Disease relevance of AIRE

• However, the role of AIRE mutations in AIH, primary sclerosing cholangitis (PSC), and primary biliary cirrhosis (PBC) is not known [1].
• Analysis of AIRE expression in the thymi of 2 Omenn syndrome patients and 1 SCID patient, by real-time RT-PCR and immunohistochemistry, demonstrated a profound reduction in the levels of AIRE mRNA and protein in patients as compared with a normal control subject [2].
• In addition, the polymorphisms presented provide the tools for investigation of the involvement of AIRE in other autoimmune diseases, particularly those affecting the endocrine system [3].
• The only association between the phenotype and the AIRE genotype was the higher prevalence of candidiasis in the patients with the most common mutation, R257X, than in those with other mutations [4].
• However, while inactivating AIRE mutations result in the 'autoimmune polyendocrinopathy syndrome type 1' (APS-1), its major features are not well reproduced in AIRE-knock-out mice [5].

Psychiatry related information on AIRE

• Prostaglandin A1 (PGA1) was infused at the rate of 1/microgram/kg/min in 10 patients with decompensated heart failure under conditions of water loading (5 patients) or water deprivation (5 patients) [6].

High impact information on AIRE

• We have isolated a novel gene from this region, AIRE (autoimmune regulator), which encodes a protein containing motifs suggestive of a transcription factor including two zinc-finger (PHD-finger) motifs, a proline-rich region and three LXXLL motifs [7].
• Autoimmune polyglandular syndrome type I (APS 1, also called APECED) is an autosomal-recessive disorder that maps to human chromosome 21q22.3 between markers D21S49 and D21S171 by linkage studies [7].
• Autoimmune polyglandular disease type I (APECED) is an autosomal recessive autoimmune disease characterized by a variable combination of the failure of the endocrine glands [8].
• Linkage disequilibrium studies have significantly increased the informativeness of the analyses and helped to locate the critical DNA region for the APECED locus to just 500 kilobases, a much more precise definition than linkage analyses alone could achieve [8].
• Characterization of the molecular and cellular mechanisms involved in APECED, and recognition that AIRE expression is sustained by effective thymopoiesis, has recently allowed to define that the autoimmunity of Omenn syndrome, a combined immunodeficiency due to defects of V(D)J recombination, also results from defective expression of AIRE [9].

Chemical compound and disease context of AIRE

• We examined clinical outcomes associated with non-randomised digoxin therapy in a postmyocardial infarction population with clinical heart failure (AIRE study) [10].
• ACE inhibition, atherosclerosis and myocardial infarction--the AIRE Study in practice.Acute Infarction Ramipril Efficacy Study [11].
• In the present study we investigated the effect of prostaglandin A1 (PGA1) on the regulation of HSP70 gene expression as well as on viral RNA and protein synthesis in CEM-SS cells during acute infection with human immunodeficiency virus type 1 (HIV-1) [12].
• The cloning efficiencies of a murine melanoma cell line (S91 CCL 53.1) and a human melanoma cell strain (C8146c) were inhibited by dexamethasone (DEX), prostaglandin A1 (PGA1), and beta-all-trans-retinoic acid (RA) in a dose-dependent manner [13].
• 48% (38/80) of APS1 patients had antibodies to tryptophan hydroxylase, whereas no reactivity to this antigen was detected in patients with other autoimmune diseases (n=372) or healthy blood donors (n=70) [14].

Biological context of AIRE

• To address this issue patients with AIH (n = 94), PSC (n = 60), and PBC (n = 30) were analyzed for the presence of mutations in exons 6, 8, and 10 of AIRE by single stranded conformation polymorphism and sequence analysis [1].
• We suggest that the transcriptional transactivation properties of AIRE together with its interaction with CBP might be important in its function as disease-causing mutations almost totally abolish the activation effect [15].
• Using a mathematical approach we have re-analyzed an Affymetrix dataset identifying AIRE responsive genes and show that they tend to localize to specific regions of the genome [16].
• Here we use a transrepression assay to demonstrate that AIRE interacts with multiple components of the transcription complex including a novel interaction with the UBA domain protein, GBDR1 [16].
• 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 [17].

Anatomical context of AIRE

• 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 [17].
• When AIRE is expressed in cultured human thymic epithelial cells, it tightly associates with nuclear matrix, suggesting that AIRE responsive genes may be localized to specific regions [16].
• AIRE recruits multiple transcriptional components to specific genomic regions through tethering to nuclear matrix [16].
• A defect of regulatory T cells in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy [17].
• In Aire(-/-) mice the expression of FoxP3 was normal and even increased in target tissues in parallel with the lymphocyte infiltration process [17].

Associations of AIRE with chemical compounds

• In agreement, we show that the common transcriptional coactivator CREB-binding protein (CBP) interacts with AIRE in vitro and in yeast nuclei through the CH1 and CH3 conserved domains [15].
• Accordingly, the nuclear export inhibitor leptomycin B partially inhibits the nuclear export of AIRE [18].
• Sodium bisulfite sequencing showed a less methylated status of AIRE promoter in the thymic epithelial cell line TEC1A3 compared with HeLa and monocytic cells U937 and THP-1 [19].
• Real-time PCR analysis showed that treatment with 5-aza-2'-deoxycytidine (5-azaCdR), a DNA methyltransferase inhibitor, up-regulated AIRE transcript levels in TEC1A3, U937, and HeLa cells and that even greater activations in TEC1A3 and U937 cells were observed using combined treatments with deacetylase inhibitor trichostatin A [19].
• The presence of a 390-bp CpG island within the proximal promoter suggested that cytosine methylation has a role in transcriptional regulation of AIRE, which was supported by in vitro methylation experiments of promoter constructs [19].

Regulatory relationships of AIRE

• These results confirm the effect of IDDM2 alleles on insulin expression in the thymus, but suggest that the levels of AIRE may exert a stronger influence than IDDM2 alleles themselves [20].
• Mitogen-activated protein kinase pathway controls autoimmune regulator (AIRE) gene expression in granulo-monocyte colony stimulating factor (GM-CSF)-stimulated myelomonocytic leukemia OTC-4 cells [21].
• At the subcellular level, AIRE is expressed in nuclear dots resembling promyelocytic leukemia nuclear bodies, which are associated with several transcriptionally active proteins [22].
• We conclude that cellular immunity to GAD detected as T cell proliferation response to GAD or IFN-gamma secretion by GAD-stimulated T cells was frequent in patients with APECED (69%) and was not restricted to the patients with clinically detectable beta-cell damage [23].

Other interactions of AIRE

• In selected families, major diabetogenes (e.g., IDDM17, autoimmune regulator gene (AIRE)) are likely to be of importance [24].
• Furthermore, the overexpression of AIRE and CBP collaboratively enhance endogenous IFNbeta mRNA expression [25].
• HLA-DRB1 and DQB1 allele genotyping and autoimmune regulator (AIRE) polymorphisms located in exons 6, 8 and 10 were investigated by PCR-based methods [26].
• Both AIRE and FOXP3, identified initially via their association with genetically manipulated mice, are critically involved in tolerance induction in humans [27].
• Characterization of a novel gene, C21orf2, on human chromosome 21q22.3 and its exclusion as the APECED gene by mutation analysis [28].

Analytical, diagnostic and therapeutic context of AIRE

• Autoantibody patterns of patients with defects in AIRE were analyzed by indirect immunofluorescence, enzyme-linked immunosorbent assay and Western blot [1].
• In the present study, we found that the AIRE gene was restrictively expressed in peripheral CD14-positive monocytes but not in CD4-positive T cells nor polymorphonuclear cells, as assessed by RT-PCR [29].
• We subsequently identified candidates for AIRE-regulated genes by using cDNA microarray technology to analyse the changes in the gene expression profile brought about by overexpressing the AIRE protein in the monocytic U937 cells [30].
• Skin cell cultures expressed the AIRE, Foxn1, and Hoxa3 transcription factors and a panel of autoantigens [31].
• In situ hybridization on mouse and human histological sections showed that AIRE expression pattern was mainly restricted to a few cells in the thymus, calling for a tissue-specific function of the gene product [32].

References