Aire deficient mice develop multiple features of APECED phenotype and show altered immune response

Ramsey, Chris; Winqvist, Ola; Puhakka, Lea; Halonen, Maria; Moro, Aune; Kämpe, Olle; Eskelin, Petra; Pelto‐Huikko, Markku; Peltonen, Leena

doi:10.1093/hmg/11.4.397

Cited by 421 publications

(402 citation statements)

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“…Generation of C57BL/6 Aire Ϫ/Ϫ mice by targeted disruption of the murine Aire gene has been described (13). The controls were parental, syngeneic wild-type (WT) mice.…”

Section: Micementioning

confidence: 99%

“…The Aire Ϫ/Ϫ mice display signs of immunological dysregulation, T cell hyperreactivity, and perturbations of TCR repertoire, and by the age of 3 mo most of them have autoantibodies and lymphocyte infiltrates in multiple organs (6,13,14). 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.…”

mentioning

confidence: 99%

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

Kekäläinen¹,

Tuovinen²,

Joensuu³

et al. 2007

The Journal of Immunology

189

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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“…Generation of C57BL/6 Aire Ϫ/Ϫ mice by targeted disruption of the murine Aire gene has been described (13). The controls were parental, syngeneic wild-type (WT) mice.…”

Section: Micementioning

confidence: 99%

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

189

142

View full text Add to dashboard Cite

show abstract

“…In mice, targeted Aire disruption leads to a marked decrease in self-antigen expression, almost eliminating the 'promiscuous' gene expression pattern [21]. These mice, like APECED patients, have multiple autoimmune responses directed against various organs [22]. A considerable amount of work has been done on this transcription factor, demonstrating its essential role for this process and its implications for autoimmune disease [19,[21][22][23].…”

Section: Introductionmentioning

confidence: 99%

“…These mice, like APECED patients, have multiple autoimmune responses directed against various organs [22]. A considerable amount of work has been done on this transcription factor, demonstrating its essential role for this process and its implications for autoimmune disease [19,[21][22][23]. However, it is not known whether gene-specific regulatory mechanisms of this thymic 'promiscuous' gene expression exist.…”

Section: Introductionmentioning

confidence: 99%

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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“…To address this issue, we quantified the distribution of Spatial in the thymic medulla of Aire and RANKL-deficient mice (Fig. 3B,C) [40,41]. In comparison to WT mice, we found that Spatial expression is reduced $28-fold and $15-fold in Aire À/À and RANKL À/À mice, respectively.…”

Section: Rank Signals Regulate Spatial Expression Through the Transcrmentioning

confidence: 97%

Spatial (Tbata) expression in mature medullary thymic epithelial cells

et al. 2010

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The Spatial gene is expressed in highly polarized cell types such as testis germ cells, brain neurons and thymic epithelial cells (TEC). Its expression was documented in testis and brain but poorly characterized in thymus. Here, we characterize for the first time Spatial-expressing TEC throughout ontogeny and adult mouse thymus. Spatial is expressed in thymicfated domain by embryonic day E10.5 and persists in subcapsular, cortical, medullary epithelial cells and in MTS24 1 progenitor TEC. Using mouse strains in which thymocyte development is blocked at various stages, we show that Spatial expression is independent of thymocyte-derived signals during thymus organogenesis. Analyses on purified thymic cell subsets show that Spatial short isoforms are expressed in cortical TEC (cTEC) and mature medullary TEC (mTEC). Spatial long isoforms were detected in the same TEC population. Spatial presents a nuclear distribution specific to mature mTEC expressing UEA1 and Aire. Aire-and RANKL-deficient mice revealed that Spatial expression is drastically reduced in the thymus of these mutants. These findings reveal a critical function of Aire in regulating Spatial expression, which is compatible with promiscuous Spatial gene expression. 530 IntroductionThe vertebrate thymus is responsible for the production of functional nonautoreactive T lymphocytes. In this primary lymphoid organ, T-cell precursors commonly called thymocytes undergo a series of developmental stages through interactions with thymic stromal cells, resulting in the generation of mature T lymphocytes that are exported to the periphery [1,2]. The unique function of the thymus resides mainly in the thymic epithelium, which forms the major subcompartment of the stroma [3,4]. The thymic epithelium itself is commonly divided into two main regions, the cortex and the medulla, and each of these regions contains several ultrastructurally and phenotypically distinct types of thymic epithelial cells (TEC) [5,6]. TEC are required both for thymus organogenesis and for the promotion of most if not all stages of thymocyte maturation [3,4]. Understanding the molecular mechanisms regulating TEC differentiation and function provides crucial insights into mechanisms controlling T-cell development in the thymus.Using DNA chip technology we isolated the Spatial gene (Stromal Protein Associated with Thymii and Lymph node), also known as Tbata (thymus, brain and testes associated), by an approach based on differential screening between different knock-out mice models exhibiting distinct thymic immunodeficiencies [7]. This analysis led to the identification of three adult variants of the Spatial gene expressed in the thymus [8]. In addition, we also described two other isoforms isolated in the testis [8][9][10]. According to the size of alternative spliced variants, we have respectively named Spatial isoforms: Spatial-a (1035 bp), Spatial-b (1002 bp), Spatial-g (933 bp) for the short isoforms identified in the thymus; Spatial-d (1353 bp) and Spatial-e (1454 bp) for the long isoforms ...

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Aire deficient mice develop multiple features of APECED phenotype and show altered immune response

Cited by 421 publications

References 40 publications

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

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

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

Spatial (Tbata) expression in mature medullary thymic epithelial cells

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