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

Nature Medicine volume 28, pages 766–779 (2022)Cite this article

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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.

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Fig. 1: PBs, IgG-secreting PCs and IFN-imprinted naive B cells are expanded in the inflamed colons of patients with UC.
Fig. 2: Major disruptions of B cell populations in inflamed colon of patients with UC.
Fig. 3: Colonic PCs have reduced diversity, longer CDR3 regions and fewer somatic mutations in patients with UC.
Fig. 4: CXCL13+ TPH cells are expanded in the inflamed mucosa of patients with UC.
Fig. 5: Circulating β7-integrin-expressing PBs are expanded in patients with active UC and relate to disease activity.
Fig. 6: An increase in gut-homing PBs/PCs is associated with disease complications and activity in two validation cohorts of patients with active UC.

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Data availability

All requests for raw and analyzed data and materials will be promptly reviewed by the corresponding author and the study team. We have provided source data files for all the figures. Raw sequencing reads of scRNA-seq samples, as well as UMI tables, are available in the Gene Expression Omnibus under accession number GSE182270. Additional raw data are provided in Supplementary Tables 1–22. Source data are provided with this paper.

Code availability

The R code developed for clustering and analyses in this study is available at our GitHub page: https://github.com/effiken/Uzzan_et_al. Source data are provided with this paper.

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Acknowledgements

We thank the patients who participated in the study. The authors would like to thank the Biorepository and Pathology Core at the Icahn School of Medicine at Mount Sinai for carrying out some of the immunostaining experiments. This work was supported by NIH/NIDDK grant R01 112296 (S.M.). Additional support was provided by a Rainin Foundation Synergy Grant to S.M., G.J.R. and J.F.C. A.C. was supported by P01 AI061093 and Ministerio de Ciencia, Innovación y Universidades grants RTI2018-093894-B-I00 and RTI2018-093894-B-I00. Other sources of support included K23KD111995 (R.C.U.), a Career Development Award from the Crohn’s and Colitis Foundation (R.C.U.), R01 AI119006 (G.D.V.), R01 AI157137 (G.D.V.), DK121009 (S.A.L.) and DK110352 (S.A.L.). M.U. was supported by an ECCO-IOBD fellowship, by a grant from the French National Society of Gastroenterology (Bourse Robert Tournut) and by the Fondation pour la Recherche Médicale (FDM 41552). J.C.M. was supported by ‘Prix pour les jeunes chercheurs’ de la Fondation Bettencourt-Schueller, the Philippe Foundation, NExT ‘Junior Talent’ and ANR JCJC (ANR-20-CE17-0009). E.K.G. was supported by a postdoctoral fellowship from the Swedish Research Council (2015-06486). Q.Z. is the recipient of a research fellowship from Takeda Pharmaceuticals. M.R.C. and T.D.C. were supported by a Medical Research Council New Investigator Research Grant (MR/N024907/1) and by a Wellcome Trust Investigator Award (220268/Z/20/Z). The sampling of the IBD cohort (Crohn’s disease and UC) was jointly designed as part of the research alliance between Janssen Biotech and the Icahn School of Medicine at Mount Sinai. Beyond this exception, no other funders had a role in analyses, design or interpretation.

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Author notes

  1. These authors contributed equally: Mathieu Uzzan, Jerome C. Martin.

Authors and Affiliations

  1. Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Mathieu Uzzan, Alexandra E. Livanos, Tomas Castro-Dopico, Adam K. Rosenstein, Minami Tokuyama, Keshav Sharma, Ryan Ungaro, Divya Jha, Harpriya Singh, Benjamin L. Cohen, Akihiro Seki, Louise Leyre, Sakteesh Gurunathan, Marla Dubinsky, Zoe Gottlieb, Peter Legnani, James George, Bruce E. Sands, Jean Frederic Colombel & Saurabh Mehandru

  2. Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Mathieu Uzzan, Jerome C. Martin, Alexandra E. Livanos, Tomas Castro-Dopico, Adam K. Rosenstein, Keshav Sharma, Divya Jha, Jeremy Fischer, Harpriya Singh, Francesca Cossarini, Akihiro Seki, Louise Leyre, Emilie K. Grasset, Glaucia Furtado, Sergio A. Lira, Andrea Cerutti, Miriam Merad, Ephraim Kenigsberg & Saurabh Mehandru

  3. Paris Est Créteil University UPEC, Assistance Publique-Hôpitaux de Paris (AP-HP), Henri Mondor Hospital, Fédération Hospitalo-Universitaire, InnovaTive theRapy for immUne disordErs (TRUE), Gastroenterology Department, Créteil, France

    Mathieu Uzzan

  4. Université de Nantes, INSERM, CHU Nantes, Centre de Recherche en Transplantation et Immunologie, Nantes, France

    Jerome C. Martin

  5. CHU Nantes, Laboratoire d’Immunologie, Center for Immuno Monitoring Nantes-Atlantique (CIMNA), Nantes, France

    Jerome C. Martin

  6. Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY, USA

    Luka Mesin & Gabriel D. Victora

  7. Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK

    Tomas Castro-Dopico, Zewen K. Tuong & Menna R. Clatworthy

  8. Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Ruiqi Huang, Bojan Losic, Andrew Kasarkis, Mayte Suárez-Fariñas & Carmen Argmann

  9. Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Ruiqi Huang, Francesca Petralia, Roman Kosoy, Adeeb Rahman, Haritz Irizar & Ephraim Kenigsberg

  10. Translational Clinical Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain

    Giuliana Magri, Sonia Tejedor Vaquero & Andrea Cerutti

  11. Washington University School of Medicine, St. Louis, MO, USA

    Shashi Kumar & Gwendalyn J. Randolph

  12. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Qing Zhao & Charles O. Elson

  13. Icahn Institute for Data Science and Genomic Technology, New York, NY, USA

    Roman Kosoy, Bojan Losic, Andrew Kasarkis, Mayte Suárez-Fariñas & Carmen Argmann

  14. Biomarker Discovery, OMNI, Genentech Inc., South San Francisco, CA, USA

    Mary E. Keir & Nandhini Ramamoorthi

  15. OMNI Biomarker Development, Genentech Inc., South San Francisco, CA, USA

    William E. O’Gorman

  16. Human Immune Monitoring Core, Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Adeeb Rahman

  17. Immunai, New York NY, USA

    Adeeb Rahman

  18. Department of Medicine Division of Clinical Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Emilie K. Grasset

  19. Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Alexander J. Greenstein

  20. Janssen R&D, Spring House, Philadelphia, PA, USA

    Aleksandar Stojmirovic & Carrie Brodmerkel

  21. Sema4, Stamford, CT, USA

    Andrew Kasarkis

  22. Cellular Genetics, Wellcome Sanger Institute, Hinxton, UK

    Zewen K. Tuong & Menna R. Clatworthy

  23. Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Huaibin M. Ko

  24. Catalan Institute for Research and Advanced Studies (ICREA), Barcelona, Spain

    Andrea Cerutti

  25. Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, CA, USA

    Jason A. Hackney

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  1. Mathieu Uzzan
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Contributions

S.M., M.U. and J.M. drafted the manuscript. S.M. designed the study, supervised experimental data collection and coordinated integration of collaboration between all participating laboratories. All other authors contributed to experimental data and analyses, and, along with S.M., M.U. and J.M., they critically reviewed and edited the final version of the manuscript.

Corresponding author

Correspondence to Saurabh Mehandru.

Ethics declarations

Competing interests

S.M. and J.F.C. have an unrestricted, investigator-initiated grant from Takeda Pharmaceuticals to examine novel homing mechanisms to the gastrointestinal tract. R.C.U. has served as an advisory board member or consultant for Eli Lilly, Janssen, Pfizer and Takeda. Mount Sinai coauthors (from Genetics and Genomics, Icahn Institute for Data Science and Genomic Technology, Human Immune Monitoring Center, Population Health Science and Policy, Division of Gastroenterology, Pediatric GI and Hepatology, Susan and Leonard Feinstein IBD Clinical Center at the Icahn School of Medicine at Mount Sinai) were partially funded as part of the research alliance between Janssen Biotech and the Icahn School of Medicine at Mount Sinai. J.P. and C.B. are employees of Janssen Research and Development, and J.R.F. is a former employee of Janssen Research and Development and is currently employed at Alnylam Pharmaceuticals. M.K., N.R., W.O. and J.H. are all employees of Genentech. M.D. is a consultant for Janssen, Abbvie, Arena, Bristol Meyers Squibb, Boehringer Ingelheim, Eli Lilly, Janssen, Pfizer, Prometheus Labs and Takeda. C.E. has received research support from Merck. R.U. has served as an advisory board member or consultant for AbbVie, Bristol Meyers Squibb, Janssen, Pfizer and Takeda and has received research support from AbbVie, Boehringer Ingelheim, Eli Lilly and Pfizer. J.F.C. reports receiving research grants from AbbVie, Janssen Pharmaceuticals and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, Ferring Pharmaceuticals, Shire and Takeda; receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, GlaxoSmithKline, Geneva, Iterative Scopes, Janssen Pharmaceuticals, Kaleido Biosciences, Landos, Otsuka, Pfizer, Prometheus, Sanofi, Takeda and TiGenix; and holding stock options in Intestinal Biotech Development. B.L.C. receives the following financial support: advisory boards and consultant for Abbvie, Celgene/Bristol Myers Squibb, Eli Lilly, Pfizer, Sublimity Therapeutics, Takeda and TARGET RWE; CME companies: Cornerstones and Vindico; speaking fees: Abbvie; and educational grant: Pfizer. B.S. discloses research grants from Takeda, Pfizer, Theravance Biopharma R&D and Janssen; consulting fees from 4D Pharma, Abivax, Abbvie, Alimentiv, Allergan, Amgen, Arena Pharmaceuticals, AstraZeneca, Bacainn Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Capella Bioscience, Celgene, Celltrion Healthcare, ClostraBio, Enthera, F. Hoffmann-La Roche, Ferring, Galapagos, Gilead, GlaxoSmithKline, GossamerBio, Immunic, Index Pharmaceuticals, Innovation Pharmaceuticals, Ironwood Pharmaceuticals, Janssen, Kaleido, Kallyope, Eli Lilly, MiroBio, Morphic Therapeutic, Oppilan Pharma, OSE Immunotherapeutics, Otsuka, Palatin Technologies, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Redhill Biopharma, Rheos Medicines, Salix Pharmaceuticals, Seres Therapeutics, Shire, Sienna Biopharmaceuticals, Sun Pharma, Surrozen, Takeda, Target PharmaSolutions, Teva Branded Pharmaceutical Products R&D, Thelium, Theravance Biopharma R&D, TLL Pharma, USWM Enterprises, Ventyx Biosciences, Viela Bio, Vivante Health and Vivelix Pharmaceuticals; and stock in Vivante Health and Ventyx Biosciences. All other authors declare no competing interests.

Peer review

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Nature Medicine thanks Jose Ordovas-Montanes and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Saheli Sadanand was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Outline of the patients and samples included in the study.

HC: Healthy controls; aUC: active ulcerative colitis; qUC: quiescent ulcerative colitis; PBMC = peripheral blood mononuclear cells.

Extended Data Fig. 2 Lineage grouping within 7 major cellular compartments from single-cell RNA sequencing of colonic biopsies.

a, Grouping single-cell RNA sequencing cell clusters by similarity. Heatmap showing Pearson correlation coefficients between the log-averaged expression profiles of clusters. Ordering was determined by hierarchical clustering, which unbiasedly grouped the clusters by cellular lineage (color-coded bar). b, Heatmap showing color-coded down-sampled UMI counts of representative lineage marker genes in 100 randomly selected cells per cluster. The color code on the left indicates the lineage annotation of the different clusters as follows: red=T cells; orange=innate lymphoid cells; blue= plasma cells; yellow= B cells; green= mononuclear phagocytes; purple- mast cells; teal= stromal cells. c, Major cellular compartment subtypes frequencies within total lamina propria cells. The number of cells in each cellular subtype is divided by the total number of lamina propria cells and visualized in a stacked bar for each sample (HC and patients with UC).

Extended Data Fig. 3 Characterization of the 20 colonic clusters of B cells from single-cell RNA sequencing of colonic biopsies.

a, UMI counts in B lymphocyte and plasma cell clusters. box plots represent the third quartile (top of the box), median (center lines) and first quartile (bottom of the box) of measurements, and the whiskers represent 1.5 times the interquartile range from the top or bottom of the box. b, Heat-map showing color-coded down-sampled UMI counts of highly-variable genes between clusters of B cells (n = 7621 cells) and PC (n = 21425 cells). Clusters are demarcated by gray bars. Cells were down-sampled to 2000 UMIs/cell. Detailed cell counts per B and PB/PC cluster per sample are accessible in Supplementary Table 2. c, Correlation matrix of gene modules defined by gene-to-gene correlation analysis of single cells within the B lymphocyte clusters. d, Heat-map showing color-coded down-sampled UMI counts of gene programs identifying naïve, memory and germinal center-like B lymphocytes. Clusters are demarcated by gray bars. Cells were down-sampled to 2000 UMIs/cell. e,I FN signature scores on the indicated cell types. Supplementary Table 2 shows cell-counts per cluster, box plots represent the third quartile (top of the box), median (center lines) and first quartile (bottom of the box) of measurements, and the whiskers represent 1.5 times the interquartile range from the top or bottom of the box.

Extended Data Fig. 4 JH, VH family usage and clonal relationships.

a-d, IgH V and J gene family usage in short-lived colonic PC (a,c) and in circulating gut-homing PBs (b,d). Data are shown as individual data, mean and standard deviation; Mann- Whitney test, two tailed. e, Mean IgH amino acid CDR3 length per patient excluding JH6 + clones. Mann-Whitney test, two tailed, no significant difference. Panels a-e are based on 4 HC and 4 active UC patients f, Clonal relationships of all clones analyzed for each HC and UC patient. Numbers within circles stand for total number of clones.

Extended Data Fig. 5 Serological reactivity against microbiota antigens.

Thirty-two bacterial proteins and extracts (described in detail in Supplementary Table 8) were arrayed in triplicate on 16 pad nitrocellulose slides. After blocking, patient serum was added to the respective pads to determine reactivity against these antigens. a-b, Representation of increased IgG (a) and IgA (b) reactivity against microbial antigens 14-2 F, M18-1, COE1 and EcLW in patients with UC. c, IgG and IgA serological reactivity against 32 microbial antigens. Data are shown as individual data, mean and standard deviation, t-test, two-tailed. Details of the data from panel c are also provided in Supplementary Table 7.

Extended Data Fig. 6 Generation of a molecular signature of an IgG-activated or LPS colonic macrophage activation response.

a, Generation of a molecular signature of IgG-activated macrophages using transcriptomic analysis of murine colonic macrophages stimulated ex vivo with IgG immune complexes. The signature was restricted to human- and disease-relevant genes using a second dataset of IgG IC-stimulated human monocytes (GSE102728) and elastic-net regularized logistic regression on a training mucosal UC dataset (GSE38713), respectively. A second microbial gene signature using transcriptomic analysis of colonic macrophages from DSS-treated mice and refined on LPS-treated human monocytes was also generated. b, List of constituent genes for the immune complexes signature and the LPS signature. The right panel shows the number of exclusive and shared genes between the 2 signatures.

Extended Data Fig. 7 Proportion of “resident-like” and inflammatory macrophages and their respective molecular signature.

a, Proportion of “resident-like” macrophages and inflammatory macrophages among total colonic macrophages represented in individual samples of healthy controls UC and patients. b, Heat-map showing color-coded down-sampled UMI counts of gene programs identifying LPS signature (red), immune complexes (IC) signature (green) and resident macrophage genes signatures (black).

Extended Data Fig. 8 Characterization of T cell clusters from single-cell RNA sequencing of colonic biopsies.

a, Heat-map showing the relative expression of 5 transcriptional scores (rows) (see Methods) in single T cells (n = 11281 cells) (columns). Cell clusters are demarcated by gray bars. Detailed cell counts per T cluster per sample are accessible in Supplementary Table 2. b, Euclidean distance for lineage normalized cell type frequencies was compared within healthy controls (HC), (HC-HC, blue), patients with UC (UC-UC, red) and between HC and patients with UC (HC-UC, grey) for T cells, Wilcoxon rank-sum test. c, Relative expression of genes identifying T cell subsets. Heatmap is showing log-2 transformed expression per subset divided by the mean expression across all subsets.

Extended Data Fig. 9 Representative histological examination of a surgical specimen from a UC patient before immunofluorescent staining.

Macroscopic view of colon after resection. Black arrow delineates disease margin, which runs strikingly anti-parallel to the length of the colon. b, H&E section showing disease margin (yellow) line with proximal region on the left and margin progressing toward disease distally on the right. Note the increased number of small follicles on the diseased side. c, Normal isolated lymphoid follicle in the colon. d, Proximal colon from UC patient with delimited disease in the region that appears macroscopically healthy, with abnormal fibrotic accumulation beneath the epithelial lining. e, Macroscopically normal proximal specimen from a UC patient that contains diffuse inflammatory infiltrate despite a healthy macroscopic appearance. For panels b-e, white bars = 200 μm.

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Uzzan, M., Martin, J.C., Mesin, L. et al. Ulcerative colitis is characterized by a plasmablast-skewed humoral response associated with disease activity. Nat Med 28, 766–779 (2022). https://doi.org/10.1038/s41591-022-01680-y

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