NOD2 Variants and Antibody Response to Microbial Antigens in Crohn's Disease Patients and Their Unaffected Relatives

Department of Surgery, Cedars-Sinai Medical Center, Los Ángeles, California, United States
Gastroenterology (Impact Factor: 16.72). 02/2007; 132(2):576-86. DOI: 10.1053/j.gastro.2006.11.013
Source: PubMed


The Cdcs1 locus of the C3Bir mouse confers severe colitis associated with a decrease in innate immune function and an increase in adaptive T-cell responses to commensal bacterial products. The aim of our study was to determine if defects in innate immunity are similarly associated with increased adaptive immune responses to microbial antigens in Crohn's disease patients.
Sera from 732 patients, 220 unaffected relatives, and 200 healthy controls were tested for antibodies to oligomannan, the Pseudomonas fluorescens-related protein, Escherichia coli outer membrane porin C, CBir1 flagellin, and DNA from the same subjects was tested for 3 Crohn's disease-associated variants of the NOD2 gene, and 5 toll-like receptor (TLR) 2, 2 TLR4, and 2 TLR9 variants. The magnitude of responses to microbial antigens was examined according to variant status.
NOD2 variant carriage increased in frequency with increasing number of positive antibodies and increasing cumulative quantitative response as measured by quartile sum (P for trend, .0008 and .0003, respectively). Mean antibody and quartile sums were higher for patients carrying any NOD2 variant versus those carrying none (2.24 vs 1.92 and 10.60 vs 9.72; P = .0008 and P = 0.0003, respectively). The mean quartile sum was higher for unaffected relatives carrying any NOD2 variant versus those carrying none (10.67 vs 9.75, respectively; P = .02). No association was found between any TLR variant and the magnitude of response.
Patients with Crohn's disease and unaffected relatives carrying variants of the NOD2 gene have increased adaptive immune responses to microbial antigens.

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Available from: Carol J Landers
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    • "However, recently [40] [41] [42] [43] polymorphisms of this gene, like R702W, G908R, and L1007finsC, were found to confer a predisposition to anti-microbial antibodies development. Furthermore, Devlin et al. [25] demonstrated that both in Crohn's disease patients and their unaffected relatives carrying any NOD2 variant, the number of positive antibodies and their semi-quantitative levels were higher than in those with no variants. It is therefore possible that relatives, who share the same genetic background, are more prone to develop anti-microbial antibodies. "
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    ABSTRACT: BACKGROUND: Antibodies directed towards bacterial antigens are considered as serological markers of Crohn's disease. Their role in disease pathogenesis is still under investigation. AIM: Assess the serologic response towards microbial antigens in Crohn's disease patients, their unaffected first-degree relatives and healthy controls. METHODS: This retrospective study included 60 Crohn's disease patients, 86 unaffected first-degree relatives and 100 healthy controls. Their sera were tested for anti-chitobioside, anti-laminaribioside, anti-mannobioside, anti-Saccharomyces cerevisiae and anti-outer membrane porin C of Escherichia coli. RESULTS: The prevalence of anti-chitobioside and anti-laminaribioside was higher in Crohn's disease patients and their first-degree relatives than in healthy controls (51.67%, 61.63% and 8%, respectively, for anti-chitobioside and 76.17%, 88.37% and 23.00% for anti-laminaribioside; p<0.0001). The cumulative semiquantitative immune response against all the tested antibodies was higher in unaffected relatives than in healthy controls (p<0.001). The quantitative analysis revealed that serum levels of anti-chitobioside, anti-laminaribioside and anti-mannobioside were similar in first-degree relatives and Crohn's disease patients and higher than healthy controls (p<0.001). CONCLUSIONS: Both qualitative and quantitative analysis revealed that unaffected first-degree relatives have increased antibody response to microbial antigens. This impaired immunological response towards enteric microorganisms may result from a genetic predisposition.
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    • "Additionally, anti-CBir1 activity is associated with penetrating, fibrostenosing disease [16]. Further detection of these serologies have also aided in revealing that mucosal dysregulation exists in unaffected relatives who carry genetic markers for IBD in comparison with controls who do not [17,20]. "
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    ABSTRACT: Ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) share similarities and are classified as spondyloarthropathies. In IBD, anti-Saccharomyces cerevisiae antibody (ASCA), anti-I2 (associated with anti-Pseudomonas activity), anti-Escherichia coli outer membrane porin C (anti-OmpC), anti-flagellin (anti-CBir1), and antineutrophil cytoplasmic antibodies (ANCA) possess clinical significance. Because of the overlap between the two conditions, a pilot study was designed to compare the frequency of these antibodies in AS patients compared to normal controls. Serum stored from 80 AS patients and 80 control subjects was available for analysis. ASCA, anti-I2, anti-OmpC, anti-CBir1, and ANCA studies were completed on all serum samples using Enzyme-Linked Immunosorbent Assay (ELISA) methodology. The following analyses were performed: comparison of positivity based on the established values in IBD, median values, the number of subjects in each serology in the 4th quartile of a normal distribution, and the mean quartile sum of all the antibodies. There was no difference in positivity rates between AS and control groups with the established IBD values. The median anti-I2 response was significantly higher in AS than in controls (11.78 vs 7.86, p = 0.017). Significantly more AS patients had quartile scores of 4 for the following antibody responses: ASCA IgG (26% vs 13%, p = 0.016, OR = 2.49, CI 1.168 - 5.313), ASCA IgG and IgA (27% vs 12%, p = 0.006, OR = 2.9, CI: 1.342 - 6.264), and anti - I2 (25% vs 14%, p = 0.0424, OR = 2.15, CI: 1.018 - 4.538). The mean quartile sum of the antibody responses was elevated in AS patients when ANCA was excluded (10.526 vs 9.519, p = 0.03). When ANCA was included, this difference lost significance. The data from this pilot study points towards mucosal dysregulation as an important pathway in AS. We were able to demonstrate that anti-I2 could play a pathologic role in AS. The elevated mean total antibody response being significant only with ANCA exclusion is consistent with the histopathological evidence that intestinal inflammation in AS is similar to Crohn's disease. To better define the roles of these antibodies in AS, larger studies with more precisely defined patient characteristics are required.
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    • "The present data further support this opinion. In addition, this excess of yeast and bacteria translocation through PP of KO mice is in agreement with recent reports showing that mutated CD patients and their unaffected relatives develop more frequently antibodies to Saccharomyces cerevisiae, Pseudomonas fluorescens–related protein, Escherichia coli outer membrane porin C and CBir1 flagellin [38]. The excessive bacteria and yeast passage reported here may participate in the enhancement of adaptive immune responses to microbial antigens. "
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