title: Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice.
abstract: Autoimmune regulator (AIRE) gene mutation is responsible for the development of organ-specific autoimmune disease with monogenic autosomal recessive inheritance. Although Aire has been considered to regulate the elimination of autoreactive T cells through transcriptional control of tissue-specific Ags in thymic epithelial cells, other mechanisms of AIRE-dependent tolerance remain to be investigated. We have established Aire-deficient mice and examined the mechanisms underlying the breakdown of self-tolerance. The production and/or function of immunoregulatory T cells were retained in the Aire-deficient mice. The mice developed Sjogren's syndrome-like pathologic changes in the exocrine organs, and this was associated with autoimmunity against a ubiquitous protein, alpha-fodrin. Remarkably, transcriptional expression of alpha-fodrin was retained in the Aire-deficient thymus. These results suggest that Aire regulates the survival of autoreactive T cells beyond transcriptional control of self-protein expression in the thymus, at least against this ubiquitous protein. Rather, Aire may regulate the processing and/or presentation of self-proteins so that the maturing T cells can recognize the self-Ags in a form capable of efficiently triggering autoreactive T cells. With the use of inbred Aire-deficient mouse strains, we also demonstrate the presence of some additional factor(s) that determine the target-organ specificity of the autoimmune disease caused by Aire deficiency.
authors.affiliation: Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kuroda
authors.forename: Tasuku
authors.initials: T
authors.lastname: Mitani
authors.forename: Naoki
authors.initials: N
authors.lastname: Takeda
authors.forename: Naozumi
authors.initials: N
authors.lastname: Ishimaru
authors.forename: Rieko
authors.initials: R
authors.lastname: Arakaki
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Bando
authors.forename: Keisuke
authors.initials: K
authors.lastname: Izumi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Nomura
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: Tomoo
authors.initials: T
authors.lastname: Ueno
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Takahama
authors.forename: Daisuke
authors.initials: D
authors.lastname: Uchida
authors.forename: Shijie
authors.initials: S
authors.lastname: Sun
authors.forename: Fumiko
authors.initials: F
authors.lastname: Kajiura
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Mouri
authors.forename: Hongwei
authors.initials: H
authors.lastname: Han
authors.forename: Akemi
authors.initials: A
authors.lastname: Matsushima
authors.forename: Gen
authors.initials: G
authors.lastname: Yamada
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000096:biosynthesis / Q000276:immunology*; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000276:immunology; D005088:Exocrine Glands / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008819:Mice, Nude; D008840:Microfilament Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000276:immunology; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics / Q000276:immunology / Q000473:pathology; D017634:Self Tolerance / Q000235:genetics; D012859:Sjogren's Syndrome / Q000235:genetics / Q000276:immunology / Q000473:pathology; D013045:Species Specificity; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D000096927:AIRE Protein; D013049:Spectrin
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D002352:Carrier Proteins; D008840:Microfilament Proteins; D014157:Transcription Factors; D000096927:AIRE Protein; D013049:Spectrin