Defective acute inflammation in Crohn's disease: a clinical investigation

Marks, Daniel; Harbord, Marcus; MacAllister, Raymond J.; Rahman, Farooq; Young, J B; Al‐Lazikani, Bissan; Lees, W. R.; Novelli, Marco; Bloom, Stuart; Segal, Anthony W.

doi:10.1016/s0140-6736(06)68265-2

Cited by 351 publications

(334 citation statements)

References 53 publications

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“…2 The identification of nucleotide-binding oligomerization domain containing 2 (NOD2) as the first major susceptibility gene for CD provided important evidence of an impaired innate inflammatory response having a key role in the pathogenesis of CD. 3 The innate immune system is based on the ability to recognize pathogenassociated molecular patterns by pattern recognition receptors. NOD-like receptors are included among the pattern recognition receptors, together with many other molecules, such as Toll-like receptors (TLRs).…”

Section: Introductionmentioning

confidence: 99%

Association of Toll-like receptor 10 and susceptibility to Crohn's disease independent of NOD2

et al. 2011

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Impaired innate inflammatory response has a key role in the Crohn's disease (CD) pathogenesis. The aim of this study was to investigate the possible role of the TLR10-TLR1-TLR6 gene cluster in CD susceptibility. A total of 508 CD patients (284, cohort 1 and 224, cohort 2) and 576 controls were included. TLR10-TLR1-TLR6 cluster single-nucleotide polymorphisms genotyping, NOD2 mutations and TLR10 mRNA quantification were performed using TaqMan assays. Nucleotide-binding oligomerization domain containing 2 (NOD2) and Toll-like receptor (TLR) loci interaction was analyzed by logistic regression and multifactor-dimensionality reduction (MDR). Entropy-based analysis was used to interpret combination effects. One TLR10 haplotype (TLR10 GGGG ) was found associated with CD susceptibility in both cohorts, individuals with two copies had approximately twofold more risk of CD susceptibility than individuals having no copies (odds ratio ¼ 1.89, P-value ¼ 0.0002). No differences in the mRNA levels were observed among the genotypes. The strongest model for predicting CD risk according to the MDR analysis was a two-locus model including NOD2 mutations and TLR10 GGGG haplotype (P c o0.0001). The interaction gain attributed to the combination of both genes was negative (IG ¼ À2.36%), indicating redundancy or independent effects. Our results support association of the TLR10 gene with CD susceptibility. The effect of TLR10 would be independent of NOD2, suggesting different signaling pathways for both genes.

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Section: Introductionmentioning

confidence: 99%

Association of Toll-like receptor 10 and susceptibility to Crohn's disease independent of NOD2

et al. 2011

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“…8 The pathogenesis is not fully understood but there are several hypotheses involving the loss of antimicrobial activity and a deregulated immune response. Reduced antimicrobial activity results from decreased production of antimicrobial peptides, 9,10 decreased autocrine cytokine release 11 and increased gut permeability, 12 leading to bacterial translocation that elicits an immune response through toll-like receptor (TLR) signalling. This response is deregulated with increased production of Th1 and probably Th17 cytokines due to reduced inhibition of TLR-mediated cytokine release ('loss of tolerance') [13][14][15][16] or decreased production of IL-10.…”

Section: Introductionmentioning

confidence: 99%

NOD2 polymorphisms predict severe acute graft-versus-host and treatment-related mortality in T-cell-depleted haematopoietic stem cell transplantation

Velden

Blijlevens

Maas

et al. 2009

Bone Marrow Transplant

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Single nucleotide polymorphisms (SNPs) in the NOD2 gene have significant impact on both treatment-related mortality (TRM) and acute GVHD (aGVHD) in haematopoietic stem cell transplantation (HSCT). The effect of these polymorphisms when using T-cell-depleted grafts has been poorly studied. We retrospectively analysed NOD2 polymorphisms in a cohort of 85 patients and donors who received an HLA-identical sibling partially T-cell-depleted HSCT (0.5 Â 10 6 CD3 þ T cells per kg) following idarubicin-containing conditioning regimens. NOD2 polymorphisms were present in 14 of 85 (16.5%) of patients and 18 of 85 (21%) of donors. The risk of severe aGVHD (grade III-IV) and the 1-year TRM was significantly higher in the presence of NOD2 polymorphisms (hazard ratio (HR) 6.0, P ¼ 0.02 for severe aGVHD and HR 3.3, P ¼ 0.02 for TRM, respectively) and was most prominent in cases where patient and donor both had a polymorphism (HR 10.5, P ¼ 0.002 and HR 3.9, P ¼ 0.002). There was also a trend towards increased risk of bacteraemia due to coagulasenegative staphylococci in patients with an NOD2 polymorphism. We conclude that NOD2 polymorphism screening should be used to optimize donor selection and antimicrobial prophylaxis to reduce the occurrence of aGVHD and TRM following allogeneic HSCT.

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“…The current hypothesis for CD pathogenesis suggests that it develops in response to an overly aggressive adaptive immune response to the commensal flora (2). However, it has been recently suggested that CD may result from deficits in innate immunity (3)(4)(5). In this context, the intestinal epithelium seems to play a major role, allowing sensing of the luminal environment and differential regulation of the gut immune system (6).…”

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confidence: 99%

Probiotics promote gut health through stimulation of epithelial innate immunity

Pagnini

Saeed

Bamias

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Probiotic formulations are widely available and have a variety of proposed beneficial effects, including promotion of gut health. The mechanisms of action of probiotic bacteria in the intestine are still unclear but are generally attributed to an antiinflammatory effect. Here, we demonstrate that the multiple probiotic formulation VSL#3 prevents the onset of intestinal inflammation by local stimulation of epithelial innate immune responses (i.e., increased production of epithelial-derived TNF-α and restoration of epithelial barrier function in vivo). We also demonstrate that probiotic bacteria stimulate epithelial production of TNF-α and activate NF-κB in vitro. Our results support the hypothesis that probiotics promote gut health through stimulation, rather than suppression, of the innate immune system. Furthermore, our findings provide the perspective that defects in innate immunity may play a critical role in the pathogenesis and progression of intestinal disorders, such as inflammatory bowel disease.

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Defective acute inflammation in Crohn's disease: a clinical investigation

Cited by 351 publications

References 53 publications

Association of Toll-like receptor 10 and susceptibility to Crohn's disease independent of NOD2

Association of Toll-like receptor 10 and susceptibility to Crohn's disease independent of NOD2

NOD2 polymorphisms predict severe acute graft-versus-host and treatment-related mortality in T-cell-depleted haematopoietic stem cell transplantation

Probiotics promote gut health through stimulation of epithelial innate immunity

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