title: Immunoproteasome overexpression underlies the pathogenesis of thyroid oncocytes and primary hypothyroidism: studies in humans and mice.
abstract: 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.
authors.affiliation: Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
authors.forename: Hiroaki J
authors.initials: HJ
authors.lastname: Kimura
authors.forename: Cindy Y
authors.initials: CY
authors.lastname: Chen
authors.forename: Shey-Cherng
authors.initials: SC
authors.lastname: Tzou
authors.forename: Roberto
authors.initials: R
authors.lastname: Rocchi
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Landek-Salgado
authors.forename: Koichi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Miho
authors.initials: M
authors.lastname: Kimura
authors.forename: Noel R
authors.initials: NR
authors.lastname: Rose
authors.forename: Patrizio
authors.initials: P
authors.lastname: Caturegli
mesh_terms: 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*
chemical_list: D007371:Interferon-gamma; D046988:Proteasome Endopeptidase Complex