Innate immune defence: NOD2 and autophagy in the pathogenesis of Crohn’s disease

Division of Gastroenterology and Hepatology, University Hospital Basel, Switzerland.
Schweizerische medizinische Wochenschrift (Impact Factor: 2.09). 01/2011; 140:w13135. DOI: 10.4414/smw.2010.13135
Source: PubMed


Crohn's disease (CD) is a chronic inflammatory disorder of the gut with a poorly understood aetiology. Epidemiological studies suggest that the disease occurs in genetically susceptible individuals as a consequence of defects in mucosal barrier function and disregulated immune recognition of commensal gut flora. Of more than 30 genetic loci associated with CD, two genes with important polymorphisms, encoding the intracellular bacterial sensor NOD2/CARD15 and the autophagic regulator ATG16L1, have gained particular prominence as they suggest an important paradigm of CD pathogenesis. Both proteins exert crucial functions in innate immune defence through intracellular bacterial recognition and destruction of bacteria. This review focuses on the physiological functions of the protein products of both genes and discusses how innate immune defences are linked to autophagic processes through recruitment of ATG16L1 by the bacterial sensor NOD2 at sites of microbial infection.

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Available from: Petr Hruz, May 21, 2014
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    • "Laboratory blood tests may show elevated sedimentation rates and white cell counts, both of which are associated with intestinal inflammation. Complete blood counts from patients with IBD may reveal anemia caused by vitamin B12 deficiency and autoimmune hemolysis.29 Moreover, increasing amounts and levels of serological markers may be useful in the diagnosis of IBD and also for differentiation between Crohn’s disease and ulcerative colitis.30,31 "
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    ABSTRACT: Inflammatory bowel disease (IBD) is defined as a chronic intestinal inflammation that results from host-microbial interactions in a genetically susceptible individual. IBDs are a group of autoimmune diseases that are characterized by inflammation of both the small and large intestine, in which elements of the digestive system are attacked by the body's own immune system. This inflammatory condition encompasses two major forms, known as Crohn's disease and ulcerative colitis. Patients affected by these diseases experience abdominal symptoms, including diarrhea, abdominal pain, bloody stools, and vomiting. Moreover, defects in intestinal epithelial barrier function have been observed in a number of patients affected by IBD. In this review, we first describe the types and symptoms of IBD and investigate the role that the epithelial barrier plays in the pathophysiology of IBD as well as the major cytokines involved. We then discuss steps used to diagnose this disease and the treatment options available, and finally provide an overview of the recent research that aims to develop new therapies for such chronic disorders.
    Full-text · Article · Jun 2014 · Journal of Inflammation Research
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    • "It is involved in the innate immune response directed against components of the bacterial cell wall (Hugot et al., 2001). To date, more than 30 variations in this gene have been reported (Hruz and Eckmann, 2011). However, three main genetic variants, in the form of single nucleotide polymorphisms (encoding the p.Arg702Trp and p.Gly908Arg substitutions) and a frameshift polymorphism (p.Leu1007fsinsC)] have been shown to increase the risk for CD in Caucasian populations (Adler et al., 2011; Lesage et al., 2002). "
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    ABSTRACT: Crohn's disease is a chronic inflammatory bowel disease, with multifactorial traits, that can involve any part of the gastrointestinal tract. In recent years, a dozen genome-wide association scan and meta-analysis were published bringing the number of susceptibility alleles to more than 30 variations. However, the major susceptibility gene for Crohn's disease is NOD2, located on proximal 16q, which is involved in the innate immune response. Three main variants of this gene: two single nucleotide polymorphisms p.Arg702Trp and p.Gly908Arg substitutions and frameshift polymorphism p.Leu1007fsinsC are involved in susceptibility to Crohn's disease. There is no data about the frequency of these allelic variants in Moroccan patients with Crohn's disease. The aim of our study is to genotype the NOD2 gene to assess the involvement of these three variants in susceptibility to Crohn's disease for Moroccans. We carried out genotyping for the three variants p.Arg702Trp, p.Gly908Arg and p.Leu1007fsinsC of NOD2 gene using PCR-sequencing among 101 Moroccan patients with Crohn's disease and 107 healthy controls. The three main variants of NOD2 gene were present in Moroccan patients with no significant difference compared to controls. This preliminary study shows no evidence association of NOD2 gene with Crohn's disease in the Moroccan population.
    Full-text · Article · Jan 2012 · Gene
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    ABSTRACT: A genome-wide association study (GWAS) of leprosy reported four specific genetic polymorphisms of NOD2 that were associated with susceptibility to Mycobacterium leprae in China. Considering the role of NOD2 in innate immune defence, we performed a study in a Chinese population to determine whether the same SNPs of NOD2 that were associated with disease caused by M. leprae were also associated with disease caused by Mycobacterium tuberculosis. We performed a frequency-matched case-control study in 1043 patients with pulmonary tuberculosis and 808 unaffected controls. All subjects were >15 years old and were Han Chinese from Jiangsu Province. We extracted DNA from a blood sample from each study participant. SNPs of rs3135499, rs7194886, rs8057341 and rs9302752 in the NOD2 gene were genotyped using a TaqMan-based allelic discrimination system. Using all possible patients with tuberculosis as cases, no significant association was found between the four specific SNPs and the risk of tuberculosis. In a subgroup analysis restricted to cases with bacteriologically confirmed tuberculosis (sputum culture positive), the variant genotype of rs7194886 was significantly associated with an altered risk of tuberculosis. Compared with the CC genotype, individuals carrying the CT/TT genotype of rs7194886 had an increased risk [odds ratio (OR) 1.35, 95% confidence interval (CI) (1.05-1.72)]. The association was stronger among tobacco smokers and males. By haplotype analysis, rs9302752C-rs7194886T was associated with an increased risk of bacteriologically confirmed tuberculosis (sputum culture positive) (P = 0.039), but it was not significant after correcting for multiple comparisons. In summary, genetic polymorphisms of the SNP rs7194886 in the NOD2 gene, which were discovered in the GWAS of leprosy, might also be associated with the pulmonary tuberculosis in the Chinese population.
    No preview · Article · Jan 2012 · International Journal of Immunogenetics
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