Introduction and aims: A number of antibodies against microbial epitopes or against self-antigens have been associated with Crohn's disease (CD). The development of antibodies reflects a loss of tolerance to intestinal bacteria that underlies CD, resulting in an exaggerated adaptive immune response to these bacteria. We 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 therefore was to investigate the influence of mutations in these innate immune receptor genes (NOD2/CARD15, NOD1/CARD4, TUCAN/CARDINAL/CARD8, TLR4, TLR2, TLR1 and TLR6) on the development of antimicrobial and antiglycan antibodies in IBD.
Materials and methods: A cohort of 1163 unrelated patients with IBD (874 CD, 259 UC, 30 IC) and 312 controls were analysed for gASCA IgG, ALCA IgG, ACCA IgA, AMCA IgG and Omp IgA) and were genotyped for variants in NOD2/CARD15, TUCAN/CARDINAL/CARD8, NOD1/CARD4, TLR4, TLR1, TLR2 and TLR6.
Results: When compared with CD patients without CARD15 mutations, the presence of at least one CARD15 variant in CD patients more frequently led to gASCA positivity (66.1% vs. 51.5%, p<0.0001) and ALCA positivity (43.3% vs. 34.9%, p=0.018) and higher gASCA titers (85.7 vs. 51.8 EU, p<0.0001), independent of ileal involvement. A gene dosage effect, with increasing gASCA and ALCA positivity for patients carrying 0, 1 and 2 CARD15 variants respectively, was seen for both markers. Similarly, CD patients carrying NOD1/CARD4 indel had a higher prevalence of gASCA antibodies than wild type patients (63.8% vs. 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% vs. 35%, p=0.013) and Omp antibodies (20.5% vs. 34.6%, p=0.009) respectively.
Conclusion: We found that variants in innate immune receptor genes 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 understanding the aetiology of the seroreactivity observed in IBD.
- Inflammatory Bowel Diseases
- Intracellular Signaling Peptides and Proteins