Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: a model of immune dysregulation

PURPOSE OF REVIEW: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome is a fatal syndrome of overwhelming autoimmunity. Recent identification of FOXP3 as the causative gene and realization that this same gene defect occurs in the mutant mouse Scurfy has yielded new insights and hopes of unraveling the mechanism of autoimmunity in this and possibly other diseases. In this review, we describe the clinical features of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome/Scurfy and compare this phenotype with similar syndromes caused by other single gene mutations. We examine therapeutic options to treat the syndrome, study its immunologic basis, and investigate the structure and function of the FOXP3 protein. RECENT FINDINGS: The Scurfy mutant mouse has a characteristic phenotype that causes death by approximately 3 weeks of age. It is known that the effector cells in the Scurfy mouse are CD4+ T cells and that a population of normal T cells can control the overwhelming autoimmunity that they induce. Recent data have demonstrated that this process requires antigenic stimulation and that the degree to which the immune system responds is inversely proportional to the level of FOXP3 protein (Forkhead box P3) expression in peripheral T cells. Suppression of immune activation by FOXP3 may occur due to its ability to bind to DNA through a putative forkhead DNA-binding motif and to repress transcriptional activation from certain promoters in T cells. SUMMARY: Because of the dramatic phenotype and rapidity of onset, immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome and Scurfy provide a powerful model in which to study mechanisms of T cell regulation. A more complete understanding of this syndrome will provide important insights into mechanisms of immune suppression, tolerance, and autoimmunity.