DOP013Systemic antibody responses against herpesviruses and Bacteroides associate with disease progression in Inflammatory Bowel Disease

Abstract Background Biological mechanisms driving disease progression in patients with inflammatory bowel disease (IBD) remain largely unclear. Identification of immune signatures with prognostic value in IBD provides a unique window of opportunity with risk stratification potential and helps unravelling potential immune mechanisms. Here we aimed to define systemic antibody responses associated with disease progression in IBD using a high-throughput phage-display immunoprecipitation sequencing (PhIP-Seq) assay. Methods Serum samples from 416 patients from the 1000IBD cohort with established IBD and follow-up data were analyzed (Fig. 1). Disease progression was defined as requiring IBD-related surgery (both) or developing intestinal stenosis (CD). Systemic antibody repertoires were defined against 344,000 microbial, viral, and immune-derived peptide antigens. Multivariable Cox proportional hazards regression analyses were performed to investigate associations between antibody responses and disease progression risk. Results Patients were followed for a median of 11 years and 5 months IQR: 111-157 months. In total, 100 patients (24%) experienced disease progression during follow-up, 72 of which with CD (17%) and 28 with UC (7%) Distinct groups of antigens were targeted in patients experiencing disease progression in CD (Fig. 2A), including overrepresented antibody responses (antibody prevalence ratio 1) against Bacteroides, Streptococcus (both P0.01), bacterial flagellins, enteroviruses, and underrepresented responses (antibody prevalence ratio1) against herpesviruses (cytomegalovirus (CMV), Epstein–Barr virus (EBV)) and Haemophilus bacteria (all P0.001). In UC, overrepresented antibody responses were primarily directed at CMV, while underrepresented antibody responses were observed for EBV, Mycoplasma (P 0.001), and Bacteroides species (P 0.01) (Fig. 2B). Conclusion Massive parallel serology with epitope-level resolution revealed disease-specific immune reactivities linked to disease progression in IBD, showing divergent signatures between CD and UC. These findings suggest distinct microbial–immune pathways underlying disease progression and highlight potential prognostic biomarkers warranting validation in longitudinal studies. Conflict of interest: Griesbaum, Maximilian: No conflict of interest Veenstra, Fokkelien: No conflict of interest Geertsema, Sem: No conflict of interest AL-Radi, Zainab: No conflict of interest Weinberger, Adina: No conflict of interest Segal, Eran: No conflict of interest Vogl, Thomas: No conflict of interest Bourgonje, Arno R.: A.R.B. received speaker’s fees from AbbVie and Ferring, outside the submitted work. Weersma, Rinse K: R.K.W. acted as consultant for Takeda Pharmaceuticals received unrestricted research grants from Takeda, Johnson & Johnson, Tramedico and Ferring and received speaker’s fees from MSD, Abbvie and Janssen Pharmaceuticals.