Affinage

AIRE

Autoimmune regulator · UniProt O43918

Length
545 aa
Mass
57.7 kDa
Annotated
2026-06-09
100 papers in source corpus 28 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AIRE is a multidomain nuclear transcriptional regulator that enforces central immune tolerance by driving promiscuous expression of peripheral tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs), and its loss-of-function mutations cause the autoimmune disorder APECED (PMID:12376594, PMID:11854172, PMID:9398839). The protein contains tandem PHD zinc fingers, an HSR homomultimerization domain, a SAND domain, and LXXLL motifs, localizes to discrete nuclear bodies, and possesses intrinsic transactivation capacity dependent on its PHD fingers and homomultimerization (PMID:9398839, PMID:10344583, PMID:11524731, PMID:14974083). AIRE preferentially engages genes whose promoters carry hallmarks of inactive chromatin and that are predisposed to double-strand breaks—including Z-DNA-forming and NFE2L2-motif promoters that adopt a poised state—and it concentrates with its partners at super-enhancers in a manner strictly dependent on topoisomerase 1 (PMID:19744957, PMID:28135252, PMID:38480882). Once engaged, AIRE recruits the P-TEFb elongation complex to increase RNA polymerase II occupancy and couple transcription to pre-mRNA splicing; this activity is potentiated by N-terminal phosphorylation that triggers SCF(FBXO3)-mediated ubiquitylation and is antagonized by DAXX and by HDAC1/2-dependent deacetylation (PMID:21724609, PMID:27365398, PMID:20185822, PMID:25158603). AIRE expression in mTECs is itself controlled by RANK/NF-κB signaling acting through a conserved CNS1 enhancer and by epigenetic licensing involving CTCF eviction, DNA demethylation, and lineage transcription factors (PMID:26364592, PMID:27941786). Functionally, AIRE shapes the autoreactive T-cell repertoire by mediating clonal deletion of self-reactive thymocytes and by diverting tolerance-prone clonotypes into the Foxp3+ Treg lineage, acting both directly and through TRA hand-off to Batf3-dependent dendritic cells and through control of mTEC subset heterogeneity (PMID:15492124, PMID:25220213, PMID:27130899, PMID:34930780). AIRE additionally functions in extrathymic Aire-expressing cells (eTACs), where RANK-dependent expression supports negative selection and maternal-fetal tolerance during pregnancy (PMID:34767455, PMID:34272228).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 High

    Establishing the molecular identity of the APECED gene answered whether a single locus underlies this autoimmune syndrome and predicted a transcription-factor function from its domain architecture.

    Evidence Positional cloning and patient mutation sequencing with domain analysis

    PMID:9398839

    Open questions at the time
    • Domain function inferred from sequence, not yet tested biochemically
    • No cellular site of action defined
  2. 1999 Medium

    Determining AIRE's subcellular localization addressed where it acts, placing it in nuclear body-like speckles consistent with transcriptional regulation.

    Evidence Immunocytochemistry in transfected cells and ex vivo

    PMID:10344583

    Open questions at the time
    • Speckle composition unknown
    • No target genes identified
  3. 2002 High

    Linking AIRE loss to reduced ectopic TRA transcription in mTECs answered what cellular process AIRE serves, defining promiscuous gene expression in the thymic medulla as the basis of central tolerance.

    Evidence Aire-knockout mice with thymic stromal expression profiling and autoimmune readout

    PMID:11854172 PMID:12376594

    Open questions at the time
    • Mechanism of gene selection unknown
    • Direct vs indirect targets not distinguished
  4. 2001 Medium

    Demonstrating transactivation capacity and that patient mutations impair it confirmed AIRE acts as a transcriptional activator and linked specific mutations to functional defects.

    Evidence GAL4-fusion reporter transactivation assay and mutant localization studies

    PMID:11524731

    Open questions at the time
    • No native DNA-binding specificity defined
    • Single lab heterologous assay
  5. 2004 High

    Mapping domain roles and quaternary structure clarified how AIRE assembles and which domains drive activity, showing HSR-mediated homomultimerization and PHD-dependent transactivation are required.

    Evidence Mutagenesis of 16 disease mutations with transactivation, Co-IP, and localization assays; heterozygous/homozygous KO with TCR-transgenic readout

    PMID:14974083 PMID:15492124

    Open questions at the time
    • Composition of high-molecular-weight complexes undefined
    • Structural basis of multimerization not solved
  6. 2007 Medium

    Resolving conflicting reports on lymphotoxin signaling established that LTβR controls mTEC organization and number rather than directly regulating Aire expression.

    Evidence LTβR-KO and LTα-KO mice with Aire and target-gene analysis, contradicting an earlier 2003 claim

    PMID:14517552 PMID:17947641

    Open questions at the time
    • The true upstream signal driving Aire was not yet identified
    • Indirect effects on TRA expression remained possible
  7. 2009 High

    Defining the chromatin signature of AIRE targets answered which genes it selects, showing it activates loci marked by inactive chromatin and converts them to an active, Pol II-loaded state.

    Evidence Genome-wide expression plus ChIP in HEK293 cells and mTECs

    PMID:19744957

    Open questions at the time
    • How AIRE reads inactive marks not mechanistically resolved
    • Elongation machinery not yet identified
  8. 2011 High

    Identifying P-TEFb recruitment answered how AIRE drives transcription, showing it promotes Pol II elongation and co-transcriptional splicing via CDK9.

    Evidence Co-IP, DNA-tethering transactivation, CDK9 inhibition, and APECED truncation mutation analysis

    PMID:21724609

    Open questions at the time
    • Stoichiometry and direct contact surface with P-TEFb undefined
    • Splicing target spectrum not catalogued
  9. 2014 Medium

    Characterizing AIRE post-translational regulation and repressors revealed how its activity is tuned, identifying DAXX-mediated repression and acetylation/HDAC1-2 control of stability and localization.

    Evidence Yeast two-hybrid, Co-IP, colocalization, mass-spectrometry PTM mapping, and transactivation assays

    PMID:20185822 PMID:25158603

    Open questions at the time
    • Physiological triggers of acetylation/deacetylation unknown
    • In vivo relevance of DAXX repression not tested
  10. 2016 High

    Defining the FBXO3 axis answered how AIRE activity is positively switched, showing N-terminal phosphorylation triggers SCF(FBXO3) ubiquitylation that enhances P-TEFb binding and transactivation.

    Evidence Co-IP, ubiquitylation assay, phospho-site mutagenesis, transcriptional activity assays

    PMID:27365398

    Open questions at the time
    • Kinase responsible for phosphorylation not identified
    • Link to upstream signaling unresolved
  11. 2016 High

    Decoding the epigenetic licensing of the Aire locus answered why expression is mTEC-restricted, identifying CTCF eviction, demethylation, CNS1/NF-κB control, and specific trans-activators.

    Evidence CNS1-KO mice, ATAC-seq, bisulfite-seq, CTCF ChIP, and RANK/NF-κB stimulation experiments

    PMID:26364592 PMID:27941786

    Open questions at the time
    • Hierarchy among the trans-activators not established
    • How RANK signal integrates with chromatin opening unresolved
  12. 2017 High

    Localizing AIRE and its partners to super-enhancers and identifying topoisomerase 1 as the cardinal partner answered how AIRE assembles its activating machinery at the genome.

    Evidence ChIP-seq for AIRE and partners, Co-IP, and super-enhancer analysis in mTECs

    PMID:28135252

    Open questions at the time
    • Role of DNA topology/breaks in activation not yet mechanistically explained
    • Full partner interaction map incomplete
  13. 2024 High

    Connecting target selection to DNA double-strand breaks and poised promoters explained the genomic logic of AIRE specificity, showing it targets Z-DNA-forming, NFE2L2-motif, DSB-prone poised promoters.

    Evidence CNN model of AIRE specificity, F1 hybrid natural-variation analysis, genome-wide DSB mapping, chromatin accessibility assays

    PMID:38480882

    Open questions at the time
    • Causal role of DSBs in activation vs correlation not fully separated
    • How AIRE physically senses poised state unresolved
  14. 2016 High

    Tracing the immunological output answered how thymic TRA expression shapes the repertoire, showing AIRE mediates clonal deletion of self-reactive T cells and biases tolerance-prone clonotypes into the Treg lineage, partly via Batf3-dependent DC hand-off.

    Evidence TCR clonotype sequencing of autoimmune infiltrates and Treg repertoires; Batf3-KO epistasis and BM chimeras; TCR-transgenic deletion assays

    PMID:15492124 PMID:25220213 PMID:27130899

    Open questions at the time
    • Rules determining deletion vs Treg diversion per antigen unclear
    • Antigen transfer mechanism to DCs not fully defined
  15. 2022 High

    Dissecting indirect mechanisms refined the model of how AIRE expands the TRA repertoire, showing it controls mTEC subset heterogeneity and suppresses ectopic CTLA-4 that would otherwise deplete DC co-stimulatory ligands needed for Treg development.

    Evidence Gain- and loss-of-function mice with single-cell transcriptomics; conditional mTEC CTLA-4 depletion with co-culture and autoimmunity rescue

    PMID:34930780 PMID:35172142

    Open questions at the time
    • Balance of direct vs subset-driven TRA induction not quantified genome-wide
    • Generality of the CTLA-4 axis across antigens unknown
  16. 2021 High

    Defining extrathymic Aire-expressing cells extended AIRE's tolerance role beyond the thymus, showing RANK-dependent eTACs mediate negative selection and are required for maternal-fetal immune tolerance.

    Evidence Single-cell multiomics, transgenic self-antigen models, RANK-dependency, and cell-type-specific maternal ablation with Rag1 rescue

    PMID:34272228 PMID:34767455

    Open questions at the time
    • Molecular relationship between eTAC and mTEC AIRE function unresolved
    • Antigen repertoire of eTACs not fully mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How AIRE's biochemical activity at poised, DSB-prone super-enhancers mechanistically integrates its diverse cell-type-specific roles (thymic mTECs, eTACs, and reported extra-immune functions) remains unresolved.
  • No structural model linking domain organization to chromatin engagement
  • Causal role of DNA breaks in transcriptional activation undefined
  • Extra-immune roles (spermatogenesis, fibrocytes, ESCs) remain mechanistically isolated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 2 GO:0042393 histone binding 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 3
Partners
CDK9DAXXFBXO3HDAC1HDAC2TOP1
Complex memberships
AIRE homomultimer / high-molecular-weight complexP-TEFb-associated transcription elongation complexSCF(FBXO3)

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Aire-deficient mice show a specific reduction in ectopic transcription of genes encoding peripheral tissue-restricted antigens in medullary thymic epithelial cells (mTECs), establishing that Aire promotes promiscuous gene expression of peripheral antigens in the thymic medulla to impose central tolerance. Knockout mouse model with gene expression analysis in thymic stromal cells; autoimmune phenotype readout Science High 11854172 12376594
1997 AIRE encodes a protein with two PHD-type zinc-finger motifs, a proline-rich region, three LXXLL motifs, and a putative nuclear targeting signal, consistent with a transcription factor; loss-of-function mutations cause APECED. Positional cloning, sequencing of patient mutations, domain analysis Nature genetics High 9398839
1999 AIRE protein localizes to nuclear body-like structures (discrete nuclear speckles) in cell nuclei, suggesting involvement in transcriptional regulation. Subcellular localization by immunocytochemistry in transfected cells and ex vivo Annals of medicine Medium 10344583
2001 AIRE protein can activate transcription of a reporter gene when fused to a heterologous DNA-binding domain, confirming transactivation capacity; certain patient mutations alter subcellular localization or reduce transactivation. Reporter gene transactivation assay with GAL4-fusion constructs; subcellular localization studies of mutants Human mutation Medium 11524731
2003 Lymphotoxin-β receptor (LTβR) signaling is required for Aire expression in thymic medullary epithelial cells; stimulation of LTβR by agonistic antibody increases Aire and tissue-restricted antigen expression in thymus and cultured thymic epithelial cells. LT-deficient and LTβR-deficient mouse models; agonistic antibody stimulation; gene expression analysis Nature immunology Medium 14517552
2007 The lymphotoxin pathway does not directly regulate Aire expression or function in medullary thymic epithelial cells; instead, LT signaling controls mTEC organization and cell number. Aire expression and its target genes are unaffected in LTβR- or LTα-chain-deficient mice. LTβR-KO and LTα-KO mouse models; Aire expression analysis; target gene analysis Journal of immunology Medium 17947641
2004 AIRE's HSR domain mediates homomultimerization; PHD zinc fingers are necessary for transactivation capacity; mutations in HSR or SAND domains disrupt homomultimerization; AIRE is present in soluble high-molecular-weight complexes; HSR domain mutations and PHD deletions disrupt these complexes. In vitro mutagenesis, transactivation assays, co-immunoprecipitation, subcellular localization of 16 disease-causing mutations Human mutation High 14974083
2004 Complete loss of Aire abolishes thymic expression of insulin promoter-driven transgene and endogenous insulin gene, resulting in impaired clonal deletion of islet-reactive T cells; loss of a single Aire copy diminishes thymic insulin expression and causes a ~300% increase in islet-reactive CD4 T cells escaping deletion. Heterozygous and homozygous Aire-KO mice crossed to TCR-transgenic models; gene expression and T cell repertoire analysis Journal of experimental medicine High 15492124
2009 AIRE preferentially activates genes marked by histone modifications associated with inactive chromatin (low H3K4me3 and AcH3 on promoters); during AIRE-mediated activation, target genes acquire H3 modifications associated with active transcription and recruit RNA polymerase II. Genome-wide expression analysis combined with chromatin immunoprecipitation (ChIP) in stably transfected HEK293 cells and mouse mTECs Human molecular genetics High 19744957
2011 AIRE interacts with P-TEFb; a patient APECED mutation truncating the C-terminus of AIRE disrupts P-TEFb binding and abolishes transcriptional activity. Via P-TEFb, AIRE increases RNA polymerase II occupancy on target genes and enhances co-transcriptional pre-mRNA splicing. Inhibition of CDK9 (kinase subunit of P-TEFb) inhibits AIRE-induced splicing. Co-immunoprecipitation, heterologous DNA-tethering transactivation assay, CDK9 inhibition, analysis of APECED patient truncation mutation Nucleic acids research High 21724609
2016 AIRE is phosphorylated on two specific residues near its N-terminus, which triggers binding to the F-box protein FBXO3 E3 ubiquitin ligase. The SCF(FBXO3) complex then ubiquitylates AIRE, increases its binding to P-TEFb, and potentiates AIRE transcriptional activity. Co-immunoprecipitation, ubiquitylation assay, phosphorylation-site mutagenesis, transcriptional activity assays Journal of biological chemistry High 27365398
2010 DAXX is a novel AIRE-interacting protein identified by yeast two-hybrid screening; interaction validated by co-immunoprecipitation and colocalization in mammalian cells; DAXX exerts a strong repressive effect on AIRE transcriptional activity in transactivation assays. Yeast two-hybrid, co-immunoprecipitation, colocalization, transactivation assay Journal of biological chemistry Medium 20185822
2014 AIRE acetylation sites were mapped by mass spectrometry; specific acetylated lysines influence subcellular localization; HDAC1 and HDAC2 deacetylate AIRE; acetylation increases AIRE nuclear stability while interaction with deacetylase complexes inhibits AIRE transcriptional activity and promotes proteasomal degradation. Mass spectrometry mapping of acetylation sites, mutagenesis, co-immunoprecipitation with HDAC1/2, transactivation assays Journal of biomedical science Medium 25158603
2017 AIRE and its partners (notably DNA-damage response proteins) preferentially localize to and activate super-enhancers (long chromatin stretches overloaded with transcriptional regulators). Topoisomerase 1 was identified as a cardinal AIRE partner that colocalizes on super-enhancers and is required for AIRE's interaction with all its other associates. Genome-wide chromatin mapping (ChIP-seq for AIRE and partners), co-immunoprecipitation, super-enhancer analysis in mTECs Nature immunology High 28135252
2015 A conserved noncoding sequence 1 (CNS1) upstream of the Aire locus, containing two NF-κB binding sites, is critical for thymic Aire expression. CNS1-deficient mice lack thymic Aire expression, downregulate Aire-dependent genes, have impaired mTEC terminal differentiation, and reduced Treg production. CNS1 is required for RANK-induced Aire expression and is activated by NF-κB complexes containing RelA. CNS1-knockout mouse model, reporter assays, NF-κB binding site mutagenesis, RANK stimulation experiments European journal of immunology High 26364592
2016 The Aire locus is insulated by the global chromatin organizer CTCF and hypermethylated in non-expressing cells; in mTECs, Aire expression is enabled by eviction of CTCF, demethylation of exon 2 and the proximal promoter, and coordinated action of transcription activators Irf4, Irf8, Tbx21, Tcf7, and Ctcfl acting on mTEC-specific accessible chromatin regions. ATAC-seq/chromatin accessibility analysis, bisulfite sequencing (DNA methylation), CTCF ChIP, transcription factor binding analysis in sorted mTECs Nature immunology High 27941786
2024 AIRE preferentially targets genes whose promoters form Z-DNA and have NFE2L2-binding motifs; Z-DNA-forming and NFE2L2-binding motifs are positively associated with DNA double-stranded break (DSB) generation at promoters; promoters with strong DSB generation enter a poised state with accessible chromatin and pre-assembled transcriptional machinery; AIRE preferentially targets these poised promoters. Convolutional neural network trained on AIRE target specificity, F1 hybrid mouse natural genetic variation analysis, genome-wide DSB mapping, chromatin accessibility assays Nature High 38480882
2008 AIRE regulates T-cell-independent B-cell responses through elevated BAFF; Aire-deficient mice and APS1 patients have increased serum BAFF levels; AIRE-deficient bone marrow-derived dendritic cells produce significantly more BAFF than wild-type cells upon IFN-γ stimulation (but not IL-10); this suggests a cell-intrinsic role for AIRE in peripheral dendritic cells regulating IFN-γ receptor signaling. Bone marrow transfer into nude mice, in vitro BAFF production assay with dendritic cells, serum BAFF measurements in mice and patients PNAS Medium 19011083
2008 Aire mRNA is expressed in the testis; in Aire-deficient mice, the scheduled apoptotic wave of germ cells necessary for normal spermatogenesis is reduced and sporadic adult apoptosis is increased; this effect is independent of the adaptive immune system (not abolished by Rag-1 deficiency), indicating a cell-intrinsic proapoptotic role for Aire in spermatogenesis. RT-PCR for Aire expression in testis, Aire-KO and Aire-KO × Rag1-KO double-mutant analysis of germ cell apoptosis Journal of immunology Medium 18209027
2014 AIRE controls the expression of thyroid-specific proteins (TSH receptor, thyroglobulin, sodium-iodide symporter, thyroperoxidase) in fibrocytes; siRNA knockdown of AIRE in fibrocytes reduces expression of these thyroid proteins as well as PAX8 and TTF-1; fibrocytes from an individual with an inactivating AIRE mutation show substantially reduced levels of these proteins. siRNA knockdown of AIRE, Western blot, real-time PCR, gene promoter analysis, cell transfections, natural AIRE mutation patient cells Journal of clinical endocrinology and metabolism Medium 24708100
2010 Aire regulates the expression of differentiation-associated genes and self-renewal in embryonic stem cells; Aire knockdown in mouse ESCs reduces clone-forming efficiency and attenuates cell cycle progression, indicating a role for Aire in ESC self-renewal beyond its thymic function. Aire knockdown in mouse ESCs, clone-forming efficiency assay, cell cycle analysis Biochemical and biophysical research communications Low 20226168
2014 Approximately half of Aire-dependent clonal deletion or Treg cell selection utilizes a pathway dependent on antigen presentation by bone marrow-derived APCs, specifically Batf3-dependent CD8α+ dendritic cells, which have enhanced ability to present antigens acquired from stromal cells. Genetic epistasis using Batf3-KO mice, bone marrow chimeras, T cell repertoire analysis by TCR sequencing Immunity High 25220213
2016 Aire enforces tolerance by directing autoreactive T cell clonotypes preferentially into the Foxp3+ Treg lineage; in Aire-deficient mice, the predominant conventional T cell clonotypes infiltrating target organs are those that would have been Treg-biased in wild-type mice, indicating diversion from Treg to pathogenic conventional T cell fate. TCR clonotype sequencing of autoimmune infiltrates in Aire-/- mice compared to Foxp3+ Treg repertoire in Aire+/+ mice Immunity High 27130899
2021 Extrathymic Aire-expressing cells (eTACs) consist of CCR7+ Aire-expressing migratory dendritic cells (AmDCs) and an Airehi RORγt+ population (Janus cells, JCs); both have highest transcriptional and genomic homology to CCR7+ migratory DCs; eTACs have RANK-dependent Aire expression; transgenic self-antigen expression by eTACs is sufficient to induce negative selection and prevent autoimmune diabetes. Single-cell multiomics (scRNA-seq + scATAC-seq), transgenic mouse models, RANK-dependency experiments, autoimmune diabetes prevention assay Science immunology High 34767455
2021 Maternal ablation of extrathymic Aire-expressing cells (eTACs), but not medullary thymic epithelial cells, during early pregnancy causes intrauterine growth restriction (IUGR) in both allogeneic and syngeneic pregnancies; the IUGR phenotype is immune-mediated (rescued in Rag1-deficient mice) and involves expansion of activated T cells including T follicular helper cells. Cell-type-specific ablation mouse models, Rag1-deficient rescue experiment, single-cell RNA sequencing of immune compartment Science immunology High 34272228
2021 Aire controls mTEC heterogeneity as a primary mechanism for TRA expression; many so-called Aire-dependent genes are not direct transcriptional targets but are induced indirectly through Aire-dependent control of mTEC subset composition; Ccl25 emerged as a canonical direct Aire target confirmed both in vitro and in vivo. Engineered mice with augmented Aire expression, single-cell transcriptomic analysis of mTECs, integration with Aire-deficient mTEC data, in vitro and in vivo validation of Ccl25 Journal of immunology High 34930780
2022 In Aire-deficient mTECs, CTLA-4 is aberrantly expressed; this ectopic CTLA-4 on mTECs binds CD80/CD86 on thymic dendritic cells, depleting co-stimulatory ligands from DCs and thereby impairing DCs' ability to present self-antigens and provide co-stimulation for Treg production; depletion of CTLA-4 specifically from mTECs rescues Treg production and prevents autoimmunity in Aire-deficient mice. Conditional CTLA-4 depletion in mTECs, co-culture assays, flow cytometry for CD80/CD86 expression, Treg quantification, autoimmunity readout in mice Cell reports High 35172142

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Projection of an immunological self shadow within the thymus by the aire protein. Science (New York, N.Y.) 1810 12376594
1997 Positional cloning of the APECED gene. Nature genetics 1029 9398839
2009 Aire. Annual review of immunology 476 19302042
2002 Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. Human molecular genetics 355 11854172
2016 AIRE-Deficient Patients Harbor Unique High-Affinity Disease-Ameliorating Autoantibodies. Cell 232 27426947
2004 Gene dosage--limiting role of Aire in thymic expression, clonal deletion, and organ-specific autoimmunity. The Journal of experimental medicine 225 15492124
2014 Distinct contributions of Aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus. Immunity 219 25220213
2016 AIRE expands: new roles in immune tolerance and beyond. Nature reviews. Immunology 186 26972725
2008 Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nature reviews. Immunology 183 19008896
2016 Aire Enforces Immune Tolerance by Directing Autoreactive T Cells into the Regulatory T Cell Lineage. Immunity 166 27130899
2003 Lymphotoxin pathway directs thymic Aire expression. Nature immunology 164 14517552
2002 APS-I/APECED: the clinical disease and therapy. Endocrinology and metabolism clinics of North America 156 12092452
2007 A decade of AIRE. Nature reviews. Immunology 145 17641664
2011 Control of central and peripheral tolerance by Aire. Immunological reviews 123 21488892
2016 AIRE-mutations and autoimmune disease. Current opinion in immunology 105 27504588
2006 Oral and oesophageal squamous cell carcinoma--a complication or component of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS-I). Oral oncology 103 16997613
2017 The transcriptional regulator Aire binds to and activates super-enhancers. Nature immunology 102 28135252
2001 APECED mutations in the autoimmune regulator (AIRE) gene. Human mutation 102 11524731
1998 Gene defect behind APECED: a new clue to autoimmunity. Human molecular genetics 98 9735375
2010 Aire and T cell development. Current opinion in immunology 97 21163636
2004 APECED-causing mutations in AIRE reveal the functional domains of the protein. Human mutation 93 14974083
2002 Expression of AIRE gene in peripheral monocyte/dendritic cell lineage. Immunology letters 91 11803052
2008 The lymphotoxin pathway regulates Aire-independent expression of ectopic genes and chemokines in thymic stromal cells. Journal of immunology (Baltimore, Md. : 1950) 89 18390720
2018 Twenty Years of AIRE. Frontiers in immunology 83 29483906
2019 AIRE expression controls the peripheral selection of autoreactive B cells. Science immunology 82 30979797
2011 Mucocutaneous candidiasis and autoimmunity against cytokines in APECED and thymoma patients: clinical and pathogenetic implications. European journal of immunology 79 21574164
2007 Lymphotoxin pathway and Aire influences on thymic medullary epithelial cells are unconnected. Journal of immunology (Baltimore, Md. : 1950) 78 17947641
2005 Autoimmune polyendocrinopathy syndrome type 1 (APS1) and AIRE gene: new views on molecular basis of autoimmunity. Journal of autoimmunity 78 16290093
2020 PGE1 and PGA1 bind to Nurr1 and activate its transcriptional function. Nature chemical biology 76 32451509
2009 AIRE in the thymus and beyond. Current opinion in immunology 75 19833494
2008 Primary immune deficiency disorders presenting as autoimmune diseases: IPEX and APECED. Journal of clinical immunology 73 18264745
2005 AIRE and APECED: molecular insights into an autoimmune disease. Immunological reviews 72 15790357
2021 Single-cell multiomics defines tolerogenic extrathymic Aire-expressing populations with unique homology to thymic epithelium. Science immunology 69 34767455
2007 Expression of autoimmune regulator gene (AIRE) and T regulatory cells in human thymomas. Clinical and experimental immunology 69 17590173
2004 Aire: an update. Current opinion in immunology 68 15511668
2009 AIRE activated tissue specific genes have histone modifications associated with inactive chromatin. Human molecular genetics 67 19744957
2008 Expression of Aire and the early wave of apoptosis in spermatogenesis. Journal of immunology (Baltimore, Md. : 1950) 67 18209027
2001 Novel AIRE mutations and P450 cytochrome autoantibodies in Central and Eastern European patients with APECED. Human mutation 63 11524733
2011 Decreased AIRE expression and global thymic hypofunction in Down syndrome. Journal of immunology (Baltimore, Md. : 1950) 61 21856934
2010 Recent insights into the role and molecular mechanisms of the autoimmune regulator (AIRE) gene in autoimmunity. Autoimmunity reviews 61 20850570
2010 The role of AIRE in human autoimmune disease. Nature reviews. Endocrinology 61 21102544
2020 Identification of novel, clinically correlated autoantigens in the monogenic autoimmune syndrome APS1 by proteome-wide PhIP-Seq. eLife 59 32410729
2018 Age-Associated Decline in Thymic B Cell Expression of Aire and Aire-Dependent Self-Antigens. Cell reports 58 29386114
2018 Sugary Kefir Strain Lactobacillus mali APS1 Ameliorated Hepatic Steatosis by Regulation of SIRT-1/Nrf-2 and Gut Microbiota in Rats. Molecular nutrition & food research 54 29508520
2014 Expression of thyrotropin receptor, thyroglobulin, sodium-iodide symporter, and thyroperoxidase by fibrocytes depends on AIRE. The Journal of clinical endocrinology and metabolism 50 24708100
2017 Update on Aire and thymic negative selection. Immunology 49 28871661
2015 A highly conserved NF-κB-responsive enhancer is critical for thymic expression of Aire in mice. European journal of immunology 48 26364592
2013 Gastrointestinal manifestations in APECED syndrome. Journal of clinical gastroenterology 48 23314667
2018 The Role of Autoimmune Regulator (AIRE) in Peripheral Tolerance. Journal of immunology research 46 30255105
2017 Insights into immune tolerance from AIRE deficiency. Current opinion in immunology 46 29065385
2008 AIRE regulates T-cell-independent B-cell responses through BAFF. Proceedings of the National Academy of Sciences of the United States of America 46 19011083
2016 Transcriptional programs that control expression of the autoimmune regulator gene Aire. Nature immunology 44 27941786
2008 Expression of AIRE in thymocytes and peripheral lymphocytes. Autoimmunity 43 18324482
2007 What's new in the Aire? Trends in immunology 42 17556019
1999 Cloning of the APECED gene provides new insight into human autoimmunity. Annals of medicine 42 10344583
1997 Plasmid pGA1 from Corynebacterium glutamicum codes for a gene product that positively influences plasmid copy number. Journal of bacteriology 40 9045809
2011 Expression and function of the autoimmune regulator (Aire) gene in non-thymic tissue. Clinical and experimental immunology 38 21303359
2010 AIRE gene mutations and autoantibodies to interferon omega in patients with chronic hypoparathyroidism without APECED. Clinical endocrinology 38 20718774
2022 Pathogenic TNF-α drives peripheral nerve inflammation in an Aire-deficient model of autoimmunity. Proceedings of the National Academy of Sciences of the United States of America 37 35058362
2013 The biophysical and biochemical properties of the autoimmune regulator (AIRE) protein. Biochimica et biophysica acta 35 24275490
2013 The many faces of aire in central tolerance. Frontiers in immunology 34 24130560
2005 Disruption of immunological tolerance: role of AIRE gene in autoimmunity. Autoimmunity reviews 32 16431348
2002 A novel missense mutation of AIRE gene in a patient with autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED), accompanied with progressive muscular atrophy: case report and review of the literature in Japan. Endocrine journal 30 12625412
2024 AIRE relies on Z-DNA to flag gene targets for thymic T cell tolerization. Nature 29 38480882
2013 APECED: A Paradigm of Complex Interactions between Genetic Background and Susceptibility Factors. Frontiers in immunology 29 24167503
2008 The heterotrimeric Galpha protein pga1 regulates biosynthesis of penicillin, chrysogenin and roquefortine in Penicillium chrysogenum. Microbiology (Reading, England) 29 18957609
2023 Dominant-negative heterozygous mutations in AIRE confer diverse autoimmune phenotypes. iScience 28 37235056
2024 Aire in Autoimmunity. Annual review of immunology 27 38360547
2016 FBXO3 Protein Promotes Ubiquitylation and Transcriptional Activity of AIRE (Autoimmune Regulator). The Journal of biological chemistry 27 27365398
2011 Patient mutation in AIRE disrupts P-TEFb binding and target gene transcription. Nucleic acids research 27 21724609
2021 Extrathymic Aire-expressing cells support maternal-fetal tolerance. Science immunology 25 34272228
2021 Aire Controls Heterogeneity of Medullary Thymic Epithelial Cells for the Expression of Self-Antigens. Journal of immunology (Baltimore, Md. : 1950) 25 34930780
2010 Characterisation of Pga1, a putative Candida albicans cell wall protein necessary for proper adhesion and biofilm formation. Mycoses 25 20406396
2010 The role of Aire in clonal selection. Immunology and cell biology 25 21079643
2002 Population genetics and functions of the autoimmune regulator (AIRE). Endocrinology and metabolism clinics of North America 25 12092453
2021 AIRE deficiency, from preclinical models to human APECED disease. Disease models & mechanisms 24 33729987
2015 The Thymic Orchestration Involving Aire, miRNAs, and Cell-Cell Interactions during the Induction of Central Tolerance. Frontiers in immunology 24 26236310
2022 Aire suppresses CTLA-4 expression from the thymic stroma to control autoimmunity. Cell reports 22 35172142
2021 Infections in the monogenic autoimmune syndrome APECED. Current opinion in immunology 22 34418591
2020 Investigating the Mechanistic Differences of Obesity-Inducing Lactobacillus kefiranofaciens M1 and Anti-obesity Lactobacillus mali APS1 by Microbolomics and Metabolomics. Frontiers in microbiology 22 32733406
2010 DAXX is a new AIRE-interacting protein. The Journal of biological chemistry 22 20185822
2014 AIRE acetylation and deacetylation: effect on protein stability and transactivation activity. Journal of biomedical science 21 25158603
2010 Aire regulates the expression of differentiation-associated genes and self-renewal of embryonic stem cells. Biochemical and biophysical research communications 21 20226168
2008 Aire and Foxp3 expression in a particular microenvironment for T cell differentiation. Neuroimmunomodulation 21 19077444
2018 Aire Disruption Influences the Medullary Thymic Epithelial Cell Transcriptome and Interaction With Thymocytes. Frontiers in immunology 20 29867946
1999 Cloning and characterisation of PGA1 and PGA2: two G protein alpha-subunits from pea that promote growth in the yeast Saccharomyces cerevisiae. The Plant journal : for cell and molecular biology 19 10476071
2018 Beyond APECED: An update on the role of the autoimmune regulator gene (AIRE) in physiology and disease. Autoimmunity reviews 18 29427825
2017 AIRE: a missing link to explain female susceptibility to autoimmune diseases. Annals of the New York Academy of Sciences 18 29291257
2016 Novel Findings into AIRE Genetics and Functioning: Clinical Implications. Frontiers in pediatrics 18 27597936
2009 Novel and recurrent mutations in the AIRE gene of autoimmune polyendocrinopathy syndrome type 1 (APS1) patients. Clinical genetics 18 19758376
2016 Estrogen turns down "the AIRE". The Journal of clinical investigation 17 26999606
2015 Molecular Interactions and Implications of Aldose Reductase Inhibition by PGA1 and Clinically Used Prostaglandins. Molecular pharmacology 17 26487510
2013 Human APECED; a Sick Thymus Syndrome? Frontiers in immunology 17 24109480
2010 Heterotrimeric Gα protein Pga1 from Penicillium chrysogenum triggers germination in response to carbon sources and affects negatively resistance to different stress conditions. Fungal genetics and biology : FG & B 17 21146624
2022 Phylogeny, Structure, Functions, and Role of AIRE in the Formation of T-Cell Subsets. Cells 16 35053310
2022 Differentiation of Pluripotent Stem Cells Into Thymic Epithelial Cells and Generation of Thymic Organoids: Applications for Therapeutic Strategies Against APECED. Frontiers in immunology 15 35844523
2015 Aire-Overexpressing Dendritic Cells Induce Peripheral CD4⁺ T Cell Tolerance. International journal of molecular sciences 15 26729097
2007 Pga1 is an essential component of Glycosylphosphatidylinositol-mannosyltransferase II of Saccharomyces cerevisiae. Molecular biology of the cell 15 17615295
2002 Autoimmune regulator (AIRE) gene on chromosome 21: implications for autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) any more common manifestations of endocrine autoimmunity. Journal of endocrinological investigation 15 12398240
1987 Alterations of MCF-7 human breast cancer cell after prostaglandins PGA1 and PGF2 alpha treatment. Experimental cell biology 15 3471601

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