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IBD-associated TL1A gene (TNFSF15) haplotypes determine increased expression of TL1A protein.

ABSTRACT: The recently identified member of the TNF superfamily TL1A (TNFSF15) increases IFN-gamma production by T cells in peripheral and mucosal CCR9+ T cells. TL1A and its receptor DR3 are up-regulated during chronic intestinal inflammation in ulcerative colitis and Crohn's disease (CD). TL1A gene haplotypes increase CD susceptibility in Japanese, European, and US cohorts.Here we report that the presence of TL1A gene haplotype B increases risk in Jewish CD patients with antibody titers for the E. coli outer membrane porin C (OmpC+) (Haplotype B frequency in Jewish CD patients: 24.9% for OmpC negative and 41.9% for OmpC positive patients, respectively, P< or =0.001). CD14+ monocytes isolated from Jewish OmpC+ patients homozygous for TL1A gene haplotype B express higher levels of TL1A in response to FcgammaR stimulation, a known inducing pathway of TL1A, as measured by ELISA. Furthermore, the membrane expression of TL1A is increased on peripheral monocytes from Jewish but not non-Jewish CD patients with the risk haplotype.These findings suggest that TL1A gene variation exacerbates induction of TL1A in response to FcgammaR stimulation in Jewish CD patients and this may lead to chronic intestinal inflammation via overwhelming T cell responses. Thus, TL1A may provide an important target for therapeutic intervention in this subgroup of IBD patients.

SUBMITTER: Michelsen KS

PROVIDER: S-EPMC2648040 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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IBD-associated TL1A gene (TNFSF15) haplotypes determine increased expression of TL1A protein.

Michelsen Kathrin S KS Thomas Lisa S LS Taylor Kent D KD Yu Qi T QT Mei Ling L Landers Carol J CJ Derkowski Carrie C McGovern Dermot P B DP Rotter Jerome I JI Targan Stephan R SR

PloS one 20090305 3

<h4>Background</h4>The recently identified member of the TNF superfamily TL1A (TNFSF15) increases IFN-gamma production by T cells in peripheral and mucosal CCR9+ T cells. TL1A and its receptor DR3 are up-regulated during chronic intestinal inflammation in ulcerative colitis and Crohn's disease (CD). TL1A gene haplotypes increase CD susceptibility in Japanese, European, and US cohorts.<h4>Methodology and principal findings</h4>Here we report that the presence of TL1A gene haplotype B increases ri ...[more]

PMID: 19262684

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Project description:Abstract Background and Aim TL1A (TNFSF15) is a major Crohn's disease (CD) susceptibility gene, especially in the East Asian population, and is also known to be associated with some clinical phenotypes, such as stricturing and penetrating behavior. This study aims to investigate the association between TL1A genotype and the long?term therapeutic outcomes of infliximab and adalimumab in Japanese CD patients. Methods We investigated 119 biologic?naïve CD patients treated with infliximab or adalimumab. TL1A ?358C/T (rs6478109) was genotyped as a tag single nucleotide polymorphism (SNP) for CD risk or nonrisk haplotype of TL1A (the ?358C allele is a risk allele for CD development). We compared the long?term therapeutic outcomes of anti?tumor necrosis factor (TNF) antibodies between the TL1A ?358C/C group and the C/T+T/T group. Results Sixty?nine cases (58.0%) were homozygous for the risk allele (TL1A ?358C/C group), and 50 cases (42.0%) were heterozygous for the risk allele or homozygous for the protective allele (TL1A ?358C/T+T/T group). No significant differences were found in the cumulative retention rates and the relapse?free survival between the TL1A genotypes. However, the surgery?free survival was significantly lower in the TL1A ?358C/C group than in the C/T+T/T group (log?rank test, P?<?0.05). Multivariate analysis showed that TL1A ?358C/C was identified as an independent risk factor for surgery (hazard ratio, 4.67; 95% confidence interval, 1.39–22.1; P = 0.025). Conclusion An association was found between the TL1A genotype and the therapeutic outcomes of anti?TNF therapy. Our data indicate that the design of customized therapy with anti?TNF antibodies using TL1A genomic information could be effective in the future. In this study, we investigated the association between TL1A genotype and the long?term therapeutic outcomes of infliximab and adalimumab in Crohn's disease (CD) patients. We investigated 119 biologic?naïve CD patients treated with infliximab or adalimumab and found an association between the TL1A genotype and surgery?free survival during anti?tumor necrosis factor (TNF) therapy. The patients whose genotypes are homozygous for the TL1A ?358C (risk allele of CD development) show lower surgery?free survival with anti?TNF treatment.

Project description:TL1A and its functional receptor DR3 are members of the TNF/TNFR superfamilies of proteins. Binding of APC-derived TL1A to lymphocytic DR3 provides co-stimulatory signals for activated lymphocytes. DR3 signaling affects the proliferative activity of and cytokine production by effector lymphocytes, but also critically influences the development and suppressive function of regulatory T-cells. DR3 was also found to be highly expressed by innate lymphoid cells (ILCS), which respond to stimulation by TL1A. Several recent studies with transgenic and knockout mice as well as neutralizing or agonistic antibodies for these two proteins, have clearly shown that TL1A/DR3 are important mediators of several chronic immunological disorders, including Inflammatory Bowel Disease (IBD). TL1A and DR3 are abundantly localized at inflamed intestinal areas of patients with IBD and mice with experimental ileitis or colitis and actively participate in the immunological pathways that underlie mucosal homeostasis and intestinal inflammation. DR3 signaling has demonstrated a dichotomous role in mucosal immunity. On the one hand, during acute mucosal injury it exerts protective functions by ameliorating the severity of acute inflammatory responses and facilitating tissue repair. On the other hand, it critically participates in the pro-inflammatory pathways that underlie chronic inflammatory responses, such as those that take place in IBD. These effects are mediated through modulation of the relative mucosal abundance and function of Th1, Th2, Th17, Th9, and Treg lymphocytes, but also of all types of ILCs. Recently, an important role was demonstrated for TL1A/DR3 as potential mediators of intestinal fibrosis that is associated with the presence of gut inflammation. These accumulating data have raised the possibility that TL1A/DR3 pathways may represent a valid therapeutic target for chronic immunological diseases. Nevertheless, applicability of such a therapeutic approach will greatly rely on the net result of TL1A/DR3 manipulation on the various cell populations that will be affected by this approach.

Dataset Information

IBD-associated TL1A gene (TNFSF15) haplotypes determine increased expression of TL1A protein.

Publications

IBD-associated TL1A gene (TNFSF15) haplotypes determine increased expression of TL1A protein.

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