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Neonatal Exposure to Low-Dose 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Causes Autoimmunity Due to the Disruption of T Cell Tolerance¹

Naozumi Ishimaru^*, Atsuya Takagi, Masayuki Kohashi^*, Akiko Yamada^*, Rieko Arakaki^*, Jun Kanno and Yoshio Hayashi^2,*

^* Department of Oral Molecular Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramotocho, Tokushima, Japan; and Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences, Kamiyoga, Setagayaku, Tokyo, Japan

Although 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to influence immune responses, the effects of low-dose TCDD on the development of autoimmunity are unclear. In this study, using NFS/sld mice as a model for human Sjögren’s syndrome, in which the lesions are induced by the thymectomy on day 3 after birth, the autoimmune lesions in the salivary glands, and in later phase, inflammatory cell infiltrations in the other organs were developed by neonatal exposure to nonapoptotic dosage of TCDD without thymectomy on day 3 after birth. We found disruption of thymic selection, but not thymic atrophy, in TCDD-administered mice. The endogenous expression of aryl hydrocarbon receptor in the neonatal thymus was significantly higher than that in the adult thymus, suggesting that the neonatal thymus may be much more sensitive to TCDD compared with the adult thymus. In addition, the production of T_H1 cytokines such as IL-2 and IFN- from splenic CD4⁺ T cells and the autoantibodies relevant for Sjögren’s syndrome in the sera from TCDD-exposed mice were significantly increased compared with those in control mice. These results suggest that TCDD/aryl hydrocarbon receptor signaling in the neonatal thymus plays an important role in the early thymic differentiation related to autoimmunity.

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¹ This work was supported by a Health Sciences Research Grant (H17, 18, and 19-kagaku-ippan-003) from the Ministry of Health, Labor and Welfare, Japan and a Grant-in-Aid for Scientific Research (no. 17109016) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

² Address correspondence and reprint requests to Dr. Yoshio Hayashi, Department of Oral Molecular Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, 3-18-15 Kuramotocho, Tokushima 770-8504, Japan. E-mail address: hayashi{at}dent.tokushima-u.ac.jp

³ Abbreviations used in this paper: TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; 3d-Tx, thymectomized 3 days after birth; AhR, aryl hydrocarbon receptor; AIRE, autoimmune regulator; ARNT, AhR nuclear translocator; DN, double negative; DP, double positive; DRE, dioxin responsive element; IRF, IFN regulatory factor; SP, single positive; SS, Sjögren’s syndrome; TEC, thymic epithelial cell; Treg, regulatory T; XRE, xenobiotic response element.