Aire-Deficient C57BL/6 Mice Mimicking the Common Human 13-Base Pair Deletion Mutation Present with Only a Mild Autoimmune Phenotype (original) (raw)
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Transcriptional regulation by AIRE: molecular mechanisms of central tolerance
Nature Reviews Immunology, 2008
The negative selection of T cells in the thymus is necessary for the maintenance of self tolerance. Thymic medullary epithelial cells have a key function in this process as they express a large number of tissue-specific self antigens that are presented to developing T cells. Mutations in the transcriptional regulator AIRE cause a breakdown of central tolerance associated with decreased expression of self antigens in the thymus. In this Review, we discuss the role of AIRE in the thymus and recent advances in our understanding of how AIRE might function to regulate gene expression. Autoimmunity is caused by the breakdown of mechanisms that maintain immune tolerance to self tissues. Most self-reactive T cells are deleted in the thymus, resulting in central tolerance [G], which is further supported by regulatory mechanisms outside of primary lymphoid tissues, which are collectively known as peripheral tolerance. As the main mechanism of central tolerance, the negative selection [G] of self-reactive thymocytes occurs mainly in the medullary compartment of the thymus 1, 2. The medullary thymic epithelial cells (mTECs) express a large number of genes, including tissue-specific antigens (TSAs, also named tissue-restricted antigens or peripheral tissue antigens) that are normally present only in specialized peripheral organs and are apparently not required for the direct function of mTECs 3, 4. During negative selection, these encoded TSAs are presented by mTECs or dendritic cells to differentiating thymocytes as self antigens5, 6, leading to the
Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in Aire
Journal of Clinical Investigation, 2008
Homozygous loss-of-function mutations in AIRE cause autoimmune polyglandular syndrome type 1 (APS 1), which manifests in a classic triad of hypoparathyroidism, adrenal insufficiency, and candidiasis. Interestingly, a kindred with a specific G228W AIRE variant presented with an autosomal dominant autoimmune phenotype distinct from APS 1. We utilized a novel G228W-knockin mouse model to show that this variant acted in a dominant-negative manner to cause a unique autoimmunity syndrome. In addition, the expression of a large number of Aire-regulated thymic antigens was partially inhibited in these animals, demonstrating the importance of quantitative changes in thymic antigen expression in determining organ-specific autoimmunity.
F1000 - Post-publication peer review of the biomedical literature, 2009
Aire induces ectopic expression of peripheral tissue antigens (PTAs) in thymic medullary epithelial cells, which promotes immunological tolerance. Beginning with a broad screen of histone peptides, we demonstrate that the mechanism by which this single factor controls the transcription of thousands of genes involves recognition of the amino-terminal tail of histone H3, but not of other histones, by one of Aire's plant homeodomain (PHD) fingers. Certain posttranslational modifications of H3 tails, notably dimethylation or trimethylation at H3K4, abrogated binding by Aire, whereas others were tolerated. Similar PHD finger-H3 tail-binding properties were recently reported for BRAF-histone deacetylase complex 80 and DNA methyltransferase 3L; sequence alignment, molecular modeling, and biochemical analyses showed these factors and Aire to have structure-function relationships in common. In addition, certain PHD1 mutations underlying the polyendocrine disorder autoimmune polyendocrinopathy-candidiasesectodermaldystrophy compromised Aire recognition of H3. In vitro binding assays demonstrated direct physical interaction between Aire and nucleosomes, which was in part buttressed by its affinity to DNA. In vivo Aire interactions with chromosomal regions depleted of H3K4me3 were dependent on its H3 tail-binding activity, and this binding was necessary but not sufficient for the up-regulation of genes encoding PTAs. Thus, Aire's activity as a histone-binding module mediates the thymic display of PTAs that promotes self-tolerance and prevents organ-specific autoimmunity.
Proceedings of the National Academy of Sciences, 2008
Aire induces ectopic expression of peripheral tissue antigens (PTAs) in thymic medullary epithelial cells, which promotes immunological tolerance. Beginning with a broad screen of histone peptides, we demonstrate that the mechanism by which this single factor controls the transcription of thousands of genes involves recognition of the amino-terminal tail of histone H3, but not of other histones, by one of Aire's plant homeodomain (PHD) fingers. Certain posttranslational modifications of H3 tails, notably dimethylation or trimethylation at H3K4, abrogated binding by Aire, whereas others were tolerated. Similar PHD finger-H3 tail-binding properties were recently reported for BRAF-histone deacetylase complex 80 and DNA methyltransferase 3L; sequence alignment, molecular modeling, and biochemical analyses showed these factors and Aire to have structure-function relationships in common. In addition, certain PHD1 mutations underlying the polyendocrine disorder autoimmune polyendocrinopathy-candidiasesectodermaldystrophy compromised Aire recognition of H3. In vitro binding assays demonstrated direct physical interaction between Aire and nucleosomes, which was in part buttressed by its affinity to DNA. In vivo Aire interactions with chromosomal regions depleted of H3K4me3 were dependent on its H3 tail-binding activity, and this binding was necessary but not sufficient for the up-regulation of genes encoding PTAs. Thus, Aire's activity as a histone-binding module mediates the thymic display of PTAs that promotes self-tolerance and prevents organ-specific autoimmunity.
Aire deficient mice develop multiple features of APECED phenotype and show altered immune response
Human Molecular Genetics, 2002
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic autosomal recessive disease caused by mutations in the AIRE gene. Here we have produced knock-out mice for the Aire gene. The Aire -/mice develop normally; however, autoimmune features of APECED in Aire -/mice are evident, including multiorgan lymphocytic infiltration, circulating autoantibodies and infertility.
Transcriptional programs that control expression of the autoimmune regulator gene Aire
Nature immunology, 2016
Aire is a transcriptional regulator that induces promiscuous expression of thousands of genes encoding tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs). While the target genes of Aire are well characterized, the transcriptional programs that regulate its own expression have remained elusive. Here we comprehensively analyzed both cis-acting and trans-acting regulatory mechanisms and found that the Aire locus was insulated by the global chromatin organizer CTCF and was hypermethylated in cells and tissues that did not express Aire. In mTECs, however, Aire expression was facilitated by concurrent eviction of CTCF, specific demethylation of exon 2 and the proximal promoter, and the coordinated action of several transcription activators, including Irf4, Irf8, Tbx21, Tcf7 and Ctcfl, which acted on mTEC-specific accessible regions in the Aire locus.
AIRE's CARD Revealed, a New Structure for Central Tolerance Provokes Transcriptional Plasticity
Journal of Biological Chemistry, 2007
antigens in the thymus in order to delete autoreactive clones. It is now known that the Autoimmune Regulator protein (AIRE) which is expressed in thymic medullary epithelial cells plays a key role in regulating the thymic transcription of these peripheral tissue specific antigens. Mutations in the AIRE gene are associated with a severe multi-organ autoimmune syndrome (APECED) and autoimmune reactivities are manifest in AIRE deficient mice. Functional AIRE protein is expressed as distinct nuclear puncta though no structural basis existed to explain their relevance to disease. In addressing the cell biologic basis for APECED we made the unexpected discovery that an AIRE mutation hotspot lies in a caspase recruitment domain (CARD). Combined homology modeling and invitro data now show how APECED mutations influence the activity of this transcriptional regulator. We also provide novel in-vivo evidence for AIRE's association with a global transcription cofactor, which may underlie AIRE's focal, genome wide, alteration of the transcriptome.