TY - JOUR
T1 - Alteration of intra-pancreatic target-organ specificity by abrogation of Aire in NOD mice
AU - Niki, Shino
AU - Oshikawa, Kiyotaka
AU - Mouri, Yasuhiro
AU - Hirota, Fumiko
AU - Matsushima, Akemi
AU - Yano, Masashi
AU - Han, Hongwei
AU - Bando, Yoshimi
AU - Izumi, Keisuke
AU - Matsumoto, Masaki
AU - Nakayama, Keiichi I.
AU - Kuroda, Noriyuki
AU - Matsumoto, Mitsuru
PY - 2006/5/1
Y1 - 2006/5/1
N2 - 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 β cell islets, in which Aire has been abrogated. Remarkably, acinar cells rather than β 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.
AB - 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 β cell islets, in which Aire has been abrogated. Remarkably, acinar cells rather than β 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.
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U2 - 10.1172/JCI26971
DO - 10.1172/JCI26971
M3 - Article
C2 - 16628255
AN - SCOPUS:33646413687
VL - 116
SP - 1292
EP - 1301
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 5
ER -