Alteration of intra-pancreatic target-organ specificity by abrogation of Aire in NOD mice.
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.
Niki
Shino
S
Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima, Japan.
Oshikawa
Kiyotaka
K
Mouri
Yasuhiro
Y
Hirota
Fumiko
F
Matsushima
Akemi
A
Yano
Masashi
M
Han
Hongwei
H
Bando
Yoshimi
Y
Izumi
Keisuke
K
Matsumoto
Masaki
M
Nakayama
Keiichi I
KI
Kuroda
Noriyuki
N
Matsumoto
Mitsuru
M
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
D014157:Transcription Factors; D000096927:AIRE Protein