Common variable immunodeficiency (CVID) is the most common type of symptomatic primary immunodeficiency. It is a complex disease, in which genetics plays a relevant role, but there are multiple factors that can cause it. A study led by the Infection and Immunity in Pediatric Patients and Translational Immunology groups at the Vall d'Hebron Research Institute (VHIR) has identified, in a group of women with the disease, a genetic mechanism that would be involved in the manifestation of the pathology. The study, carried out in collaboration with the Genetics Medicine group of VHIR, has been published in Journal of Clinical Immunology.

CVID is mainly characterized by a deficiency in the production of antibodies. "The lack of antibodies makes patients with CVID more prone to severe and recurrent infections, which has an impact on their quality of life and also on their survival. Knowing the genetic and molecular basis of CVID will help us to offer better clinical care", says Dr. Pere Soler, head of the Paediatric Infectious Diseases and Immunodeficiencies Unit at Vall d'Hebron University Hospital and of the Infection and Immunity in Pediatric Patients group at VHIR.

The work has focused on the study of three women with CVID who had mutations in genes related to the immune response found on the X chromosome, one of the chromosomes that determine sex. "In this case we have focused on studying a mechanism that causes the disease specifically in the female sex. In a disease as complex as CVID it is necessary to take into account the gender perspective to understand all cases", says Dr. Roger Colobran, head of the Translational Immunology group at VHIR and head of the Immunogenetics Area at Vall d'Hebron University Hospital.

Usually, in people with two X chromosomes, as in the female sex, one chromosome is randomly inactivated during development, so that approximately 50% of the cells have the paternal chromosome activated and 50% have the maternal chromosome activated. Thus, if there is a mutation, it is more difficult to produce symptoms because the mutated gene will be expressed in only half of the cells. "In this study, however, we have identified some women with IDCV who have genetic mutations on the X chromosome and in whom there is a skewed inactivation of this chromosome. In these patients, the cells are more likely to keep the mutated gene active, which promotes the disease to manifest", says Dr. Marina Garcia-Prat, researcher of the Infection and Immunity in Pediatric Patients group at VHIR and co-lead author of the study.

The results highlight the need to analyze the inactivation of the X chromosome in patients suspected of having these genetic variants. As Dr. Laura Batlle-Masó, researcher of the Infection and Immunity in Pediatric Patients group at VHIR and co-lead author of the study highlights, "we confirm that the skewed inactivation of the X chromosome in women is another piece that helps us to understand CVID, which is key to make an accurate genetic diagnosis for each patient". This study is in line with making personalized medicine an increasingly present reality. The diagnosis makes it possible to better define the prognosis of the disease, can help to prescribe more specific treatments and allows genetic counseling for the patient and her family.

This study has been funded by the Instituto de Salud Carlos III (project PI20/00761, with co-funding from the European Regional Development Fund), the Jeffrey Modell Foundation, Grifols (through the Investigator-Sponsored Research program) and the Ministry of Universities (Plan de Recuperación, Transformación y Resiliencia, through a grant from the Pompeu Fabra University). This study was also supported by the European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN-RITA).