Epigenetic Mechanisms in two primary immunodeficiencies: Hyper-IgM Syndrome and Common Variable Immunodeficiency

Abstract

The proper function of the immune system requires complex regulatory mechanisms and a highly strict balance in the amount and function of immune and non-immune elements. Part of the primary immunodeficiencies result from mutations in specific genes and their clinical manifestations can be recapitulated through the generation of knockout mice models that support the role of these genes. However, an important number of these disorders cannot be explained by genetic alterations and, to date, there is not an alternative explanation to understand it. This makes difficult the diagnosis process, the establishment of prognosis markers and complicates the finding of specific treatments or the improvement of the existing ones. Epigenetic mechanisms, mainly DNA methylation and histone modifications, are elements of gene control and have emerged to provide explanation to a wide variety of diseases including those related to the immune system. For that reason, this doctoral thesis was focused on investigating the influence of the epigenetic mechanisms in two primary immunodeficiencies: Hyper-IgM Syndrome and Common Variable Immunodeficiency.

This was achieved by the establishment of the following specific objectives:

1. To investigate the influence of activation-induced cytidine deaminase (AID), commonly mutated in Hyper-IgM Syndrome, in the setting of epigenetic modifications in an inducible B cell model.

2. To analyze the effects of AID mutations in the acquisition of epigenetic alterations.

3. To determine the participation of epigenetic alterations in CVID by focusing on the DNA methylation profiling of B cells isolated from monozygotic twins discordant for CVID.

4. To expand the results obtained with monozygotic twins discordant for CVID in three different B cell subsets from a cohort of healthy donors and CVID patients.