APECED: a monogenic autoimmune disease providing new clues to self-tolerance

https://doi.org/10.1016/S0167-5699(98)01293-6Get rights and content

Abstract

The cloning of AIRE, the gene for autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) promises to unravel some of the mysteries of autoimmunity. Here, Pärt Peterson and colleagues discuss recent studies of AIRE and the implications for disease therapy.

Section snippets

Identification of the AIRE gene

The gene defective in APECED was localized by linkage analysis to chromosome 21 (21q22.3) using families initially from Finland and later from other areas10, 11. These linkage analysis results indicated that the same genomic region was responsible for APECED in all ethnic groups examined. Recently, two international groups reported the identification by positional cloning of the gene responsible for APECED, named AIRE (autoimmune regulator)12, 13(Fig. 1). AIRE is a novel gene comprising 14

AIRE may be a transcriptional regulator

The AIRE protein shows homologies at the PHD-finger regions with several proteins that have been implicated in the regulation of transcription. These homologous proteins include a Mi-2 autoantigen, transcription intermediary factor 1 (TIF1), Sp100 and LYSP100. Interestingly, Mi-2 is a nuclear protein recognized by sera of dermatomyositis patients[16]. TIF1, a transcriptional coactivator, is known to interact and mediate the transcriptional activity of nuclear receptors such as the oestrogen

How might AIRE act in autoimmunity?

AIRE is one of the first genes characterized in humans outside the HLA region that is unequivocally involved in the regulation of autoimmunity. The fact that the defective gene results in a variety of autoimmune diseases indicates that AIRE has a crucial role in maintenance of immunological self-tolerance. Self-tolerance is achieved in the thymus by clonal deletion of self-reactive T cells. In the periphery, a variety of mechanisms, such as the induction of T-cell anergy because of the lack of

Conclusion

The identification of AIRE as the gene whose mutation causes APECED will clearly provide new insight into autoimmunity. The predicted structure of the AIRE protein suggests that it acts as a transcription factor or as a transcriptional coactivator. The finding should not only facilitate the genetic diagnosis of APECED patients and the development of therapy for this disease, but also enhance general understanding of the largely unknown mechanisms of autoimmunity and tolerance.

Acknowledgements

P.P., M.H. and K.J.E.K. were supported by EU Concerted Actions Project (BMH4-CT95-0729). K.N., J.K. and N.S. were supported in part by the Fund for Human Genome Sequencing Project from the Japan Science and Technology Corporation; Grants in Aid of Scientific Research on Priority Areas and Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan; and the Fund for `Research for the Future' Program from the Japan Society for the Promotion of Science. S.E.A. was

References (23)

  • K. Krohn et al.

    Lancet

    (1992)
  • O. Winqvist et al.

    Lancet

    (1992)
  • G. Gebre-Medhin et al.

    FEBS Lett.

    (1997)
  • R. Aasland et al.

    Trends Biochem. Sci.

    (1995)
  • S. Thenot et al.

    J. Biol. Chem.

    (1997)
  • A. Winoto

    Semin. Immunol.

    (1997)
  • S. Sakaguchi et al.

    J. Autoimmun.

    (1996)
  • P. Ahonen et al.

    New Engl. J. Med.

    (1990)
  • R. Uibo et al.

    J. Clin. Endocrinol. Metab.

    (1994)
  • T. Tuomi et al.

    J. Clin. Endocrinol. Metab.

    (1996)
  • K. Arulanantham et al.

    New Engl. J. Med.

    (1979)
  • Cited by (94)

    • The biophysical and biochemical properties of the autoimmune regulator (AIRE) protein

      2014, Biochimica et Biophysica Acta - Molecular Basis of Disease
      Citation Excerpt :

      The homologous murine gene, Aire (printed in lower case to avoid confusion), is located in the chromosome 10, and shows 77% nucleotide correspondence with human AIRE [5–7]. Since the delineation of its sequence, it has been evident that AIRE has a multidomain structure typical of the proteins able to bind to chromatin and to regulate the process of gene transcription [8–10]. Its organization resembles that of the 100-, 110-, and 140-kDa members of the speckled-protein family (Sp100, Sp110 and Sp140, respectively), which have been identified in the nuclear bodies (NBs) and carry out the above functions [11–14].

    • Mechanisms of autoimmunity

      2013, Clinical Immunology: Principles and Practice: Fourth Edition
    • Autoimmune regulator is acetylated by transcription coactivator CBP/p300

      2012, Experimental Cell Research
      Citation Excerpt :

      These self-antigens are presented to maturing thymocytes triggering apoptosis of highly autoreactive T-cells, thereby helping to maintain immunological tolerance in the body [3]. Mutations in the AIRE gene lead to a severe autoimmune disease called APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) (OMIM 240300) [4,5]. AIRE contains several domains required for transcriptional activity: a CARD domain for oligomerization [6], a SAND domain, which is a DNA binding domain present in several other proteins [7], two PHD-type zinc fingers, of which one binds to chromatin at loci marked with an unmethylated lysine 4 on histone H3 [8,9], nuclear localization signals [5,10,11], and four LXXLL sequences, which are putative nuclear receptor recognition motifs [12,13].

    • Mechanisms of autoimmunity: Barriers to Defining Mechanisms of Human Autoimmune Disease

      2008, Clinical Immunology: Principles and Practice Expert Consult: Online and Print
    • Mechanisms of autoimmunity

      2008, Clinical Immunology
    View all citing articles on Scopus
    View full text