SEARCH FOR GENETIC ALTERATIONS OF THE FAS SYSTEM IN THE AUTOIMMUNE/LYMPHOPROLIFERATIVE SYNDROME (ALPS)

Autoimmune lymphoproliferative syndrome (ALPS) is a severe inherited immunologic disease characterized by development of severe autoimmune diseases and accumulation of lymphocytes in the spleen and lymph nodes. The disease develops in the pediatric age and may be lethal because of severe hemolytic anemia or thrombocytopenia. Patients reaching the adult age display high risk of developing lympoma. ALPS is caused by genetic alterations decreasing function of the Fas receptor, involved in switching-off of immune responses. In some cases, the causal gene is known, but often it is not. In the past, our research group contributed to knowledge of this disease (whose inherited component has been recognized in 1995) by describing a variant named "Dianzani autoimmune lymphoproliferative disease" (DALD) and identifying a gene increasing the risk of its development, i.e. the gene of ostepontin, a protein regulating immune responses. Moreover, we found that mild alterations of Fas function can also be involved in development of common autoimmune diseases, such as juvenile dibetes mellitus (type-1 diabetes mellitus) and multiple sclerosis. Aim of this projects is 1) to detect the gene alterations causing ALPS by using advanced techniques of genomics, proteomics, and gene cloning, and 2) to functionally characterize these alterations. Identification of these genes will allow genetic dissection of ALPS and will be a crucial tool for diagnosis, that, to date, requires complex functional assays that cannot be performed in common laboratories of clinical analyses. Moreover, it will have a therapeutic value, in particular for selection of the familiar donor for bone marrow transplantation and to open the way to gene therapy.