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

AbstractBACKGROUND:
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.
METHODOLOGY AND PRINCIPAL FINDINGS:
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.
CONCLUSIONS AND SIGNIFICANCE:
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.
AuthorsKathrin S Michelsen, Lisa S Thomas, Kent D Taylor, Qi T Yu, Ling Mei, Carol J Landers, Carrie Derkowski, Dermot P B McGovern, Jerome I Rotter, Stephan R Targan
JournalPloS one (PLoS One) Vol. 4 Issue 3 Pg. e4719 ( 2009) ISSN: 1932-6203 [Electronic] United States
PMID19262684 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies, Bacterial
  • Escherichia coli Proteins
  • OmpC protein
  • Porins
  • Receptors, IgG
  • TNFSF15 protein, human
  • Tumor Necrosis Factor Ligand Superfamily Member 15
Topics
  • Antibodies, Bacterial (blood)
  • Crohn Disease (ethnology, genetics)
  • Escherichia coli Proteins (immunology)
  • Genetic Variation
  • Genotype
  • Haplotypes
  • Humans
  • Inflammatory Bowel Diseases (genetics)
  • Jews
  • Porins (immunology)
  • Receptors, IgG (physiology)
  • Transcriptional Activation
  • Tumor Necrosis Factor Ligand Superfamily Member 15 (analysis, genetics)

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