title: Monozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naïve-to-memory B-cell transition.
abstract: Common variable immunodeficiency (CVID), the most frequent primary immunodeficiency characterized by loss of B-cell function, depends partly on genetic defects, and epigenetic changes are thought to contribute to its aetiology. Here we perform a high-throughput DNA methylation analysis of this disorder using a pair of CVID-discordant MZ twins and show predominant gain of DNA methylation in CVID B cells with respect to those from the healthy sibling in critical B lymphocyte genes, such as PIK3CD, BCL2L1, RPS6KB2, TCF3 and KCNN4. Individual analysis confirms hypermethylation of these genes. Analysis in naive, unswitched and switched memory B cells in a CVID patient cohort shows impaired ability to demethylate and upregulate these genes in transitioning from naive to memory cells in CVID. Our results not only indicate a role for epigenetic alterations in CVID but also identify relevant DNA methylation changes in B cells that could explain the clinical manifestations of CVID individuals.
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Avda Gran Via 199-203, 08908L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Virginia C
authors.initials: VC
authors.lastname: Rodríguez-Cortez
authors.affiliation: Department of Clinical Immunology, University Hospital La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain.|Physiopathology of Lymphocytes in Immunodeficiencies Group, IdiPAZ Institute for Health Research, Paseo de la Castellana 261, 28046 Madrid, Spain.
authors.forename: Lucia
authors.initials: L
authors.lastname: Del Pino-Molina
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Avda Gran Via 199-203, 08908L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Rodríguez-Ubreva
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Avda Gran Via 199-203, 08908L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Ciudad
authors.affiliation: Unit of Computational Medicine, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, L8:05, SE-171 76 Stockholm, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Gómez-Cabrero
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Avda Gran Via 199-203, 08908L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Company
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Avda Gran Via 199-203, 08908L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Urquiza
authors.affiliation: Unit of Computational Medicine, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, L8:05, SE-171 76 Stockholm, Sweden.
authors.forename: Jesper
authors.initials: J
authors.lastname: Tegnér
authors.affiliation: Department of Immunology, University Hospital Son Espases, Carretera de Valldemossa, 79, 07120 Palma de Mallorca, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodríguez-Gallego
authors.affiliation: Department of Clinical Immunology, University Hospital La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain.|Physiopathology of Lymphocytes in Immunodeficiencies Group, IdiPAZ Institute for Health Research, Paseo de la Castellana 261, 28046 Madrid, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: López-Granados
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Avda Gran Via 199-203, 08908L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Esteban
authors.initials: E
authors.lastname: Ballestar
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism*; D016022:Case-Control Studies; D017074:Common Variable Immunodeficiency / Q000378:metabolism*; D019175:DNA Methylation; D005786:Gene Expression Regulation; D006801:Humans; D007156:Immunologic Memory; D014430:Twins, Monozygotic