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AIRE
autoimmune regulator
The AIRE gene encodes the autoimmune regulator protein, which plays a critical role in the development and function of the immune system by preventing autoimmune reactions. The AIRE gene provides instructions for producing the autoimmune regulator protein, primarily active in the thymus.
AIRE is located on the long (q) arm of chromosome 21, at band 21q22.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The AIRE gene, or autoimmune regulator, is fundamental to immune system function, particularly in the thymus. Its encoded protein is crucial for immune self-tolerance, helping T cells to recognise and avoid attacking the body's own cells and tissues [PMID:33676228]. Dysfunction of the AIRE gene can lead to autoimmune conditions where the immune system mistakenly targets the body's own organs [PMID:29665510].
What the gene does
The AIRE protein is predominantly active within the thymus, an organ vital for immune system development. Here, it facilitates the 'thymic education' of T cells, which are a type of immune cell. This process ensures that T cells learn to differentiate between endogenous proteins and foreign pathogens. The autoimmune regulator protein achieves this by promoting the expression of a wide array of self-antigens in the thymus. T cells that react strongly to these self-antigens are typically eliminated, preventing them from causing autoimmune damage [PMID:29665510]. This mechanism is critical for establishing central immune tolerance, ensuring the immune system only targets harmful invaders while sparing healthy bodily tissues.
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Chromosome location
The AIRE gene is situated on chromosome 21 at position 21q22.3. This specific location on the long arm of chromosome 21 houses the genetic information necessary for producing the autoimmune regulator protein.
Protein structure
The AIRE protein consists of 545 amino acids and features several distinct domains and motifs. It contains an N-terminal HSR domain (amino acids 1-105) and two PHD-type zinc fingers: PHD-type 1 (amino acids 296-343) and PHD-type 2 (amino acids 434-475). There are also several LXXLL motifs, including LXXLL motif 1 (amino acids 7-11), LXXLL motif 2 (amino acids 63-67), LXXLL motif 3 (amino acids 414-418), and LXXLL motif 4 (amino acids 516-520). Disordered regions are found at amino acids 101-178, 234-290, 348-382, and 489-508. Additionally, specific regions (amino acids 295-298, 304-312, and 331-335) are involved in interaction with histone H3 not methylated at 'Lys-4'. The SAND domain is located between amino acids 181-280.
Key variants
Variants within the AIRE gene can lead to altered protein function, which may impair the immune system's ability to maintain self-tolerance. These genetic changes can affect the various domains and motifs crucial for the protein's proper action, potentially disrupting T cell education in the thymus. Most known pathogenic variants are associated with an autosomal recessive inheritance pattern.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1045C>T | p.Gln349Ter | Pathogenic | ★★☆☆ | Polyglandular autoimmune syndrome, type 1 |
c.1233del | p.Ser412fs | Pathogenic/Likely pathogenic | ★★☆☆ | Polyglandular autoimmune syndrome, type 1 |
c.1235del | p.Ser412fs | Pathogenic/Likely pathogenic | ★★☆☆ | Polyglandular autoimmune syndrome, type 1 |
c.1311C>A | p.Cys437Ter | Pathogenic | ★★☆☆ | Polyglandular autoimmune syndrome, type 1 |
c.1347C>A | p.Cys449Ter | Pathogenic | ★★☆☆ | Polyglandular autoimmune syndrome, type 1 |
c.173C>G | p.Ala58Gly | Pathogenic/Likely pathogenic | ★★☆☆ | Polyglandular autoimmune syndrome, type 1 |
c.195G>A | p.Trp65Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Polyglandular autoimmune syndrome, type 1 |
c.349del | p.Ala117fs | Pathogenic | ★★☆☆ | Polyglandular autoimmune syndrome, type 1 |
c.449del | p.Gly150fs | Pathogenic/Likely pathogenic | ★★☆☆ | Polyglandular autoimmune syndrome, type 1 |
c.510_522del | p.Glu171fs | Pathogenic/Likely pathogenic | ★★☆☆ | Polyglandular autoimmune syndrome, type 1 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the AIRE gene are primarily associated with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED), also known as Autoimmune Polyendocrine Syndrome type 1 (APS type 1). APECED is an inherited condition characterised by a combination of endocrine gland deficiencies, chronic mucocutaneous candidiasis, and ectodermal dystrophies, all stemming from immune system dysregulation [PMID:29665510].
Inheritance pattern
Conditions caused by pathogenic AIRE variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The AIRE gene is included in several UK NHS national genomic testing panels. It is part of panels for Autoimmune Polyendocrinopathy Syndrome (R155), Congenital adrenal hypoplasia (R150), Familial hypoparathyroidism (R153), and Primary immunodeficiency or monogenic inflammatory bowel disease (R15). It is also listed on panels for COVID-19 research, DDG2P, Multi-organ autoimmune diabetes, Rare genetic inflammatory skin disorders (R332), and Retinal disorders (R32).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the AIRE gene?
The AIRE gene provides instructions for the autoimmune regulator protein, which is critical for preventing the immune system from attacking the body's own tissues. It helps T cells in the thymus learn to distinguish between self and non-self proteins.
What condition is most commonly associated with AIRE gene variants?
Variants in the AIRE gene are most commonly associated with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED), also known as Autoimmune Polyendocrine Syndrome type 1 (APS type 1).
How is APECED inherited?
APECED is inherited in an autosomal recessive pattern, meaning an individual must inherit two copies of the altered AIRE gene (one from each parent) to develop the condition.
References
- Anderson MS, Su MA. AIRE expands: new roles in immune tolerance and beyond. Nature reviews. Immunology. 2016. PMID: 26972725
- Ferre EM, Rose SR, Rosenzweig SD. Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. JCI insight. 2016. PMID: 27588307
- De Martino L, Capalbo D, Improda N. Novel Findings into AIRE Genetics and Functioning: Clinical Implications. Frontiers in pediatrics. 2016. PMID: 27597936
- Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. Journal of clinical immunology. 2015. PMID: 26141571
- Gallo V, Giardino G, Capalbo D. Alterations of the autoimmune regulator transcription factor and failure of central tolerance: APECED as a model. Expert review of clinical immunology. 2013. PMID: 23256763
- Laan M, Peterson P. The many faces of aire in central tolerance. Frontiers in immunology. 2013. PMID: 24130560
- De Martino L, Capalbo D, Improda N. APECED: A Paradigm of Complex Interactions between Genetic Background and Susceptibility Factors. Frontiers in immunology. 2013. PMID: 24167503
- Puel A, Döffinger R, Natividad A. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. The Journal of experimental medicine. 2010. PMID: 20123958
- Kisand K, Bøe Wolff AS, Podkrajsek KT. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. The Journal of experimental medicine. 2010. PMID: 20123959