Central tolerance to self revealed by the autoimmune regulator

Abstract

The autoimmune regulator (Aire) was initially identified as the gene causing multiorgan system autoimmunity in humans, and deletion of this gene in mice also resulted in organ-specific autoimmunity. Aire regulates the expression of tissue-specific antigens (TSAs) in medullary thymic epithelial cells (mTECs), which play a critical role in the negative selection of autoreactive T cells and the generation of regulatory T cells. More recently, the role of Aire in the development of mTECs have helped elucidate its ability to present the spectrum of TSAs needed to prevent autoimmunity. Molecular characterization of the functional domains of Aire have revealed multiple binding partners that assist Aire’s function in altering gene transcription and chromatin remodeling. These recent advances have further highlighted the importance of Aire in central tolerance.

Polyglandular autoimmune syndromes

“…Most frequent mutations of AIRE are R257X in exon 6 and 67-979del13 bp in exon 8 [20,28]. The coded protein is a transcriptional factor primarily found in medullary thymic epithelial cells where central self-tolerance is provided via negative or positive selection, respectively [29]. By upregulating the number of expressed and presented self-antigens in healthy individuals, the transcription factor protects against autoimmune diseases by eliminating autoreactive T cells.…”

Prédisposition aux pathologies auto-immmunes

“…Est-il plausible que le maintien ou l'entretien du processus de tolérance dépende de l'équilibre de facteurs liés à l'âge au cours du vieillissement ? Si, ces dernières années, de nombreuses équipes se sont attachées à comprendre le rôle régulateur de AIRE dans la mise en place de la tolérance centrale via la régulation de l'expression des TSA, il a égale-ment été montré que AIRE joue un rôle majeur dans la maturation des CETm, dans la sélection des lymphocytes T régulateurs et dans la sécrétion de cytokines [37,38] (➜). L'ensemble de ces études a mis en exergue un méca-nisme subtil de promotion de tolérance centrale.…”

Identification of autoimmune polyendocrine syndrome type 1 in patients with isolated hypoparathyroidism

“…Autoimmune polyendocrine syndrome type 1 (APS1; OMIM 240300), also known as autoimmune polyendocrine‐candidiasis‐ectodermal dystrophy (APECED) syndrome, is a rare autosomal recessive genetic disorder caused by mutations in the autoimmune regulator ( AIRE) gene . AIRE is a transcription factor, primarily expressed in the medullary epithelial cells of the thymus, required for the presentation of tissue‐restricted antigens to T cells and hence for central tolerance . Mutations in the AIRE gene result in progressive autoimmunity and clinical involvement of a wide variety of tissues .…”

“…1,2 AIRE is a transcription factor, primarily expressed in the medullary epithelial cells of the thymus, required for the presentation of tissue-restricted antigens to T cells and hence for central tolerance. 3,4 Mutations in the AIRE gene result in progressive autoimmunity and clinical involvement of a wide variety of tissues. [5][6][7][8][9] The diagnosis of APS1 requires the presence of at least two of the following three components: chronic mucocutaneous candidiasis (MCC), hypoparathyroidism (HP) and primary adrenal insufficiency (PAI).…”