Modifier loci condition autoimmunity provoked by Aire deficiency

Jiang, Wanlin; Anderson, Mark S.; Bronson, Roderick T.; Mathis, Diane; Benoist, Christophe

doi:10.1084/jem.20050693

Cited by 212 publications

(278 citation statements)

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“…2a), with a mean difference of 0.67 fg/pg 18S. As was previously established in recent literature [21,33,34], the AIRE transcription factor has a major role in the expression of the Ins2 gene in the thymus. Therefore, it was important to assess whether this decrease in the Ins2 mRNA was due to a decrease in the expression of Aire, which was also quantified by real-time PCR.…”

Section: Resultssupporting

confidence: 52%

Regulation of insulin gene expression by cytokines and cell–cell interactions in mouse medullary thymic epithelial cells

Levi

Polychronakos

2009

Diabetologia

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Aims/hypothesis The expression of tissue-specific selfantigens in the thymus is essential for self-tolerance. Genetic susceptibility to type 1 diabetes correlates inversely with thymic insulin expression and, in mice, lowered levels of this expression result in T cell responses against insulin. This study was undertaken to examine whether thymic insulin expression is regulated by the same metabolic stimuli as in beta cells or by different inputs, possibly of an immune nature. Methods Ins2 mRNA changes in mouse thymus were evaluated in vivo, following intraperitoneal glucose injection. We also examined the effect of a high glucose concentration on Ins2 mRNA in clones of insulin-expressing medullary thymus epithelial cell lines (mTECs). The same in vitro system was used to evaluate the effect of IFN-γ and cell-tocell contact with thymocytes in co-culture. Results Ins2 mRNA was significantly increased in the pancreas following a glucose load, but remained unchanged in the thymus. Furthermore, stimulation of insulin-expressing mTECs in vitro with IFN-γ, a cytokine involved in T cell negative selection, decreased levels of insulin expression even though expression of Aire was increased. Last, coculture of mTECs with thymocytes resulted in an upregulation of both Aire and insulin expression. Conclusions/interpretation We conclude that regulation of insulin transcription in the thymus is not dependent on metabolic stimuli but it may, instead, be under the control of cytokines and cell-to-cell interactions with lymphoid cells. That this regulation is not always coordinated with that of Aire, a non-specific master switch, suggests insulinspecific mechanisms.

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Section: Resultssupporting

confidence: 52%

Regulation of insulin gene expression by cytokines and cell–cell interactions in mouse medullary thymic epithelial cells

Levi

Polychronakos

2009

Diabetologia

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“…This finding has a parallel in a recent study of NOD mice in which Treg cells were shown to participate in early insulitis and prevent the onset of T cell-mediated tissue destruction (32). Also, it has been suggested that the immunopathology developing in Aire Ϫ/Ϫ NOD mice might reflect the combined effect of failed central tolerance and defects of regulation intrinsic to the NOD strain (15), and a cross between Aire Ϫ/Ϫ and FoxP3 Ϫ/Ϫ mice proved rapidly lethal (19). It is tempting to speculate that the difference in Treg cell function and the participation of Treg cells in the murine tissue infiltrates might explain why Aire Ϫ/Ϫ mice remain clinically healthy while AIRE Ϫ/Ϫ humans invariably develop APECED.…”

Section: Discussionsupporting

confidence: 55%

“…However, in striking contrast to AIRE Ϫ/Ϫ humans who invariably develop clinical autoimmunity, the Aire Ϫ/Ϫ mice remain clinically healthy or in a few cases develop manifestations not seen in human APECED. These manifestations include an inflammation of lacrimal glands in one mouse strain (14) and inflammation of the exocrine pancreas in Aire Ϫ/Ϫ NOD mice (15). Simultaneous expression of an Ag targeted to pancreatic islets and a transgenic TCR specific to it triggers diabetes in Aire Ϫ/Ϫ mice, but thymic expression of the model Ag was shown to be Aire-independent (10).…”

mentioning

confidence: 99%

A Defect of Regulatory T Cells in Patients with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

Kekäläinen¹,

Tuovinen²,

Joensuu³

et al. 2007

The Journal of Immunology

190

142

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Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic recessive disease characterized by autoimmunity against multiple tissues, offers a unique possibility to study the breakdown of self-tolerance in humans. It is caused by mutations in the autoimmune regulator gene (AIRE), which encodes a transcriptional regulator. Work using Aire−/− mice suggests that Aire induces ectopic expression of peripheral Ags and promotes their presentation in the thymus. We have explored reasons for the difference between the comparatively mild phenotype of Aire-deficient mice and human APECED patients. We provide evidence that, unlike in the Aire−/− mice, in the patients a key mediator of active tolerance, the CD4+CD25+ regulatory T (Treg) cell subset is impaired. This was shown by significantly decreased expression of FOXP3 mRNA and protein, decreased function, and alterations in TCR repertoire. Also, in the normal human thymus a concentric accumulation of AIRE+ cells was seen around thymic Hassall’s corpuscles, suggesting that in the patients these cells may be involved in the observed Treg cell failure. In Aire−/− mice the expression of FoxP3 was normal and even increased in target tissues in parallel with the lymphocyte infiltration process. Our results suggest that a Treg cell defect is involved in the pathogenesis of APECED and emphasize the importance of active tolerance mechanisms in preventing human autoimmunity.

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“…Furthermore, the number of endothelial cells in Aire -/-lungs was also increased. Jiang et al [57] recently reported that Aire -/-mice backcrossed in the NOD background die of pneumonitis. We have also observed lymphocytic infiltrates in the lungs of C57BL/6 Aire -/-mice (unpublished observation).…”

Section: Discussionmentioning

confidence: 99%

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

et al. 2006

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Patients with autoimmune polyendocrine syndrome type I (APS I)suffer from endocrine and non-endocrine disorders due to mutations in the autoimmune regulator gene (AIRE). Mouse Aire is expressed both in thymic medullary epithelial cells and in peripheral antigen-presenting cells, suggesting a role in both central and peripheral tolerance. We here report that Aire -/-dendritic cells (DC) activate naive T cells more efficiently than do Aire +/+ DC. Expression array analyses of Aire -/-DC revealed differential regulation of 68 transcripts, among which, the vascular cell adhesion molecule-1 (VCAM-1) transcript was up-regulated in Aire -/-DC. Concurrently, the expression of the VCAM-1 protein was up-regulated on both Aire -/-DC and monocytes from APS I patients. Blocking the interaction of VCAM-1 prevented enhanced Aire -/-DC stimulation of T cell hybridomas. We determined an increased number of DC in spleen and lymph nodes and of monocytes in the blood from Aire -/-mice, and an increased number of blood monocytes in APS I patients. Our findings imply a role for Aire in peripheral DC regulation of T cell activation, and suggest that Aire participates in peripheral tolerance.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2006/35240_s.pdf IntroductionInactivation of the autoimmune regulator gene (AIRE) [1][2][3] causes autoimmunity in patients with autoimmune polyendocrine syndrome type I (APS I, APECED, OMIM 240300) and in a gene targeted mouse model [4,5]. APS I is a rare monogenic autosomal recessive disease without HLA association [6,7], which is prevalent in isolated populations [8][9][10]. APS I patients develop a progressive loss of tolerance against self antigens and suffer from multiorgan failures due to the immunological destruction of adrenals, parathyroid glands and b cells of the islets of Langerhans [11]. Many of the APS I organ-specific autoantigens have been identified and characterized [12,13]. In addition, as a sign of immune dysfunction, these patients have difficulties clearing Candida albicans infections in mucosal membranes [14]. Functional studies of AIRE suggest a role as a transcription factor and in vitro transactivating studies support this notion [15][16][17][18]. Moreover, the PHD1 domain of AIRE has been suggested to have an E3 ubiquitin ligase activity in cell-free assays [19], findings in variance with a recent report [20]. Aire is highly expressed in a subset of the medullary thymic epithelial cells (mTEC) as well as in DC in the spleen and lymph nodes [21][22][23][24], indicating a potential role in immunological tolerance.To characterize the function of Aire, we previously engineered an Aire-deficient mouse targeting the most common APS I mutation [4]. Aire-deficient mice develop multiple organ-specific autoantibodies and lymphocytic infiltrates, thus mimicking some of the features of human APS I [4]. Subsequently, the role of Aire in negative selection was demonstrated [5]. These findings were further supported using TCR transgenic mic...

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Modifier loci condition autoimmunity provoked by Aire deficiency

Cited by 212 publications

References 50 publications

Regulation of insulin gene expression by cytokines and cell–cell interactions in mouse medullary thymic epithelial cells

Regulation of insulin gene expression by cytokines and cell–cell interactions in mouse medullary thymic epithelial cells

A Defect of Regulatory T Cells in Patients with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

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