DOP027 High-throughput antibody epitope repertoire profiling links NOD2 risk-variants to specific antibody responses in Crohn’s disease
Erlmeier, L Bourgonje, AR Hidding, IJ Weinberger, A Segal, E Vogl, T Zhernakova, A Weersma, RK
Erlmeier, L
Bourgonje, AR
Hidding, IJ
Weinberger, A
Segal, E
Vogl, T
Zhernakova, A
Weersma, RK
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Computational Biology
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Journal article
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English
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Abstract Background Genome-wide association studies have identified hundreds of risk loci for Crohn’s Disease (CD), with variants in NOD2 showing the largest effects. NOD2 is a cytosolic receptor that detects the bacterial cell-wall motif muramyl dipeptide (MDP) and helps maintain host-microbiota homeostasis. NOD2 risk variants alter the MDP-sensing domain, reducing receptor responsiveness. This impairs bacterial clearance at the mucosal surface, leading to bacterial invasion and dysregulated immune responses. A 2007 study showed NOD2 risk-variant carriers with CD had higher antibody responses against bacterial flagellins, but this work was limited to a narrow set of antigens1. Recently, phage-display immunoprecipitation sequencing (PhIP-Seq) has emerged as a high-throughput platform enabling massively parallel serology against 100,000s of antigens at epitope-level resolution and revealing hundreds of novel CD-specific reactivities2,3. Using PhIP-Seq, we here aimed to investigate whether NOD2 risk-variant carriers also exhibit altered immune responses. Methods We profiled serum antibody epitope repertoires of 1,263 individuals (255 patients with CD and 1,008 population-based controls), targeting 344,000 microbial, immune and food antigens. NOD2 variant status was derived from genome-wide genotyping and carriers were defined as individuals with ≥1 risk allele. We performed peptide-level association testing combined with enrichment analyses to investigate the antigens linked with carriers among CD patients and controls. Results We detected 2,680 bound antigens in 5-95% of 1,263 individuals (Tab.1). Among patients with CD, the ten most positively associated antigens in NOD2 risk-variant carriers were all flagellins derived from Agathobacter, Roseburia, Borreliaceae, Eubacterium spp. and Clostridiales. This increased flagellin reactivity was further supported by enrichment analysis, whereas among controls NOD2 risk-variant carriers displayed significant reduction of anti-flagellin responses (Fig.1A). Next, when grouped by taxonomic origin, we observed a strong increase in antibody responses against Clostridiales and Staphylococcus antigens, alongside a markedly less prevalent response against CMV (Fig.1B). Notably, Cins1007fs showed binding patterns opposite to the other main variants. NOD2 risk-variants were not associated with CD location and behavior. Conclusion This study represents the most comprehensive analysis to date of antibody epitope repertoires in NOD2 risk-variant carriers with CD. We extend previously established links to anti-flagellin immunity and identify new associations, including altered immune responses against human herpesviruses, which may contribute to our understanding of CD pathogenesis in genetically susceptible individuals. References: 1.Devlin SM, Yang H, Ippoliti A, et al. NOD2 Variants and Antibody Response to Microbial Antigens in Crohn`s Disease Patients and Their Unaffected Relatives. Gastroenterology. 2007;132(2):576-586. doi:10.1053/j.gastro.2006.11.013 2.Bourgonje AR, Andreu-Sanchez S, Vogl T, et al. Phage-display immunoprecipitation sequencing of the antibody epitope repertoire in inflammatory bowel disease reveals distinct antibody signatures. Immunity. Jun 13 2023;56(6):1393-1409 e6. doi:10.1016/j.immuni.2023.04.017 3.Vogl T, Klompus S, Leviatan S, et al. Population-wide diversity and stability of serum antibody epitope repertoires against human microbiota. Nature Medicine. 2021/08/01 2021;27(8):1442-1450. doi:10.1038/s41591-021-01409-3 Conflict of interest: Erlmeier, Ludwig: No conflict of interest Bourgonje, Arno R.: A.R.B. received speaker’s fees from AbbVie and Ferring, outside the submitted work. Hidding, Iwan J.: No conflict of interest Weinberger, Adina: No conflict of interest Segal, Eran: No conflict of interest Vogl, Thomas: No conflict of interest Zhernakova, Alexandra: No conflict of interest Weersma, Rinse K: No conflict of interest
Citation
L. Erlmeier, A.R. Bourgonje, I.J. Hidding, A. Weinberger, E. Segal, T. Vogl, A. Zhernakova, R.K. Weersma, "DOP027 High-throughput antibody epitope repertoire profiling links NOD2 risk-variants to specific antibody responses in Crohn’s disease," Journal of Crohn's and Colitis, vol. 20, no. Supplement_1, pp. jjaf231.064-, 2026, https://doi.org/10.1093/ecco-jcc/jjaf231.064.
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Journal of Crohn's and Colitis
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32 Biomedical and Clinical Sciences, 3202 Clinical Sciences
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Oxford University Press