GENETICS AND BIOLOGY OF OMENN SYNDROME

T- B- SCID is a heterogeneous group of disorders whose molecular basis have been identified by our and other groups. We focused on the analysis of those forms due to RAG-dependent defects and on a peculiar syndrome, named Omenn Syndrome (OS). The patients affected by this disease show severe erythrodermia, presence of autoreactive T cells, and complete absence of B cells, in spite of the presence of high levels of IgE. The prognosis is severe and so far, the only therapy available is bone marrow transplantation, even though the success of this treatment is still limited. Our group showed that partial activity due to missense mutations of Rag genes allows the maturation of a few T cell clones infiltrating skin and gut. Many aspects of Omenn syndrome still remain unclear and the study of a murine model recapitulating the Omenn phenotype can help us to better understand the role of the factor influencing the pathogenesis of this disease. In addition, the murine model will be an excellent tool to address fundamental biological questions still unanswered which could not be easily solved by the investigations in humans.This model will be also useful for gene therapy studies. To this purpose, we are generating a murine model bearing a RAG2 defect, R229Q, found in human Omenn and T- B- SCID patient. The immune system of these mice will be analysed in depth (Aim1). The murine model will be used to test the feasibility of gene therapy (Aim 2). Finally, we plan to investigate new cases showing Omenn or T- B- SCID phenotype, without any molecular defects in known genes (Aim 3).