Disease relevance of Aire

• Inactivation of the autoimmune regulator (Aire) gene causes a rare recessive disorder, autoimmune polyendocrine syndrome 1 (APS1), but it is not known if Aire-dependent tolerance mechanisms are susceptible to the quantitative genetic changes thought to underlie more common autoimmune diseases [1].
• Aire-deficient mice develop hematopoetic irregularities and marginal zone B-cell lymphoma [2].
• The Aire-/- mice develop normally; however, autoimmune features of APECED in Aire-/- mice are evident, including multiorgan lymphocytic infiltration, circulating autoantibodies and infertility [3].
• Normal thymic architecture and negative selection are associated with Aire expression, the gene defective in the autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) [4].

High impact information on Aire

• It has also been postulated that Aire is involved in development of regulatory T cells, although supporting evidence is lacking [5].
• The cellular mechanism of Aire control of T cell tolerance [6].
• Surprisingly, supplementing its influence on the transcription of genes encoding peripheral-tissue antigens, Aire somehow enhances the antigen-presentation capability of medullary epithelial cells [6].
• In this issue of Immunity, Anderson et al. provide another clue to the riddle that is Aire--why do human beings and mice lacking Aire develop diffuse and pathogenic autoimmunity [7]?
• Lymphotoxin pathway directs thymic Aire expression [8].

Biological context of Aire

• APECED is a model of organ-specific autoimmunity and isolation and characterization of the homologous mouse gene, Aire, will provide tools for dissection of the mechanisms underlying this human disorder and defining molecular pathways involved in organ-specific autoimmunity [9].
• We have isolated and completely sequenced the mouse Aire gene which is split into 14 exons over 13 kb and encodes a predicted protein of 552 amino acids [9].
• We have mapped mouse Aire to mouse chromosome 10 by FISH, to the same region as Pwp2 and Pfkl, confirming synteny to the corresponding region of human chromosome 21 [9].
• Here, we report the genomic sequence (18,413 bp) for the entire Aire gene and its 5' flanking region, which contains putative regulatory sequences [10].
• In mice with a targeted mutation, complete loss of Aire abolished expression of an insulin promoter transgene in thymic epithelium, but had no effect in pancreatic islets or the testes [1].

Anatomical context of Aire

• Aire promotes the tolerization of thymocytes by inducing the expression of a battery of peripheral-tissue antigens in thymic medullary epithelial cells [6].
• Thymic deletion induced by antigen under control of the thyroglobulin promoter was abolished in Aire homozygotes and less efficient in heterozygotes, providing an explanation for thyroid autoimmunity in APS1 [1].
• We propose that Aire, in addition to its function in the thymus, also has a peripheral regulatory role by controlling the development of antigen-presenting cells (APCs) and marginal zone B-cell activation [2].
• These findings suggest that the Aire gene is not necessary for normal T cell education and development, while a defect in immune response detected in challenged Aire-/- mice underlines the crucial role of AIRE/Aire in maintaining homeostatic regulation in the immune system [3].
• Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice [11].

Associations of Aire with chemical compounds

• Defect internalization and tyrosine kinase activation in Aire deficient antigen presenting cells exposed to Candida albicans antigens [12].
• Recombinant AIRE also oligomerizes spontaneously upon phosphorylation by cAMP dependent protein kinase A or protein kinase C. Similarly, thymic AIRE protein is phosphorylated at the tyrosine and serine/threonine residues [13].

Other interactions of Aire

• Conversely, stimulation of lymphotoxin-beta receptor by agonistic antibody leads to increased expression of Aire and tissue-restricted antigens in both intact thymi and cultured thymic epithelial cell line [8].
• Structural characteristics and biochemical data suggest that Aire might have a direct role in nuclear transcription and that it can function as an ubiquitin ligase [14].
• Remarkably, transcriptional expression of alpha-fodrin was retained in the Aire-deficient thymus [11].
• Furthermore, in a study using NOD mice with a fixed genetic background, thymic stromal cells but not bone-marrow-derived cells were found to be relevant to the Aire-dependent alteration of target-cell specificity in the pancreas [15].
• We substantiate this hypothesis by identifying Mucin 6 as a stomach-specific antigen targeted by autoantibodies in gastritis-prone mice lacking thymic expression of aire and demonstrate that transcription of the Mucin 6 gene in thymic medullary epithelial cells is indeed Aire-dependent [16].

Analytical, diagnostic and therapeutic context of Aire

• As reports of the tissue expression pattern of the murine Aire gene are discordant, a comprehensive survey of Aire expression was undertaken in adult and embryonic tissues at the mRNA and protein levels using real-time RT-PCR, in situ hybridization, and immunohistochemistry [17].
• By RT-PCR Aire mRNA was detected in thymus, lymph node, spleen and testis although the second round PCR amplified Aire specific band from most mouse tissues analyzed [18].
• Competitive RT-PCR assays demonstrated highest expression level of Aire mRNA in thymus [19].
• Here we demonstrate the low expression level of the mouse Aire gene as it is undetectable by Northern blot analyses [19].

References