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

2015; Nature Portfolio; Volume: 6; Issue: 1 Linguagem: Inglês

10.1038/ncomms8335

2041-1723

Virginia C. Rodríguez‐Cortez, Lucía del Pino Molina, Javier Rodríguez‐Ubreva, Laura Ciudad, David Gómez-Cabrero, Carlos Company, José Urquiza, Jesper Tegnér, Carlos Rodríguez‐Gallego, Eduardo López‐Granados, Esteban Ballestar,

Blood disorders and treatments

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.