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. 2007 Nov;56(11):1536-42.
doi: 10.1136/gut.2007.125468. Epub 2007 Jun 26.

Mutations in pattern recognition receptor genes modulate seroreactivity to microbial antigens in patients with inflammatory bowel disease

Liesbet Henckaerts  1 , Marie Pierik, Marie Joossens, Marc Ferrante, Paul Rutgeerts, Séverine Vermeire
Affiliations

Mutations in pattern recognition receptor genes modulate seroreactivity to microbial antigens in patients with inflammatory bowel disease

Liesbet Henckaerts et al. Gut. 2007 Nov.

Abstract

Background and aims: A number of antibodies against microbial epitopes or self-antigens have been associated with Crohn's disease. The development of antibodies reflects a loss of tolerance to intestinal bacteria that underlies Crohn's disease, resulting in an exaggerated adaptive immune response to these bacteria. It was hypothesised that the development of antimicrobial antibodies is influenced by the presence of genetic variants in pattern recognition receptor genes. The aim of this study was therefore to investigate the influence of mutations in these innate immune receptor genes (nucleotide oligomerisation domain (NOD) 2/caspase recruitment domain (CARD) 15, NOD1/CARD4, TUCAN/CARDINAL/CARD8, Toll-like receptor (TLR) 4, TLR2, TLR1 and TLR6) on the development of antimicrobial and antiglycan antibodies in inflammatory bowel disease (IBD).

Materials and methods: A cohort of 1163 unrelated patients with IBD (874 Crohn's disease, 259 ulcerative colitis, 30 indeterminate colitis) and 312 controls were analysed for anti-Saccharomyces cerevisiae antibodies (gASCA) IgG, anti-laminaribioside antibodies (ALCA) IgG, anti-chitobioside antibodies (ACCA) IgA, anti-mannobioside antibodies (AMCA) IgG and outer membrane porin (Omp) IgA and were genotyped for variants in NOD2/CARD15, TUCAN/CARDINAL/CARD8, NOD1/CARD4, TLR4, TLR1, TLR2 and TLR6.

Results: When compared with Crohn's disease patients without CARD15 mutations, the presence of at least one CARD15 variant in Crohn's disease patients more frequently led to gASCA positivity (66.1% versus 51.5%, p < 0.0001) and ALCA positivity (43.3% versus 34.9%, p = 0.018) and higher gASCA titers (85.7 versus 51.8 ELISA units, p < 0.0001), independent of ileal involvement. A gene dosage effect, with increasing gASCA and ALCA positivity for patients carrying none, one and two CARD15 variants, respectively, was seen for both markers. Similarly, Crohn's disease patients carrying NOD1/CARD4 indel had a higher prevalence of gASCA antibodies than wild-type patients (63.8% versus 55.2%, p = 0.014), also with a gene dosage effect. An opposite effect was observed for the TLR4 D299G and TLR2 P631H variants, with a lower prevalence of ACCA antibodies (23.4% versus 35%, p = 0.013) and Omp antibodies (20.5% versus 34.6%, p = 0.009), respectively.

Conclusion: Variants in innate immune receptor genes were found to influence antibody formation against microbial epitopes. In this respect, it is intriguing that an opposite effect of CARD15 and TLR4 variants was observed. These findings may contribute to an understanding of the aetiology of the seroreactivity observed in IBD.

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Conflict of interest statement

Conflict of interest: None declared.

References

    1. Hugot J P, Chamaillard M, Zouali H.et al Association of NOD2 leucine‐rich repeat variants with susceptibility to Crohn's disease. Nature 2001411599–603. - PubMed
    1. Ogura Y, Bonen D K, Inohara N.et al A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 2001411603–606. - PubMed
    1. Hampe J, Cuthbert A, Croucher P J P.et al Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet 20013571925–1928. - PubMed
    1. Vermeire S, Wild G, Kocher K.et al CARD15 genetic variation in a Quebec population: prevalence, genotype‐phenotype relationship, and haplotype structure. Am J Hum Genet 20027174–83. - PMC - PubMed
    1. Croucher P J P, Mascheretti S, Hampe J.et al Haplotype structure and association to Crohn's disease of CARD15 mutations in two ethnically divergent populations. Eur J Hum Genet 2003116–16. - PubMed

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