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

Mathieu Uzzan; Jerome C. Martin; Luka Mesin; Alexandra E. Livanos; Tomas Castro-Dopico; Ruiqi Huang; Francesca Petralia; Giuliana Magri; Shashi Kumar; Qing Zhao; Adam K. Rosenstein; Minami Tokuyama; Keshav Sharma; Ryan Ungaro; Roman Kosoy; Divya Jha; Jeremy Fischer; Harpriya Singh; Mary E. Keir; Nandhini Ramamoorthi; William E.O’ Gorman; Benjamin L. Cohen; Adeeb Rahman; Francesca Cossarini; Akihiro Seki; Louise Leyre; Sonia Tejedor Vaquero; Sakteesh Gurunathan; Emilie K. Grasset; Bojan Losic; Marla Dubinsky; Alexander J. Greenstein; Zoe Gottlieb; Peter Legnani; James George; Haritz Irizar; Aleksandar Stojmirovic; Carrie Brodmerkel; Andrew Kasarkis; Bruce E. Sands; Glaucia Furtado; Sergio A. Lira; Zewen K. Tuong; Huaibin M. Ko; Andrea Cerutti; Charles O. Elson; Menna R. Clatworthy; Miriam Merad; Mayte Suárez-Fariñas; Carmen Argmann; Jason A. Hackney; Gabriel D. Victora; Gwendalyn J. Randolph; Ephraim Kenigsberg; Jean Frederic Colombel; Saurabh Mehandru

doi:10.1038/s41591-022-01680-y

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

Mathieu Uzzan, Jerome C. Martin, Luka Mesin, Alexandra E. Livanos, Tomas Castro-Dopico, Ruiqi Huang, Francesca Petralia, Giuliana Magri, Shashi Kumar, Qing Zhao, Adam K. Rosenstein, Minami Tokuyama, Keshav Sharma, Ryan Ungaro, Roman Kosoy, Divya Jha, Jeremy Fischer, Harpriya Singh, Mary E. Keir, Nandhini RamamoorthiWilliam E.O’ Gorman, Benjamin L. Cohen, Adeeb Rahman, Francesca Cossarini, Akihiro Seki, Louise Leyre, Sonia Tejedor Vaquero, Sakteesh Gurunathan, Emilie K. Grasset, Bojan Losic, Marla Dubinsky, Alexander J. Greenstein, Zoe Gottlieb, Peter Legnani, James George, Haritz Irizar, Aleksandar Stojmirovic, Carrie Brodmerkel, Andrew Kasarkis, Bruce E. Sands, Glaucia Furtado, Sergio A. Lira, Zewen K. Tuong, Huaibin M. Ko, Andrea Cerutti, Charles O. Elson, Menna R. Clatworthy, Miriam Merad, Mayte Suárez-Fariñas, Carmen Argmann, Jason A. Hackney, Gabriel D. Victora, Gwendalyn J. Randolph, Ephraim Kenigsberg, Jean Frederic Colombel, Saurabh Mehandru

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

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	https://doi.org/10.1038/s41591-022-01680-y
State	Published - Apr 2022

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Uzzan, M., Martin, J. C., Mesin, L., Livanos, A. E., Castro-Dopico, T., Huang, R., Petralia, F., Magri, G., Kumar, S., Zhao, Q., Rosenstein, A. K., Tokuyama, M., Sharma, K., Ungaro, R., Kosoy, R., Jha, D., Fischer, J., Singh, H., Keir, M. E., ... Mehandru, S. (2022). Ulcerative colitis is characterized by a plasmablast-skewed humoral response associated with disease activity. Nature Medicine, 28(4), 766-779. https://doi.org/10.1038/s41591-022-01680-y

@article{8afbef021bb94765a2dea6839ce02e70,

title = "Ulcerative colitis is characterized by a plasmablast-skewed humoral response associated with disease activity",

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.",

author = "Mathieu Uzzan and Martin, {Jerome C.} and Luka Mesin and Livanos, {Alexandra E.} and Tomas Castro-Dopico and Ruiqi Huang and Francesca Petralia and Giuliana Magri and Shashi Kumar and Qing Zhao and Rosenstein, {Adam K.} and Minami Tokuyama and Keshav Sharma and Ryan Ungaro and Roman Kosoy and Divya Jha and Jeremy Fischer and Harpriya Singh and Keir, {Mary E.} and Nandhini Ramamoorthi and Gorman, {William E.O{\textquoteright}} and Cohen, {Benjamin L.} and Adeeb Rahman and Francesca Cossarini and Akihiro Seki and Louise Leyre and Vaquero, {Sonia Tejedor} and Sakteesh Gurunathan and Grasset, {Emilie K.} and Bojan Losic and Marla Dubinsky and Greenstein, {Alexander J.} and Zoe Gottlieb and Peter Legnani and James George and Haritz Irizar and Aleksandar Stojmirovic and Carrie Brodmerkel and Andrew Kasarkis and Sands, {Bruce E.} and Glaucia Furtado and Lira, {Sergio A.} and Tuong, {Zewen K.} and Ko, {Huaibin M.} and Andrea Cerutti and Elson, {Charles O.} and Clatworthy, {Menna R.} and Miriam Merad and Mayte Su{\'a}rez-Fari{\~n}as and Carmen Argmann and Hackney, {Jason A.} and Victora, {Gabriel D.} and Randolph, {Gwendalyn J.} and Ephraim Kenigsberg and Colombel, {Jean Frederic} and Saurabh Mehandru",

note = "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, Innovaci{\'o}n 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{\textquoteright}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 M{\'e}dicale (FDM 41552). J.C.M. was supported by {\textquoteleft}Prix pour les jeunes chercheurs{\textquoteright} de la Fondation Bettencourt-Schueller, the Philippe Foundation, NExT {\textquoteleft}Junior Talent{\textquoteright} 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{\textquoteright}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, Innovaci{\'o}n 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{\textquoteright}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 M{\'e}dicale (FDM 41552). J.C.M. was supported by {\textquoteleft}Prix pour les jeunes chercheurs{\textquoteright} de la Fondation Bettencourt-Schueller, the Philippe Foundation, NExT {\textquoteleft}Junior Talent{\textquoteright} 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{\textquoteright}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: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = apr,

doi = "10.1038/s41591-022-01680-y",

language = "English",

volume = "28",

pages = "766--779",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "4",

}

Uzzan, M, Martin, JC, Mesin, L, Livanos, AE, Castro-Dopico, T, Huang, R, Petralia, F, Magri, G, Kumar, S, Zhao, Q, Rosenstein, AK, Tokuyama, M, Sharma, K, Ungaro, R, Kosoy, R, Jha, D, Fischer, J, Singh, H, Keir, ME, Ramamoorthi, N, Gorman, WEO, Cohen, BL, Rahman, A, Cossarini, F, Seki, A, Leyre, L, Vaquero, ST, Gurunathan, S, Grasset, EK , Losic, B , Dubinsky, M, Greenstein, AJ, Gottlieb, Z, Legnani, P, George, J, Irizar, H, Stojmirovic, A, Brodmerkel, C, Kasarkis, A, Sands, BE , Furtado, G , Lira, SA, Tuong, ZK, Ko, HM, Cerutti, A, Elson, CO, Clatworthy, MR, Merad, M, Suárez-Fariñas, M , Argmann, C, Hackney, JA, Victora, GD, Randolph, GJ, Kenigsberg, E , Colombel, JF & Mehandru, S 2022, 'Ulcerative colitis is characterized by a plasmablast-skewed humoral response associated with disease activity', Nature Medicine, vol. 28, no. 4, pp. 766-779. https://doi.org/10.1038/s41591-022-01680-y

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 -

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

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