Aire

Abstract

Mutations in the transcriptional regulator, Aire, cause APECED, a polyglandular autoimmune disease with monogenic transmission. Animal models of APECED have revealed that Aire plays an important role in T cell tolerance induction in the thymus, mainly by promoting ectopic expression of a large repertoire of transcripts encoding proteins normally restricted to differentiated organs residing in the periphery. The absence of Aire results in impaired clonal deletion of self-reactive thymocytes, which escape into the periphery and attack a variety of organs. In addition, Aire is a proapoptotic factor, expressed at the final maturation stage of thymic medullary epithelial cells, a function that may promote cross-presentation of the antigens encoded by Aire-induced transcripts in these cells. Transcriptional regulation by Aire is unusual in being very broad, context-dependent, probabilistic, and noisy. Structure/function analyses and identification of its interaction partners suggest that Aire may impact transcription at several levels, including nucleosome displacement during elongation and transcript splicing or other aspects of maturation.

Ovarian autoimmune disease: clinical concepts and animal models

“…74 Briefly, AIRE was originally considered a transcription factor based on its nuclear localization, it ability to bind DNA and the presence of a SAND (Sp100, AIRE-1, NucP41/75, DEAF-1) functional domain. [75][76][77] However, AIRE also contains two PHD (Plant HomeoDomain)-type zinc fingers that confer its ability to associate with numerous protein partners and that are essential for regulation of gene expression. [78][79][80] These PHD domains associate with histone 3 at unmethylated lysine 4 residues (H3K4me0), which are typically within transcriptionally inactive chromatin regions, and in combination with DNA-dependent protein kinase, appear to promote subsequent transcription.…”

Elevated Mcl-1 inhibits thymocyte apoptosis and alters thymic selection

“…3 Notably, medullary epithelial cells expressing the transcriptional regulator Aire (autoimmune regulator) produce a broad range of peripheral tissue antigens for presentation to the maturing thymocytes and thereby extend the scope of negative selection. 4 At each of the checkpoints, thymocyte life or death is primarily determined by the balance between opposing factions of the Bcl-2 protein family, which associate at the outer mitochondrial membrane to regulate 'intrinsic' or stressinduced apoptosis. 5 If the Bcl-2 pro-survival family members prevail, mitochondrial membrane integrity is preserved.…”

AIRE Gene Mutation in Chinese APS-1 Patients

“…AIRE protein activates the transcription of genes encoding for tissuerestricted antigens (TRAs) in a subset of mTECs: the presentation of TRAs to the maturating thymocytes induces the clonal deletion of selfreactive thymocytes and constitutes the main form of central tolerance. Dysregulation of thymic AIRE expression in genetically transmitted and acquired diseases other than APS-1 may contribute to further forms of autoimmunity [8][9][10][11][12].…”