Ulcerative Colitis is characterized by an intense and plasmablast skewed humoral response that associates with treatment resistance and disease complications

B cells, critical for intestinal homeostasis, remain under-studied in ulcerative colitis (UC). Using single-cell RNA sequencing, single cell IgH gene sequencing, and protein-level validation across three large UC cohorts, we mapped the cellular and clonotypic landscape of mucosal and circulating B cells in UC. We found major perturbations within the mucosal B cell compartment, including an expansion of naïve B cells and IgG+ plasma cells (PC) with curtailed diversity and maturation. Furthermore, we isolated an autoreactive plasma cell clone from inflamed UC intestines. We also identified a subset of intestinal CXCL13-expressing T follicular helper cells that were associated with the pathogenic B cell response. Finally, across three distinct cohorts, we confirmed that changes in intestinal humoral immunity are reflected in circulation by the expansion of gut-homing plasmablasts that associate with disease activity and predict disease complications. Our data demonstrate a highly dysregulated B cell response in UC and revisit the role of B cells in disease pathogenesis. Single cell RNA sequencing was performed on cells extracted from colonic biopsies of inflamed mucosa (ulcerative colitis patients, n=5) and normal colonic mucosa (healthy controls, n=4) Please note that sample titles have been updated on Sep 21, 2021.