title: Aire-deficient C57BL/6 mice mimicking the common human 13-base pair deletion mutation present with only a mild autoimmune phenotype.
abstract: 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. 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.
authors.affiliation: Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Hubert
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Kinkel
authors.forename: Pauline E
authors.initials: PE
authors.lastname: Crewther
authors.forename: Ping Z F
authors.initials: PZ
authors.lastname: Cannon
authors.forename: Kylie E
authors.initials: KE
authors.lastname: Webster
authors.forename: Maire
authors.initials: M
authors.lastname: Link
authors.forename: Raivo
authors.initials: R
authors.lastname: Uibo
authors.forename: Moira K
authors.initials: MK
authors.lastname: O'Bryan
authors.forename: Anthony
authors.initials: A
authors.lastname: Meager
authors.forename: Simon P
authors.initials: SP
authors.lastname: Forehan
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.forename: Lauréane
authors.initials: L
authors.lastname: Mittaz
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: Pärt
authors.initials: P
authors.lastname: Peterson
authors.forename: William R
authors.initials: WR
authors.lastname: Heath
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Scott
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020029:Base Pairing / Q000235:genetics; D001483:Base Sequence; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D018716:Molecular Mimicry / Q000235:genetics* / Q000276:immunology*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D000096927:AIRE Protein
chemical_list: D014157:Transcription Factors; D000096927:AIRE Protein