Projection of an Immunological Self Shadow Within the Thymus by the Aire Protein

  title={Projection of an Immunological Self Shadow Within the Thymus by the Aire Protein},
  author={Mark S. Anderson and Emily S. Venanzi and Ludger Klein and Zhibin Chen and Stuart P Berzins and Shannon J. Turley and Harald von Boehmer and Roderick T Bronson and Andrée Dierich and Christophe Benoist and Diane Mathis},
  pages={1395 - 1401}
Humans expressing a defective form of the transcription factor AIRE (autoimmune regulator) develop multiorgan autoimmune disease. We used aire- deficient mice to test the hypothesis that this transcription factor regulates autoimmunity by promoting the ectopic expression of peripheral tissue– restricted antigens in medullary epithelial cells of the thymus. This hypothesis proved correct. The mutant animals exhibited a defined profile of autoimmune diseases that depended on the absence of aire… 

Loss of Aire-dependent thymic expression of a peripheral tissue antigen renders it a target of autoimmunity

This work identifies Mucin 6 as a stomach-specific antigen targeted by autoantibodies in gastritis-prone mice lacking thymic expression of aire and demonstrates that transcription of the MucIn 6 gene inThymic medullary epithelial cells is indeed Aire-dependent.

Central tolerance to self revealed by the autoimmune regulator

Molecular characterization of the functional domains of Aire has revealed multiple binding partners that assist Aire's function in altering gene transcription and chromatin remodeling, which has further highlighted the importance of Aires in central tolerance.

Control of central and peripheral tolerance by Aire

The autoimmune regulator (Aire) protein plays an important role in turning on these antigens, and the absence of even one Aire‐induced tissue‐specific antigen in the thymus can lead to autoimmunity in the antigen‐expressing target organ.

AIRE in the thymus and beyond.

Development of Autoimmunity against Transcriptionally Unrepressed Target Antigen in the Thymus of Aire-Deficient Mice1

Results suggest that Aire regulates the survival of autoreactive T cells beyond transcriptional control of self-protein expression in the thymus, at least against this ubiquitous protein, α-fodrin.

Lymphotoxin pathway directs thymic Aire expression

It is shown here that lymphotoxin signaling is necessary for the expression of Aire and its downstream target genes and the essential cross-talk between thymocytes and thymic stroma that is required for central tolerance.

[Induction of central tolerance by the factor Aire: molecular and epigenetic regulation].

This review summarizes current knowledge on the mode of action of Aire at the molecular and epigenetic levels in controlling the expression of tissue-restricted antigens and discusses recently described additional roles of this transcription factor in the induction of central T-cell tolerance.

The Autoimmune Regulator (AIRE) Gene, the Master Activator of Self-Antigen Expression in the Thymus

It has appeared clear that AIRE uniquely induces the expression of thousands of tissue-restricted self-antigens in the thymus, which are presented to developing T cells, resulting in the deletion of the self-reactive ones and the generation of regulatory T cells in order to establish and maintain immunological tolerance.

The Autoimmune Regulator Directly Controls the Expression of Genes Critical for Thymic Epithelial Function

Using the chromatin immunoprecipitation technique, it is demonstrated here that Aire binds in vivo to specific DNA sequence motifs and directly regulates thymic expression of genes important forThymic functions including expression of autoantigens, cytokines, transcription factors, and posttranslational modifiers.

Expression of the Autoimmune Regulator Gene and Its Relevance to the Mechanisms of Central and Peripheral Tolerance

  • R. Perniola
  • Biology, Medicine
    Clinical & developmental immunology
  • 2012
As AIRE and its murine homolog are also expressed in the secondary lymphoid organs, the extent and relevance of AIRE participation in the mechanisms of peripheral tolerance need to be thoroughly defined.



RNA and protein expression of the murine autoimmune regulator gene (Aire) in normal, RelB‐deficient and in NOD mouse

The results suggest that the Aire protein is associated with the normal development and action of a subset of thymic medullary stromal cells involved in tolerance induction.

Development, organization and function of the thymic medulla in normal, immunodeficient or autoimmune mice.

This work has shown that thymic stromal cell architecture phenotype is found in autoimmune diseases suggesting that abnormalities in the establishment of medullary microenvironments might be linked to the development of autoimmunity.

Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells

The role of T-cell tolerance to proteolipid protein (PLP) in susceptibility to experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, is analyzed and lack of tolerance to this epitope offers an explanation for the exquisite susceptibility of SJL/J mice to EAE.

Normal Thymic Architecture and Negative Selection Are Associated with Aire Expression, the Gene Defective in the Autoimmune-Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED)1

The spatial and temporal pattern of murine Aire expression during thymic ontogeny and T cell selection is reported on and it is shown that Aire may determineThymic stromal organization and with it the induction of self-tolerance.

Sampling of complementing self‐antigen pools by thymic stromal cells maximizes the scope of central T cell tolerance

It is shown that antigen expression in a minor fraction of medullary thymic epithelial cells leads to deletion of specific CD4 T cells, and this deletion is not dependent on cross‐presentation by hemopoietic antigen‐presenting cells, which have been ascribed a predominant role in negative selection.

Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self

It is found that this promiscuous gene expression was a cell-autonomous property of medullary epithelial cells and was maintained during the entire period of thymic T cell output, which may facilitate tolerance induction to self-antigens that would otherwise be temporally or spatially secluded from the immune system.

T cell tolerance and autoimmunity.

This review provides an overview of the T cell tolerance mechanisms invoked in the thymus and in the periphery to prevent the induction of autoimmunity.

Subcellular Location and Expression Pattern of Autoimmune Regulator (Aire), the Mouse Orthologue for Human Gene Defective in Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED)

It is shown that Aire has a dual subcellular location and that it is expressed in multiple immunologically relevant tissues such as the thymus, spleen, lymph nodes, and bone marrow, suggesting that APECED protein might also have a function(s) outside the immune system.

Thymic expression of autoantigens correlates with resistance to autoimmune disease.

A correlation between constitutive expression of ocular autoantigens in the thymus (mRNA and protein) and resistance to EAU is shown, suggesting that resistance to an organ-specific autoimmune disease may be regulated at least in part by capacity to establish central tolerance to the relevant autoantigen.