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