Pediatric Diabetes 2010: 11: 85–87 2010 John Wiley & Sons A/S
doi: 10.1111/j.1399-5448.2010.00652.x
All rights reserved Pediatric Diabetes
Perspectives
Aire’s partnerships: An answer for many
questions and new questions in search of
answers
The focus of this perspective is the recent publication to self-antigens; it is this loss of tolerance which
by Abramson et al. (1) on the role of the Aire leads to the T-cell mediated destruction of β cells. In
(Autoimmune Regulator), which is a transcription this context, the work of Abramson and coworkers
factor involved in promoting the surveillance of self- (1), when taken together with what is known in
antigens and the maintenance of immune tolerance. diseases related to Aire inactivation, provides a
This protein is mainly expressed in the medulla thought-provoking framework of information that can
of the thymus and is important in the prevention enlighten our understanding of the pathogenesis of
of autoimmune disease including Type 1 diabetes T1D and provide eventual avenues for therapy.
(T1D). In humans, a defective AIRE causes Regulation of normal tolerance to potential
Polyglandular Autoimmune Syndrome (APS) type self-antigens is essential for understanding the
I or Autoimmune Polyendocrinopathy-Candidiasis- pathophysiology of autoimmune diseases. Negative
Ectodermal Dystrophy (APECED), a rare autosomal selection of self-reactive T-cells in the thymus is critical
recessive disorder involving multiple endocrine organs for immune tolerance and requires surveillance of self-
(4,5). APS-I is diagnosed when at least two of the antigens. A key component of this tolerance is the
following three clinical manifestations of this disease function of thymic medullary epithelial cells (MECs),
are identified: i) Chronic mucocutaneous candidiasis; which possess the ability to ectopically transcribe
ii) Hypoadrenocorticism iii) Hypoparathyroidism. ‘‘promiscuously’’ a large number of antigens normally
APS-I has its peak of incidence in early childhood expressed in peripheral organs. Nagamine and
and its frequency is similar in both females and collaborators (6) and the Finnish-German APECED
males, while APS-II is more frequent in middle age, Consortium (7) independently identified the gene
more commonly associated with diabetes mellitus and responsible for APECED and designated it AIRE
without mutations in AIRE. Although less frequent (Autoimmune Regulator). However, the specific
in APS-I, other endocrine features of this syndrome molecular interactions of Aire to modulate self-
include T1D as well as testicular or ovarian failure. antigen expression have not been elucidated in detail.
Alopecia, vitiligo pernicious anemia and chronic active The publication by Abramson et al(1) addresses the
hepatitis can also occur in APS-I and all likely share a potential multiple intracellular roles of Aire. As
common autoimmune etiology. The relevance of Aire the authors state, and as also described in the
has been underscored by inactivating mutations of accompanying commentary by Kyewski and Peterson
Aire in mouse models of a polyendocrine autoimmune (8), the pleiotropic effects of Aire, combined with the
disease (2, 3), which mimic the clinical features structure of Aire itself, strongly suggested that Aire
of APS-I. does not act as a traditional transcription factor. The
Abramson’s et al. publication (1) offers a new work presented (1), indicates that Aire acts through a
relevant insight to understand the pathophysiology variety of partners and pathways that can be grouped
of autoimmune endocrine diseases, including T1D. into four major functional mechanisms encompassing
Whereas the paper addresses normal physiological (i) nuclear transport, (ii) chromatin binding/structure,
interactions of Aire, it also becomes clear that (iii) transcription and (iv) pre-mRNA processing.
modifications in these interactions can lead to loss Their results (1) also imply that Aire interacts with
of tolerance in autoimmune diseases. Although the expression of gene sequences through recognition of
specific role of Aire in T1D has not been completely hypomethylated H3 tails. This suggests that Aire
elucidated, it is well documented that T1D is an interacts with epigenetic processes in expression of
autoimmune disease characterized by loss of tolerance self-antigens. Additionally, the data indicate that Aire
85
doi: 10.1111/j.1399-5448.2010.00652.x
All rights reserved Pediatric Diabetes
Perspectives
Aire’s partnerships: An answer for many
questions and new questions in search of
answers
The focus of this perspective is the recent publication to self-antigens; it is this loss of tolerance which
by Abramson et al. (1) on the role of the Aire leads to the T-cell mediated destruction of β cells. In
(Autoimmune Regulator), which is a transcription this context, the work of Abramson and coworkers
factor involved in promoting the surveillance of self- (1), when taken together with what is known in
antigens and the maintenance of immune tolerance. diseases related to Aire inactivation, provides a
This protein is mainly expressed in the medulla thought-provoking framework of information that can
of the thymus and is important in the prevention enlighten our understanding of the pathogenesis of
of autoimmune disease including Type 1 diabetes T1D and provide eventual avenues for therapy.
(T1D). In humans, a defective AIRE causes Regulation of normal tolerance to potential
Polyglandular Autoimmune Syndrome (APS) type self-antigens is essential for understanding the
I or Autoimmune Polyendocrinopathy-Candidiasis- pathophysiology of autoimmune diseases. Negative
Ectodermal Dystrophy (APECED), a rare autosomal selection of self-reactive T-cells in the thymus is critical
recessive disorder involving multiple endocrine organs for immune tolerance and requires surveillance of self-
(4,5). APS-I is diagnosed when at least two of the antigens. A key component of this tolerance is the
following three clinical manifestations of this disease function of thymic medullary epithelial cells (MECs),
are identified: i) Chronic mucocutaneous candidiasis; which possess the ability to ectopically transcribe
ii) Hypoadrenocorticism iii) Hypoparathyroidism. ‘‘promiscuously’’ a large number of antigens normally
APS-I has its peak of incidence in early childhood expressed in peripheral organs. Nagamine and
and its frequency is similar in both females and collaborators (6) and the Finnish-German APECED
males, while APS-II is more frequent in middle age, Consortium (7) independently identified the gene
more commonly associated with diabetes mellitus and responsible for APECED and designated it AIRE
without mutations in AIRE. Although less frequent (Autoimmune Regulator). However, the specific
in APS-I, other endocrine features of this syndrome molecular interactions of Aire to modulate self-
include T1D as well as testicular or ovarian failure. antigen expression have not been elucidated in detail.
Alopecia, vitiligo pernicious anemia and chronic active The publication by Abramson et al(1) addresses the
hepatitis can also occur in APS-I and all likely share a potential multiple intracellular roles of Aire. As
common autoimmune etiology. The relevance of Aire the authors state, and as also described in the
has been underscored by inactivating mutations of accompanying commentary by Kyewski and Peterson
Aire in mouse models of a polyendocrine autoimmune (8), the pleiotropic effects of Aire, combined with the
disease (2, 3), which mimic the clinical features structure of Aire itself, strongly suggested that Aire
of APS-I. does not act as a traditional transcription factor. The
Abramson’s et al. publication (1) offers a new work presented (1), indicates that Aire acts through a
relevant insight to understand the pathophysiology variety of partners and pathways that can be grouped
of autoimmune endocrine diseases, including T1D. into four major functional mechanisms encompassing
Whereas the paper addresses normal physiological (i) nuclear transport, (ii) chromatin binding/structure,
interactions of Aire, it also becomes clear that (iii) transcription and (iv) pre-mRNA processing.
modifications in these interactions can lead to loss Their results (1) also imply that Aire interacts with
of tolerance in autoimmune diseases. Although the expression of gene sequences through recognition of
specific role of Aire in T1D has not been completely hypomethylated H3 tails. This suggests that Aire
elucidated, it is well documented that T1D is an interacts with epigenetic processes in expression of
autoimmune disease characterized by loss of tolerance self-antigens. Additionally, the data indicate that Aire
85
