Reference

natureNature Communications 6, 7335.

Authors

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

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.

Description

La inmunodeficiencia común variable (CVID) se caracteriza por niveles bajos de inmunoglobulinas y una mayor susceptibilidad a infecciones. La mayoría de los pacientes con CVID presentan infecciones recurrentes. Aunque la CVID tiene un componente genético, se acepta que existen otros mecanismos que determinan la aparición de la enfermedad. En este estudio, la comparación de los patrones epigenéticos en linfocitos B de una pareja de gemelos idénticos discordantes para esta enfermedad, ha permitido identificar la existencia de alteraciones epigenéticas en el gemelo con la inmunodeficiencia que no están presentes en el gemelo sano. El análisis de la metilación de dichos genes en linfocitos en diferentes estados de maduración en una cohorte de pacientes de CVID respecto a controles sanos mostró que sus células B han perdido parcialmente la capacidad de desmetilar dichos genes durante el proceso de generar linfocitos maduros.

 

groupoArticuloMesSept2015

 

REFERENCIA DEL GRUPO INVESTIGADOR

 

El grupo de Cromatina y Enfermedad del Institut d'Investigació Biomèdica de Bellvitge (IDIBELL) está dirigido por el Dr Esteban Ballestar y centra su actividad investigadora en el estudio de mecanismos de desregulación epigenética en el sistema inmune, especialmente en el contexto de enfermedad autoinmune, inmunodeficiencia y en distintos modelos de diferenciación relevantes en enfermedades del sistema inmune. En los últimos años el laboratorio ha publicado diversos trabajos relacionados con la adquisición de alteraciones epigenéticas en distintos tipos celulares de enfermedades autoinmunes como el lupus eritematoso sistémico y la artritis reumatoide. http://www.idibell.cat/modul/chromatin-and-disease/en

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