Ulcerative colitis is characterized by a plasmablast-skewed humoral response associated with disease activity

Mathieu Uzzan, Jerome C. Martin, Luka Mesin, Alexandra E. Livanos, Tomas Castro-Dopico, Ruiqi Huang, Francesca Petralia, Giuliana Magri, Shashi Kumar, Qing Zhao, Adam K. Rosenstein, Minami Tokuyama, Keshav Sharma, Ryan Ungaro, Roman Kosoy, Divya Jha, Jeremy Fischer, Harpriya Singh, Mary E. Keir, Nandhini RamamoorthiWilliam E.O’ Gorman, Benjamin L. Cohen, Adeeb Rahman, Francesca Cossarini, Akihiro Seki, Louise Leyre, Sonia Tejedor Vaquero, Sakteesh Gurunathan, Emilie K. Grasset, Bojan Losic, Marla Dubinsky, Alexander J. Greenstein, Zoe Gottlieb, Peter Legnani, James George, Haritz Irizar, Aleksandar Stojmirovic, Carrie Brodmerkel, Andrew Kasarkis, Bruce E. Sands, Glaucia Furtado, Sergio A. Lira, Zewen K. Tuong, Huaibin M. Ko, Andrea Cerutti, Charles O. Elson, Menna R. Clatworthy, Miriam Merad, Mayte Suárez-Fariñas, Carmen Argmann, Jason A. Hackney, Gabriel D. Victora, Gwendalyn J. Randolph, Ephraim Kenigsberg, Jean Frederic Colombel, Saurabh Mehandru

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)766-779
Number of pages14
JournalNature medicine
Volume28
Issue number4
DOIs
StatePublished - Apr 2022

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