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 language | English |
---|---|
Pages (from-to) | 766-779 |
Number of pages | 14 |
Journal | Nature Medicine |
Volume | 28 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2022 |
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In: Nature Medicine, Vol. 28, No. 4, 04.2022, p. 766-779.
Research output: Contribution to journal › Article › peer-review
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 - Funding Information: 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. Funding Information: 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. Funding Information: 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. 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 -