FROM FOXP3 MUTATION TO IPEX: GENOTYPE/PHENOTYPE, IMMUNE PATHOGENETIC MECHANISMS AND THERAPEUTIC OPTIONS

The syndrome known as Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) is a severe disease due to mutation of a gene called FOXP3, transmitted to male children from the healthy carrier mothers. The disease begins in early infancy with untreatable diarrhoea, usually accompanied by insulin-dependent diabetes mellitus and eczema, with elevated serum IgE. Although rare, the disease is often fatal and can be easily misdiagnosed. Presently, there is no real therapy since the currently used immunosuppressive drugs are only partially efficacious. Bone marrow transplantation, still performed in a limited number of cases, seems to cure the disease only when applied early after diagnosis. Mutation of the FOXP3 gene if mutated in animal models, leads to an impaired development of regulatory T cells (Treg), a key T cell subset for keeping the immune system under control and preventing autoimmunity. However, the studies we have carried on demonstrated that in IPEX patients not only Treg are impaired in their correct function, but also effector T cells are defective. These results in line to what is reported in the literature, suggest that in humans FOXP3 gene has a complex role in immune responses. The present research is focused on continuing patients' recruitment to better define the clinical manifestations of the disease and provide more precise criteria for the diagnosis. In addition, cellular and molecular studies of cells isolated from IPEX patients will be performed, aimed at unravelling the immune mechanisms that from the mutation lead to the altered function of mutated FOXP3 cells and therefore to the pathology. Moreover, we will study in vivo and in vitro responses of lymphocytes to different immunosuppressive drugs. The outcome of these studies on IPEX as a disease model, will be instrumental for generating innovative strategies to treat also other more common diseases caused by altered immune responses.