The intraflagellar transport system, a novel regulator of immune synapse assembly: functional dissection in T-cell antigen receptor trafficking and assessment as disease target in common variable immunodeficiency

Common variable immunodeficiency (CVID) is the most frequent genetic disease of the immune system. This pathology is characterized by a severe deficiency in antibody production, which results in impaired immune responses, increased susceptibility to bacterial infections and a trend to develop, with high frequency, irreversible lung damage, granulomatous and gastrointestinal disease, autoimmune disorders and cancer. The current therapy for CVID is based on lifelong intravenous delivery of antibodies at frequent intervals, which not only implies a negative impact in the quality of life in these patients, but often leads to severe anaphylactic complications. Moreover, while effective against acute bacterial infections, this treatment does not resolve the disease complications, which are the major cause of death in CVID. Identifying the defective genes will provide clinicians with both a novel diagnostic tool and targets for the development of more specific and effective therapeutic alternatives. While prioritary, this is an ambitious goal, as recent progress in the quest of the gene responsible for this disease suggests that CVID actually groups a number of distinct genetic disorders. With this project we want to contribute to this challenging task by characterizing a new component of the molecular machinery controlling the activation of T lymphocytes, a process which is impaired in approximately 40% of CVID and is associated with a more severe disease presentation. The results will not only provide novel candidate disease genes essential for a precise molecular diagnosis, but also assist in the development of more specific therapies tailored to correct the functional defect in the large proportion of CVID with impaired T-cell function.