132 Previous studies have investigated antimicrobial antibodies as serological predictors of disease.42-45 Established anti-flagellin antibodies such as anti-CBir1, anti-Fla-X and anti-A4Fla2 (also derived from Lachnospiraceae flagellins) could accurately predict the The antibody epitope repertoire in IBD development of CD years before the actual diagnosis.44 A recent study demonstrated that pre-existent anti-flagellin antibody responses were associated with future development of CD, independent of subclinical inflammation, intestinal barrier function and genetic risk.45 This leads to speculate that serum antibody responses preceding CD-onset may constitute one of the earliest pathogenic events, as the latter study only indicated partial mediation by preclinical intestinal inflammation. Although our study was different in the sense that we did not examine a pre-disease cohort but rather patients with established IBD, systemic antibody epitope repertoires showed a highly accurate discrimination between CD and population-derived individuals, suggesting that the application of PhIP-Seq technology may also be a robust and powerful approach to predict the onset of CD and to improve our understanding of its preclinical pathogenesis. The size of the PhIP-Seq library, the possibility of high-throughput measurements and the rational selection of peptide antigens make PhIP-Seq an attractive and promising tool to characterize antibody profiles for these purposes. Notably, stratifying patients by antibody epitope repertoires may potentially aid in primary disease prevention, in a similar manner to that performed for other immune-mediated inflammatory diseases.46,47 ASCA andANCA antibodies arewell-known serological markers for CD andUC, respectively, and their presence may predict the development of IBD.48,49 Although their exact clinical utility remains questionable, they are often included in the serum biomarker panels used to predict or detect IBD.44,49,50 We observed that ASCA IgG- and IgA-antibodies, constituting established serological markers for CD, were strongly associated with increased anti-flagellin antibody peptides compared to ASCA-negative patients. However, this contradicts findings from a recent study that did not find associations between anti-flagellin antibodies and ASCA IgG/IgA.45 This may imply that anti-bacterial and anti-fungal antibodies reflect similar antibody reactivity or point to overlap in the ability of bacteria and fungi to elicit antibody responses. However, the definitive role of different antimicrobial antibody responses in the pathophysiology of IBD remains to be determined. In the present study, we observed no evident similarities, but instead rather spurious associations between gut microbial abundances and serum antibody responses. We can think of several plausible explanations for this observation. For example, serum antibody responses could be elicited from other sites of the body (e.g. the oral cavity, small intestine) beyond the colon or represent long-lasting immunity triggered by transiently present microbes. To what extent these lasting immune effects are captured, however, remains unknown. For instance, antimicrobial antibody responses in patients with a history of ileocecal resection corresponded well to typical shifts of bacterial populations that are known to occur following postoperative microbial recolonization in patients with CD.51,52 Similarly, patients who underwent colon resections in the past showed decreased antibody responses against EBV, whose presence is associated with severe, refractory colitis and a higher colectomy requirement in patients with UC.53,54 These observations underscore that profound changes in antigen exposures may not be directly reflected by antibody epitope repertoires and instead reflect the long-term adaptability Chapter 4
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