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

The syndrome of Immune dysfunction, Polyendocrinopathy Enteropathy (IPEX) is a fatal disease, with inheritance linked to the maternal X chromosome. The onset is in early childhood and it is characterised by several symptoms, including type I diabetes, eczema and severe diarrhea. Presently, there is no real therapy as the immunosuppressive drugs are partially efficacious, and bone marrow transplantation has been performed only in few cases. A mutation in a gene called FOXP3 is responsible for the disease but its function is not clear in humans. In mice, FOXP3 is important for the function of cells of the immune system, called T regulatory cells (Tr), which can keep the immune system under control and prevent autoimmunity. In mice with mutation of FOXP3, Tr cells are absent. We will select a group of patients with symptoms of IPEX, and study the type and site of mutations. Since we characterized in vitro Tr cells in normal donors and in several diseases, we will study the effect of FOXP3 mutated gene on the function of Tr cells in IPEX patients and in the mothers, who are healthy although carrying the mutation. To investigate if the gene has also different, not yet described, functions in human, we will study other cells in the immune system, such as T effector cells and dendritic cells. Using gene transfer techniques, we will introduce FOXP3 gene in normal T cells to study its effect and in FOXP3 mutated T cells, to test if their function can be restored. In parallel, we will evaluate the efficacy of immunosuppressive therapy, testing in vitro the effect of different drugs and studying the immune function of patients that are under immunosuppression or that have been transplanted, as the patient we are following at HSR-TIGET. Results of this study will allow a better correlation between genotype and clinical phenotype of IPEX and a better understanding of the immune pathogenesis of the disease, for a more rational therapeutic approach.