Epigenetic Priming in Immunodeficiencies

Immunodeficienciesare disorders of the immune system that increase susceptibility to infections and cancer, and are therefore associated with elevated morbidity and mortality. Immunodeficienciescan be primary (not caused by other condition or exposure) or secondary due to the exposure to different agents (infections, chemicals, aging, etc.). Most primary immunodeficiencies(PIDs) are of genetic origin, caused by mutations affecting genes with key roles in the development or function of the cells of the immune system. A large percentage of PIDs are associated with a defective development and/or function of lymphocytes and, especially, B cells, the ones in charge of generating the different types of antibodies. B cell development is a tightly regulated process in which many different factors participate. Among the regulators of B cell differentiation, a correct epigeneticcontrol of cellular identity is essential for normal cell function. With the advent of next-generation sequencing techniques, more and more alterations in different types of epigeneticregulators are being described at the root of PIDs, both in humans and in animal models. At the same time, it is becoming increasingly clear that epigeneticalterations triggered by the exposure to environmental agentshave a key role in the development of secondary immunodeficiencies(SIDs). Due to their largely reversible nature, epigeneticmodifications are quickly becoming key therapeutic targets in other diseases where their contribution has been known for more time, like cancer. Here, we establish a parallelism between immunodeficienciesand the nowadays accepted role of epigeneticsin cancer initiation and progression, and propose that epigeneticsforms a “third axis” (together with genetics and external agents) to be considered in the etiology of immunodeficiencies, and linking PIDs and SIDs at the molecular level. We therefore postulate that immunodeficienciesarise due to a variable contribution of i) genetic, ii) environmental and iii) epigeneticcauses, which in fact form a continuum landscape of all possible combinations of these factors. Additionally, this implies the possibility of a fully epigenetically-triggered mechanism for some immunodeficiencies. This concept would have important prophylactic and translational implications, and would also imply a more blurred frontier between primary and secondary immunodeficiencies.