Monozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naïve-to-memory B-cell transition

• Published in: Nature communications 2015-06, Vol.6 (1), p.7335-7335, Article 7335
• Main Authors: Rodríguez-Cortez, Virginia C., del Pino-Molina, Lucia, Rodríguez-Ubreva, Javier, Ciudad, Laura, Gómez-Cabrero, David, Company, Carlos, Urquiza, José M., Tegnér, Jesper, Rodríguez-Gallego, Carlos, López-Granados, Eduardo, Ballestar, Esteban
• Format: Article
• Language: English
• Subjects: 13/31; 38/15; 38/22; 38/23; 38/47; 38/77; 631/250/1619/40; 631/250/2502/2170; 692/699/249/1570; B-Lymphocytes - metabolism; Binding sites; Case-Control Studies; Common Variable Immunodeficiency - metabolism; Deoxyribonucleic acid; Disease; DNA; DNA Methylation; Epigenetics; Etiology; Gene expression; Gene Expression Regulation; Genes; Genomes; Hospitals; Humanities and Social Sciences; Humans; Immunologic Memory; Immunology; Lymphocytes; Medicin och hälsovetenskap; Methylation; multidisciplinary; Mutation; Primary immunodeficiencies; Science; Science (multidisciplinary); Twins; Twins, Monozygotic
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms8335

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. Epigenetic changes are thought to contribute to the aetiology of common variable immunodeficiency (CVID), a disease characterized by loss of B-cell function. Here, by comparing DNA methylation profile in B cells from monozygotic twins discordant for CVID, the authors show a gain of DNA methylation in CVID B cells.