期刊
NATURE MEDICINE
卷 28, 期 4, 页码 766-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41591-022-01680-y
关键词
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资金
- NIH/NIDDK [R01 112296]
- Rainin Foundation Synergy Grant
- Ministerio de Ciencia, Innovacion y Universidades [RTI2018-093894-B-I00]
- Crohn's and Colitis Foundation [R01 AI119006, R01 AI157137, DK121009, DK110352]
- French National Society of Gastroenterology
- Fondation pour la Recherche Medicale [FDM 41552]
- Prix pour les jeunes chercheurs' de la Fondation Bettencourt-Schueller
- Philippe Foundation
- ANR JCJC [ANR-20-CE17-0009]
- Swedish Research Council [201506486]
- Takeda Pharmaceuticals
- Medical Research Council New Investigator Research Grant [MR/N024907/1]
- Wellcome Trust Investigator Award [220268/Z/20/Z]
- ECCO-IOBD fellowship
- NExT 'Junior Talent'
- [P01 AI061093]
- [K23KD111995]
- Wellcome Trust [220268/Z/20/Z] Funding Source: Wellcome Trust
The study revealed highly dysregulated B cell response in UC patients, with major alterations in colonic B cells, reduced clonal diversity of plasma cells, and the potential of circulating gut-homing plasmablasts as a biomarker for disease activity.
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 alpha v beta 6 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. Multi-modal profiling reveals major alterations in colonic B cells in patients with ulcerative colitis, including reduced clonal diversity of plasma cells, and suggests that circulating gut-homing plasmablasts could serve as a biomarker for disease activity.
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