title: Alteration of intra-pancreatic target-organ specificity by abrogation of Aire in NOD mice.
abstract: Factors that determine the spectrum of target organs involved in autoimmune destruction are poorly understood. Although loss of function of autoimmune regulator (AIRE) in thymic epithelial cells is responsible for autoimmunity, the pathogenic roles of AIRE in regulating target-organ specificity remain elusive. In order to gain insight into this issue, we have established NOD mice, an animal model of type 1 diabetes caused by autoimmune attack against beta cell islets, in which Aire has been abrogated. Remarkably, acinar cells rather than beta cell islets were the major targets of autoimmune destruction in Aire-deficient NOD mice, and this alteration of intra-pancreatic target-organ specificity was associated with production of autoantibody against pancreas-specific protein disulfide isomerase (PDIp), an antigen expressed predominantly by acinar cells. Consistent with this pathological change, the animals were resistant to the development of diabetes. The results suggest that Aire not only is critical for the control of self-tolerance but is also a strong modifier of target-organ specificity through regulation of T cell repertoire diversification. We also demonstrated that transcriptional expression of PDIp was retained in the Aire-deficient NOD thymus, further supporting the concept that Aire may regulate the survival of autoreactive T cells beyond transcriptional control of self-protein expression in the thymus.
authors.affiliation: Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima, Japan.
authors.forename: Shino
authors.initials: S
authors.lastname: Niki
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Oshikawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Mouri
authors.forename: Fumiko
authors.initials: F
authors.lastname: Hirota
authors.forename: Akemi
authors.initials: A
authors.lastname: Matsushima
authors.forename: Masashi
authors.initials: M
authors.lastname: Yano
authors.forename: Hongwei
authors.initials: H
authors.lastname: Han
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Bando
authors.forename: Keisuke
authors.initials: K
authors.lastname: Izumi
authors.forename: Masaki
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kuroda
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics; D003920:Diabetes Mellitus / Q000235:genetics / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010179:Pancreas / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*; D000096927:AIRE Protein
chemical_list: D014157:Transcription Factors; D000096927:AIRE Protein