Aire's partnerships: An answer for many questions and new questions in search of answers

The focus of this perspective is the recent publication by Abramson et al. (1) on the role of the Aire (Autoimmune Regulator), which is a transcription factor involved in promoting the surveillance of selfantigens and the maintenance of immune tolerance. This protein is mainly expressed in the medulla of the thymus and is important in the prevention of autoimmune disease including Type 1 diabetes (T1D). In humans, a defective AIRE causes Polyglandular Autoimmune Syndrome (APS) type I or Autoimmune Polyendocrinopathy-CandidiasisEctodermal Dystrophy (APECED), a rare autosomal recessive disorder involving multiple endocrine organs (4,5). APS-I is diagnosed when at least two of the following three clinical manifestations of this disease are identified: i) Chronic mucocutaneous candidiasis; ii) Hypoadrenocorticism iii) Hypoparathyroidism. APS-I has its peak of incidence in early childhood and its frequency is similar in both females and males, while APS-II is more frequent in middle age, more commonly associated with diabetes mellitus and without mutations in AIRE. Although less frequent in APS-I, other endocrine features of this syndrome include T1D as well as testicular or ovarian failure. Alopecia, vitiligo pernicious anemia and chronic active hepatitis can also occur in APS-I and all likely share a common autoimmune etiology. The relevance of Aire has been underscored by inactivating mutations of Aire in mouse models of a polyendocrine autoimmune disease (2, 3), which mimic the clinical features of APS-I. Abramson’s et al. publication (1) offers a new relevant insight to understand the pathophysiology of autoimmune endocrine diseases, including T1D. Whereas the paper addresses normal physiological interactions of Aire, it also becomes clear that modifications in these interactions can lead to loss of tolerance in autoimmune diseases. Although the specific role of Aire in T1D has not been completely elucidated, it is well documented that T1D is an autoimmune disease characterized by loss of tolerance to self-antigens; it is this loss of tolerance which leads to the T-cell mediated destruction of β cells. In this context, the work of Abramson and coworkers (1), when taken together with what is known in diseases related to Aire inactivation, provides a thought-provoking framework of information that can enlighten our understanding of the pathogenesis of T1D and provide eventual avenues for therapy. Regulation of normal tolerance to potential self-antigens is essential for understanding the pathophysiology of autoimmune diseases. Negative selection of self-reactive T-cells in the thymus is critical for immune tolerance and requires surveillance of selfantigens. A key component of this tolerance is the function of thymic medullary epithelial cells (MECs), which possess the ability to ectopically transcribe ‘‘promiscuously’’ a large number of antigens normally expressed in peripheral organs. Nagamine and collaborators (6) and the Finnish-German APECED Consortium (7) independently identified the gene responsible for APECED and designated it AIRE (Autoimmune Regulator). However, the specific molecular interactions of Aire to modulate selfantigen expression have not been elucidated in detail. The publication by Abramson et al(1) addresses the potential multiple intracellular roles of Aire. As the authors state, and as also described in the accompanying commentary by Kyewski and Peterson (8), the pleiotropic effects of Aire, combined with the structure of Aire itself, strongly suggested that Aire does not act as a traditional transcription factor. The work presented (1), indicates that Aire acts through a variety of partners and pathways that can be grouped into four major functional mechanisms encompassing (i) nuclear transport, (ii) chromatin binding/structure, (iii) transcription and (iv) pre-mRNA processing. Their results (1) also imply that Aire interacts with expression of gene sequences through recognition of hypomethylated H3 tails. This suggests that Aire interacts with epigenetic processes in expression of self-antigens. Additionally, the data indicate that Aire