25 Outline of this thesis PART I: IMMUNE-BASED BIOMARKERS IN IBD In Part I of this thesis, we focus on immune-based biomarker signatures in the context of IBD, with a special emphasis on antimicrobial immune activity. In Chapter 2, we review the current knowledge about the main humoral immunological alterations in IBD and currently available serological indicators. Furthermore, we present the state-of-the-art antibody profiling technologies and their clinical potential through systematic and in-depth profiling of the human antibody epitope repertoire. In Chapter 3 and Chapter 4, we characterise the blood antibody epitope repertoire by leveraging a phage-display immunoprecipitation sequencing (PhIP-Seq) workflow, which allowed profiling of circulating antibodies against 344,000 different microbial, immune- and food antigens. In Chapter 3, we study the role of genetic, lifestyle and intrinsic factors in shaping the human antibody epitope repertoire in a large cohort of population-based individuals. Subsequently, in Chapter 4, we compare antibody profiles of these individuals with those from patients with IBD. Specifically, in patients with IBD, we study the relationships between antibodies and disease-specific phenotypes, the capacity of antibody epitope repertoires to discriminate patients from controls, as well as the associations with (disrupted) fecal microbiome composition. In Chapter 5, we use a different approach to study antimicrobial immune responses, by combining magnetic-activated cell sorting (MACS), flow cytometry (FC) and 16S rRNA sequencing techniques to quantify fractions of IgG-coated bacteria after incubating fecal samples with autologous serum. Following this, we aimed to investigate to which bacterial groups the humoral IgG immune response is directed to in patients with IBD and healthy individuals. In Chapter 6, we switch from serological markers to mucosal (transcriptional) signatures of immune regulation, by studying the interplay between mucosal (immune) gene expression signatures and the mucosa-attached microbiota composition. PART II: INFLAMMATORY- AND FIBROSIS BIOMARKERS IN IBD In Part II of this thesis, we focus on the utility of inflammatory, gut permeability and fibrosis biomarkers with respect to disease activity and disease behaviour in the context of IBD. In Chapter 7, we study the associations between a series of Th1- and Th17-associated pro- and anti-inflammatory cytokines, chemokines, adhesion molecules and markers for vascular injury and repair versus the levels of fecal calprotectin in stool samples of patients with CD. In Chapter 8, we take a rationally-selected panel of inflammatory biomarkers (based on findings described in Chapter 7) and study their associations with measures of clinical, biochemical and endoscopic disease activity in a larger cohort of patients with IBD. In this chapter, we present a distinct set of four circulating inflammatory biomarkers that demonstrate a reasonable ability to discriminate between patients with mild vs. patients with moderate-to-severe endoscopic disease activity. In Chapter 9, we focus on 52Cr-EDTA as a potential biomarker for gut permeability in patients with CD, and present its association to disease activity as reflected by fecal calprotectin levels. In Chapter 10, we examine the potential of extracellular matrix and collagen remodelling biomarkers for discriminating between disease behaviour subclasses in patients with CD. In addition, we also aimed to study their capability to predict future disease course, i.e. the future progression of General introduction and outline of the thesis
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