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

PLoS One. 2009;4(3):e4719. doi: 10.1371/journal.pone.0004719. Epub 2009 Mar 5.


Background: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Bacterial / blood
  • Crohn Disease / ethnology
  • Crohn Disease / 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
  • Tumor Necrosis Factor Ligand Superfamily Member 15 / genetics*


  • Antibodies, Bacterial
  • Escherichia coli Proteins
  • OmpC protein
  • Porins
  • Receptors, IgG
  • TNFSF15 protein, human
  • Tumor Necrosis Factor Ligand Superfamily Member 15