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Detection of Muramyl Dipeptide-Sensing Pathway Defects in Patients with Crohn's Disease


van Heel, DA and Hunt, KA and King, K and Ghosh, S and Gabe, SM and Mathew, CG and Forbes, A and Playford, RJ, Detection of Muramyl Dipeptide-Sensing Pathway Defects in Patients with Crohn's Disease, Inflammatory Bowel Diseases, 12, (7) pp. 598-605. ISSN 1078-0998 (2006) [Refereed Article]

DOI: doi:10.1097/01.ibd.0000225344.21979.89


BACKGROUND AND AIMS: Crohn's disease is strongly associated with double mutations in NOD2/CARD15. Three common mutations (Arg702Trp, Gly908Arg, Leu1007fs) impair innate immune responses to bacterial muramyl dipeptide. Rare NOD2 variants occur, but it is difficult to both identify them and assess their functional effect. We assessed the true frequency of defective muramyl dipeptide sensing in Crohn's disease and developed a rapid diagnostic assay. MATERIALS AND METHODS: An ex vivo assay was established and validated based on muramyl dipeptide stimulation of peripheral blood mononuclear cell cytokine production. Muramyl dipeptide-induced enhancement of interleukin (IL)-8 secretion and synergistic increase in lipopolysaccharide-induced IL-1β secretion were studied. Assay results were compared with NOD2 genotype status (3 common mutations and rare variants) in 91 individuals including a prospective cohort of 49 patients with Crohn's disease. RESULTS: The assay was highly sensitive and specific for detection of profound defects in muramyl dipeptide sensing caused by double NOD2 mutations (IL-8 P = 0.0002; IL-1β P = 0.0002). Disease state, active inflammation, or concurrent use of immunosuppressive medication did not influence results. Healthy NOD2 heterozygotes had modest impairment of muramyl dipeptide induced IL-8 secretion (P = 0.003). Only 1 of 7 patients with Crohn's disease with both a common mutation and a rare variant had a profound muramyl dipeptide-sensing defect. CONCLUSIONS: Profound defects in muramyl dipeptide sensing were found in 10% of patients with Crohn's disease. Defects were caused exclusively by inherited mutations in NOD2. The ex vivo assay has multiple potential applications as a clinical diagnostic tool to distinguish patients with muramyl dipeptide-sensing defects and for research investigation. Copyright © 2006 by Lippincott Williams & Wilkins.

Item Details

Item Type:Refereed Article
Research Division:Biomedical and Clinical Sciences
Research Group:Clinical sciences
Research Field:Gastroenterology and hepatology
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Playford, RJ (Professor Ray Playford)
ID Code:72965
Year Published:2006
Web of Science® Times Cited:22
Deposited By:Research Division
Deposited On:2011-09-05
Last Modified:2011-09-05

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