Theautoimmune regulator (AIRE) is aprotein that in humans is encoded by theAIREgene.[5][6] It is a 13kbp gene on chromosome 21q22.3 that encodes 545 amino acids.[7] AIRE is atranscription factor expressed in themedulla[broken anchor] (inner part) of thethymus. It is part of themechanism which eliminates self-reactive T cells that would cause autoimmune disease. It exposes T cells to normal, healthy proteins from all parts of the body, and T cells that react to those proteins are destroyed.
EachT cell recognizes a specificantigen when it is presented in complex with amajor histocompatibility complex (MHC) molecule by anantigen presenting cell. This recognition is accomplished by theT cell receptors expressed on the cell surface. T cells receptors are generated byrandomly shuffled gene segments which results in a highly diverse population of T cells—each with a unique antigen specificity. Subsequently, T cells with receptors that recognize the body's own proteins need to be eliminated while still in the thymus. Through the action of AIRE,medullary thymic epithelial cells (mTEC) express major proteins from elsewhere in the body (tissue-restricted antigens, TRA) and T cells that respond to those proteins are eliminated through cell death (apoptosis). Thus AIRE drivesnegative selection of self-recognizing T cells.[8] When AIRE is defective, T cells that recognize antigens normally produced by the body can exit the thymus and enter circulation. This can result in a variety ofautoimmune diseases.
The gene was first reported by two independent research groups Aaltonen et al. and Nagamine et al. in 1997 who were able to isolate and clone the gene from human chromosome 21q22.3. Their work was able to show that mutations in theAIRE gene are responsible for the pathogenesis of Autoimmune polyglandular syndrome type I.[6][5][9] More insight into the AIRE protein was later provided by Heino et al. in 2000. They showed that AIRE protein is mainly expressed in the thymic medullary epithelial cells usingimmunohistochemistry.[10]
In the thymus, the autoimmune regulator (AIRE) induces the transcription of a broad array of organ-specific genes, resulting in the production of proteins that are normally restricted to peripheral tissues. This ectopic expression creates an "immunological self-shadow" that exposes developing T cells to peripheral antigens, thereby facilitating the negative selection of self-reactive T cells and promoting central tolerance. This discovery was achieved through the combined efforts of researchers inDiane Mathis' lab— includingMark Anderson (immunologist)—and those in theChristopher Goodnow lab, whereAdrian Liston led this work.
Studies have shown that AIRE is also expressed in a subset of stromal cells in secondary lymphoid tissues, though these cells express a distinct set of tissue‐restricted antigens compared to medullary thymic epithelial cells.[11][12] It is important that self-reactiveT cells that bind strongly to self-antigen are eliminated in the thymus (via the process ofnegative selection), otherwise they may later encounter and bind to their corresponding self-antigens and initiate an autoimmune reaction. So the expression of non-local proteins by AIRE in the thymus reduces the threat ofautoimmunity by promoting the elimination of auto-reactiveT cells that bind antigens not normally found in the thymus. Furthermore, it has been found that AIRE is expressed in a population ofstromal cells located insecondary lymphoid tissues, however these cells appear to express a distinct set of TRAs compared to mTECs.[13]
TheAIRE gene is expressed in many other tissues as well.[14] TheAIRE gene is also expressed in the 33D1+ subset ofdendritic cells in mouse and in human dendritic cells.[15]
AIRE is composed of a multidomain structure that is able to bind tochromatin and act as a regulator of gene transcription. The specific makeup of AIRE includes acaspase activation and recruitment domain (CARD),nuclear localization signal (NLS),SAND domain, and twoplant-homeodomain (PHD) fingers.[16] The SAND domain is located in the middle of the amino-acid chain (aa 180-280) and mediates the binding of AIRE tophosphate groups of DNA.[17] Another potential role for this domain is to anchor AIRE to heterologous proteins.[18] The twocysteine-rich PHD finger domains at theC-terminus of AIRE are PHD1 (aa 299-340) and PHD2 (aa 434-475) which are separated by aproline-rich region of amino acids.[19] These finger domains serve to read chromatin marks through the degree of methylation at the tail ofhistone H3. More specifically, PHD1 is able to recognize unmethylation at the H3 tail as an epigenetic mark.[20]
AIRE protein rendition with both PHD fingers shown
An integral characteristic of AIRE is its ability to homomerize into dimers and trimers which allows it to bind to specific oligonucleotide motifs.[21] This property comes from thehomogeneously staining region (HSR) located at theN-terminus. Because of the α-helicalfour-helix bundle structure, HSR’s are sensitive to conformational changes of the gene.[22] Variants and deletions involving this domain cause an inability to activate gene transcription by preventing oligomer formation and can result in APS-1.
Instead of binding to consensus sequences of targetgene promoters, like conventional transcription factors, AIRE engages in coordinated sequences that are performed by its multimolecular complexes. The first AIRE partner that was identified is theCREB-binding protein (CBP) that is localized in nuclear bodies and is aco-activator of many transcription factors.[22] Other AIRE partners include positive transcription elongation factor b (P-TEFb) and DNA activated protein kinase (DNA-PK).[23][24] DNA-PK phosphorylates AIRE in vitro at Thr68 and Ser156.[24] Another partner isDNA-topoisomerase (DNA-TOP) IIα. This isomerase enzyme works on DNA topology and removes positive and negative DNA supercoils by causing transient DNA breaks. In turn, this causes relaxation of local chromatin and helps the initiation and post-initiation events of gene transcription.[25] By performing double-stranded DNA breaks, DNA-TOPIIα recruits DNA-PK and poly-(ADP-ribose) polymerase (PARP1) which are involved in DNA break and repair through non-homologous end joining.[26]
TheAIRE gene is mutated in the rare autoimmune syndromeautoimmune polyendocrinopathy syndrome type 1 (APS-1), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).[5][6] Different mutations are more common among certain populations in the world.[27] The most commonexonic mutations ofAIRE occur on exons 1, 2, 6, 8, and 10. Exons 1 and 2 encode the HSR, exon 6 encodes the SAND domain, exon 8 is in the PHD-1 domain, and exon 10 is located in the proline-rich region between the two PHD finger domains.[28] Known mutations in AIRE include Arg139X, Arg257X, and Leu323SerfsX51.[29]
^abListon A, Lesage S, Wilson J, Peltonen L, Goodnow CC (April 2003). "Aire regulates negative selection of organ-specific T cells".Nature Immunology.4 (4):350–4.doi:10.1038/ni906.PMID12612579.S2CID4561402.
^Lindmark E, Chen Y, Georgoudaki AM, Dudziak D, Lindh E, Adams WC, et al. (May 2013). "AIRE expressing marginal zone dendritic cells balances adaptive immunity and T-follicular helper cell recruitment".Journal of Autoimmunity.42:62–70.doi:10.1016/j.jaut.2012.11.004.hdl:10616/41469.PMID23265639.
^Gibson TJ, Ramu C, Gemünd C, Aasland R (July 1998). "The APECED polyglandular autoimmune syndrome protein, AIRE-1, contains the SAND domain and is probably a transcription factor".Trends in Biochemical Sciences.23 (7):242–4.doi:10.1016/s0968-0004(98)01231-6.PMID9697411.
^Aasland R, Gibson TJ, Stewart AF (February 1995). "The PHD finger: implications for chromatin-mediated transcriptional regulation".Trends in Biochemical Sciences.20 (2):56–9.doi:10.1016/s0968-0004(00)88957-4.PMID7701562.
^Fardi Golyan F, Ghaemi N, Abbaszadegan MR, Dehghan Manshadi SH, Vakili R, Druley TE, et al. (November 2019). "Novel mutation in AIRE gene with autoimmune polyendocrine syndrome type 1".Immunobiology.224 (6):728–733.doi:10.1016/j.imbio.2019.09.004.PMID31526676.S2CID202671335.
^Iioka T, Furukawa K, Yamaguchi A, Shindo H, Yamashita S, Tsukazaki T (August 2003). "P300/CBP acts as a coactivator to cartilage homeoprotein-1 (Cart1), paired-like homeoprotein, through acetylation of the conserved lysine residue adjacent to the homeodomain".Journal of Bone and Mineral Research.18 (8):1419–29.doi:10.1359/jbmr.2003.18.8.1419.PMID12929931.S2CID8125330.
Ruan QG, She JX (March 2004). "Autoimmune polyglandular syndrome type 1 and the autoimmune regulator".Clinics in Laboratory Medicine.24 (1):305–17.doi:10.1016/j.cll.2004.01.008.PMID15157567.
Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, et al. (December 1997). "Positional cloning of the APECED gene".Nature Genetics.17 (4):393–8.doi:10.1038/ng1297-393.PMID9398839.S2CID1583134.
Björses P, Pelto-Huikko M, Kaukonen J, Aaltonen J, Peltonen L, Ulmanen I (February 1999). "Localization of the APECED protein in distinct nuclear structures".Human Molecular Genetics.8 (2):259–66.doi:10.1093/hmg/8.2.259.PMID9931333.
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