Ulcerative Colitis: Chamaillard M

Dubuquoy L, Rousseaux C, Thuru X, Peyrin-Biroulet L, Romano O, Chavatte P, Chamaillard M, Desreumaux P. · INSERM U795 ex E114, Clinique des Maladies de l'Appareil Digestif et de la Nutrition, Hôpital Swynghedauw, rue A Verhaeghe, F-59037 Lille Cedex, France. · Gut. · Pubmed #16905700 No free full text.

Abstract: The peroxisome proliferator activated receptor gamma(PPARgamma) is a nuclear receptor highly expressed in the colon and playing a key role in bacterial induced inflammation. Regulation of colon inflammation by this receptor has been well demonstrated in many experimental models of colitis but also in patients with ulcerative colitis, characterised by impaired expression of PPARgamma confined to their colon epithelial cells. Recent data showing that PPARgamma was the major functional receptor mediating the common aminosalicylate activities in inflammatory bowel diseases (IBD) have also reinforced the roles of this receptor in the control of intestinal inflammation. The aims of this review are to discuss the potential roles of PPARgamma in the physiopathology of IBD, as well as the emerging therapeutic strategies targeting this receptor.

Koslowski MJ, Kübler I, Chamaillard M, Schaeffeler E, Reinisch W, Wang G, Beisner J, Teml A, Peyrin-Biroulet L, Winter S, Herrlinger KR, Rutgeerts P, Vermeire S, Cooney R, Fellermann K, Jewell D, Bevins CL, Schwab M, Stange EF, Wehkamp J. · Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany. · PLoS One. · Pubmed #19221600 links to  free full text

Abstract: Reduced expression of Paneth cell antimicrobial alpha-defensins, human defensin (HD)-5 and -6, characterizes Crohn's disease (CD) of the ileum. TCF-4 (also named TCF7L2), a Wnt signalling pathway transcription factor, orchestrates Paneth cell differentiation, directly regulates the expression of HD-5 and -6, and was previously associated with the decrease of these antimicrobial peptides in a subset of ileal CD. To investigate a potential genetic association of TCF-4 with ileal CD, we sequenced 2.1 kb of the 5' flanking region of TCF-4 in a small group of ileal CD patients and controls (n = 10 each). We identified eight single nucleotide polymorphisms (SNPs), of which three (rs3814570, rs10885394, rs10885395) were in linkage disequilibrium and found more frequently in patients; one (rs3814570) was thereby located in a predicted regulatory region. We carried out high-throughput analysis of this SNP in three cohorts of inflammatory bowel disease (IBD) patients and controls. Overall 1399 healthy individuals, 785 ulcerative colitis (UC) patients, 225 CD patients with colonic disease only and 784 CD patients with ileal involvement were used to determine frequency distributions. We found an association of rs3814570 with ileal CD but neither with colonic CD or UC, in a combined analysis (allele positivity: OR 1.27, 95% CI 1.07 to 1.52, p = 0.00737), which was the strongest in ileal CD patients with stricturing behaviour (allele frequency: OR 1.32, 95% CI 1.08 to1.62, p = 0.00686) or an additional involvement of the upper GIT (allele frequency: OR 1.38, 95% CI 1.03 to1.84, p = 0.02882). The newly identified genetic association of TCF-4 with ileal CD provides evidence that the decrease in Paneth cell alpha-defensins is a primary factor in disease pathogenesis.

Vandewalle-El Khoury P, Colombel JF, Joossens S, Standaert-Vitse A, Collot M, Halfvarson J, Ayadi A, Landers CJ, Vermeire S, Rutgeerts P, Targan SR, Chamaillard M, Mallet JM, Sendid B, Poulain D. · Inserm, U799, Lille, France. · Am J Gastroenterol. · Pubmed #18047546 No free full text.

Abstract: OBJECTIVES: Anti-S. cerevisiae mannan antibodies (ASCA) are human antibodies associated with Crohn's disease (CD) reacting with Saccharomyces cerevisiae (S. cerevisiae) mannan polymer. As mannan is a complex and variable repertoire of oligomannoses acting as epitopes, we chemically synthesized (Sigma) two major oligomannose epitopes, Man alpha-1,3 Man alpha-1,2 Man (SigmaMan3) and Man alpha-1,3 Man alpha-1,2 Man alpha-1,2 Man (SigmaMan4), and then explored how antisynthetic mannoside antibodies (ASigmaMA) compare with ASCA as markers of CD. METHODS: The study involved different cohorts of CD and ulcerative colitis (UC) patients and healthy controls who had been studied previously in several medical centers in Europe, the United States, and North Africa to determine the clinical value of ASCA in terms of differential diagnosis, evolution of indeterminate colitis (IC), and serotype-phenotype correlations. The comparison of ASigmaMA and ASCA included a total of 1,365 subjects: 772 CD, 261 UC, 43 IC, and 289 controls. RESULTS: The specificity of ASigmaMA was similar to that of ASCA (89% vs 93%), although the sensitivity was lower (38% vs 55%). Unexpectedly, 24% of the CD patients who were negative for ASCA and/or other CD-associated serologic markers were positive for ASigmaMA. ASigmaMA were associated with colonic involvement in CD (odds ratio [OR] 1.609, 95% confidence interval [CI] 1.033-2.506, P = 0.03) and were 100% predictive of CD in patients with IC. CONCLUSIONS: ASigmaMA reveal the heterogeneity of the antioligomannose antibody response in CD patients and increase the sensitivity of CD diagnosis when combined with ASCA. The subset of ASCA-negative CD patients diagnosed by ASigmaMA had preferentially a colonic involvement, which confirms the high predictive value of ASigmaMA for determining IC evolution toward CD.

Philippe D, Chakass D, Thuru X, Zerbib P, Tsicopoulos A, Geboes K, Bulois P, Breisse M, Vorng H, Gay J, Colombel JF, Desreumaux P, Chamaillard M. · INSERM, Lille, France. · Gut. · Pubmed #16299031 links to  free full text

Abstract: BACKGROUND AND AIMS: Recent studies with mu opioid receptor (MOR) deficient mice support a physiological anti-inflammatory effect of MOR at the colon interface. To better understand the potential pharmacological effect of certain opiates in inflammatory bowel diseases (IBD), we (1) evaluated the regulation in vivo and in vitro of human MOR expression by inflammation; and (2) tested the potential anti-inflammatory function of a specific opiate (DALDA) in inflamed and resting human mucosa. PATIENTS AND METHODS: Expression of MOR mRNA and protein was evaluated in healthy and inflamed small bowel and colonic tissues, isolated peripheral blood mononuclear cells and purified monocytes, and CD4+ and CD8+ T cells from healthy donors and IBD patients. The effect of cytokines and nuclear factor kappaB (NFkappaB) activation on MOR expression in lymphocyte T and monocytic human cell lines was assessed. Finally, DALDA induced anti-inflammatory effect was investigated in mucosal explants from controls and IBD patients. RESULTS: MOR was expressed in ileal and colonic enteric neurones as well as in immunocytes such as myeloid cells and CD4+ and CD8+ T cells. Overexpressed in active IBD mucosa, MOR was significantly enhanced by cytokines and repressed by NFkappaB inhibitor in myeloid and lymphocytic cell lines. Furthermore, ex vivo DALDA treatment dampened tumour necrosis factor alpha mRNA expression in the colon of active IBD patients. CONCLUSIONS: Given the increased expression of MOR and the ex vivo beneficial effect of DALDA in active IBD, natural and/or synthetic opioid agonists could help to prevent overt pathological intestinal inflammation.

Zouali H, Lesage S, Merlin F, Cézard JP, Colombel JF, Belaiche J, Almer S, Tysk C, O'Morain C, Gassull M, Christensen S, Finkel Y, Modigliani R, Gower-Rousseau C, Macry J, Chamaillard M, Thomas G, Hugot JP, Anonymous00017, Anonymous00018. · Fondation Jean Dausset-CEPH, Paris, France. · Gut. · Pubmed #12477763 links to  free full text

Abstract: BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex genetic disorders. CARD15/NOD2, a member of the Ced4 superfamily which includes Apaf-1 and CARD4/NOD1, has recently been associated with genetic predisposition to CD but additional genetic factors remain to be identified. Because CARD4/NOD1 shares many structural and functional similarities with CARD15, we tested its putative role in IBD. PATIENTS AND METHODS: The 11 exons of CARD4 were screened for the presence of variants in 63 unrelated IBD patients. The only non-private genetic variation encoding for a substitution in the peptidic chain was genotyped in 381 IBD families (235 CD, 58 UC, 81 mixed, and seven indeterminate colitis families) using a polymerase chain reaction-restriction fragment length polymorphism procedure. Genotyping data were analysed by the transmission disequilibrium test. RESULTS: Five of nine sequence variations identified in the coding sequence of the gene encoded for non-conservative changes (E266K, D372N, R705Q, T787M, and T787K). Four were present in only one family. The remaining variant (E266K), which exhibited an allele frequency of 0.28, was not associated with CD, UC, or IBD. Furthermore, IBD patients carrying sequence variations in their CARD4 gene had a similar phenotype to those with a normal sequence. CONCLUSION: Our results suggest that CARD4 does not play a major role in genetic susceptibility to IBD.

Lesage S, Zouali H, Cézard JP, Colombel JF, Belaiche J, Almer S, Tysk C, O'Morain C, Gassull M, Binder V, Finkel Y, Modigliani R, Gower-Rousseau C, Macry J, Merlin F, Chamaillard M, Jannot AS, Thomas G, Hugot JP, Anonymous00210, Anonymous00211, Anonymous00212. · Fondation Jean Dausset-CEPH, 27 rue Juliette Dodu, 75010 Paris, France. · Am J Hum Genet. · Pubmed #11875755 links to  free full text

Abstract: CARD15/NOD2 encodes a protein involved in bacterial recognition by monocytes. Mutations in CARD15 have recently been found in patients with Crohn disease (CD), a chronic inflammatory condition of the digestive tract. Here, we report the mutational analyses of CARD15 in 453 patients with CD, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (UC), and 103 healthy control subjects. Of 67 sequence variations identified, 9 had an allele frequency >5% in patients with CD. Six of them were considered to be polymorphisms, and three (R702W, G908R, and 1007fs) were confirmed to be independently associated with susceptibility to CD. Also considered as potential disease-causing mutations (DCMs) were 27 rare additional mutations. The three main variants (R702W, G908R, and 1007fs) represented 32%, 18%, and 31%, respectively, of the total CD mutations, whereas the total of the 27 rare mutations represented 19% of DCMs. Altogether, 93% of the mutations were located in the distal third of the gene. No mutations were found to be associated with UC. In contrast, 50% of patients with CD carried at least one DCM, including 17% who had a double mutation. This observation confirmed the gene-dosage effect in CD. The patients with double-dose mutations were characterized by a younger age at onset (16.9 years vs. 19.8 years; P=.01), a more frequent stricturing phenotype (53% vs. 28%; P=.00003; odds ratio 2.92), and a less frequent colonic involvement (43% vs. 62%; P=.003; odds ratio 0.44) than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of patients with CD with or without mutation. These findings provide tools for a DNA-based test of susceptibility and for genetic counseling in inflammatory bowel disease.

Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G. · Fondation Jean Dausset CEPH, 27 rue J. Dodu 75010 Paris, France. · Nature. · Pubmed #11385576 No free full text.

Abstract: Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.

Lesage S, Zouali H, Colombel JF, Belaiche J, Cézard JP, Tysk C, Almer S, Gassull M, Binder V, Chamaillard M, Le Gall I, Thomas G, Hugot JP. · Fondation Jean Dausset/CEPH and Unité INSERM 434, 27 rue Juliette Dodu, 75010 Paris, France. · Gut. · Pubmed #11076876 links to  free full text

Abstract: BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) includes ulcerative colitis and Crohn's disease, both of which are multifactorial diseases involving the interaction of genetic and environmental factors. A region on chromosome 12 centred around the marker locus D12S83 has previously been associated with IBD predisposition. The aim of the study was to investigate this genetic region in an independent panel of European families affected by Crohn's disease. METHODS: A sample of 95 families with two or more affected relatives and 75 simplex nuclear families were genotyped for 19 microsatellite loci located on chromosome 12. A search for linkage and linkage disequilibrium was performed using non-parametric two point and multipoint analyses with the Analyze and Genehunter packages. RESULTS: No evidence of linkage or linkage disequilibrium was observed for any of the marker loci, including D12S83 (p=0.35 for the two point linkage test). Multipoint linkage analysis also failed to reveal positive linkage on chromosome 12. Power calculations allowed us to reject the hypothesis that the genetic region of chromosome 12 centred on D12S83 contains a susceptibility locus with a relative risk (lambda(s)) equal to or greater than 2.0 in these families. CONCLUSION: Failure to detect linkage or linkage disequilibrium in these families suggests that the chromosome 12 locus previously reported to be associated with genetic predisposition to IBD does not play a role in all European family samples. This observation is compatible with heterogeneity in the genetic basis of susceptibility to the disease and/or exposure to various environmental factors among Caucasian families.