AIRE – The Autoimmune Regulator

Abstract

Autoimmune diseases, caused by continuous immune responses against self‐antigens, have an uncertain aetiology. Although breakdown of self‐tolerance is considered to be the key event in the disease process, the underlying mechanisms are still enigmatic. So far, only a small number of genes that seem to be relevant to the pathogenesis of autoimmune diseases have been found. One of these genes is the autoimmune regulator (AIRE), mutation in which is responsible for the development of autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy (APECED) showing autosomal recessive inheritance. AIRE is a transcriptional regulator expressed predominantly by medullary thymic epithelial cells. Elucidation of how defective function of AIRE results in the development of organ‐specific autoimmunity is expected to shed light on not only the pathogenesis of autoimmune disease but also the fundamental question of how the immune system is educated to discriminate between self and nonself in the thymus.

Key Concepts

  • Autoimmune regulator (AIRE) is responsible for the development of organ‐specific autoimmune disease in a monogenic fashion.
  • AIRE is expressed predominantly by thymic stromal cells (medullary thymic epithelial cells: mTECs) and controls the negative selection and production of regulatory T cells in the thymus.
  • Production of a wide variety of autoantibodies (e.g. anti‐IFNs and anti‐Th17 cytokines) associated with autoimmune pathology and/or candidiasis infection is a prominent feature of AIRE deficiency.
  • AIRE deficiency results in reduced transcription of a wide variety of tissue‐restricted antigen genes by mTECs.
  • AIRE regulates the differentiation program of mTECs.
  • Elucidation of AIRE function is expected to clarify the fundamental issue of how the immune system discriminates self from nonself.
  • Identification of the target genes controlled by AIRE is essential for clarifying the exact function of AIRE in self‐tolerance.

Keywords: AIRE ; autoimmune disease; thymus; medullary thymic epithelial cell (mTEC); central tolerance; tissue‐restricted antigen; promiscuous gene expression; knockout mouse; negative selection; regulatory T cell

Figure 1. Genomic organisation of human AIRE. (a) The human AIRE gene is located on the long arm of chromosome 21 (21q22.3). (b, c) AIRE encodes a predicted 58‐kDa protein carrying a homogeneously staining region (HSR), a conserved nuclear localisation signal (NLS), the Sp100, AIRE, NucP41/75 region and Deaf1 (SAND) domain and two plant homeodomain (PHD)‐type zinc fingers. The PHD1 domain has been demonstrated to bind preferentially with the unmethylated H3K4 histone tail (H3K4me0).
Figure 2. mTECs expressing Aire protein in mice. (a) The location of mTECs expressing Aire protein demonstrated by the use of an Aire‐reporter strain (Aire/GFP knock‐in mice) (Yano et al., ). One thymic medulla immunostained with anti‐keratin 5 (red) is shown. Because of the nature of GFP protein, Aire+ mTECs are marked with GFP (stained green) throughout, including the cytoplasm. Scale bar: 100 µm. (b) Endogenous Aire protein in mice stained with anti‐Aire antibody (red) appearing as nuclear dots. Staining with anti‐keratin 5 reveals the dendritic‐cell shapes of mTECs (green). Scale bar: 10 µm.
Figure 3. Impaired central tolerance due to lack of Aire. Immature thymocytes at the double‐negative (DN) stages (DN1‐4) mature to the double‐positive (DP) stage in the cortex (upper), where thymocytes recognising the peptide/MHC complex survive (positive selection). These develop into single‐positive cells (SP) and migrate to the medulla (lower). In wild‐type mice (lower left), SP cells interacting with TRAs with high affinity (+++) die due to apoptosis (negative selection). Although not depicted in this scheme, TRAs may be presented by DCs after being transferred from mTECs in an Aire‐dependent manner (Figure ). SP cells interacting with TRAs with intermediate affinity (++) become Tregs. SP cells interacting only weakly with TRAs (+) can become effector T cells to protect the body. In Aire‐deficient mice (lower right), negative selection and the production of Tregs are impaired, most likely due to the reduction in TRAs at the transcriptional level.
Figure 4. Alteration in the program of mTEC differentiation due to lack of Aire. mTECs develop from their progenitors through three stages characterised by the levels of CD80 and/or MHC‐II expression (not depicted). In wild‐type mice (upper), immature mTECs receive cytokine signals (RANKL, CD40L and LT) provided by lymphoid‐tissue inducer (LTi) and thymocytes to become mature mTECs (upper center) expressing many TRAs supported by Aire. The level of CD80 expression is highest at this stage. The cells eventually lose their ability to express Aire together with many TRAs (post‐Aire) with a concomitant increase in the expression of keratinocyte‐related molecules such as involucrin. Then, they either die or form Hassall's bodies (HB) just before cell death. In the absence of Aire (lower), mTECs do not undergo the normal differentiation program, showing more globular cell shapes and reduced TRA transcription. Their CD80 level remains rather high until they die in the absence of Aire. Nevertheless, the half‐life of mTECs lacking Aire is indistinguishable from that of wild‐type mTECs.
Figure 5. Aire‐dependent antigen transfer from mTECs to BM‐APCs. In the RIP‐OVA Tg model, where immature mTEClow express self‐Ag (OVA), OVA must be transferred to BM‐APCs (i.e. thymic DCs and thymic B cells), which is an Aire‐dependent process, to elicit clonal deletion (negative selection) and Treg production. However, Tregs can be also induced directly by mTEChigh expressing OVA in an Aire‐dependent manner. In contrast, both OVA and Aire expressed by BM‐APCs are irrelevant to these processes in this transgenic model. Originally published in The Journal of Immunology. Mouri, Y., Ueda, Y., Yamano, T., Matsumoto, M., Tsuneyama, K., Kinashi, T., and Matsumoto, M. 2017. Mode of Tolerance Induction and Requirement for Aire Are Governed by the Cell Types That Express Self‐Antigen and Those That Present Antigen. J. Immunol. Copyright © [2017] The American Association of Immunologists, Inc.
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Further Reading

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Matsumoto, Minoru, Nishijima, Hitoshi, Morimoto, Junko, Tsuneyama, Koichi, and Matsumoto, Mitsuru(Feb 2019) AIRE – The Autoimmune Regulator. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027281]