Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX) is one of a group of clinical syndromes that present with multisystem autoimmune disease suggesting a phenotype of immune dysregulation. Clinically, IPEX manifests most commonly with diarrhea, insulin-dependent diabetes mellitus, thyroid disorders, and eczema. FOXP3, the gene responsible for IPEX, maps to chromosome Xp11.23-Xq13.3 and encodes a putative DNA-binding protein of the forkhead family. Recent data indicate that FOXP3 is expressed primarily in the CD4+CD25+ regulatory T-cell subset, where it may function as a transcriptional repressor and key modulator of regulatory T-cell fate and function. This review describes the clinical features of IPEX and the structure, function, and known mutations of FOXP3 that provide important insights into its role in maintenance of immune homeostasis.
Abbreviations:BMT bone marrow transplantation, IDDM insulin-dependent diabetes mellitus, IPEX immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance
The immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance syndrome (IPEX; OMIM 304930) is a fatal, recessive disorder that presents most commonly in early childhood. Characteristic symptoms of the disorder include early-onset insulin-dependent diabetes mellitus (IDDM), severe enteropathy, eczema, variable autoimmune phenomena, and severe infections. The Human Genome Organization has recently established IPEX as the official designation for this condition, previously identified as X-linked syndrome of polyendocrinopathy, immune dysfunction, and diarrhea (XPID) [1] or X-linked autoimmunity-allergic dysregulation syndrome (XLAAD) [2].
The syndrome was first recognized in 1982 by Powell et al. [3•], who described a large family of five generations with several affected males; the syndrome subsequently was mapped to chromosome Xp11.23-Xq13.3 by linkage analysis [1,4]. IPEX shares many phenotypic features with the natural mutant mouse scurfy described more than 40 years ago [5]. Scurfy mice present with X-linked recessive inheritance of scaly skin; small, thickened ears; runting secondary to diarrhea and malabsorption; progressive anemia; thrombocytopenia; leucocytosis; lymphadenopathy; hepatosplenomegaly; and hypogonadism. Scurfy mice typically die by 3 to 4 weeks of age. The thymus is typically small for age but has normal cellular architecture. There is massive infiltration of activated lymphocytes into the liver and into lymph nodes and spleen, which have abnormal cellular architecture [6,7].
Previous studies in scurfy mice have demonstrated that the clinical phenotype is the result of immune dysregulation. CD4+ T cells from affected males are constitutively activated, expressing high levels of several activation markers and increased levels of cytokine production [8-10]. Both depletion and adoptive transfer experiments indicate that CD4+ T cells are primarily responsible for the disease phenotype in mice [9,11].
Foxp3, the gene responsible for scurfy syndrome, encodes a transcription factor belonging to the forkhead/winged-helix family [12••]. Considering the clinical similarities between the scurfy mouse and IPEX, the authors and others have identified the human orthologue of the mouse Foxp3 gene (FOXP3) as the causative gene for IPEX [2,13,14].