Aire gene

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 13.06.2021

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APECED; Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy; Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy Protein; autoimmune regulator

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AIRE is the acronym for "autoimmune regulator" and refers to a transcription factor that is mainly expressed in the thymus and which interacts with the CREB binding protein of the transcription coactivator. In humans, AIRE is encoded by the AIRE gene. The transcription factor AIRE is part of an important regulatory immune mechanism that recognises and eliminates autoreactive T cells that would otherwise initiate autoimmunological processes.

General information
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For the expression of a protein, its coding gene must be activated. This activation is usually achieved by binding transcription factors to the promoter of the gene. In the epithelial cells of the thymus (mTEC) this gene activation is induced by AIRE. Of great importance for this process is the fact that it is not gene-specific, but non-specific, stochastic. In this way, multiple (probably all) human proteins are expressed in the mTECs of the thymus. The calculated probability for the expression of a specific protein in a specific mTEC is 0.03 to 0.05. One in 20 to 35 mTEC cells will most likely express a specific protein. Without AIRE, the expression of these peripheral tissue antigens (PTA) is absent. The result is complex autoimmune diseases (see APECED below).

Mature T lymphocytes recognize only one specific antigen. This specific recognition mechanism takes place via the T cell receptors on the surface of the T cell. These T-cell receptors are in turn produced by randomly assembled gene segments. This infinitely varied "randomness" explains the "antigenetic pluripotency" of the different T cell populations with receptors against the multiple "peripheral tissue antigens (PTA)". It is remarkable that these PTAs are formed ectopically, i.e. they are formed in a different location. This distinguishes the formation of these proteins, which are formed ectopically in the thymus, from the proteins that are formed in other body tissues. These proteins are subject to cell-typical immunological control.

This immunological mechanism of self-recognition and self-purification finally enables maturing thymocytes to become tolerant towards peripheral organs (Liston A et al. 2003). It is crucial for physiological immunoreactivity that autoreactive T cells, which bind to autoantigens, are eliminated in the thymus (via the process of negative selection). Autoimmunity or the "horror autotoxicus" is thus prevented by the selection of non autoimmune T-lymphocytes in the thymus. Only such autoimmune T lymphocytes (thymocyte anergy) may leave the thymus and become active (Perniola R 2018).

If defective transcription factors are encoded by mutations in the AIRE gene, T cells, which physiologically recognise the antigens produced by their own organism as such, can no longer fulfil this task (Gardner J et al. 2008).

Clinical picture
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Mutations in the AIRE gene are found in the rare autoimmune polyendocrinopathy syndrome type 1 (APS-1 or autoimmune polyendocrinopathy candidiasis ectodermaldystrophy- APECED).

In this disease, multiple autoimmune reactions occur that are not directed against a single endogenous antigen but against a variety of different antigens.

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  1. Aaltonen J et al (1997) An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat. gene 17: 399-403.
  2. Anderson M, Su M (2011). "Aire and T cell development." Curr. Opin. Immunol. 23 (2): 198-206. doi:10.1016/j.coi.2010.11.007.
  3. Gardner J et al (2008) Projection of an immunological self shadow within the thymus by the aire protein. Science. 298: 1395–1401
  4. Gardner J et al (2008) Deletional tolerance mediated by extrathymic Aire-expressing cells. Science. 321: 843-847. doi:10.1126/science.1159407. PMC 2532844. PMID 18687966.
  5. Liston A et al(2003) Aire regulates negative selection of organ-specific T cells. Nat Immunol 4: 350-354.
  6. Perniola R (2018) Twenty Years of AIRE. Front Immunol 9:98.


Last updated on: 13.06.2021