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Autoimmune polyglandular syndromes

Nature Reviews Endocrinology volume 6, pages 270–277 (2010)Cite this article

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Abstract

The autoimmune polyglandular syndromes—a group of syndromes comprising a combination of endocrine and nonendocrine autoimmune diseases—differ in their component diseases and in the immunologic features of their pathogenesis. One of the three main syndromes, type 1 autoimmune polyglandular syndrome (APS-1), has a unique pathogenic mechanism owing to mutations in the autoimmune regulator (AIRE) gene, which results in the loss of central tolerance—a process by which developing T cells with potential reactivity for self-antigens are eliminated during early differentiation in the thymus. Patients with IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) syndrome harbor mutations in the forkhead box P3 (FOXP3) gene in regulatory T cells, which leads to severe autoimmunity and immune deficiency. Although both of these disorders are rare, their well-defined mechanisms of disease provide a basis for the understanding of the more common condition, APS-2. In this syndrome, alleles of human leukocyte antigens (HLAs) determine the targeting of specific tissues by autoreactive T cells, which leads to organ-specific autoimmunity as a result of this loss of tolerance. Non-HLA genes also contribute to autoimmunity in APS-2 and, depending on the polymorphism, potentially predispose to a loss of tolerance or influence which organ is specifically targeted. This Review discusses the genetic basis of APS-1, APS-2 and IPEX syndrome, with an emphasis on the mechanisms of autoimmunity and presents currently available therapies to treat their underlying autoimmune disorders.

Key Points

  • The type 1 autoimmune polyglandular syndrome results from mutations in the AIRE gene, which modulates transcription of peripheral self-antigens in the thymus presented by human leukocyte antigen (HLA) molecules to maturing T cells

  • The type 2 autoimmune polyglandular syndrome is the most frequent autoimmune polyglandular syndrome, with underlying pathologies that develop years to decades apart in an affected individual

  • Patients with Addison disease have a 50% risk of developing a second autoimmune disease during their lifetime

  • Mutations in HLA genes, which encode the MHC (major histocompatibility complex) class II molecules expressed by antigen-presenting cells, contribute to the targeting of specific tissues by autoreactive T cells

  • Non-HLA genes contribute to the risk of autoimmune disease, as they may reduce the threshold of autoimmunity or influence the organs affected in type 2 autoimmune polyglandular syndrome

  • IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) syndrome results from mutations in the forkhead box protein P3 (FOXP3) gene, which is necessary for normal function of regulatory T cells

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Figure 1: Stages in the development of Addison disease.
Figure 2: Pathogenic model for the autoimmune polyglandular syndromes.

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Acknowledgements

Charles P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.

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  1. Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, 1775 Aurora Court, MS B140, PO Box 6511, Aurora, 80045, CO, USA

    Aaron W. Michels & Peter A. Gottlieb

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Michels, A., Gottlieb, P. Autoimmune polyglandular syndromes. Nat Rev Endocrinol 6, 270–277 (2010). https://doi.org/10.1038/nrendo.2010.40

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