Alteration of intra-pancreatic target-organ specificity by abrogation of Aire in NOD mice
Shino Niki, … , Noriyuki Kuroda, Mitsuru Matsumoto
Shino Niki, … , Noriyuki Kuroda, Mitsuru Matsumoto
Published May 1, 2006
Citation Information: J Clin Invest. 2006;116(5):1292-1301. https://doi.org/10.1172/JCI26971.
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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 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.

Authors

Shino Niki, Kiyotaka Oshikawa, Yasuhiro Mouri, Fumiko Hirota, Akemi Matsushima, Masashi Yano, Hongwei Han, Yoshimi Bando, Keisuke Izumi, Masaki Matsumoto, Keiichi I. Nakayama, Noriyuki Kuroda, Mitsuru Matsumoto

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Figure 2

Augmented autoimmune phenotypes with altered intra-pancreatic target-organ specificity in Aire-deficient NOD mice.

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Augmented autoimmune phenotypes with altered intra-pancreatic target-org...
(A) Augmentation of existing autoimmune phenotypes of NOD mice by abrogation of Aire. In Aire-deficient NOD mice, lymphocytic infiltration in the pancreas was much more severe than that in control littermates (left panels). In many Aire-deficient NOD mice, acinar tissues were completely destroyed by marked lymphocytic infiltration, leaving relatively well-preserved β cell islets together with pancreatic ducts densely surrounding the β cell islets alone (middle panels). The 2 boxed panels are photographs taken of the same sample with different magnifications. Sialoadenitis was also much more severe in Aire-deficient NOD mice (right panels). (B) Lymphoid cell infiltration in the liver, lung, and thyroid gland from Aire-deficient NOD mice. (C) NOD-scid mice transferred with mature T cells purified from Aire-deficient NOD mice showed lymphocytic infiltration predominantly in acinar tissues, and the structure of the β cell islets was relatively well preserved (middle and right panels). In contrast, NOD-scid mice transferred with Aire-sufficient NOD mouse T cells showed lymphocytic infiltration into β cell islets, resulting in reduced size and numbers of β cell islets (left panel). Arrows indicate the 1 small β cell islet remaining. Original magnification, ×100, except where indicated.