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* Division of Immunology and
Division of Molecular Medicine, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia;
Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia;
Immunology Group, Institute for General and Molecular Pathology, University of Tartu, Tartu, Estonia;
¶ Monash Institute of Reproduction and Development, Australian Research Council Centre of Excellence in Biotechnology and Development, Monash University, Clayton, Victoria, Australia;
|| Biotherapeutics, National Institute for Biological Standards and Control, South Mimms, U.K.;
# Department of Genetic Medicine and Development, University of Geneva Medical School, and University Hospitals, Geneva, Switzerland;
** Division of Bioinformatics, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; and
Molecular Pathology, Biomedicum, Tartu University, Tartu, Estonia
Autoimmune regulator (AIRE) is an important transcription regulator that mediates a role in central tolerance via promoting the "promiscuous" expression of tissue-specific Ags in the thymus. Although several mouse models of Aire deficiency have been described, none has analyzed the phenotype induced by a mutation that emulates the common 13-bp deletion in human APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) by disrupting the first plant homeodomain in exon 8. Aire-deficient mice with a corresponding mutation showed some disturbance of the medullary epithelial compartment, but at the phenotypic level their T cell compartment appeared relatively normal in the thymus and periphery. An increase in the number of activated T cells was evident, and autoantibodies against several organs were detected. At the histological level, lymphocytic infiltration of several organs indicated the development of autoimmunity, although symptoms were mild and the quality of life for Aire-deficient mice appeared equivalent to wild-type littermates, with the exception of male infertility. Vβ and CDR3 length analysis suggested that each Aire-deficient mouse developed its own polyclonal autoimmune repertoire. Finally, given the prevalence of candidiasis in APECED patients, we examined the control of infection with Candida albicans in Aire-deficient mice. No increase in disease susceptibility was found for either oral or systemic infection. These observations support the view that additional genetic and/or environmental factors contribute substantially to the overt nature of autoimmunity associated with Aire mutations, even for mutations identical to those found in humans with APECED.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by fellowships from La Fondation pour la Recherche Medicale (FRM) and the Sixth Framework Programme of the European Union, Marie Curie, contract 040998 (to F.-X.H.), by Australian Postgraduate Awards (to S.A.K. and K.E.W.), the Swiss National Science Foundation (to S.E.A.), a Howard Hughes Medical Institute international scholar award (to W.R.H.), National Health and Medical Research Council (NHMRC) fellowships (171601 and 461204), NHMRC program grants (257501, 264573, 406700), Estonian targeted funding grant SF0180035s08 (to M.L. and R.U.), Euro-Thymaide and EurAPS, Sixth Framework Programme of the European Union, Wellcome Trust (to P.P.), and by the Nossal Leadership Award from the Walter and Eliza Hall Institute of Medical Research (to H.S.S.).
2 Address correspondence and reprint requests to Dr. François-Xavier Hubert and Dr. Hamish Scott, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia. E-mail addresses: hubert{at}wehi.edu.au and hamish.scott{at}imvs.sa.gov.au
3 Current address: Immunology and Inflammation, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
4 Current address: Division of Molecular Pediatrics, Maternité, Clinique Infantile 02-33, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland.
5 Current address: Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.
6 Current address: Division of Molecular Pathology, Institute of Medical and Veterinary Science and The Hanson Institute, Box 14 Rundle Mall Post Office, Adelaide, South Australia 5000 and School of Medicine, University of Adelaide, Adelaide, South Australia 5005, Australia.
7 Abbreviations used in this paper: APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; AIRE, autoimmune regulator; APS1, autoimmune polyglandular syndrome type 1; β-gal, β-galactosidase; ES, embryonic stem; HSR, homogeneous staining region; LU, laboratory unit; mTEC, medullary thymic epithelial cells; MHC-II, MHC class II; PGK-Neo, phosphoglycerate kinase neomycin; PHD, plant homeodomain; SAND, Sp100, AIRE-1, NucP41/75, and DEAF-1; TEC, thymic epithelial cells; TSA, tissue-specific Ag; WT, wild type.
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