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IBD-associated TL1A gene (TNFSF15) haplotypes determine increased expression of TL1A protein. PLoS One 2009;4(3):e4719

Date

03/06/2009

Pubmed ID

19262684

Pubmed Central ID

PMC2648040

DOI

10.1371/journal.pone.0004719

Scopus ID

2-s2.0-61849115157 (requires institutional sign-in at Scopus site)   76 Citations

Abstract

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.

Author List

Michelsen KS, Thomas LS, Taylor KD, Yu QT, Mei L, Landers CJ, Derkowski C, McGovern DP, Rotter JI, Targan SR

Author

Ling Mei MD Associate Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Antibodies, Bacterial
Crohn Disease
Escherichia coli Proteins
Genetic Variation
Genotype
Haplotypes
Humans
Inflammatory Bowel Diseases
Jews
Porins
Receptors, IgG
Transcriptional Activation
Tumor Necrosis Factor Ligand Superfamily Member 15