Affinage

AIRE

Autoimmune regulator · UniProt O43918

Length
545 aa
Mass
57.7 kDa
Annotated
2026-04-28
100 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AIRE is a transcriptional regulator that enforces immunological self-tolerance by driving ectopic expression of thousands of tissue-restricted antigens in medullary thymic epithelial cells (mTECs), enabling negative selection of autoreactive T cells and regulatory T cell generation (PMID:12376594, PMID:25220213). AIRE oligomerizes via its HSR domain, localizes to nuclear dots, and preferentially activates genes whose promoters harbor Z-DNA-forming sequences and DNA double-strand breaks that create a poised chromatin state; it acts from super-enhancers in TOP1-scaffolded multiprotein complexes that loop to target promoters, while its phosphorylation-dependent ubiquitylation by SCF(FBXO3) enhances P-TEFb recruitment for transcriptional elongation (PMID:11533054, PMID:38480882, PMID:28135252, PMID:27365398). AIRE simultaneously exerts rapid chromatin-repressive activity that limits the amplitude of antigen expression, negatively autoregulates its own transcription via the CNS1 enhancer, and suppresses ectopic CTLA-4 in mTECs to preserve dendritic cell co-stimulatory capacity for Treg selection (PMID:29335648, PMID:34477806, PMID:35172142). Loss-of-function mutations cause autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED/APS-1), while dominant-negative PHD-domain mutations break tolerance in heterozygotes; AIRE also functions in extrathymic Aire-expressing cells including Janus cells to extend peripheral deletional tolerance (PMID:9398839, PMID:34477806, PMID:34767455).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Positional cloning established that AIRE is the causative gene for APECED, and its domain architecture (PHD fingers, SAND domain, LXXLL motifs) predicted a transcriptional regulator function — transforming a Mendelian disease locus into a candidate transcription factor.

    Evidence Positional cloning and mutation analysis in APECED families

    PMID:9398839

    Open questions at the time
    • No direct evidence of transcriptional activity
    • Disease mutations not functionally characterized
    • Expression pattern in thymus not established
  2. 1999 High

    Demonstration that AIRE localizes to discrete nuclear dot structures (distinct from PML bodies) in thymus and lymphoid tissues supported the transcriptional regulator prediction and raised the question of what these subnuclear compartments represent.

    Evidence Immunofluorescence and immunohistochemistry in transfected cells and primary thymic/lymphoid tissue

    PMID:9931333

    Open questions at the time
    • Identity and function of nuclear dot structures unknown
    • No chromatin or DNA-binding data
  3. 2001 High

    Biochemical reconstitution showed AIRE forms phosphorylation-enhanced oligomers that bind specific DNA motifs, and disease mutations map to domains required for multimerization (HSR) and transactivation (PHD fingers), directly linking APECED pathogenesis to disrupted AIRE biochemistry.

    Evidence Recombinant protein DNA-binding assays, co-immunoprecipitation from thymic extracts, mutagenesis of 16 disease mutations with reporter assays

    PMID:11533054 PMID:14974083

    Open questions at the time
    • In vivo transcriptional targets unknown
    • Nature of high-molecular-weight complexes unresolved
    • Post-translational modification sites not mapped
  4. 2002 High

    Aire-knockout mice revealed the central biological function: AIRE drives ectopic expression of peripheral tissue-restricted antigens in mTECs, and its absence causes multi-organ autoimmunity with altered T-cell repertoire — establishing AIRE as the master regulator of promiscuous gene expression for central tolerance.

    Evidence Two independent Aire-KO mouse models with gene expression profiling, autoimmune phenotyping, and T-cell repertoire analysis

    PMID:11854172 PMID:12376594

    Open questions at the time
    • Mechanism by which AIRE activates thousands of unrelated genes unknown
    • Direct versus indirect target genes not distinguished
    • Contribution to Treg generation not assessed
  5. 2008 Medium

    Evidence for extrathymic AIRE functions emerged: AIRE-deficient dendritic cells show impaired innate cytokine responses and elevated BAFF production, and AIRE has a direct proapoptotic role in testicular germ cells independent of adaptive immunity — expanding the functional repertoire beyond thymic tolerance.

    Evidence Patient-derived monocyte-derived DCs with transcriptome analysis; bone marrow chimeras with BAFF assays; Aire/Rag1 double-KO testis histology

    PMID:18209027 PMID:18600308 PMID:19011083

    Open questions at the time
    • Molecular mechanism of AIRE action in DCs uncharacterized
    • Testicular function not independently replicated
    • Relationship between thymic and extrathymic AIRE activities unclear
  6. 2011 High

    Aire was shown to control mTEC terminal differentiation within a transient 1–2 day expression window, and its loss blocks mTEC maturation — revealing that AIRE shapes the cellular context in which tolerance is established, not only the antigen repertoire.

    Evidence Aire-KO mice with LacZ reporter, mTEC purification, flow cytometry, RANK/CD40 rescue experiments

    PMID:22448160

    Open questions at the time
    • Whether differentiation control is separable from antigen induction unknown
    • Downstream effectors of mTEC differentiation not identified
  7. 2014 High

    The downstream antigen presentation pathway was resolved: Aire-induced antigens are presented both directly by mTECs and indirectly via Batf3-dependent cross-presenting DCs, establishing antigen transfer from mTECs to DCs as a critical arm of Aire-dependent tolerance.

    Evidence Mixed bone marrow chimeras, Batf3-KO DC depletion, TCR repertoire sequencing

    PMID:25220213

    Open questions at the time
    • Molecular mechanism of antigen transfer from mTECs to DCs unresolved
    • Relative contribution of direct versus indirect presentation to Treg versus deletion unclear
  8. 2015 High

    The transcriptional control of Aire itself was established: RANK-NF-κB signaling activates Aire through a conserved CNS1 enhancer bearing two NF-κB sites, and Jmjd6-dependent splicing of Aire intron 2 is required for mature protein production — defining both transcriptional and post-transcriptional regulatory layers.

    Evidence CNS1-KO mice with NF-κB binding site mutagenesis; Jmjd6-KO mice with RT-PCR splicing analysis and Aire protein quantification

    PMID:26364592 PMID:26531897

    Open questions at the time
    • Whether other NF-κB family members besides RelA contribute is untested
    • How Jmjd6 specifically targets Aire intron 2 is unknown
  9. 2016 High

    Three regulatory dimensions were added: estrogen-driven CpG methylation at the AIRE promoter explains sex-biased autoimmunity susceptibility; SCF(FBXO3)-mediated phosphorylation-dependent ubiquitylation of AIRE enhances P-TEFb binding for transcriptional elongation; and multi-omics defined the epigenetic architecture (CTCF insulation, demethylation, Irf4/Irf8/Tbx21/Tcf7/Ctcfl action) controlling mTEC-specific Aire locus activation.

    Evidence ERα-KO mice with bisulfite methylation; Co-IP/ubiquitylation/reporter assays; ATAC-seq, bisulfite-seq, ChIP-seq in mTECs

    PMID:26999605 PMID:27365398 PMID:27941786

    Open questions at the time
    • Structural basis of FBXO3-AIRE interaction not solved
    • Which kinase phosphorylates the N-terminal residues in vivo is unidentified
    • How these regulatory layers are integrated in single cells is unknown
  10. 2017 High

    AIRE was shown to act from super-enhancers via TOP1-scaffolded multiprotein complexes, with TOP1 required for assembly of all other AIRE-associated factors — providing a chromatin-level mechanism for how AIRE reaches thousands of dispersed target genes through enhancer-promoter looping.

    Evidence ChIP-seq, co-immunoprecipitation, protein interaction mapping, TOP1 depletion

    PMID:28135252

    Open questions at the time
    • 3D genome organization of AIRE-dependent loops not mapped at single-locus resolution
    • How TOP1 is recruited to super-enhancers before AIRE is unknown
    • Role of DNA-damage-response partners at super-enhancers not mechanistically defined
  11. 2018 High

    AIRE was discovered to possess an intrinsic rapid chromatin-repressive function opposing Brg1-mediated chromatin opening, revealing that AIRE simultaneously activates and restrains transcription — explaining why tissue-restricted antigens are expressed at moderate, not maximal, levels in mTECs.

    Evidence ATAC-seq time course after inducible AIRE recruitment, disease mutation analysis, Brg1 loss-of-function

    PMID:29335648

    Open questions at the time
    • Effector mechanism of repression (histone modification, nucleosome remodeling) not identified
    • Whether activation and repression are mediated by the same or distinct AIRE complexes is unknown
  12. 2021 High

    Three advances refined the model: dominant-negative PHD mutations revealed that AIRE negatively autoregulates its own expression by binding CNS1; single-cell multiomics defined extrathymic Aire-expressing cells (Janus cells, AmDCs) as RANK-dependent peripheral tolerance mediators; and Ccl25 was identified as a direct AIRE target while many 'Aire-dependent' genes were shown to reflect indirect effects on mTEC differentiation.

    Evidence Knock-in mouse models with multi-omics; single-cell RNA-seq/ATAC-seq with functional tolerance assays; mTEC transcriptomics with in vitro validation

    PMID:34477806 PMID:34767455 PMID:34930780

    Open questions at the time
    • Full catalog of direct versus indirect AIRE targets not established
    • Functional contribution of Janus cells versus AmDCs to peripheral tolerance not quantified
    • Mechanism by which dominant-negative mutations poison wild-type AIRE complexes is not structurally resolved
  13. 2022 High

    AIRE was shown to suppress ectopic CTLA-4 expression in mTECs; in its absence, mTEC-expressed CTLA-4 strips CD80/CD86 from thymic DCs, impairing their co-stimulatory capacity for Treg selection — revealing an unexpected non-cell-autonomous mechanism by which AIRE supports Treg generation.

    Evidence Aire-KO mice with conditional CTLA-4 deletion in mTECs, co-stimulation assays, Treg quantification, autoimmunity rescue

    PMID:35172142

    Open questions at the time
    • Whether CTLA-4 suppression is a direct or indirect transcriptional effect of AIRE is not determined
    • Quantitative contribution of this mechanism versus antigen presentation to autoimmunity severity unknown
  14. 2024 High

    The long-standing question of how AIRE selects its targets without a specific DNA-binding motif was resolved: AIRE preferentially activates genes whose promoters contain Z-DNA-forming sequences that generate DSBs and create a poised chromatin state with pre-assembled transcriptional machinery, and AIRE-dependent tolerance to ameloblast antigens prevents autoimmune enamel defects in humans and mice.

    Evidence CNN-based motif discovery, allele-specific analysis in F1 hybrids, Z-DNA and DSB mapping, ATAC-seq/ChIP-seq; autoantibody profiling in APS-1 patients and Aire-KO mice

    PMID:37993717 PMID:38480882

    Open questions at the time
    • How AIRE protein recognizes or is recruited to Z-DNA/DSB-marked poised promoters is structurally unresolved
    • Whether Z-DNA recognition is mediated by AIRE directly or via a partner protein is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include: the structural basis of AIRE complex assembly at super-enhancers, the identity of the factor(s) that directly sense Z-DNA/DSB marks to recruit AIRE, the molecular mechanism of AIRE's chromatin-repressive activity, and the extent to which direct versus indirect gene regulation accounts for AIRE's target repertoire in vivo.
  • No high-resolution structure of AIRE in complex with chromatin or partners
  • Chromatin-repressive effector mechanism unidentified
  • Full direct target gene catalog not established genome-wide

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 3 GO:0042393 histone binding 2
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 2
Pathway
R-HSA-168256 Immune System 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-4839726 Chromatin organization 3
Partners
DAXXFBXO3JMJD6P-TEFBRANKTOP1
Complex memberships
AIRE-TOP1 super-enhancer complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 AIRE was identified as the gene responsible for APECED; the encoded protein contains two PHD-type zinc-finger motifs, a SAND putative DNA-binding domain, a proline-rich region, and three LXXLL nuclear receptor-binding motifs, predicting function as a transcriptional regulator. Positional cloning, mutation analysis, domain prediction Nature genetics High 9398839
1999 AIRE protein localizes to discrete nuclear dot-like structures (distinct from PML nuclear bodies) in transfected mammalian cells and in thymus, spleen, and lymph node cells, consistent with a role in transcriptional regulation. Transient transfection, immunofluorescence, double immunolabeling, immunohistochemistry Human molecular genetics High 9931333
2001 Recombinant AIRE forms homodimers and homotetramers (also detected in thymic extracts); oligomerization is enhanced by phosphorylation via PKA or PKC. AIRE dimers/tetramers (but not monomers) bind DNA at ATTGGTTA and TTATTA-box motifs. Endogenous thymic AIRE is phosphorylated at tyrosine and serine/threonine residues. In vitro binding assays, competition assays, co-immunoprecipitation from thymic extracts, recombinant protein phosphorylation The Journal of biological chemistry High 11533054
2001 APECED-causing mutations alter subcellular localization of AIRE, reduce its transactivation capacity, and disrupt homomultimerization. The HSR domain mediates homomultimerization; PHD zinc fingers are required for transactivation; mutations in HSR or SAND domains reduce multimerization; deletions of PHD fingers disrupt high-molecular-weight complex formation. In vitro mutagenesis, transactivation reporter assays, subcellular localization studies, co-immunoprecipitation Human mutation High 14974083
2002 AIRE in thymic medullary epithelial cells (mTECs) drives ectopic expression of peripheral tissue-restricted antigens; Aire-deficient mice show specific reduction in ectopic transcription of peripheral antigen genes in mTECs and develop multi-organ autoimmune disease dependent on absence of Aire in thymic stromal cells. Aire-knockout mouse model, gene expression analysis, immunohistochemistry, disease phenotyping Science (New York, N.Y.) High 12376594
2002 Aire-deficient mice develop multiorgan lymphocytic infiltration, circulating autoantibodies, and infertility; TCR-Vβ repertoire is altered in peripheral T cells; peripheral T cells show 3–5-fold increased proliferation upon immunization challenge, indicating a defect in immune homeostatic regulation. Aire-knockout mouse generation, flow cytometry, TCR repertoire analysis, immunization/proliferation assays Human molecular genetics High 11854172
2003 Lymphotoxin-β receptor (LTβR) signaling is required for Aire expression and its downstream tissue-restricted antigen target genes in thymic epithelial cells; stimulation of LTβR with agonistic antibody increases Aire expression and tissue-restricted antigen levels in thymus and thymic epithelial cell cultures. LTβR-deficient and LTα-deficient mouse analysis, agonistic antibody treatment, thymic epithelial cell culture, gene expression Nature immunology Medium 14517552
2007 Lymphotoxin pathway does not directly regulate Aire expression or function in mTECs; instead, it regulates mTEC organization and cell numbers. The sets of genes controlled by Aire and lymphotoxin show minimal overlap. LTβR- and LTα-knockout mouse analysis, Aire expression and function in mTECs, gene expression comparison Journal of immunology (Baltimore, Md. : 1950) Medium 17947641
2008 AIRE-deficient dendritic cells show drastically reduced transcriptional responses of cytokine genes to pathogens, and expression of components of innate immune signaling pathways is reduced, indicating a cell-intrinsic role for AIRE in peripheral dendritic cell function. In vitro monocyte-derived DC differentiation from APECED patients, transcriptome analysis, functional assays with pathogen stimulation Journal of molecular medicine (Berlin, Germany) Medium 18600308
2008 Aire-deficient mice have increased T-cell-independent type II B-cell responses linked to elevated BAFF serum levels. Aire-deficient bone marrow-derived dendritic cells produce more BAFF than wild-type upon IFN-γ stimulation, indicating a cell-intrinsic role for AIRE in regulating IFN-γ-receptor signaling in peripheral DCs and modulating B-cell activation. Bone marrow transfer, in vitro BAFF production assays, cytokine stimulation, ELISA in patient sera and mouse serum Proceedings of the National Academy of Sciences of the United States of America Medium 19011083
2008 Aire is expressed in testicular spermatogonia and spermatocytes; in Aire-deficient mice, the scheduled apoptotic wave of germ cells required for normal spermatogenesis is reduced and sporadic adult apoptosis is increased. This effect is independent of the adaptive immune system (Rag-1-deficient mice still show the effect), indicating a direct proapoptotic role for Aire in testis. Aire-KO and Rag-1-KO mouse models, histological analysis of apoptosis in testis, gene expression Journal of immunology (Baltimore, Md. : 1950) Medium 18209027
2010 DAXX is a direct AIRE-interacting protein identified by yeast two-hybrid; interaction validated by co-immunoprecipitation and colocalization in mammalian cells. DAXX exerts a strong repressive effect on AIRE's transcriptional activity in transactivation assays. Yeast two-hybrid, co-immunoprecipitation, co-localization by immunofluorescence, transactivation assays The Journal of biological chemistry Medium 20185822
2011 Aire controls mTEC terminal differentiation; loss of Aire results in a marked block of mTEC differentiation partially rescued by RANK and CD40 ligands. Aire is expressed transiently (1–2 day window) during mTEC maturation; its loss leads to rapid downregulation of MHC II and CD80, and of most Aire-dependent and Aire-independent TSAs except keratinocyte-specific genes. Aire-KO mice, LacZ reporter transgenic model, mTEC purification, flow cytometry, gene expression, rescue experiments with RANK/CD40 ligands Frontiers in immunology High 22448160
2012 Aire mediates ectopic expression of a huge repertoire of tissue-restricted antigens via an unconventional transcriptional mechanism that does not require intermediary tissue-specific transcription factors (e.g., Pdx1 in TECs is not required for expression of insulin or somatostatin, or for thymocyte deletion). Conditional knockout of Pdx1 in TECs, gene expression analysis, thymocyte deletion and Treg generation assays in vivo European journal of immunology Medium 23041971
2014 Aire-induced antigen expression in mTECs enables negative selection and Treg generation via two pathways: direct mTEC presentation and indirect cross-presentation by bone marrow-derived APCs (particularly Batf3-dependent CD8α+ DCs), which have enhanced ability to present antigens from stromal cells. Mixed bone marrow chimeras, DC subset depletion (Batf3-KO), TCR repertoire sequencing, genetic epistasis Immunity High 25220213
2015 A conserved noncoding sequence 1 (CNS1) upstream of Aire, containing two NF-κB binding sites, is critical for thymic Aire expression. CNS1-deficient mice lack Aire expression, show downregulation of Aire-dependent genes, impaired mTEC differentiation, and reduced Treg production. RANK signaling induces Aire through NF-κB/RelA acting on CNS1. CNS1-knockout mice, NF-κB binding site mutagenesis, RANK stimulation, gene expression, flow cytometry European journal of immunology High 26364592
2015 Jmjd6, a dioxygenase catalyzing lysyl hydroxylation of splicing regulatory proteins, is required for proper splicing of Aire intron 2. Jmjd6 deficiency does not affect Aire transcript abundance but prevents effective splicing out of intron 2, resulting in marked reduction of mature Aire protein in mTECs and spontaneous multi-organ autoimmunity. Jmjd6-knockout mice, RT-PCR/splicing analysis, Aire protein quantification in mTECs, autoimmunity phenotyping Nature communications High 26531897
2016 Estrogen downregulates AIRE expression in thymic epithelial cells by inducing epigenetic changes (increased CpG methylation) at the AIRE promoter; estrogen receptor α-deficient mice lack sex disparity in AIRE expression; male castration decreases AIRE expression. Females express less AIRE (mRNA and protein) after puberty. Human thymic transcriptome analysis, purified murine TECs, estrogen receptor-α-KO mice, estrogen treatment of cultured human TECs and thymic tissue grafts, bisulfite methylation analysis The Journal of clinical investigation High 26999605
2016 FBXO3 E3 ubiquitin ligase binds to AIRE that is phosphorylated at two specific N-terminal residues; the SCF(FBXO3) complex ubiquitylates AIRE, increases its binding to the positive transcription elongation factor b (P-TEFb), and potentiates AIRE's transcriptional activity, thereby ensuring proper elongation of tissue-specific antigen genes. Co-immunoprecipitation, ubiquitylation assay, phosphorylation-dependent binding assay, transcriptional reporter assays The Journal of biological chemistry Medium 27365398
2016 Aire expression in mTECs is controlled by multiple cis- and trans-regulatory mechanisms: the Aire locus is insulated by CTCF and hypermethylated in non-expressing cells; in mTECs, CTCF is evicted, exon 2 and proximal promoter are specifically demethylated, and transcription activators Irf4, Irf8, Tbx21, Tcf7, and Ctcfl act on mTEC-specific accessible regions. ATAC-seq, bisulfite sequencing, ChIP-seq, transcription factor knockdown/KO in mTECs Nature immunology High 27941786
2017 Aire and its partners (notably those implicated in the DNA-damage response) preferentially localize to and activate super-enhancers. Topoisomerase 1 (TOP1) is a cardinal Aire partner that colocalizes on super-enhancers and is required for the interaction of Aire with all its other associates. Aire-containing complexes are proposed to loop from super-enhancers to local and distal transcriptional start sites. ChIP-seq, co-immunoprecipitation, protein interaction mapping, TOP1 depletion Nature immunology High 28135252
2018 Aire has an intrinsic rapid chromatin-repressive function that restricts chromatin accessibility and opposes Brg1-mediated opening across the genome; this repression occurs within minutes of Aire recruitment and restrains the amplitude of active transcription of tissue-specific genes. Disease-causing mutations that impair Aire-induced activation also impair repressive function. ATAC-seq time course after Aire recruitment, disease mutation analysis, Brg1 and Aire loss-of-function experiments Nature immunology High 29335648
2021 Dominant-negative AIRE mutations in PHD1 and PHD2 domains (C311Y, C446G) cause breakdown of central tolerance in heterozygous mice; these mutations produce dysfunctional AIRE protein with altered chromatin-binding capacity and reduced gene induction (shown by RNAseq, ATACseq, ChIPseq); furthermore, AIRE negatively autoregulates its own expression by binding its proximal enhancer (CNS1), reducing chromatin accessibility at this locus. Engineered knock-in mouse models, RNAseq, ATACseq, ChIPseq, protein analysis The Journal of experimental medicine High 34477806
2021 Single-cell multiomics reveals that extrathymic Aire-expressing cells (eTACs) consist of CCR7+ Aire-expressing migratory dendritic cells (AmDCs) and Janus cells (JCs, co-expressing Aire and RORγt); both have RANK-dependent Aire expression and high transcriptional/genomic homology to mTECs. Transgenic self-antigen expression by eTACs is sufficient to induce negative selection and prevent autoimmune diabetes. Single-cell RNA-seq, single-cell ATAC-seq, transgenic mouse models, flow cytometry, functional tolerance assays Science immunology High 34767455
2021 Aire controls mTEC heterogeneity to indirectly regulate expression of most tissue-restricted antigens; Ccl25 is identified as a canonical direct transcriptional target of Aire both in vitro and in vivo. A large proportion of so-called Aire-dependent genes may not be direct transcriptional targets but reflect Aire's influence on mTEC differentiation states. Aire-augmented and Aire-deficient mTEC transcriptomics, single-cell analysis, in vitro and in vivo validation of Ccl25 as direct target Journal of immunology (Baltimore, Md. : 1950) Medium 34930780
2022 In Aire-deficient mTECs, CTLA-4 is ectopically expressed; this CTLA-4 binds CD80/CD86 on thymic dendritic cells, stripping co-stimulatory ligands from DCs and impairing their ability to present self-antigens transferred from mTECs, thereby reducing thymic Treg production. Depletion of CTLA-4 from Aire-deficient mTECs rescues Treg production and reduces autoimmunity. Aire-KO mice, conditional CTLA-4 depletion in mTECs, co-stimulation and antigen presentation assays, Treg quantification, autoimmunity phenotyping Cell reports High 35172142
2024 AIRE preferentially targets genes whose promoters contain Z-DNA-forming sequences and NFE2L2-binding motifs; Z-DNA formation enhances DNA double-stranded break generation at promoters, which promotes a poised chromatin state with accessible chromatin and pre-assembled transcriptional machinery. AIRE preferentially activates genes with poised promoters rather than binding a specific DNA sequence motif. Convolutional neural network, F1 hybrid allele-specific analysis, genome-wide Z-DNA mapping, DSB mapping, ATAC-seq, ChIP-seq Nature High 38480882
2024 APS-1 patients and mice deficient in Aire develop autoantibodies (predominantly IgA) against ameloblast-specific proteins whose thymic expression is induced by AIRE; this breaks central tolerance and leads to autoimmune amelogenesis imperfecta (enamel defects). Autoantibody profiling in APS-1 and coeliac patients, thymic expression analysis of ameloblast antigens, AIRE-KO mouse phenotyping Nature High 37993717

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.) 1801 12376594
1997 Positional cloning of the APECED gene. Nature genetics 1027 9398839
2010 Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. The Journal of experimental medicine 510 20123959
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 354 11854172
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 183 26972725
2008 Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nature reviews. Immunology 183 19008896
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 155 12092452
2016 Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases. The Journal of clinical investigation 154 26999605
2007 A decade of AIRE. Nature reviews. Immunology 145 17641664
2001 The autoimmune regulator (AIRE) is a DNA-binding protein. The Journal of biological chemistry 124 11533054
2011 Control of central and peripheral tolerance by Aire. Immunological reviews 123 21488892
1999 Localization of the APECED protein in distinct nuclear structures. Human molecular genetics 116 9931333
2016 AIRE-mutations and autoimmune disease. Current opinion in immunology 104 27504588
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 97 9735375
2010 Aire and T cell development. Current opinion in immunology 96 21163636
2012 Post-Aire maturation of thymic medullary epithelial cells involves selective expression of keratinocyte-specific autoantigens. Frontiers in immunology 94 22448160
2004 APECED-causing mutations in AIRE reveal the functional domains of the protein. Human mutation 93 14974083
1998 Characterization of mutations in patients with autoimmune polyglandular syndrome type 1 (APS1). Human genetics 91 9921903
2018 Twenty Years of AIRE. Frontiers in immunology 82 29483906
2007 Modulation of Aire regulates the expression of tissue-restricted antigens. Molecular immunology 81 17599412
2011 Mucocutaneous candidiasis and autoimmunity against cytokines in APECED and thymoma patients: clinical and pathogenetic implications. European journal of immunology 78 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
2009 AIRE in the thymus and beyond. Current opinion in immunology 75 19833494
2020 PGE1 and PGA1 bind to Nurr1 and activate its transcriptional function. Nature chemical biology 74 32451509
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
2000 Organ-specific and non-organ-specific autoantibodies in children and young adults with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). European journal of endocrinology 69 11022196
2011 Mutagenesis of cysteine 81 prevents dimerization of the APS1 subunit of ADP-glucose pyrophosphorylase and alters diurnal starch turnover in Arabidopsis thaliana leaves. The Plant journal : for cell and molecular biology 68 22098298
2004 Aire: an update. Current opinion in immunology 68 15511668
2021 Single-cell multiomics defines tolerogenic extrathymic Aire-expressing populations with unique homology to thymic epithelium. Science immunology 67 34767455
2008 Expression of Aire and the early wave of apoptosis in spermatogenesis. Journal of immunology (Baltimore, Md. : 1950) 67 18209027
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 55 32410729
2017 The immunobiology and clinical features of type 1 autoimmune polyglandular syndrome (APS-1). Autoimmunity reviews 54 29108822
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 52 29508520
2015 ACHT4-driven oxidation of APS1 attenuates starch synthesis under low light intensity in Arabidopsis plants. Proceedings of the National Academy of Sciences of the United States of America 52 26424450
2017 Update on Aire and thymic negative selection. Immunology 48 28871661
2015 A highly conserved NF-κB-responsive enhancer is critical for thymic expression of Aire in mice. European journal of immunology 48 26364592
1999 Isolation and characterization of the mouse Aire gene. Biochemical and biophysical research communications 48 10049735
2013 Gastrointestinal manifestations in APECED syndrome. Journal of clinical gastroenterology 47 23314667
2005 Differential selectivity of protein modification by the cyclopentenone prostaglandins PGA1 and 15-deoxy-Delta12,14-PGJ2: role of glutathione. FEBS letters 47 16223487
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
2005 Antioxidant properties and PC12 cell protective effects of APS-1, a polysaccharide from Aloe vera var. chinensis. Life sciences 43 16150464
2008 Expression of AIRE in thymocytes and peripheral lymphocytes. Autoimmunity 42 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
2018 Rapid chromatin repression by Aire provides precise control of immune tolerance. Nature immunology 40 29335648
2021 APECED-Associated Hepatitis: Clinical, Biochemical, Histological and Treatment Data From a Large, Predominantly American Cohort. Hepatology (Baltimore, Md.) 39 32557834
2007 Study of protein targets for covalent modification by the antitumoral and anti-inflammatory prostaglandin PGA1: focus on vimentin. Journal of mass spectrometry : JMS 37 17960581
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 35 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
2008 Critical immunological pathways are downregulated in APECED patient dendritic cells. Journal of molecular medicine (Berlin, Germany) 32 18600308
2005 Disruption of immunological tolerance: role of AIRE gene in autoimmunity. Autoimmunity reviews 32 16431348
2015 Intronic regulation of Aire expression by Jmjd6 for self-tolerance induction in the thymus. Nature communications 30 26531897
2013 APECED: A Paradigm of Complex Interactions between Genetic Background and Susceptibility Factors. Frontiers in immunology 29 24167503
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