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Advances in TNF Family Research pp 279–288Cite as

Insights into TL1A and IBD Pathogenesis

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 691))

Abstract

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.

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Acknowledgement

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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Authors and Affiliations

  1. Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Suite D4063, Los Angeles, CA, 90048, USA

    David Q. Shih, Kathrin S. Michelsen, Robert J. Barrett, Eva Biener-Ramanujan, Rivkah Gonsky & Stephan R. Targan

  2. Dept. of Gastroenterology, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang City, Hebei Province, China

    Xiaolan Zhang

Authors
  1. David Q. Shih
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  2. Kathrin S. Michelsen
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  3. Robert J. Barrett
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  4. Eva Biener-Ramanujan
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  5. Rivkah Gonsky
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  6. Xiaolan Zhang
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  7. Stephan R. Targan
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Corresponding author

Correspondence to Stephan R. Targan .

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Editors and Affiliations

  1. Dept. Biological Chemistry, Weizmann Institute of Science, 1 Herzl Street, Rehovot, 76100, Israel

    David Wallach

  2. Dept. Biological Chemistry, Weizmann Institute of Science, 1 Herzl Street, Rehovot, 76100, Israel

    Andrew Kovalenko

  3. Kennedy Institute of Rheumatology, Imperial College London, Aspenlea Rd. 1, London, W6 8LH, United Kingdom

    Marc Feldmann

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Shih, D.Q. et al. (2011). Insights into TL1A and IBD Pathogenesis. In: Wallach, D., Kovalenko, A., Feldmann, M. (eds) Advances in TNF Family Research. Advances in Experimental Medicine and Biology, vol 691. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6612-4_29

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