Towards an understanding of the role of NOD2/CARD15 in the pathogenesis of Crohn's disease

Philpott, Dana J.; Viala, Jérôme

doi:10.1016/j.bpg.2003.12.004

Cited by 20 publications

(8 citation statements)

References 75 publications

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“…NOD2, otherwise known as caspase activating recruitment domain 15 (CARD15), is an intracellular protein found in monocytes, dendritic cells, Paneth cells and intestinal epithelial cells that belongs to a superfamily of apoptotic protease activating factor 1 (Apaf‐1)‐related proteins, which are correlated to signalling of apoptosis and activation of the NF‐κB pathway [40–42]. CARD15 is important in the recognition of bacterial peptidoglycans mainly found in Gram‐negative bacteria through the binding of muramyl dipeptide, leading to NF‐κB activation [43], and in the modulation of the secretion of defensins by Paneth cells [44, 45]. Three main variants of NOD2/CARD15 have been investigated and associated mainly with CD, whereas there is poor linkage to UC [45].…”

Section: Interactions Between Microflora and Gut Mucosamentioning

confidence: 99%

Probiotics and prebiotics in inflammatory bowel disease: microflora ‘on the scope’

Damaskos¹,

Kolios²

2008

Brit J Clinical Pharma

130

104

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The intestinal microflora is a large bacterial community that colonizes the gut, with a metabolic activity equal to an organ and various functions that affect the physiology and pathology of the host's mucosal immune system. Intestinal bacteria are useful in promotion of human health, but certain components of microflora, in genetically susceptible individuals, contribute to various pathological disorders, including inflammatory bowel disease. Clinical and experimental observations indicate an imbalance in protective and harmful microflora components in these disorders. Manipulation of gut flora to enhance its protective and beneficial role represents a promising field of new therapeutic strategies of inflammatory bowel disease. In this review, we discuss the implication of gut flora in the intestinal inflammation that justifies the role of probiotics and prebiotics in the prevention and treatment of inflammatory bowel disease and we address the evidence for therapeutic benefits from their use in experimental models of colitis and clinical trials.

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Section: Interactions Between Microflora and Gut Mucosamentioning

confidence: 99%

Probiotics and prebiotics in inflammatory bowel disease: microflora ‘on the scope’

Damaskos¹,

Kolios²

2008

Brit J Clinical Pharma

130

104

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“…The observed association of the type of gastrointestinal decontamination and the prognostic significance of NOD2/CARD15 status in our present study provides some additional evidence for the role of specific pathogens, because they suggest that a Gram-positive bacterial population might be relevant for activation of NOD2/CARD15-mediated or -regulated inflammation. Because MDP, the specific ligand of NOD2/CARD15, is a bacterial cell-wall compound of both Gram-negative and Gram-positive bacteria, 20 the hypothesis seems reasonable. Of course, our conclusion is based on a relatively small number of patients and confirmation of the role of decontamination in relation to NOD2/CARD15 variants in a larger prospective series of patients is urgently needed.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of NOD2/CARD15 variants in HLA-identical sibling hematopoietic stem cell transplantation: effect on long-term outcome is confirmed in 2 independent cohorts and may be modulated by the type of gastrointestinal decontamination

Holler¹

2006

Blood

166

110

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To assess the role of NOD2/CARD15 variants on the long-term outcome of allogeneic stem cell transplantation in a genetically homogeneous group, we extended our previous study (cohort I, n ‫؍‬ 78) and typed DNA for NOD2/CARD15 single nucleotide polymorphisms (SNPs) from an additional 225 recipients and their HLAidentical sibling donors (cohort II) treated at four other European centers. Results of genotyping were compared with clinical outcome. The strong association of NOD2/CARD15 variants with transplantation-related mortality (TRM) was confirmed in univariate and multivariate analysis; TRM increased from 20% in cohort I/22% in cohort II in recipient/donor pairs without any NOD2/CARD15 variants to 47% in cohort I/32% in cohort II in the presence of one variant in either donor or recipient and further to 57% in cohort I/74% in cohort II in the presence of 2 or more variants (P < .002 in both cohorts). NOD2/CARD15 SNPs were not associated with relapse rate but had a strong impact on overall survival. In an analysis of center effects, the type of gastrointestinal decontamination was the only factor interfering with the prognostic significance of NOD2/CARD15 SNPs. Our data further support an interaction between gastrointestinal defense mechanisms, activation of the innate immune system, and specific transplant-related complications.

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“…The disease is associated with high levels of proinflammatory cytokines, which are products of NF‐κB target genes, and thereby argue against a loss‐of‐function phenotype 27 . Antibodies against TNF‐α, IL‐6, and IL‐12 and direct inhibition of NF‐κB are, at least in part, effective therapies for Crohn's disease, indicating that a dampened NF‐κB response to bacterial products seems contrary to Crohn's disease susceptibility 28 …”

Section: Nod2 Function In the Mousementioning

confidence: 99%

Innate Immune Sensing of Microbes by Nod Proteins

Kufer

Banks

Philpott

2006

Annals of the New York Academy of Sciences

109

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Nod1 and Nod2 are proteins involved in innate immune defense. These intracellular surveillance proteins detect bacterial peptidoglycan, although requiring distinct motifs to achieve sensing. Detection through Nod1 and Nod2 initiates proinflammatory signaling via NF-kappaB activation, which is necessary for clearance of infecting pathogens from the host. The peptidoglycan product sensed by Nod1 is a motif characteristic of Gram-negative bacteria plus some Gram-positive bacteria, such as Bacillus and Listeria spp. The specificity of Nod1 to detect this subset of bacteria might represent a selective advantage for the host in certain cases when Gram-negative bacteria represent the main threat, such as in the epithelial cells lining the intestinal mucosa. In contrast, Nod2 has been implicated as a general sensor for both Gram-positive and Gram-negative bacteria since muramyl dipeptide (MDP), which is the minimal motif in all peptidoglycans, is the structure recognized by Nod2. Mutations in Nod2 have been associated with autoinflammatory disease in humans, including Crohn's disease. Interestingly, the most common mutation in Nod2 associated with Crohn's disease results in protein product that no longer detects MDP. Although the implications of these findings are still not fully understood, it appears that lack of bacterial sensing through a loss of interaction between mutant Nod2 and MDP contributes to the pathology of disease. A loss of surveillance activity by Nod2 may result in the inability of local responses in the intestinal mucosa to control bacterial infection, thereby initiating systemic responses and leading to aberrant inflammation.

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Towards an understanding of the role of NOD2/CARD15 in the pathogenesis of Crohn's disease

Cited by 20 publications

References 75 publications

Probiotics and prebiotics in inflammatory bowel disease: microflora ‘on the scope’

Probiotics and prebiotics in inflammatory bowel disease: microflora ‘on the scope’

Prognostic significance of NOD2/CARD15 variants in HLA-identical sibling hematopoietic stem cell transplantation: effect on long-term outcome is confirmed in 2 independent cohorts and may be modulated by the type of gastrointestinal decontamination

Innate Immune Sensing of Microbes by Nod Proteins

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