TY - JOUR
T1 - Ulcerative colitis is characterized by a plasmablast-skewed humoral response associated with disease activity
AU - Uzzan, Mathieu
AU - Martin, Jerome C.
AU - Mesin, Luka
AU - Livanos, Alexandra E.
AU - Castro-Dopico, Tomas
AU - Huang, Ruiqi
AU - Petralia, Francesca
AU - Magri, Giuliana
AU - Kumar, Shashi
AU - Zhao, Qing
AU - Rosenstein, Adam K.
AU - Tokuyama, Minami
AU - Sharma, Keshav
AU - Ungaro, Ryan
AU - Kosoy, Roman
AU - Jha, Divya
AU - Fischer, Jeremy
AU - Singh, Harpriya
AU - Keir, Mary E.
AU - Ramamoorthi, Nandhini
AU - Gorman, William E.O’
AU - Cohen, Benjamin L.
AU - Rahman, Adeeb
AU - Cossarini, Francesca
AU - Seki, Akihiro
AU - Leyre, Louise
AU - Vaquero, Sonia Tejedor
AU - Gurunathan, Sakteesh
AU - Grasset, Emilie K.
AU - Losic, Bojan
AU - Dubinsky, Marla
AU - Greenstein, Alexander J.
AU - Gottlieb, Zoe
AU - Legnani, Peter
AU - George, James
AU - Irizar, Haritz
AU - Stojmirovic, Aleksandar
AU - Brodmerkel, Carrie
AU - Kasarkis, Andrew
AU - Sands, Bruce E.
AU - Furtado, Glaucia
AU - Lira, Sergio A.
AU - Tuong, Zewen K.
AU - Ko, Huaibin M.
AU - Cerutti, Andrea
AU - Elson, Charles O.
AU - Clatworthy, Menna R.
AU - Merad, Miriam
AU - Suárez-Fariñas, Mayte
AU - Argmann, Carmen
AU - Hackney, Jason A.
AU - Victora, Gabriel D.
AU - Randolph, Gwendalyn J.
AU - Kenigsberg, Ephraim
AU - Colombel, Jean Frederic
AU - Mehandru, Saurabh
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/4
Y1 - 2022/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85124982669&partnerID=8YFLogxK
U2 - 10.1038/s41591-022-01680-y
DO - 10.1038/s41591-022-01680-y
M3 - Article
C2 - 35190725
AN - SCOPUS:85124982669
SN - 1078-8956
VL - 28
SP - 766
EP - 779
JO - Nature Medicine
JF - Nature Medicine
IS - 4
ER -