(do not exceed 30 lines in length) Autoimmune diseases are common human conditions, usually associated to high morbidity because of their chronic duration and usually treated based on their symptoms rather than on their pathogenesis. Autoimmune diseases of the thyroid gland, represented by Graves disease and Hashimoto thyroiditis, are the most common autoimmune diseases. Although most affected patients are treated symptomatically with relative ease, autoimmune thyroid diseases can serve as a model to study other more complex autoimmune diseases. We have developed a mouse model of Hashimoto thyroiditis based on the expression of interferon gamma in the thyroid gland via transgenesis. These mice mimic many features of the human counterpart, including goiter, disrupted thyroid architecture, mononuclear infiltration, oncocytic changes of the thyrocytes, and long-lasting hypothyroidism. The mice have contributed to discover that the thyroid cells affected by autoimmunity express elevated levels of a protein, called LMP2, which is a component of a proteolytic machinery called immunoproteasome. They have also showed that the thyroid becomes heavily infiltrated by macrophages suggesting a role for these cells in disease pathogenesis. The present proposal mainly aims to characterize the role of LMP2 and macrophages in autoimmune thyroiditis.

Public Health Relevance

Hashimoto thyroiditis is a common autoimmune disease that can also serve as a model for other, more severe autoimmune diseases. We have developed a mouse model of thyroiditis based on the transgenic expression of interferon gamma in the thyroid gland, and identified key factors involved in disease pathogenesis. This grant is designed to test a new treatment based on the mechanism rather than the symptoms, and to unravel the role of thyroidal macrophages.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56DK055670-08
Application #
8145772
Study Section
Special Emphasis Panel (ZRG1-EMNR-E (02))
Program Officer
Spain, Lisa M
Project Start
2000-04-01
Project End
2012-08-31
Budget Start
2010-09-30
Budget End
2012-08-31
Support Year
8
Fiscal Year
2010
Total Cost
$246,000
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Zheng, Gang; Chaux, Alcides; Sharma, Rajni et al. (2013) LMP2, a novel immunohistochemical marker to distinguish renal oncocytoma from the eosinophilic variant of chromophobe renal cell carcinoma. Exp Mol Pathol 94:29-32
Iwama, Shintaro; De Remigis, Alessandra; Bishop, Justin A et al. (2012) Hurthle cells predict hypothyroidism in interferon-ýý transgenic mice of different genetic backgrounds. Endocrinology 153:4059-66
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Suzuki, Koichi; Kimura, Hiroaki; Wu, Huhehasi et al. (2010) Excess iodide decreases transcription of NIS and VEGF genes in rat FRTL-5 thyroid cells. Biochem Biophys Res Commun 393:286-90
Caturegli, Patrizio; Kimura, Hiroaki (2010) A nonclassical model of autoimmune hypothyroidism. Thyroid 20:3-5
Kimura, Hiroaki J; Rocchi, Roberto; Landek-Salgado, Melissa A et al. (2009) Influence of signal transducer and activator of transcription-1 signaling on thyroid morphology and function. Endocrinology 150:3409-16
Gutenberg, A; Larsen, J; Lupi, I et al. (2009) A radiologic score to distinguish autoimmune hypophysitis from nonsecreting pituitary adenoma preoperatively. AJNR Am J Neuroradiol 30:1766-72

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