Abstract
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare monogenic primary immunodeficiency (PID) due to mutations of FOXP3, a key transcription factor for naturally occurring (n) regulatory T (Treg) cells. The dysfunction of Treg cells is the main pathogenic event leading to the multi-organ autoimmunity that characterizes IPEX syndrome, a paradigm of genetically determined PID with autoimmunity. IPEX has a severe early onset and can become rapidly fatal within the first year of life regardless of the type and site of the mutation. The initial presenting symptoms are severe enteritis and/or type-1 diabetes mellitus, alone or in combination with eczema and elevated serum IgE. Other autoimmune symptoms, such as hypothyroidism, cytopenia, hepatitis, nephropathy, arthritis, and alopecia can develop in patients who survive the initial acute phase. The current therapeutic options for IPEX patients are limited. Supportive and replacement therapies combined with pharmacological immunosuppression are required to control symptoms at onset. However, these procedures can allow only a reduction of the clinical manifestations without a permanent control of the disease. The only known effective cure for IPEX syndrome is hematopoietic stem cell transplantation, but it is always limited by the availability of a suitable donor and the lack of specific guidelines for bone marrow transplant in the context of this disease. This review aims to summarize the clinical histories and genomic mutations of the IPEX patients described in the literature to date. We will focus on the clinical and immunological features that allow differential diagnosis of IPEX syndrome and distinguish it from other PID with autoimmunity. The efficacy of the current therapies will be reviewed, and possible innovative approaches, based on the latest highlights of the pathogenesis to treat this severe primary autoimmune disease of childhood, will be discussed.
Highlights
Immune dysregulation, polyendocrinopathy, enteropathy, Xlinked (IPEX) syndrome is a rare monogenic primary immunodeficiency (PID), characterized by multi-organ autoimmunity
The CD4+CD25+forkhead box p3 (FOXP3)+ T regulatory (Treg) cells are present (Gavin et al, 2006; Gambineri et al, 2008), but FOXP3 expression can be reduced if FOXP3 mutation prevents the expression of the protein (Bacchetta et al, 2006) or if the patient is exposed to IS therapy (Gambineri et al, 2008)
Immune dysregulation, polyendocrinopathy, enteropathy, Xlinked syndrome can be suspected on the basis of clinical and laboratory features, and the timely recognition of the disease leads to significant therapeutic benefits
Summary
Polyendocrinopathy, enteropathy, Xlinked (IPEX) syndrome is a rare monogenic primary immunodeficiency (PID), characterized by multi-organ autoimmunity. It is caused by mutations in the transcription factor forkhead box p3 (FOXP3), the master gene of T regulatory (Treg) cells. 63 FOXP3 mutations have been published, for an overall number of 136 patients described, and of these about half have been diagnosed in the last 3 years. This indicates that the awareness of the disease has been growing with a better understanding of the role of FOXP3 and Treg cells in maintaining peripheral tolerance
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