations. CD4 + T lymphocytes were the major source of IL-10 mRNA. IL-2, IFN-g and TNF-a mRNA levels were decreased in colonic T lymphocytes, and virtually no IL-2, IFN-g , TNF-a or TGF-b positive cells were detected in basal lymphoid aggregates. However, scattered IL-10 positive cells were found here. Lamina propria outside the aggregates contained IL-10-, IFN-g , TNF-a and TGF-b but not IL-2 positive cells. T cells of UC patients did not express IL-4 or IL-5. Taken, together the data suggest a generalized activation of IL-10 producing CD4 + T cells along the intestine of UC patients. The local environment seems to determine the biological consequences of elevated IL-10.
Inflammatory Bowel Diseases, 2009
EHJG Aarntzen, W J Lesterhuis, M Van Rossum, GJ Adema, CF Figdor, CJA Punt and IJM De Vries clinical phenotypes of systemic sclerosis through a genome wide association strategy O2 Linking genotype to cell function in chronic inflammation: analysis of the IL-23/Th17 axis in spondylarthropathy M Roumier, M Coffre, H Law, C Salliot, M Dougados, E Bianchi and L Rogge O3 Cytosolic phospholipase A2α gene silencing in monocytes alters development of Th1 responses and reduces autoimmune arthritis G Courties, J Presumey, M Baron, V Escriou, P Van Lent, D Scherman, A Cantagrel, W Van den Berg, C Jorgensen, J-L Davignon and F Apparailly O4 RANKL expression in human T-lymphocytes requires cooperative signaling through the T-cell receptor and adhesion molecule CD2 BP Harvey and Z Kaymakcalan O5 Single-cell analysis techniques reveal a striking heterogeneity of human CD4 + T cell subsets M Coffre, K Placek, S Maiella, E Bianchi and L Rogge O6 Sustained T cell Rap1 activation protects against Experimental Autoimmune Encephalomyelitis (EAE) via modulation of T cell responses G Franco Salinas, S Krausz, W Dontje, PP Tak, D Baeten and K Reedquist O7 Skewed X-chromosomal inactivation impacts T regulatory cell function in systemic sclerosis JCA Broen, ILM Wolvers-Tettero, L Geurts-van Bon, MC Vonk, MJH Coenen, R Lafyatis, TRDJ Radstake and AW Langerak O8 Fra-1 regulates inflammatory and degenerative arthritis T Kireva, K Zwerina, W Baum, S Hayer, G Schett and J Zwerina POSTER PRESENTATIONS (P1-P73) P1 The neonatal Fc receptor is expressed by human lymphocytes K van Bilsen, J Bastiaans, WA Dik, EF De Haas, SG Baarsma, RW Kuipers, PM van Hagen P2 Differential association of two PTPN22 coding variants with Crohn's disease and ulcerative colitis LM Diaz-Gallo P3 Single-cell gene profiling analysis of human regulatory T cell subsets P9 Lack of adalimumab's complement dependent cytotoxicity on human cells expressing complement regulatory proteins KM Grebe, J Salfeld, Z Kaymakcalan P10 Efficacy of adalimumab in sarcoidosis LSJ Kamphuis, WK Lam-Tse, WA Dik, J Bastiaans, P van Biezen, PLA van Daele, DJ Kwekkeboom, RWAM Kuijpers, GS Baarsma, PM van Hagen, H Hooijkaas, JAM van Laar P11 Differences in virus prevalence and load in the hearts of patients with chronic dilated cardiomyopathy with and without immune-mediated inflammatory disease R Dennert, P van Paassen, C Bruggeman, P Wolffs, JW Cohen Tervaert, S Heymans P12 Inflammatory T-lymphocyte proliferation in morbid obesity K Van der Weerd, PM van Hagen, WA Dik, BS Schrijver, DH Schweitzer, AW Langerak, RM Kiewiet, MO Van Aken, JJM Van Dongen, AJ Van der Lelij, FJT Staal P13 Elevated soluble Flt1 mediates an anti-angiogenic state in patients with ANCA-associated vasculitis S Le Roux, R Pepper, A Dufay, M Néel, N Lamandé, M Rimbert,
Interleukin 10 promoter region polymorphisms in inflammatory bowel disease in Tunisian population
Inflammation Research, 2009
Objective: To test whether IL-10 promoter region polymorphisms are associated with susceptibility to inflammatory bowel disease, we examined the contribution of interleukin- 10 (IL-10) gene polymorphisms to Crohn’s disease (CD) and Ulcerative colitis disease (UC) occurrence and also to CD phenotype. Materiels and Methods: SNPs at positions -627 (C > A) and −1117 (G > A) in the IL-10 promoter were determined in a sample of 105 Tunisian patients with IBD (75 CD and 30 UC) and 90 matched healthy controls. Results: The 627 CA genotype is associated with ileal location (p = 0.015) and with stricturing (p = 510-3) and penetrating (p = 310-3) presentation of CD. An additive effect between IL10 variants and CARD15 3020 insC mutation (p = 0,006) on severe forms of CD was shown. Conclusions: In Tunisian population, the 3020insC insertion in NOD2/CARD15 gene is a marker of susceptibility to CD, while the A allele at position -627 in the IL-10 promoter increases the risk of CD ileal location and severe disease presentation. A genetic epistasis between IL-10 gene polymorphisms and CARD15/NOD2 gene mutation was suggested.
Inflammatory Bowel Diseases, 2013
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.