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Title: Impaired CpG Demethylation in Common Variable Immunodeficiency Associates With B Cell Phenotype and Proliferation Rate
Author: Pino Molina, Lucía del
Rodríguez Ubreva, Javier
Torres Canizales, Juan
Coronel Díaz, María
Kulis, Marta
Martín-Subero, José Ignacio
van der Burg, Mirjam
Ballestar Tarín, Esteban
López Granados, Eduardo
Keywords: Malalties immunològiques
Cèl·lules B
Immunologic diseases
B cells
Issue Date: 24-Apr-2019
Publisher: Frontiers Media Sa
Abstract: Common 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.
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It is part of: Frontiers in Immunology, 2019, vol. 10
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Appears in Collections:Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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