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AIRE
autoimmune regulator
The AIRE gene provides instructions for producing the autoimmune regulator protein, which is critical for immune system development and preventing autoimmune reactions. The AIRE gene encodes a protein called the autoimmune regulator, 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, also known as the autoimmune regulator gene, is fundamental for proper immune system function. It orchestrates a crucial process in the thymus, an organ vital for immune cell maturation, ensuring that T cells-a type of white blood cell-learn to distinguish between the body's own components and potential threats.
Disruptions in the AIRE gene's function can lead to autoimmune conditions, where the immune system mistakenly attacks healthy tissues. The gene is primarily associated with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED), an autosomal recessive inherited disorder.
What the gene does
The autoimmune regulator protein, encoded by the AIRE gene, is predominantly active in the thymus, where it plays an integral part in the 'thymic education' of T cells. Its primary role involves presenting a wide array of self-proteins to developing T cells.
This presentation allows T cells that react strongly against the body's own proteins to be eliminated, a process known as negative selection. By removing these self-reactive T cells, the AIRE protein prevents the immune system from launching attacks against the body's own tissues. A functional AIRE protein is therefore essential for establishing immune tolerance, safeguarding against the development of autoimmune diseases. Its activity ensures the immune system can effectively target pathogens without harming the host.
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Chromosome location
The AIRE gene is located on chromosome 21, specifically at band 21q22.3. This position indicates its precise address on the long arm of chromosome 21, providing its genomic context within the human genome.
Protein structure
The AIRE protein consists of 545 amino acids and features several distinct domains and motifs essential for its function. At its N-terminus, it contains an HSR domain (amino acids 1-105) and two LXXLL motifs (amino acids 7-11 and 63-67). A Disordered region (amino acids 101-178) precedes the SAND domain (amino acids 181-280), which also overlaps with another Disordered region (amino acids 234-290).
Further along the protein, there are three regions involved in Interaction with histone H3 not methylated at 'Lys-4' (amino acids 295-298, 304-312, and 331-335). Two PHD-type zinc fingers are present: PHD-type 1 (amino acids 296-343) and PHD-type 2 (amino acids 434-475). Additional Disordered regions (amino acids 348-382 and 489-508) and LXXLL motifs (amino acids 414-418 and 516-520) contribute to the overall structure and regulatory capabilities of the AIRE protein.
Key variants
Genetic changes, or variants, within the AIRE gene can impact the function of the autoimmune regulator protein. Over 90 distinct variants have been identified in individuals with conditions like APECED. These variants can range from small changes in DNA sequence to larger structural alterations, all of which may disrupt the protein's critical role in immune tolerance.
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.1060G>T | p.Glu354Ter | 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/Likely pathogenic | ★★☆☆ | AIRE-related disorder |
c.1347C>A | p.Cys449Ter | Pathogenic | ★★☆☆ | Polyglandular autoimmune syndrome, type 1 |
c.1497del | p.Ala500fs | 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 |
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, often abbreviated as APECED, or alternatively referred to as APS type 1. This condition is inherited in an autosomal recessive pattern. APECED is characterised by a combination of autoimmune issues affecting multiple endocrine glands, chronic fungal infections (candidiasis), and various ectodermal abnormalities affecting the skin, nails, and tooth enamel.
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 expert-curated panels within the UK National Health Service (NHS) Genomic Medicine Service. These panels include 'Autoimmune Polyendocrine Syndrome (R155)', 'Congenital adrenal hypoplasia (R150)', 'Familial hypoparathyroidism (R153)', 'Multi-organ autoimmune diabetes', 'Primary immunodeficiency or monogenic inflammatory bowel disease (R15)', 'Rare genetic inflammatory skin disorders (R332)', and 'Retinal disorders (R32)'. It is also relevant for 'COVID-19 research' and listed in 'DDG2P'.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the AIRE gene?
The AIRE gene provides instructions for the autoimmune regulator protein, which is crucial for training T cells in the thymus. This training helps T cells distinguish between the body's own tissues and foreign invaders, preventing autoimmune reactions.
Which 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 APS type 1. This is an autosomal recessive inherited condition.
How does AIRE prevent autoimmune diseases?
The AIRE protein helps prevent autoimmune diseases by eliminating self-reactive T cells during their development in the thymus. By presenting a wide range of the body's own proteins, it ensures that T cells that would otherwise attack healthy tissues are removed, thereby establishing immune tolerance.
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