Aire-Deficient C57BL/6 Mice Mimicking the Common Human 13-Base Pair Deletion Mutation Present with Only a Mild Autoimmune Phenotype

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dc.contributor.authorHubert, F.
dc.contributor.authorKinkel, S.
dc.contributor.authorCrewther, P.
dc.contributor.authorCannon, P.
dc.contributor.authorWebster, K.
dc.contributor.authorLink, M.
dc.contributor.authorUibo, R.
dc.contributor.authorO'Bryan, M.
dc.contributor.authorMeager, A.
dc.contributor.authorForehan, S.
dc.contributor.authorSmyth, G.
dc.contributor.authorMittaz, L.
dc.contributor.authorAntonarakis, S.
dc.contributor.authorPeterson, P.
dc.contributor.authorHeath, W.
dc.contributor.authorScott, H.
dc.date.issued2009
dc.description.abstractAutoimmune 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. Vbeta 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.
dc.description.statementofresponsibilityFrançois-Xavier Hubert, Sarah A. Kinkel, Pauline E. Crewther, Ping Z. F. Cannon, Kylie E. Webster, Maire Link, Raivo Uibo, Moira K. O'Bryan, Anthony Meager, Simon P. Forehan, Gordon K. Smyth, Lauréane Mittaz, Stylianos E. Antonarakis, Pärt Peterson, William R. Heath, and Hamish S. Scott
dc.identifier.citationJournal of Immunology, 2009; 182(6):3902-3918
dc.identifier.doi10.4049/jimmunol.0802124
dc.identifier.issn0022-1767
dc.identifier.issn1550-6606
dc.identifier.orcidO'Bryan, M. [0000-0001-7298-4940]
dc.identifier.orcidScott, H. [0000-0002-5813-631X]
dc.identifier.urihttp://hdl.handle.net/2440/66002
dc.language.isoen
dc.publisherAmer Assoc Immunologists
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/257501
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/264573
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/406700
dc.rightsCopyright © 2009 by The American Association of Immunologists, Inc.
dc.source.urihttp://www.jimmunol.org/content/182/6/3902.full
dc.subjectThymus Gland
dc.subjectCell Line
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectMice, Inbred CBA
dc.subjectMice, Knockout
dc.subjectHumans
dc.subjectMice
dc.subjectPolyendocrinopathies, Autoimmune
dc.subjectDisease Models, Animal
dc.subjectTranscription Factors
dc.subjectMutagenesis, Site-Directed
dc.subjectMolecular Mimicry
dc.subjectAmino Acid Sequence
dc.subjectBase Sequence
dc.subjectBase Pairing
dc.subjectSequence Homology, Amino Acid
dc.subjectPhenotype
dc.subjectMolecular Sequence Data
dc.subjectMale
dc.subjectAIRE Protein
dc.titleAire-Deficient C57BL/6 Mice Mimicking the Common Human 13-Base Pair Deletion Mutation Present with Only a Mild Autoimmune Phenotype
dc.typeJournal article
pubs.publication-statusPublished

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