ECCO Grant Dissecting the intestinal mucosa-associated HUMoral immune response in ileal Crohn’s Disease: the HUM-CD study

Abstract

Abstract Background and Aims The pathophysiology of Crohn's disease (CD) is complex and not fully understood. While CD can affect the entire gastrointestinal tract, it primarily affects the terminal ileum. The underlying mechanistic reasons for this preferential location are unknown. Patients with isolated ileal CD have higher levels of circulating IgG antibodies targeting flagellins. These antibodies are associated with the ileal location of CD as well as with a complicated phenotype (intestinal stenosis and fistulae). Cellular determinants of this humoral response in ileal CD are yet to be unraveled. Techniques to study B cells at the single-cell levels have tremendously evolved these recent years and our laboratory has developed expertise in most of these techniques. The objectives of our study are to comprehensively characterize the humoral B cell response in patients with ileal CD. Methods To fulfill our aim, we will use different approaches: 1. Extensive characterization of the B cell cellular and molecular landscape of the intestinal ileum in CD as compared to homeostasis states at the single-cell level 2. Dissection of the intestinal B cell antigen-specific response in CD and assess differences between inflamed and non-inflamed, and ileal and colonic mucosa and the cross-reactivity of the flagellin-specific response 3. Identification of the antigenic reactivity and clonal dynamics of memory B cells extracted from the terminal ileum of patients with CD. We will work from human samples, collected from ileal, colonic biopsies, and blood of patients with CD and healthy controls using Anticipated Impact Using advanced B-cell-focused single-cell techniques, we will unravel the humoral response at the ileal level and its association with clinical outcomes. By doing so, we aim to identify the main antigenic drivers and putative therapeutic targets of ileal CD.