43 discontinuous involvement, ulcerative inflammation that may occur in any part of the GI tract (the terminal ileum being most commonly affected), a ‘cobblestone appearance’ and (peri-)anal lesions; in contrast, UC is macroscopically marked by superficial inflammation found exclusively in the colon.11,12 Most patients with IBD require life-long immunomodulating treatment and/or surgical intervention, necessitating adequate disease biomarkers that may be used to predict disease behavior and therapeutic response.8 Currently, serologic testing for IBD is not recommended for routine diagnostics because the added value of serological markers is considered only marginal.13 However, in clinical practice, fewwell-known serological markers are frequently determined. These include anti-Saccharomyces cerevisiae (ASCA, most specific to CD) and perinuclear anti-neutrophil cytoplasmic antibodies (pANCA, most specific to UC). Furthermore, commercially available serum biomarker panels are sometimes applied that contain the antimicrobial antibodies anti-CBir1 or anti-OmpC, among others.14,15 Based on the notion that specific antibody responses may constitute one of the earliest pathogenic events in IBD, characterization of antibody-based biomarker signatures may facilitate early detection of IBD and/or facilitate the initial disease diagnosis.16 Most of these serological markers represent microbial antigens (see Glossary), potentially reflecting impaired epithelial barrier function, loss of immunological tolerance and increased bacterial translocation in IBD. Humoral Immunity and Host–Microbe Crosstalk in IBD The microbiota in humans largely resides within the GI tract, requiring the maintenance of a delicate balance with the host immune system. In particular, the large variety of bacterial species that make up the majority of the gut microbiota represent a tremendous antigenic space. Development of the immune system is shaped by gut microbial colonization, which aims to achieve a mutualistic host–microbe environment with immunological tolerance toward nonhazardous microbial antigens.17 Under physiological conditions, microbial antigenic structures (i.e. pathogen-associated molecular patterns, PAMPs) are recognized by antigen-presenting cells (APCs) that inhabit the intestinal mucosa, mediated by activation of innate immune receptors such as Toll-like receptors or Nod-like receptors. In addition, the gut microbiota is regulated by host immune defense components such as mucins and the mucus layer (glycocalyx), antimicrobial peptides (AMPs, e.g. defensins or C-type lectins), epithelial cytokine production (e.g. IL-33, thymic stromal lymphopoietin (TSLP), or transforming growth factor-β (TGF-β)) and secretory IgA. Conversely, themicrobiotamay also influencemucosal immunity, e.g. by promoting tolerogenic dendritic cells (DCs) and macrophages, steering differentiation of specific subsets of T-lymphocytes, or modulating affinity maturation (somatic hypermutation) of protective B-lymphocytes (plasma cells) (Figure 1).18 Antibody signatures in IBD: developments and applications
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