Insights into TL1A and IBD Pathogenesis

  • David Q. Shih
  • Kathrin S. Michelsen
  • Robert J. Barrett
  • Eva Biener-Ramanujan
  • Rivkah Gonsky
  • Xiaolan Zhang
  • Stephan R. Targan
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 691)


Inflammatory bowel diseases (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders caused by dysregulated immune responses to microbial antigens in a genetically predisposed individual. Recent and accumulating research, including genome-wide association studies (GWAS), has identified over 50 distinct genetic loci that confer susceptibility and begin to define critical molecules and pathways that converge in physiologic processes that lead to mucosal inflammation. Among the several recently discovered IBD associated gene variants in tumor necrosis factor superfamily member 15 (TNFSF15) has been shown to be associated with CD in all ethnic and age groups. TL1A is the product of the TNFSF15 gene and signals through death receptor 3 (DR3). Among the evidence indicating an important functional role of TL1A in mediating gut mucosal inflammation is the finding that neutralizing antibodies to TL1A prevented and treated chronic colitis by decreasing Th1 and Th17 responses in two T cell mediated mouse models. In addition, TL1A expression is elevated in lamina propria mononuclear cells (LPMC) from the mucosa of IBD patients and varies in association with different CD genotypes, as defined by ethnic background, haplotype, and serum microbial antibody expression. One of the etiologic theories on the pathogenesis of IBD is that impaired clearance of foreign material leads to a sustained activation of antigen presenting cells and a compensatory induction of an adaptive immune response. Consistent with the important role of TL1A in IBD, microbial organisms and FcγR signaling induce TL1A in myeloid cells leading to enhanced Th1 responses. These and other studies define TL1A as a master regulatory cytokine that plays a key role in human intestinal inflammation.


Inflammatory Bowel Disease Inflammatory Bowel Disease Patient Pediatric Inflammatory Bowel Disease Inflammatory Bowel Disease Susceptibility Pediatric Inflammatory Bowel Disease Patient 



Support for this work was provided by USPHS grants NIH DK046763 and NIH DK056328. We thank Loren C. Karp for critical reading of this manuscript.


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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • David Q. Shih
    • 1
  • Kathrin S. Michelsen
    • 1
  • Robert J. Barrett
    • 1
  • Eva Biener-Ramanujan
    • 1
  • Rivkah Gonsky
    • 1
  • Xiaolan Zhang
    • 2
  • Stephan R. Targan
    • 1
  1. 1.Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical CenterLos AngelesUSA
  2. 2.Dept. of GastroenterologyThe Second Hospital of Hebei Medical UniversityShijiazhuang CityChina

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