134 warranted with regard to all coagulation-associated peptides (e.g. fibrinogen-binding proteins of S. aureus) because patient serum was compared to control plasma, resulting in distinctly underrepresented coagulase- or fibrinogen-related peptides in patients vs. controls, which may have nothing to do with IBD. Our results provide a new line of evidence for the existence of aberrant immune responses against the gut microbiota in the pathogenesis of IBD. We observed an enrichment of antibodybound peptides targeting flagellated bacteria in the blood of patients with CD, in particular those patients with ileal disease and more aggressive disease behavior. In the context of IBD, the PhIP-Seq technology could be a powerful tool to search for systemic immune-based biomarkers and expose novel immunological targets. Furthermore, integration of PhIP-Seq data with other layers of biological information could improve our molecular understanding of IBD and expose leads for mechanistic studies to further disentangle immunopathogenesis. Thus, PhIP-Seq could become a valuable clinical application, capturing the interface between host adaptive immunity and gut microbiota and creating an “immunological fingerprint” of patients with IBD. Our results comprehensively demonstrate the vastness, diversity and nature of the human serum antibody epitope repertoire in a large cohort of patients with IBD, showing distinct antibody responses relating to a variety of disease phenotypes. Acknowledgments The authors would like to thank all participants of the 1000IBD cohort. The authors would like to thank Kate McIntyre (Scientific Editor, Dept. of Genetics, University Medical Center Groningen) for English editing. The Lifelines Biobank initiative has been made possible by a subsidy from the Dutch Ministry of Health, Welfare and Sport; the Dutch Ministry of Economic Affairs; the University Medical Center Groningen (UMCG, the Netherlands); the University of Groningen and the Northern Provinces of the Netherlands. The authors wish to acknowledge the services of the Lifelines Cohort Study, the contributing research centers delivering data to Lifelines and all study participants. Authors’ contributions Conceptualization: AB, SA-S, TV, SL, SK, INK, AW, ES, JF, AZ, RKW. Investigation: AB, SA-S, TV, SH, AVV, SL, AK, JF, AZ, RKW. Methodology: AB, SA-S, TV, SH, AVV, AK, JF, AZ, RKW. Funding acquisition: AZ, JF, RKW, CW. Supervision: JF, AZ, RKW. Writing – original draft: ARB. Writing – review and editing: all authors. Declaration of interests GD received an unrestricted research grant fromTakeda and speaker fees from Pfizer and Janssen Pharmaceuticals. RKW acted as consultant for Takeda, received unrestricted research grants from Takeda, Johnson & Johnson, Tramedico and Ferring and received speaker fees from MSD, Abbvie and Janssen Pharmaceuticals. All other authors declare no competing interests. Chapter 4
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