Loss of central and peripheral tolerance mechanisms leading to autoimmune manifestations in ADA-deficient SCID

Patients affected by adenosine (ADA)-deficiency have impaired immune defenses, are highly susceptible to severe infections, and display alterations in several organs. We have previously shown that gene therapy with hematopoietic stem cells is a safe and efficacious treatment for this disease. Patients with milder forms of the disease or patients after different treatment can display autoimmune manifestations, but the precise cause of these alterations is unknown. The goals of this proposal are to gain new insights on the causes of the immune dysregulation observed in ADA-deficiency and on the role of adenosine metabolism in contributing to the maintenance of tolerance to self-antigens. In addition we will study whether gene corrected cells can control the inappropriate development or activation of autoreactive lymphocytes. These studies will contribute to improve our understanding of the disease and advance patients-care.