title: Aire downregulates multiple molecules that have contradicting immune-enhancing and immune-suppressive functions.
abstract: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a systemic disease with autoimmune characteristics caused by mutations in a single gene called AIRE. Although a defect in negative selection has been emphasized for the pathogenesis of the autoimmune symptoms on the basis of studies of Aire-targeted mice, the function of the gene in the peripheral immune system and the cause of immunodeficiency noted in the disease have not been clarified yet. In this study, we demonstrated using murine Aire transfectants that Aire downregulates IL-1 receptor antagonist (IL-1Ra), which is important for immune suppression, and major histocompatibility complex (MHC) class II molecules, which are critical for acquired immunity. It was surprising to learn that Aire, which has been supposed to positively regulate transcription, downregulates multiple molecules. This downregulation of IL-1Ra and MHC class II molecules seems to be caused by the competition for transcriptional coactivator, CREB-binding protein (CBP), and may explain part of the contradictory (i.e., both autoimmune and immunodeficient) nature of APECED.
authors.affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan. satok.cell@tmd.ac.jp
authors.forename: Kojiro
authors.initials: K
authors.lastname: Sato
authors.forename: Utako
authors.initials: U
authors.lastname: Sato
authors.forename: Shoko
authors.initials: S
authors.lastname: Tateishi
authors.forename: Kanae
authors.initials: K
authors.lastname: Kubo
authors.forename: Reiko
authors.initials: R
authors.lastname: Horikawa
authors.forename: Toshihide
authors.initials: T
authors.lastname: Mimura
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kanda
mesh_terms: D000818:Animals; D001483:Base Sequence; D050882:CREB-Binding Protein; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D015536:Down-Regulation; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000276:immunology; D007155:Immunologic Factors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology*; D053590:Interleukin 1 Receptor Antagonist Protein; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D016884:Polyendocrinopathies, Autoimmune / Q000276:immunology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D000096927:AIRE Protein
chemical_list: D050882:CREB-Binding Protein; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D007155:Immunologic Factors; D053590:Interleukin 1 Receptor Antagonist Protein; D008070:Lipopolysaccharides; D009687:Nuclear Proteins; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D015534:Trans-Activators; D014157:Transcription Factors; D000096927:AIRE Protein; C507764:Il1rn protein, mouse; C494364:Crebbp protein, mouse