Genetic Association Analysis of the Functional c.714T>G Polymorphism and Mucosal Expression of Dectin-1 in Inflammatory Bowel Disease

Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
PLoS ONE (Impact Factor: 3.23). 11/2009; 4(11):e7818. DOI: 10.1371/journal.pone.0007818
Source: PubMed


Dectin-1 is a pattern recognition receptor (PRR) expressed by myeloid cells that specifically recognizes beta-1,3 glucan, a polysaccharide and major component of the fungal cell wall. Upon activation, dectin-1 signaling converges, similar to NOD2, on the adaptor molecule CARD9 which is associated with inflammatory bowel disease (IBD). An early stop codon polymorphism (c.714T>G) in DECTIN-1 results in a loss-of-function (p.Y238X) and impaired cytokine responses, including TNF-alpha, interleukin (IL)-1beta and IL-17 upon in vitro stimulation with Candida albicans or beta-glucan. The aim of the present study was to test the hypothesis that the DECTIN-1 c.714T>G (p.Y238X) polymorphism is associated with lower disease susceptibility or severity in IBD and to investigate the level of dectin-1 expression in inflamed and non-inflamed colon tissue of IBD patients.
Paraffin embedded tissue samples from non-inflamed and inflamed colon of IBD patients and from diverticulitis patients were immunohistochemically stained for dectin-1 and related to CD68 macrophage staining. Genomic DNA of IBD patients (778 patients with Crohn's disease and 759 patients with ulcerative colitis) and healthy controls (n = 772) was genotyped for the c.714T>G polymorphism and genotype-phenotype interactions were investigated.
Increased expression of dectin-1 was observed in actively inflamed colon tissue, as compared to non-inflamed tissue of the same patients. Also an increase in dectin-1 expression was apparent in diverticulitis tissue. No statistically significant difference in DECTIN-1 c.714T>G allele frequencies was observed between IBD patients and healthy controls. Furthermore, no differences in clinical characteristics could be observed related to DECTIN-1 genotype, neither alone, nor stratified for NOD2 genotype.
Our data demonstrate that dectin-1 expression is elevated on macrophages, neutrophils, and other immune cells involved in the inflammatory reaction in IBD. The DECTIN-1 c.714T>G polymorphism however, is not a major susceptibility factor for developing IBD.

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    • "However, little is known about the role of dectin-1 in maintaining intestinal homeostasis. Dectin-1 is highly expressed in the intestine [25] and humans with CD have also been shown to have increased numbers of dectin-1 expressing inflammatory cells in the intestine compared with healthy individuals [26]. Together this implies that dectin-1 may play a role in intestinal immunity. "
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    ABSTRACT: It is believed that inflammatory bowel diseases (IBD) result from an imbalance in the intestinal immune response towards the luminal microbiome. Dectin-1 is a widely expressed pattern recognition receptor that recognizes fungi and upon recognition it mediates cytokine responses and skewing of the adaptive immune system. Hence, dectin-1 may be involved in the pathogenesis of IBD. We assessed the responses of dectin-1 deficient macrophages to the intestinal microbiota and determined the course of acute DSS and chronic Helicobacter hepaticus induced colitis in dectin-1 deficient mice. We show that the mouse intestinal microbiota contains fungi and the cytokine responses towards this microbiota were significantly reduced in dectin-1 deficient macrophages. However, in two different colitis models no significant differences in the course of inflammation were found in dectin-1 deficient mice compared to wild type mice. Together our data suggest that, although at the immune cell level there is a difference in response towards the intestinal flora in dectin-1 deficient macrophages, during intestinal inflammation this response seems to be redundant since dectin-1 deficiency in mice does not affect intestinal inflammation in experimental colitis.
    BMC Gastroenterology 04/2012; 12(1):33. DOI:10.1186/1471-230X-12-33 · 2.37 Impact Factor
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    • "CARD9 is a caspase recruitment-domain–containing signaling protein expressed in various tissues.10,11 It is closely associated with several inflammatory diseases, including tuberculosis, inflammatory bowel disease, tuberculosis, and ankylosing spondylitis.13,29,30 In CARD9−/− mice, stimulation of dendritic cells caused a marked decrease in the production of IL-2, -6, and -10, and TNF-α and decreased numbers of Th17 cells.31,32,33 "
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    American Journal of Hypertension 03/2011; 24(6):701-7. DOI:10.1038/ajh.2011.42 · 2.85 Impact Factor
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    ABSTRACT: Innate control of fungal infection requires the specific recognition of invariant fungal molecular structures by a variety of innate immune receptors, including Toll-like receptors. In addition to the role in inducing protective immune responses, Toll-like receptor engagement may paradoxically favor fungal infections, by inducing inflammatory pathology and impairing antifungal immunity. Although the dissection of complex genetic traits modulating susceptibility to fungal infections is complex, the contribution of host genetics may hold the key to elucidating new risk factors for these severe, often fatal diseases. Understanding host-pathogen interactions at the innate immune interface will eventually lead to the development of new therapeutics and genetic markers in fungal infections.
    Expert Review of Anti-infective Therapy 10/2010; 8(10):1121-37. DOI:10.1586/eri.10.93 · 3.46 Impact Factor
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