Uzzan M, Martin JC, Mesin L, Livanos AE, Castro-Dopico T, Huang R, Petralia F, Magri G, Kumar S, Zhao Q, Rosenstein AK, Tokuyama M, Sharma K, Ungaro R, Kosoy R, Jha D, Fischer J, Singh H, Keir ME, Ramamoorthi N, O'Gorman WE, Cohen BL, Rahman A, Cossarini F, Seki A, Leyre L, Vaquero ST, Gurunathan S, Grasset EK, Losic B, Dubinsky M, Greenstein AJ, Gottlieb Z, Legnani P, George J, Irizar H, Stojmirovic A, Brodmerkel C, Kasarkis A, Sands BE, Furtado G, Lira SA, Tuong ZK, Ko HM, Cerutti A, Elson CO, Clatworthy MR, Merad M, Suárez-Fariñas M, Argmann C, Hackney JA, Victora GD, Randolph GJ, Kenigsberg E, Colombel JF, and Mehandru S
B cells, which are critical for intestinal homeostasis, remain understudied in ulcerative colitis (UC). In this study, we recruited three cohorts of patients with UC (primary cohort, n = 145; validation cohort 1, n = 664; and validation cohort 2, n = 143) to comprehensively define the landscape of B cells during UC-associated intestinal inflammation. Using single-cell RNA sequencing, single-cell IgH gene sequencing and protein-level validation, we mapped the compositional, transcriptional and clonotypic landscape of mucosal and circulating B cells. We found major perturbations within the mucosal B cell compartment, including an expansion of naive B cells and IgG + plasma cells with curtailed diversity and maturation. Furthermore, we isolated an auto-reactive plasma cell clone targeting integrin αvβ6 from inflamed UC intestines. We also identified a subset of intestinal CXCL13-expressing TFH-like T peripheral helper cells that were associated with the pathogenic B cell response. Finally, across all three cohorts, we confirmed that changes in intestinal humoral immunity are reflected in circulation by the expansion of gut-homing plasmablasts that correlates with disease activity and predicts disease complications. Our data demonstrate a highly dysregulated B cell response in UC and highlight a potential role of B cells in disease pathogenesis., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)