42 Inflammatory Bowel Disease and Antibody Responses The human gut microbiota, which includes bacteria, viruses, fungi and various other microorganisms, closely interact with the intestinal barrier, where a large number of luminal antigens enter the tissue, and the underlying mucosal immune system continuously samples these antigens as an immune surveillance mechanism.1 In IBD, increased exposure of luminal antigens to the mucosal and systemic immune system occurs, which may in turn drive intestinal inflammation.2 Thus, antimicrobial antibody responses against the gut microbiota, but also antibody responses against self-antigens (autoimmunity), are frequently observed in patients with IBD, particularly in CD.3 However, the exact nature and functional capacity of the antigens targeted is largely unknown, including their potential implications for IBD pathogenesis. A key challenge lies in the systematic characterization of the human antibody epitope repertoire, measurement of which is usually limited to a few hundred to few thousand antigen epitopes.4 However, recently developed high-throughput, high-resolution antibody profiling technologies have overcome this limitation and may thus become powerful tools for revealing novel immunological targets and improving our understanding of IBD immunopathogenesis. Importantly, these technologies harbor potential for the development of new clinical applications for IBD such as prediction of treatment responses or early detection of disease onset. In this review, we provide a concise overview of humoral immunological alterations and host–microbe interactions in IBD in concert with loss of immunological tolerance. We also critically assess the currently known serological indicators for IBD and their clinical utility and discuss both conventional and innovative state-of-the-art antibody profiling techniques. We further discuss the clinical potential of systematic antibody epitope repertoire profiling for IBD. Finally, we provide future perspectives on how to leverage antibody-based biomarker signatures to enable precision medicine in IBD. Box 1. Pathophysiology of IBD and serological antibodies Inflammatory bowel diseases (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), are chronic, immune-mediated inflammatory diseases of the gastrointestinal (GI) tract. These noncommunicable diseases are characterized by a considerable degree of interpatient heterogeneity and pathophysiological complexity.5 The incidence of IBD is rising globally, especially in Westernized countries, showing varying trends depending on genetic background but similar patterns for men and women.6 Although the exact cause of IBD is unknown, its pathogenesis is considered to be multifactorial, consisting of an interplay between genetic susceptibility, gut microbiota, host immune system and environmental triggers such as lifestyle and dietary habits.7,8 IBD clinically manifests in symptoms such as abdominal pain, diarrhea (with or without blood loss), fatigue, weight loss and several extraintestinal manifestations (e.g. arthritis, uveitis, and skin abnormalities). Patients typically show a ‘relapse–remitting’ disease course in which periods of remission alternate with disease exacerbations that require urgent medical intervention.9 However, clinical symptomatology is heterogeneous, which necessitates the use of additional diagnostics. Usually, diagnosis is based on a combination of clinical, biochemical, endoscopic, radiologic and histological investigations.10 Upon initial clinical presentation, an ileo-colonoscopy (endoscopy) must be performed. Endoscopically, CD is characterized by Chapter 2
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