For the very first time, epigenetic alterations have been linked to common variable immunodeficiency (CVID), the most commonly diagnosed primary immunodeficiency that leads to a decrease in antibodies and an increase in developing an infection. Scientists at the Bellvitge Biomedical Research Institute (IDIBELL) and La Paz Hospital (IDIPAZ) in Spain looked at monozygotic twins and measured epigenetic differences, specifically DNA methylation levels, between one twin with CVID and the other without the disease. The group of researchers, directed by Dr. Eduardo Lopez-Granados from IDIPAZ and Dr. Esteban Ballestar from IDIBELL, recently published their work in Nature Communications.
Individuals with CVID typically endure recurrent infections in the ears, nose, bronchi, sinuses, and lungs. This can also cause permanent damage to occur to the bronchi if the lung infection is frequent and severe. The reduced amount of antibodies (serum immunoglobulins) as a result of CVID is not entirely understood nor is there a definitive pattern of inheritance. Most cases of CVID actually arise in people without any history of the disease in their family. Recently, geneticists have found various gene mutations related to lymphocytes in those with the disorder, but even so, many individuals with CVID don’t necessarily have these mutations.
That’s why other mechanisms, particularly epigenetic modifications, are thought to contribute to the development of the disease. Researchers believe that environmental factors come into play because despite monozygotic twins sharing identical genetic material, one may be diagnosed with CVID while the other twin may not be.
The team of researchers investigated epigenetic marks, namely DNA methylation, in B cells in one healthy twin and compared the methylation levels to their twin with CVID. DNA methylation is the most widely studied epigenetic mechanism, defined as the addition of a methyl group (CH3) onto DNA which affects the expression of genes. DNA methylation is also known to play a crucial role in the differentiation process. After investigating over 450,000 CpG sites across the entire genome, the group of scientists detected greater DNA methylation levels in the twin diagnosed with CVID compared to their healthy sibling. The researchers also identified a collection of genes, such as PIK3CD, BCL2L1, RPS6KB2, TCF3 and KCNN4, associated with B lymphocytes, whose function is impaired in those with CVID. These genes were more methylated in the twin with the immunodeficiency compared to the healthy one.
The same group of genes was also assessed in a cohort of people with CVID and in a group of healthy individuals. When assessing methylation status at different stages of cell growth, it was found that individuals with CVID lost some of their ability to demethylate the genes as the lymphocytes transitioned. As gathered from the results of the study, those with CVID appeared to produce less memory B cells, which are the mature form of lymphocytes that go on to produce antibodies. Additionally, these memory B cells were not able to mature fully in those with CVID. These results are consistent with other studies that indicate CVID individuals are not able to properly undergo B cell differentiation.
This study marks the first time epigenetics has been implicated in common variable immunodeficiency. These results can open new doors for future research assessing the role DNA methylation plays in the development of CVID and possible treatments for this prevalent disorder.
Source: Rodríguez-Cortez, V.C., del Pino-Molina, L., Rodríguez-Ubreva, J., Ciudad, L., Gómez-Cabrero, D., Company, C., Urquiza, J.M., Tegnér, J., Rodríguez-Gallego, C., López-Granados, E., Ballestar, E. (2015). Monozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naïve-to-memory B-cell transition. Nature Communications, 6:7335.
Reference: IDIBELL. IDIBELL scientists identify the epigenetic basis of common variable immunodeficiency through the study of monozygotic twins discordant for this condition. 17 June 2015. Web.