Crohn's Patients and Healthy Infants Share Immunodominant B Cell Response to Commensal Flagellin Peptide Epitopes.

Background and Aims Inflammatory bowel disease is a chronic manifestation of dysregulated immune response to the gut microbiota in genetically pre-disposed hosts. Nearly half of patients with Crohn’s disease (CD) develop selective serum IgG response to flagellin proteins expressed by bacteria in the Lachnospiraceae family. This study aimed to identify the binding epitopes of these IgG antibodies and assess their relevance in CD and in homeostasis. Methods Sera from an adult CD cohort, a treatment-naïve pediatric CD cohort, and three independent non-IBD infant cohorts were analyzed using novel techniques including a flagellin peptide microarray and a flagellin peptide cytometric bead array. Results A dominant B cell peptide epitope in CD patients was identified, locating in the highly conserved “hinge region” between the D0 and D1 domains at the amino-terminus of Lachnospiraceae flagellins. Elevated serum IgG reactivity to the hinge peptide was strongly associated with incidence of CD and the development of disease complications in children with CD up to five years in advance. Notably, high levels of serum IgG to the hinge epitope were also found in most infants from 3 different geographic regions (Uganda, Sweden, and the USA) at one year of age, which decrements rapidly afterwards. Conclusions These findings identified a distinct subset of CD patients, united by a shared reactivity to a dominant commensal bacterial flagellin epitope that may represent failure of a homeostatic response to the gut microbiota beginning in infancy.