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

Javier Rodríguez-Ubreva (), Anna Arutyunyan, Marc Jan Bonder, Lucía Del Pino-Molina, Stephen J. Clark, Carlos de la Calle-Fabregat, Luz Garcia-Alonso, Louis-François Handfield, Laura Ciudad, Eduardo Andrés-León, Felix Krueger, Francesc Català-Moll, Virginia C. Rodríguez-Cortez, Krzysztof Polanski, Lira Mamanova, Stijn van Dongen, Vladimir Yu. Kiselev, María T. Martínez-Saavedra, Holger Heyn, Javier Martín, Klaus Warnatz, Eduardo López-Granados, Carlos Rodríguez-Gallego, Oliver Stegle, Gavin Kelsey, Roser Vento-Tormo () and Esteban Ballestar ()
Additional contact information
Javier Rodríguez-Ubreva: Josep Carreras Research Institute (IJC), Badalona
Anna Arutyunyan: Wellcome Genome Campus
Marc Jan Bonder: Wellcome Genome Campus
Lucía Del Pino-Molina: Center for Biomedical Network Research on Rare Diseases (CIBERER U767)
Stephen J. Clark: Babraham Institute
Carlos de la Calle-Fabregat: Josep Carreras Research Institute (IJC), Badalona
Luz Garcia-Alonso: Wellcome Genome Campus
Louis-François Handfield: Wellcome Genome Campus
Laura Ciudad: Josep Carreras Research Institute (IJC), Badalona
Eduardo Andrés-León: Consejo Superior de Investigaciones Científicas (IPBLN-CSIC)
Felix Krueger: Babraham Institute
Francesc Català-Moll: Josep Carreras Research Institute (IJC), Badalona
Virginia C. Rodríguez-Cortez: L’Hospitalet de Llobregat
Krzysztof Polanski: Wellcome Genome Campus
Lira Mamanova: Wellcome Genome Campus
Stijn van Dongen: Wellcome Genome Campus
Vladimir Yu. Kiselev: Wellcome Genome Campus
María T. Martínez-Saavedra: Hospital Universitario de Gran Canaria Dr Negrín
Holger Heyn: Barcelona Institute of Science and Technology (BIST)
Javier Martín: Consejo Superior de Investigaciones Científicas (IPBLN-CSIC)
Klaus Warnatz: University of Freiburg
Eduardo López-Granados: Center for Biomedical Network Research on Rare Diseases (CIBERER U767)
Carlos Rodríguez-Gallego: Hospital Universitario de Gran Canaria Dr Negrín
Oliver Stegle: Wellcome Genome Campus
Gavin Kelsey: University of Cambridge
Roser Vento-Tormo: Wellcome Genome Campus
Esteban Ballestar: Josep Carreras Research Institute (IJC), Badalona

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-29450-x

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