129 Surgical history has a modest impact on antibody responses in patients with IBD Patients with CD who had a history of ileocecal resection (n = 64) and patients with IBD who underwent colon resections (n = 65) did not demonstrate statistically significant differences in antibody-bound peptides (FDR < 0.05, Tables S16–17) compared to patients without surgical history. However, several top-associated antibody-bound peptides (although not passing the FDR threshold) are still noteworthy considering the type of surgical procedure performed (nominal P-values < 0.05). For example, patients with CD who underwent an ileocecal resection, more or less reflecting ileal disease involvement, more frequently demonstrated antibody responses against specific flagellin-coated bacteria, including both commensal (including Lachnospiraceae, Roseburia, Eubacterium and Agathobacter) and pathogenic (e.g. Salmonella, Yersinia, Legionellaceae and Helicobacter pylori) bacterial antigens. In addition, increased antibody responses against specific bacterial virulence factors, including autolysins, bacterial cell wall components and proteins involved in carbohydrate recognition (e.g. peptidoglycan-binding proteins and alphaglucosidases, respectively) were observed. In contrast, peptides representing human rhinoviruses, zinc metalloproteases and several belonging to Streptococcus pneumoniae (surface proteins, N-acetylglucosaminidase, autolysins) were less frequently observed in patients with a history of ileocecal resection. Patients who had undergone colon resections in the past showed consistently less frequent antibody responses against EBV nuclear proteins (mainly Epstein-Barr nuclear antigen 1, EBNA-1) and peptides from the type III secretion system (T3SS) of enteropathogenic E. coli (EPEC), which mediate the adherence to and invasion of intestinal epithelial cells. More specifically, the latter peptides belong to the EspD secretor protein and the translocated intimin receptor (Tir) of EPEC serotypes O157:H7 and O127:H6. Indeed, previous studies have shown that colonies with E. coli species belonging to phylogenetic group B2 are commonly isolated from patients with IBD with colonic disease involvement, particularly patients with (left-sided) UC.31-33 Anti-Saccharomyces cerevisiae antibodies and established IBD-associated anti-flagellin antibodies associate with the PhIP-Seq-based anti-flagellin antibody signature in patients with CD Patients with CD show consistently higher antibody reactivity against antigens of the yeast Saccharomyces cerevisiae (ASCA). In the present cohort, serological ASCA measurements (IgA/IgG, as measured by ELISA) were available for most patients (93%) at time of sampling. Percentages of ASCA positivity in patients with CD were 46% and 43% for IgA and IgG antibodies, respectively, whereas lower prevalence was observed among patients with UC (IgA: 11%; IgG: 17%). ASCA positivity was associated with multiple antibody-bound peptides derived from bacterial flagellins (Tables S18–19). In contrast, anti-neutrophil cytoplasmic antibodies (ANCA) (prevalence of titers ≥ 1:80: CD, 10%; UC, 33%) showed no strong signals when related to the antibody-bound peptides (Table S20). Subsequently, we aimed to identify four additional antimicrobial antibodies (antiEscherichia coli outer membrane porin C [anti-OmpC] and the anti-flagellin antibodies antiCBir1, anti-Fla2 and anti-A4-FlaX) that are characteristic for IBD and commercially available as a serological marker panel (Prometheus® ELISA test, together with ASCA and ANCA). Sequences of The antibody epitope repertoire in IBD
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