rss
Gut 56:1536-1542 doi:10.1136/gut.2007.125468
  • Inflammatory bowel disease

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

  1. Liesbet Henckaerts,
  2. Marie Pierik,
  3. Marie Joossens,
  4. Marc Ferrante,
  5. Paul Rutgeerts,
  6. Séverine Vermeire
  1. Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
  1. Dr Séverine Vermeire, Labo Gastroenterologie, E462, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium; severine.vermeire{at}uz.kuleuven.ac.be
  • Revised 30 May 2007
  • Accepted 20 June 2007
  • Published Online First 26 June 2007

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.

Footnotes

  • Conflict of interest: None declared.

  • Abbreviations:
    ACCA
    anti-chitobioside antibodies
    ALCA
    anti-laminaribioside antibodies
    AMCA
    anti-mannobioside antibodies
    ASCA
    anti-Saccharomyces cerevisiae antibodies
    CARD
    caspase recruitment domain
    EU
    ELISA units
    IBD
    inflammatory bowel disease
    LRR
    leucin-rich repeat
    NOD
    nucleotide oligomerisation domain
    Omp
    outer membrane porin
    TLR
    Toll-like receptor