Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses.

Common variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, displays impaired terminal B-cell differentiation and defective antibody responses. Incomplete genetic penetrance and ample phenotypic expressivity in CVID suggest the participation of additional pathog...

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Autores: Rodríguez-Ubreva, Javier, Arutyunyan, Anna, Bonder, Marc J., Pino Molina, Lucía del, Clark, Stephen J., Calle-Fabregat, Carlos de la, García-Alonso, Luz, Handfield, Louis-François, Ciudad, Laura, Andrés-León, Eduardo, Krueger, Felix, Català-Moll, Francesc, Rodríguez-Cortez, Virginia C., Polanski, Krzysztof, Mamanova, Lira, Dongen, Stijn van, Kiselev, Vladimir Yu, Martínez-Saavedra, María T., Heyn, Holger, Martin, Javier, Warnatz, Klaus, López-Granados, Eduardo, Rodriguez-Gallego, Carlos, Stegle, Oliver, Kelsey, Gavin, Vento-Tormo, Roser, Ballestar, Estéban
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/361245
Acesso em linha:http://hdl.handle.net/10261/361245
Access Level:acceso abierto
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oai_identifier_str oai:digital.csic.es:10261/361245
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses.
title Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses.
spellingShingle Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses.
Rodríguez-Ubreva, Javier
title_short Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses.
title_full Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses.
title_fullStr Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses.
title_full_unstemmed Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses.
title_sort Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses.
dc.creator.none.fl_str_mv Rodríguez-Ubreva, Javier
Arutyunyan, Anna
Bonder, Marc J.
Pino Molina, Lucía del
Clark, Stephen J.
Calle-Fabregat, Carlos de la
García-Alonso, Luz
Handfield, Louis-François
Ciudad, Laura
Andrés-León, Eduardo
Krueger, Felix
Català-Moll, Francesc
Rodríguez-Cortez, Virginia C.
Polanski, Krzysztof
Mamanova, Lira
Dongen, Stijn van
Kiselev, Vladimir Yu
Martínez-Saavedra, María T.
Heyn, Holger
Martin, Javier
Warnatz, Klaus
López-Granados, Eduardo
Rodriguez-Gallego, Carlos
Stegle, Oliver
Kelsey, Gavin
Vento-Tormo, Roser
Ballestar, Estéban
author Rodríguez-Ubreva, Javier
author_facet Rodríguez-Ubreva, Javier
Arutyunyan, Anna
Bonder, Marc J.
Pino Molina, Lucía del
Clark, Stephen J.
Calle-Fabregat, Carlos de la
García-Alonso, Luz
Handfield, Louis-François
Ciudad, Laura
Andrés-León, Eduardo
Krueger, Felix
Català-Moll, Francesc
Rodríguez-Cortez, Virginia C.
Polanski, Krzysztof
Mamanova, Lira
Dongen, Stijn van
Kiselev, Vladimir Yu
Martínez-Saavedra, María T.
Heyn, Holger
Martin, Javier
Warnatz, Klaus
López-Granados, Eduardo
Rodriguez-Gallego, Carlos
Stegle, Oliver
Kelsey, Gavin
Vento-Tormo, Roser
Ballestar, Estéban
author_role author
author2 Arutyunyan, Anna
Bonder, Marc J.
Pino Molina, Lucía del
Clark, Stephen J.
Calle-Fabregat, Carlos de la
García-Alonso, Luz
Handfield, Louis-François
Ciudad, Laura
Andrés-León, Eduardo
Krueger, Felix
Català-Moll, Francesc
Rodríguez-Cortez, Virginia C.
Polanski, Krzysztof
Mamanova, Lira
Dongen, Stijn van
Kiselev, Vladimir Yu
Martínez-Saavedra, María T.
Heyn, Holger
Martin, Javier
Warnatz, Klaus
López-Granados, Eduardo
Rodriguez-Gallego, Carlos
Stegle, Oliver
Kelsey, Gavin
Vento-Tormo, Roser
Ballestar, Estéban
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Generalitat de Catalunya
Josep Carreras Leukemia Foundation
Ministerio de Ciencia e Innovación (España)
Instituto de Salud Carlos III
Jeffrey Modell Foundation
Chan Zuckerberg Initiative
Wellcome Sanger Institute
European Commission
Biotechnology and Biological Sciences Research Council (UK)
Medical Research Council (UK)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description Common variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, displays impaired terminal B-cell differentiation and defective antibody responses. Incomplete genetic penetrance and ample phenotypic expressivity in CVID suggest the participation of additional pathogenic mechanisms. Monozygotic (MZ) twins discordant for CVID are uniquely valuable for studying the contribution of epigenetics to the disease. Here, we generate a single-cell epigenomics and transcriptomics census of naïve-to-memory B cell differentiation in a CVID-discordant MZ twin pair. Our analysis identifies DNA methylation, chromatin accessibility and transcriptional defects in memory B-cells mirroring defective cell-cell communication upon activation. These findings are validated in a cohort of CVID patients and healthy donors. Our findings provide a comprehensive multi-omics map of alterations in naïve-to-memory B-cell transition in CVID and indicate links between the epigenome and immune cell cross-talk. Our resource, publicly available at the Human Cell Atlas, gives insight into future diagnosis and treatments of CVID patients.
publishDate 2022
dc.date.none.fl_str_mv 2022
2024
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/361245
url http://hdl.handle.net/10261/361245
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1038/s41467-022-29450-x
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses.Rodríguez-Ubreva, JavierArutyunyan, AnnaBonder, Marc J.Pino Molina, Lucía delClark, Stephen J.Calle-Fabregat, Carlos de laGarcía-Alonso, LuzHandfield, Louis-FrançoisCiudad, LauraAndrés-León, EduardoKrueger, FelixCatalà-Moll, FrancescRodríguez-Cortez, Virginia C.Polanski, KrzysztofMamanova, LiraDongen, Stijn vanKiselev, Vladimir YuMartínez-Saavedra, María T.Heyn, HolgerMartin, JavierWarnatz, KlausLópez-Granados, EduardoRodriguez-Gallego, CarlosStegle, OliverKelsey, GavinVento-Tormo, RoserBallestar, EstébanCommon variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, displays impaired terminal B-cell differentiation and defective antibody responses. Incomplete genetic penetrance and ample phenotypic expressivity in CVID suggest the participation of additional pathogenic mechanisms. Monozygotic (MZ) twins discordant for CVID are uniquely valuable for studying the contribution of epigenetics to the disease. Here, we generate a single-cell epigenomics and transcriptomics census of naïve-to-memory B cell differentiation in a CVID-discordant MZ twin pair. Our analysis identifies DNA methylation, chromatin accessibility and transcriptional defects in memory B-cells mirroring defective cell-cell communication upon activation. These findings are validated in a cohort of CVID patients and healthy donors. Our findings provide a comprehensive multi-omics map of alterations in naïve-to-memory B-cell transition in CVID and indicate links between the epigenome and immune cell cross-talk. Our resource, publicly available at the Human Cell Atlas, gives insight into future diagnosis and treatments of CVID patients.We thank the CERCA Program/Generalitat de Catalunya and the Josep Carreras Foundation for institutional support. This publication is part of the Human Cell Atlas; www.humancellatlas.org/publications. This study was funded by: Spanish Ministry of Science and Innovation (grant number PID2020-117212RB-I00/AEI/10.13038/501100011033) (E.B.), Instituto de Salud Carlos III (ISCIII), Ref. AC18/00057, associated with i-PAD project (ERARE European Union program) (E.B.), the Jeffrey Modell Foundation (E.B.), Wellcome Sanger core funding (grant no. WT206194) (R.V.-T.), the Chan Zuckerberg Initiative (grant 2020-216799) (R.V.-T. and E.B.), an EMBO short-term fellowship (J.R.U.), Fondo de Investigación Sanitaria Instituto de Salud Carlos III (FIS PI16/01605) (L.P.-M.), the Spanish Ministry of Science, Innovation and Universities (SAF2017-89109-P; AEI/FEDER, UE) (H.H.), Instituto de Salud Carlos III, Ministry of Health (PI16/00759) and European Regional Development Fund-European Social Fund—FEDER-FSE) (C.R-G.), Grupo DISA (OA18/017) (C.R.-G.), the UK Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0426) (G.K.) and Medical Research Council (MR/S000437/1) (G.K.). We are indebted to the donors for participating in this research. We thank Antonio Garcia-Gomez for graphical design support, Sarah Teichmann for her useful feedback, Hamish King for helping with single-cell germinal center dataset availability, Xi Chen for performing scATAC-seq analysis, Kirsty Ambridge and Elena Prigmore for their involvement in single-cell RNA library generation, Martin Prete for creating online visualizations for our cell atlas and Esther Castaño and Beatriz Barroso from CCiTUB Cytometry Unit for their support with single-cell sorting and Dr. Carla Gianelli and Dr. Rebeca Rodríguez Pena for the patient follow-up in the CVID cohort.Peer reviewedNature Publishing GroupGeneralitat de CatalunyaJosep Carreras Leukemia FoundationMinisterio de Ciencia e Innovación (España)Instituto de Salud Carlos IIIJeffrey Modell FoundationChan Zuckerberg InitiativeWellcome Sanger InstituteEuropean CommissionBiotechnology and Biological Sciences Research Council (UK)Medical Research Council (UK)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2024202420222024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/361245reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1038/s41467-022-29450-xSíinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3612452026-05-22T06:33:51Z
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