Pino Molina, Lucía delRodríguez Ubreva, JavierTorres Canizales, JuanCoronel Díaz, MaríaKulis, MartaMartín-Subero, José Ignaciovan der Burg, MirjamBallestar Tarín, EstebanLópez Granados, Eduardo2020-10-272020-10-272019-04-24https://hdl.handle.net/2445/171562Common Variable Immunodeficiency (CVID) is characterized by impaired antibody production and poor terminal differentiation of the B cell compartment, yet its pathogenesis is still poorly understood. We first reported the occurrence of epigenetic alterations in CVID by high-throughput methylation analysis in CVID-discordant monozygotic twins. Data from a recent whole DNA methylome analysis throughout different stages of normal B cell differentiation allowed us to design a new experimental approach. We selected CpG sites for analysis based on two criteria: one, CpGs with potential association with the transcriptional status of relevant genes for B cell activation and differentiation; and two, CpGs that undergo significant demethylation from naive to memory B cells in healthy individuals. DNA methylation was analyzed by bisulfite pyrosequencing of specific CpG sites in sorted naive and memory B cell subsets from CVID patients and healthy donors. We observed impaired demethylation in two thirds of the selected CpGs in CVID memory B cells, in genes that govern B cell-specific processes or participate in B cell signaling. The degree of demethylation impairment associated with the extent of the memory B cell reduction. The impaired demethylation in such functionally relevant genes as AICDA in switched memory B cells correlated with a lower proliferative rate. Our new results reinforce the hypothesis of altered demethylation during B cell differentiation as a contributing pathogenic mechanism to the impairment of B cell function and maturation in CVID. In particular, deregulated epigenetic control of AICDA could play a role in the defective establishment of a post-germinal center B cell compartment in CVID.11 p.application/pdfengcc by (c) Pino Molina et al., 2019http://creativecommons.org/licenses/by/3.0/es/Malalties immunològiquesCèl·lules BImmunologic diseasesB cellsinfo:eu-repo/semantics/article2020-10-26info:eu-repo/semantics/openAccess31105700