Role of Diacylglycerol kinase alpha in SAP function: implications for T-cell mediated immune response in XLP (X-linked lymphoproliferative disease) patients and as possible pharmacological target for XLP treatment

Background - X-linked lymphoproliferative disease (XLP) is a rare congenital immunodeficiency (incidence: 1/1.000.000) caused by mutations in SH2D1A gene on X chromosome that prevent the production of a functional SAP protein. SAP is essential for the immunological functionality and in particular for the proper lymphocytes’ activation. The disease is usually asymptomatic until the patient, usually in childhood, is infected by the common virus EBV. Normally this virus causes mild to moderate symptoms (mononucleosis). However, in patients with this mutation, EBV causes acute lymphohistiocytosis extended to various organs, with even fatal outcomes. Even in the absence of EBV, the patients frequently develop lymphoproliferative diseases such as lymphoma and have reduced levels of immunoglobulins. Lymphohistiocytosis is due to an uncontrolled increase in the number of activated T lymphocytes that are not able to eliminate the infected B cells from EBV . Results - In this project we have shown that the absence of SAP in XLP patients is due to hyperactivation of the enzyme Diacylglycerol Kinase alpha. This makes lymphocytes of XLP patients less responsive to activation and resistant to cell death. At least in vitro is possible to correct the lymphocytes responses with specific diacylglycerol kinase inhibitors. This suggest the possibility of using such inhibitors for XLP therapy. Future perspectives - Thanks to a new Telethon grant we will determine whether the pharmacological inhibition of this enzyme could restore the cell death’s mechanisms that are lost in XLP patients. The first data indicate that the inhibition of Diacylglycerol Kinase alpha is capable of correcting the defects of T lymphocytes’ activation in vitro and promote death in cells inappropriately activated ones. We also intend to develop new inhibitors capable of restores the correct function of the lymphocytes in vivo.