GENETIC AND BIOCHEMICAL CHARACTERIZATION OF CVID

Common variable immunodeficiency (CVID) is the most common primary immunodeficiency. This pathology is characterized by low antibody levels, with resulting impairment of immune defenses, increased susceptibility to infections and a trend to develop autoimmune diseases and cancer. The heterogeneity of the clinical manifestations of CVID have to date hampered an understanding of the genetic basis of this disease. Recent data have demonstrated that CVID actually includes different pathologies characterized by defects not only in the cells responsible for antibody production, but also in other cells implicated in the immune response, including T lymphocytes, the primary regulators of immune defenses. The development of rational strategies against CVID requires therefore two key tools: 1) a classification system for grouping the patients according to the cell type affected; 2) a detailed understanding of the defect in the dysfunctional cells. Our project is built within this framework. We have identified a subset of CVID patients harbouring impaired T lymphocyte functions and demonstrated that the common defect is a reduction in the cellular levels of Vav, a protein which controls the plasticity of the cytoskeleton and is essential for activation of T lymphocytes, on which the subsequent antibody production by plasma cells crucially depends. The aim of this project is to identify the genetic lesion responsible for the reduced production of this molecule in T lymphocytes. The current therapeutic protocol for CVID is based on the intravenous delivery of antibodies at frequent intervals, which not only implies a negative impact on the quality of life in these patients, but often leads to serious anaphylactic complications. The identification of the genetic defect will provide a tool for the development of valid therapeutic alternatives, both pharmacological and gene-based.