HCA Data Explorer

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

Updated February 24, 2023

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.

Saurabh MehandruHenry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. saurabh.mehandru@mssm.edu.
Mathieu Uzzan1
Jerome C Martin2
Luka Mesin3
Alexandra E Livanos1
Tomas Castro-Dopico1
Ruiqi Huang4
Francesca Petralia5
Giuliana Magri6
Shashi Kumar7
Qing Zhao8
Adam K Rosenstein1
Minami Tokuyama1
Keshav Sharma1
Ryan Ungaro1
Roman Kosoy5
Divya Jha1
Jeremy Fischer2
Harpriya Singh1
Mary E Keir9
Nandhini Ramamoorthi9
William E O' Gorman10
Benjamin L Cohen1
Adeeb Rahman5
Francesca Cossarini2
Akihiro Seki1
Louise Leyre1
Sonia Tejedor Vaquero6
Sakteesh Gurunathan1
Emilie K Grasset2
Bojan Losic4
Marla Dubinsky1
Alexander J Greenstein11
Zoe Gottlieb1
Peter Legnani1
James George1
Haritz Irizar5
Aleksandar Stojmirovic12
Carrie Brodmerkel12
Andrew Kasarkis4
Bruce E Sands1
Glaucia Furtado2
Sergio A Lira2
Zewen K Tuong13
Huaibin M Ko14
Andrea Cerutti2
Charles O Elson8
Menna R Clatworthy13
Miriam Merad2
Mayte Suárez-Fariñas4
Carmen Argmann4
Jason A Hackney15
Gabriel D Victora3
Gwendalyn J Randolph7
Ephraim Kenigsberg2
Jean Frederic Colombel1
Saurabh Mehandru16
1Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
2Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
3Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY, USA.
4Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
5Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
6Translational Clinical Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
7Washington University School of Medicine, St. Louis, MO, USA.
8Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
9Biomarker Discovery, OMNI, Genentech Inc., South San Francisco, CA, USA.
10OMNI Biomarker Development, Genentech Inc., South San Francisco, CA, USA.
11Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
12Janssen R&D, Spring House, Philadelphia, PA, USA.
13Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK.
14Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
15Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, CA, USA.
16Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. saurabh.mehandru@mssm.edu.
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To reference this project, please use the following link:

https://explore.data.humancellatlas.org/projects/1688d7cc-6f5c-49ef-b353-e308b61d4e4c
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Analysis Portals

None

Project Label

Mehandru-Human-10x3pv2

Species

Homo sapiens

Sample Type

specimens

Anatomical Entity

colon

Organ Part

lamina propria of mucosa of colon

Selected Cell Types

stromal cell of lamina propria of colon

Disease Status (Specimen)

2 disease statuses

Disease Status (Donor)

2 disease statuses

Development Stage

human adult stage

Library Construction Method

10x 3' v2

Nucleic Acid Source

single cell

Paired End

false

Analysis Protocol

analysis_protocol_1

File Format

3 file formats

Cell Count Estimate

40.3k

Donor Count

9
fastq.gz64 file(s)tar1 file(s)xlsx1 file(s)