Molecular Genetics of the IPEX Syndrome

Abstract

IPEX syndrome is a rare X‐linked syndrome caused by mutations in the FOXP3 gene, which encodes the FOXP3 protein. FOXP3 is an essential transcription factor for the development and function of regulatory T (Treg) cells, a subset of CD4+ T cells responsible for the maintenance of immune tolerance. IPEX presents early in life with severe generalised autoimmunity and failure to thrive. Unless promptly diagnosed and properly treated, most affected children die within the first 2 years of life. Although several immunosuppressive regimens have been used to control IPEX, hematopoietic stem cell transplantation remains the only curative option. Inspired by the clinical heterogeneity observed in IPEX patients, valuable progress has been made towards a better understanding of the complex interactions of FOXP3 and its multi‐faceted role in orchestrating the different aspects of Treg functions. Such advances will aid in the development of sensitive diagnostic tools and targeted therapeutic strategies with potential applications extending beyond IPEX.

Key Concepts

  • IPEX is an X‐linked primary immunodeficiency syndrome in which Treg cells are unable to control auto‐reactive immune cells
  • IPEX may be significantly under‐diagnosed
  • More than 60 FOXP3 mutations reported to cause IPEX with various degrees of severity
  • IPEX research has contributed significantly to our knowledge of Treg biology
  • Efforts are focused on understanding the specific processes affected by individual mutation in order to develop mutation‐specific therapeutic strategies as well as more generalisable strategies for modulation of Treg activity

Keywords: IPEX; FOXP3; Treg; autoimmunity; X‐linked; HSCT

Figure 1. A schematic of the domains of the FOXP3 protein showing their major functions and molecular partners.
Figure 2. Reported IPEX‐causing mutations in the coding and non‐coding sequences of the FOXP3 gene.
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Further Reading

Ochs HD, Edvard Smith CI and Puck JM (2013) Primary Immunodeficiency Diseases: A Molecular and Cellular Approach, 3rd edn. Oxford: OUP.

Ochs HD, Gambineri E and Torgerson TR (2007) IPEX, FOXP3 and regulatory T‐cells: a model for autoimmunity. Immunologic Research 38 (1–3): 112–121.

Rudensky AY (2011) Regulatory T cells and Foxp3. Immunology Reviews 241 (1): 260–268.

Xavier‐da‐Silva MM, Moreira‐Filho CA, Suzuki E, et al. (2015) Fetal‐onset IPEX: report of two families and review of literature. Clinical Immunology 156 (2): 131–140.

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Bin Dhuban, Khalid, and Piccirillo, Ciriaco A(Sep 2015) Molecular Genetics of the IPEX Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024904]