45 Under pathophysiological circumstances, pathogenic bacteria (dysbiosis), injury or other stress factors trigger intestinal epithelial cells to produce pro-inflammatory cytokines (e.g. IL-1β, IL-6 and IL-18). Similarly, APCs will produce pro-inflammatory cytokines such as IL-6, IL-12 and IL-23 upon antigenic exposure, and these promote the proliferation and differentiation of effector T-lymphocyte subsets (Th1, Th2, Th9 and Th17 being the main subtypes). In addition, innate immune cell types including neutrophils, eosinophils, NK-cells and mucosa-residing fibroblasts respond to the pro-inflammatory cytokine environment by, for example, the production of epithelial barrier-protective IL-22 (which counteracts the disruptive actions of IL-9). Abbreviations: AMPs, antimicrobial peptides; IEL, intra-epithelial lymphocyte; NK-cell, natural killer cell; sIgA, secretory IgA; TGF-β, transforming growth factor β; TH, helper T-lymphocyte; Treg, regulatory T-lymphocyte; TSLP, thymic stromal lymphopoietin. Compared to healthy individuals, patients with IBD display several abnormalities of the gut microbiota, including decreased microbial diversity, lower numbers of commensal bacteria and increased proportions of potentially pathogenic bacteria.19 Simultaneously, intestinal barrier function is compromised in IBD, which may facilitate the passage of microbial antigens across the mucosa and may elicit aberrant mucosal and systemic immune responses. This occurs in combination with IBD-associated immunological defects such as defective bacterial clearance, impaired autophagy, or diminished production of AMPs, which may originate from genetic variation in IBD risk genes such as NOD2, ATG16L1, or IRGM.20 Consequently, this defective acute immune response may trigger a compensatory adaptive immune response that is accompanied by the initiation and perpetuation of chronic intestinal inflammation.21 A dysbiotic and inflammatory intestinal micro-environment is mediated by the production of pro-inflammatory cytokines (e.g. IL-1β, IL-6, TNF-α, or IL-12) by intestinal epithelial cells, DCs and macrophages, thereby overriding the anti-inflammatory defense components but promoting the development of effector CD4+ Th1-, Th2-, Th9- and/or Th17-differentiated T-lymphocytes and plasma cells to produce the corresponding neutralizing antibodies. Synchronously, other immune cells, like NKcells, γδ-T-lymphocytes, neutrophils and eosinophils, are recruited and get activated, depending on the nature of the immunological triggers and the cytokine environment.17 In this respect, the role of humoral immunity in the immunopathogenesis of IBD has long been recognized. Compared with healthy individuals, patients with IBD generally exhibit increased activation of humoral immune responses and distinct differences in the production of immunoglobulin subclasses.22 Antibody responses in IBD generally fall within two broad categories: autoimmune reactivity and antimicrobial reactivity. Although the biological relevance of autoimmune antibodies remains elusive, they are particularly observed in patients with UC. For instance, the frequency of pANCA seropositivity and associated titers is consistently higher in UC compared to CD or healthy individuals.23 Although the exact antigenic structure targeted by pANCA has never been identified, it has historically been suggested that it may represent crossreactivity with a bacterial structure directed against the perinuclear membrane of neutrophils.24 Similarly, an autoimmune response against the microfilament protein tropomyosin (especially the 1 and 5 isoforms) is typically found in the blood and intestinal mucosa of patients with UC, but not in CD.25 Conversely, antibody-formation against various microbial antigens is characteristically observed in CD. Relevant examples include ASCA, anti-flagellin antibodies (e.g. anti-CBir1), or Antibody signatures in IBD: developments and applications
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