Beyond APECED: An update on the role of the autoimmune regulator gene (AIRE) in physiology and disease

[en] The autoimmune regulator gene (AIRE) is a transcription factor expressed both in the thymus, by medullary thymic epithelial cells, and in secondary lymphoid organs. AIRE controls the local transcription of organ- specific proteins typically expressed in peripheral tissues, thus allowing the negative selection of self- reactive T cells. The crucial role played by AIRE in central immune tolerance emerged in the studies on the pathogenesis of Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy, a rare inherited polyendocrine/autoimmune disease. Thereafter, several studies found evidences indicating that AIRE impairment might be pathogenically involved in several autoimmune diseases and in tumorigenesis. In this review, we focus on recent advances relative to AIRE's effect on T cell development in physiology and disease. In particular, we address the following issues: 1) AIRE function and mTECs biology, 2) the impact of AIRE gene mutations in autoimmune diseases, and 3) the role of AIRE gene in anti-tumor immune response. © 2018 Elsevier B.V.

Disciplines :

Hematology

Author, co-author :

Conteduca, Giuseppina ; Université de Liège - ULg

Indiveri, F.; Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy, Department of Internal Medicine, Clinical Immunology Unit, University of Genoa, Genoa, Italy

Filaci, G.; Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy, Department of Internal Medicine, Clinical Immunology Unit, University of Genoa, Genoa, Italy

Negrini, S.; Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy, Department of Internal Medicine, Clinical Immunology Unit, University of Genoa, Genoa, Italy

Language :

English

Title :

Beyond APECED: An update on the role of the autoimmune regulator gene (AIRE) in physiology and disease

Publication date :

2018

Journal title :

Autoimmunity Reviews

ISSN :

1568-9972

Publisher :

Elsevier, Netherlands

Volume :

Issue :

Pages :

325-330

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 14 May 2021

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Bibliography

Malchow, S., Leventhal, D.S., Lee, V., Nishi, S., Socci, N.D., Savage, P.A., Aire enforces immune tolerance by directing autoreactive T cells into the regulatory T cell lineage. Immunity 44 (2016), 1102–1113.
Hassan, M.N., Waller, E.K., GVHD clears the Aire in thymic selection. Blood 125 (2015), 2593–2595.
Trager, U., Sierro, S., Djordjevic, G., Bouzo, B., Khandwala, S., Meloni, A., et al. The immune response to melanoma is limited by thymic selection of self-antigens. PLoS One, 7, 2012, e35005.
Anderson, M.S., Venanzi, E.S., Klein, L., Chen, Z., Berzins, S.P., Turley, S.J., et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 298 (2002), 1395–1401.
Gotter, J., Brors, B., Hergenhahn, M., Kyewski, B., Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters. J Exp Med 199 (2004), 155–166.
Klein, L., Hinterberger, M., Wirnsberger, G., Kyewski, B., Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev Immunol 9 (2009), 833–844.
Derbinski, J., Gabler, J., Brors, B., Tierling, S., Jonnakuty, S., Hergenhahn, M., et al. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J Exp Med 202 (2005), 33–45.
Sansom, S.N., Shikama-Dorn, N., Zhanybekova, S., Nusspaumer, G., Macaulay, I.C., Deadman, M.E., et al. Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia. Genome Res 24 (2014), 1918–1931.
Baik, S., Jenkinson, E.J., Lane, P.J., Anderson, G., Jenkinson, W.E., Generation of both cortical and Aire(+) medullary thymic epithelial compartments from CD205(+) progenitors. Eur J Immunol 43 (2013), 589–594.
DiPaolo, R.J., Glass, D.D., Bijwaard, K.E., Shevach, E.M., CD4+CD25+ T cells prevent the development of organ-specific autoimmune disease by inhibiting the differentiation of autoreactive effector T cells. J Immunol 175 (2005), 7135–7142.
Gardner, J.M., Metzger, T.C., McMahon, E.J., Au-Yeung, B.B., Krawisz, A.K., Lu, W., et al. Extrathymic Aire- expressing cells are a distinct bone marrow-derived population that induce functional inactivation of CD4(+) T cells. Immunity 39 (2013), 560–572.
Nishikawa, Y., Hirota, F., Yano, M., Kitajima, H., Miyazaki, J., Kawamoto, H., et al. Biphasic Aire expression in early embryos and in medullary thymic epithelial cells before end-stage terminal differentiation. J Exp Med 207 (2010), 963–971.
Anderson, G., Takahama, Y., Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends Immunol 33 (2012), 256–263.
Alexandropoulos, K., Danzl, N.M., Thymic epithelial cells: antigen presenting cells that regulate T cell repertoire and tolerance development. Immunol Res 54 (2012), 177–190.
Zhang, L., Sun, L., Zhao, Y., Thymic epithelial progenitor cells and thymus regeneration: an update. Cell Res 17 (2007), 50–55.
Gerondakis, S., Siebenlist, U., Roles of the NF-kappaB pathway in lymphocyte development and function. Cold Spring Harb Perspect Biol, 2, 2010, a000182.
Jenkinson, W.E., Bacon, A., White, A.J., Anderson, G., Jenkinson, E.J., An epithelial progenitor pool regulates thymus growth. J Immunol 181 (2008), 6101–6108.
Hubert, F.X., Kinkel, S.A., Davey, G.M., Phipson, B., Mueller, S.N., Liston, A., et al. Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance. Blood 118 (2011), 2462–2472.
Heino, M., Peterson, P., Kudoh, J., Nagamine, K., Lagerstedt, A., Ovod, V., et al. Autoimmune regulator is expressed in the cells regulating immune tolerance in thymus medulla. Biochem Biophys Res Commun 257 (1999), 821–825.
van den Boorn, J.G., Le Poole, I.C., Luiten, R.M., T-cell avidity and tuning: the flexible connection between tolerance and autoimmunity. Int Rev Immunol 25 (2006), 235–258.
Gillard, G.O., Farr, A.G., Features of medullary thymic epithelium implicate postnatal development in maintaining epithelial heterogeneity and tissue-restricted antigen expression. J Immunol 176 (2006), 5815–5824.
Perniola, R., Musco, G., The biophysical and biochemical properties of the autoimmune regulator (AIRE) protein. Biochim Biophys Acta 1842 (2014), 326–337.
Pitkanen, J., Doucas, V., Sternsdorf, T., Nakajima, T., Aratani, S., Jensen, K., et al. The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein. J Biol Chem 275 (2000), 16802–16809.
Koh, A.S., Kuo, A.J., Park, S.Y., Cheung, P., Abramson, J., Bua, D., et al. Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity. Proc Natl Acad Sci U S A 105 (2008), 15878–15883.
Org, T., Chignola, F., Hetenyi, C., Gaetani, M., Rebane, A., Liiv, I., et al. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Rep 9 (2008), 370–376.
Cheng, M.H., Shum, A.K., Anderson, M.S., What's new in the Aire?. Trends Immunol 28 (2007), 321–327.
Gaetani, M., Matafora, V., Saare, M., Spiliotopoulos, D., Mollica, L., Quilici, G., et al. AIRE-PHD fingers are structural hubs to maintain the integrity of chromatin-associated interactome. Nucleic Acids Res 40 (2012), 11756–11768.
LaFlam, T.N., Seumois, G., Miller, C.N., Lwin, W., Fasano, K.J., Waterfield, M., et al. Identification of a novel cis-regulatory element essential for immune tolerance. J Exp Med 212 (2015), 1993–2002.
Yanagihara, T., Sanematsu, F., Sato, T., Uruno, T., Duan, X., Tomino, T., et al. Intronic regulation of Aire expression by Jmjd6 for self-tolerance induction in the thymus. Nat Commun, 6, 2015, 8820.
Abramson, J., Husebye, E.S., Autoimmune regulator and self-tolerance - molecular and clinical aspects. Immunol Rev 271 (2016), 127–140.
Meredith, M., Zemmour, D., Mathis, D., Benoist, C., Aire controls gene expression in the thymic epithelium with ordered stochasticity. Nat Immunol 16 (2015), 942–949.
Anderson, M.S., Su, M.A., AIRE expands: new roles in immune tolerance and beyond. Nat Rev Immunol 16 (2016), 247–258.
Waterfield, M., Khan, I.S., Cortez, J.T., Fan, U., Metzger, T., Greer, A., et al. The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance. Nat Immunol 15 (2014), 258–265.
Macedo, C., Evangelista, A.F., Marques, M.M., Octacilio-Silva, S., Donadi, E.A., Sakamoto-Hojo, E.T., et al. Autoimmune regulator (Aire) controls the expression of microRNAs in medullary thymic epithelial cells. Immunobiology 218 (2013), 554–560.
Zuklys, S., Mayer, C.E., Zhanybekova, S., Stefanski, H.E., Nusspaumer, G., Gill, J., et al. MicroRNAs control the maintenance of thymic epithelia and their competence for T lineage commitment and thymocyte selection. J Immunol 189 (2012), 3894–3904.
Poliani, P.L., Facchetti, F., Ravanini, M., Gennery, A.R., Villa, A., Roifman, C.M., et al. Early defects in human T-cell development severely affect distribution and maturation of thymic stromal cells: possible implications for the pathophysiology of Omenn syndrome. Blood 114 (2009), 105–108.
Aschenbrenner, K., D'Cruz, L.M., Vollmann, E.H., Hinterberger, M., Emmerich, J., Swee, L.K., et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat Immunol 8 (2007), 351–358.
Kekalainen, E., Tuovinen, H., Joensuu, J., Gylling, M., Franssila, R., Pontynen, N., et al. A defect of regulatory T cells in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Immunol 178 (2007), 1208–1215.
Laakso, S.M., Laurinolli, T.T., Rossi, L.H., Lehtoviita, A., Sairanen, H., Perheentupa, J., et al. Regulatory T cell defect in APECED patients is associated with loss of naive FOXP3(+) precursors and impaired activated population. J Autoimmun 35 (2010), 351–357.
Anderson, M.S., Venanzi, E.S., Chen, Z., Berzins, S.P., Benoist, C., Mathis, D., The cellular mechanism of Aire control of T cell tolerance. Immunity 23 (2005), 227–239.
Lei, Y., Ripen, A.M., Ishimaru, N., Ohigashi, I., Nagasawa, T., Jeker, L.T., et al. Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development. J Exp Med 208 (2011), 383–394.
Malchow, S., Leventhal, D.S., Nishi, S., Fischer, B.I., Shen, L., Paner, G.P., et al. Aire-dependent thymic development of tumor-associated regulatory T cells. Science 339 (2013), 1219–1224.
Perry, J.S., Lio, C.W., Kau, A.L., Nutsch, K., Yang, Z., Gordon, J.I., et al. Distinct contributions of Aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus. Immunity 41 (2014), 414–426.
Fairweather, D., Frisancho-Kiss, S., Rose, N.R., Sex differences in autoimmune disease from a pathological perspective. Am J Pathol 173 (2008), 600–609.
Zhu, M.L., Bakhru, P., Conley, B., Nelson, J.S., Free, M., Martin, A., et al. Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator. Nat Commun, 7, 2016, 11350.
Staples, J.E., Gasiewicz, T.A., Fiore, N.C., Lubahn, D.B., Korach, K.S., Silverstone, A.E., Estrogen receptor alpha is necessary in thymic development and estradiol-induced thymic alterations. J Immunol 163 (1999), 4168–4174.
Olsen, N.J., Olson, G., Viselli, S.M., Gu, X., Kovacs, W.J., Androgen receptors in thymic epithelium modulate thymus size and thymocyte development. Endocrinology 142 (2001), 1278–1283.
Dragin, N., Bismuth, J., Cizeron-Clairac, G., Biferi, M.G., Berthault, C., Serraf, A., et al. Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases. J Clin Invest 126 (2016), 1525–1537.
Peterson, P., Org, T., Rebane, A., Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nat Rev Immunol 8 (2008), 948–957.
Derbinski, J., Pinto, S., Rosch, S., Hexel, K., Kyewski, B., Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism. Proc Natl Acad Sci U S A 105 (2008), 657–662.
Roberts, N.A., White, A.J., Jenkinson, W.E., Turchinovich, G., Nakamura, K., Withers, D.R., et al. Rank signaling links the development of invariant gammadelta T cell progenitors and Aire(+) medullary epithelium. Immunity 36 (2012), 427–437.
Dertschnig, S., Nusspaumer, G., Ivanek, R., Hauri-Hohl, M.M., Hollander, G.A., Krenger, W., Epithelial cytoprotection sustains ectopic expression of tissue-restricted antigens in the thymus during murine acute GVHD. Blood 122 (2013), 837–841.
Gardner, J.M., Devoss, J.J., Friedman, R.S., Wong, D.J., Tan, Y.X., Zhou, X., et al. Deletional tolerance mediated by extrathymic Aire-expressing cells. Science 321 (2008), 843–847.
Taniguchi, R.T., Anderson, M.S., The role of Aire in clonal selection. Immunol Cell Biol 89 (2011), 40–44.
Nichols, L.A., Chen, Y., Colella, T.A., Bennett, C.L., Clausen, B.E., Engelhard, V.H., Deletional self- tolerance to a melanocyte/melanoma antigen derived from tyrosinase is mediated by a radio-resistant cell in peripheral and mesenteric lymph nodes. J Immunol 179 (2007), 993–1003.
Hinterberger, M., Aichinger, M., Prazeres da Costa, O., Voehringer, D., Hoffmann, R., Klein, L., Autonomous role of medullary thymic epithelial cells in central CD4(+) T cell tolerance. Nat Immunol 11 (2010), 512–519.
An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet, 17, 1997, 399–403.
Kisand, K., Peterson, P., Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol 35 (2015), 463–478.
Improda, N., Capalbo, D., Cirillo, E., Cerbone, M., Esposito, A., Pignata, C., et al. Cutaneous vasculitis in patients with autoimmune polyendocrine syndrome type 1: report of a case and brief review of the literature. BMC Pediatr, 14, 2014, 272.
Soderbergh, A., Rorsman, F., Halonen, M., Ekwall, O., Bjorses, P., Kampe, O., et al. Autoantibodies against aromatic L-amino acid decarboxylase identifies a subgroup of patients with Addison's disease. J Clin Endocrinol Metab 85 (2000), 460–463.
Sun, L., Li, H., Luo, H., Zhao, Y., Thymic epithelial cell development and its dysfunction in human diseases. Biomed Res Int, 2014, 2014, 206929.
Ulinski, T., Perrin, L., Morris, M., Houang, M., Cabrol, S., Grapin, C., et al. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome with renal failure: impact of posttransplant immunosuppression on disease activity. J Clin Endocrinol Metab 91 (2006), 192–195.
Papavassiliou, P., Charalsawadi, C., Rafferty, K., Jackson-Cook, C., Mosaicism for trisomy 21: a review. Am J Med Genet A 167A (2015), 26–39.
Vranekovic, J., Bozovic, I.B., Grubic, Z., Wagner, J., Pavlinic, D., Dahoun, S., et al. Down syndrome: parental origin, recombination, and maternal age. Genet Test Mol Biomarkers 16 (2012), 70–73.
Lima, F.A., Moreira-Filho, C.A., Ramos, P.L., Brentani, H., Lima Lde, A., Arrais, M., et al. Decreased AIRE expression and global thymic hypofunction in Down syndrome. J Immunol 187 (2011), 3422–3430.
Gimenez-Barcons, M., Casteras, A., Armengol Mdel, P., Porta, E., Correa, P.A., Marin, A., et al. Autoimmune predisposition in Down syndrome may result from a partial central tolerance failure due to insufficient intrathymic expression of AIRE and peripheral antigens. J Immunol 193 (2014), 3872–3879.
Bellacchio, E., Palma, A., Corrente, S., Di Girolamo, F., Helen Kemp, E., Di Matteo, G., et al. The possible implication of the S250C variant of the autoimmune regulator protein in a patient with autoimmunity and immunodeficiency: in silico analysis suggests a molecular pathogenic mechanism for the variant. Gene 549 (2014), 286–294.
Kochi, Y., Suzuki, A., Yamada, R., Yamamoto, K., Ethnogenetic heterogeneity of rheumatoid arthritis-implications for pathogenesis. Nat Rev Rheumatol 6 (2010), 290–295.
Stahl, E.A., Raychaudhuri, S., Remmers, E.F., Xie, G., Eyre, S., Thomson, B.P., et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 42 (2010), 508–514.
Terao, C., Yamada, R., Ohmura, K., Takahashi, M., Kawaguchi, T., Kochi, Y., et al. The human AIRE gene at chromosome 21q22 is a genetic determinant for the predisposition to rheumatoid arthritis in Japanese population. Hum Mol Genet 20 (2011), 2680–2685.
Garcia-Lozano, J.R., Torres-Agrela, B., Montes-Cano, M.A., Ortiz-Fernandez, L., Conde-Jaldon, M., Teruel, M., et al. Association of the AIRE gene with susceptibility to rheumatoid arthritis in a European population: a case control study. Arthritis Res Ther, 15, 2013, R11.
Shao, S., Li, X.R., Cen, H., Yin, Z.S., Association of AIRE polymorphisms with genetic susceptibility to rheumatoid arthritis in a Chinese population. Inflammation 37 (2014), 495–499.
Ferrera, F., Rizzi, M., Sprecacenere, B., Balestra, P., Sessarego, M., Di Carlo, A., et al. AIRE gene polymorphisms in systemic sclerosis associated with autoimmune thyroiditis. Clin Immunol 122 (2007), 13–17.
Takahashi, T., Asano, Y., Sugawara, K., Yamashita, T., Nakamura, K., Saigusa, R., et al. Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: possible roles in scleroderma. J Exp Med 214 (2017), 1129–1151.
Olsen, E., Hordinsky, M., McDonald-Hull, S., Price, V., Roberts, J., Shapiro, J., et al. Alopecia areata investigational assessment guidelines. National Alopecia Areata Foundation. J Am Acad Dermatol 40 (1999), 242–246.
Kolivras, A., Thompson, C., Distinguishing diffuse alopecia areata (AA) from pattern hair loss (PHL) using CD3(+) T cells. J Am Acad Dermatol 74 (2016), 937–944.
Bertolini, M., Uchida, Y., Paus, R., Toward the clonotype analysis of alopecia Areata-specific, intralesional human CD8+ T lymphocytes. J Investig Dermatol Symp Proc 17 (2015), 9–12.
Elela, M.A., Gawdat, H.I., Hegazy, R.A., Fawzy, M.M., Abdel Hay, R.M., Saadi, D., et al. B cell activating factor and T-helper 17 cells: possible synergistic culprits in the pathogenesis of alopecia areata. Arch Dermatol Res 308 (2016), 115–121.
Tazi-Ahnini, R., Cork, M.J., Gawkrodger, D.J., Birch, M.P., Wengraf, D., McDonagh, A.J., et al. Role of the autoimmune regulator (AIRE) gene in alopecia areata: strong association of a potentially functional AIRE polymorphism with alopecia universalis. Tissue Antigens 60 (2002), 489–495.
Tazi-Ahnini, R., McDonagh, A.J., Wengraf, D.A., Lovewell, T.R., Vasilopoulos, Y., Messenger, A.G., et al. The autoimmune regulator gene (AIRE) is strongly associated with vitiligo. Br J Dermatol 159 (2008), 591–596.
Al-Shobaili, H.A., Update on the genetics characterization of vitiligo. Int J Health Sci (Qassim) 5 (2011), 167–179.
Zhu, M.L., Nagavalli, A., Su, M.A., Aire deficiency promotes TRP-1-specific immune rejection of melanoma. Cancer Res 73 (2013), 2104–2116.
Conteduca, G., Ferrera, F., Pastorino, L., Fenoglio, D., Negrini, S., Sormani, M.P., et al. The role of AIRE polymorphisms in melanoma. Clin Immunol 136 (2010), 96–104.
Conteduca, G., Fenoglio, D., Parodi, A., Battaglia, F., Kalli, F., Negrini, S., et al. AIRE polymorphism, melanoma antigen-specific T cell immunity, and susceptibility to melanoma. Oncotarget 7 (2016), 60872–60884.
Akiyama, N., Shinzawa, M., Miyauchi, M., Yanai, H., Tateishi, R., Shimo, Y., et al. Limitation of immune tolerance-inducing thymic epithelial cell development by Spi-B-mediated negative feedback regulation. J Exp Med 211 (2014), 2425–2438.
Gray, D., Abramson, J., Benoist, C., Mathis, D., Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire. J Exp Med 204 (2007), 2521–2528.
Metzger, T.C., Khan, I.S., Gardner, J.M., Mouchess, M.L., Johannes, K.P., Krawisz, A.K., et al. Lineage tracing and cell ablation identify a post-Aire-expressing thymic epithelial cell population. Cell Rep 5 (2013), 166–179.
Khan, I.S., Mouchess, M.L., Zhu, M.L., Conley, B., Fasano, K.J., Hou, Y., et al. Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance. J Exp Med 211 (2014), 761–768.
Su, M.A., Anderson, M.S., Breaking through the central tolerance ceiling to unleash anticancer immune responses. Oncoimmunology, 3, 2014, e950169.