Immunoproteasome overexpression underlies the pathogenesis of thyroid oncocytes and primary hypothyroidism: studies in humans and mice.
BACKGROUND
Oncocytes of the thyroid gland (Hürthle cells) are found in tumors and autoimmune diseases. They have a unique appearance characterized by abundant granular eosinophilic cytoplasm and hyperchromatic nucleus. Their pathogenesis has remained, thus far, unknown.


RESULTS
Using transgenic mice chronically expressing IFNgamma in thyroid gland, we showed changes in the thyroid follicular epithelium reminiscent of the human oncocyte. Transcriptome analysis comparing transgenic to wild type thyrocytes revealed increased levels of immunoproteasome subunits like LMP2 in transgenics, suggesting an important role of the immunoproteasome in oncocyte pathogenesis. Pharmacologic blockade of the proteasome, in fact, ameliorated the oncocytic phenotype. Genetic deletion of LMP2 subunit prevented the development of the oncocytic phenotype and primary hypothyroidism. LMP2 was also found expressed in oncocytes from patients with Hashimoto thyroiditis and Hürthle cell tumors.


CONCLUSIONS
In summary, we report that oncocytes are the result of an increased immunoproteasome expression secondary to a chronic inflammatory milieu, and suggest LMP2 as a novel therapeutic target for the treatment of oncocytic lesions and autoimmune hypothyroidism.
Kimura
Hiroaki J
HJ
Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Chen
Cindy Y
CY
Tzou
Shey-Cherng
SC
Rocchi
Roberto
R
Landek-Salgado
Melissa A
MA
Suzuki
Koichi
K
Kimura
Miho
M
Rose
Noel R
NR
Caturegli
Patrizio
P
D018249:Adenoma, Oxyphilic / Q000378:metabolism; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D050031:Hashimoto Disease / Q000235:genetics; D006801:Humans; D007037:Hypothyroidism / Q000378:metabolism* / Q000473:pathology*; D007107:Immune System / Q000502:physiology*; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D024862:Oxyphil Cells / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex; D013961:Thyroid Gland / Q000473:pathology*
D007371:Interferon-gamma; D046988:Proteasome Endopeptidase Complex