title: Fibroblasts expressing the thyrotropin receptor overarch thyroid and orbit in Graves' disease.
abstract: BACKGROUND
  Graves' disease (GD) is a systemic autoimmune syndrome comprising manifestations in thyroid and orbital connective tissue. The link between these two tissues in GD eludes our understanding. Patients with GD have increased frequency of circulating monocyte lineage cells known as fibrocytes. These fibrocytes infiltrate orbital connective tissues in thyroid-associated ophthalmopathy and express functional TSH receptor (TSHR).
  
  
  OBJECTIVE
  The aim of the study was to identify and characterize CD34(+) fibrocytes in thyroid tissue.
  
  
  METHODS
  Patients undergoing surgical thyroidectomy at two academic medical centers were recruited to the study.
  
  
  METHODS
  We performed immunohistochemistry, flow cytometry, real-time PCR, cytokine-specific ELISA, and cell differentiation.
  
  
  RESULTS
  CD34(+)ColI(+)CXCR4(+)TSHR(+) cells can be identified in situ in thyroid tissue from donors with GD, Hashimoto's thyroiditis, or in normal-appearing tissue. Thyroid fibroblasts cultivated from these glands express a CD34(-)ColI(+)CXCR4(+)TSHR(+) phenotype. TSHR levels are higher than those in orbital fibroblasts. When treated with TSH, thyroid fibroblasts generate IL-6 and IL-8. The induction of IL-6 can be blocked by dexamethasone, a chemical inhibitor of Akt/Pkb, and by knocking down Akt with a specific small interfering RNA. When treated with TGF-β or rosiglitazone, thyroid fibroblasts differentiate into myofibrocytes or adipocytes, respectively.
  
  
  CONCLUSIONS
  ColI(+)CXCR4(+)TSHR(+) thyroid fibroblasts resemble orbital fibroblasts and circulating fibrocytes. CD34(+) fibrocytes appear to infiltrate both tissues in GD. Thyroid fibroblasts lose CD34 display in culture, unlike orbital fibroblasts and circulating fibrocytes. Fibrocytes and their fibroblast derivatives may participate in the pathogenesis of thyroid autoimmunity after TSHR activation. They could represent a therapeutic target for these diseases.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Kellogg Eye Center, Brehm Tower, 1000 Wall Street, Ann Arbor, Michigan 48105, USA. terrysmi@med.umich.edu
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Smith
authors.forename: Dolly A
authors.initials: DA
authors.lastname: Padovani-Claudio
authors.forename: Ying
authors.initials: Y
authors.lastname: Lu
authors.forename: Nupur
authors.initials: N
authors.lastname: Raychaudhuri
authors.forename: Roshini
authors.initials: R
authors.lastname: Fernando
authors.forename: Stephen
authors.initials: S
authors.lastname: Atkins
authors.forename: Erin F
authors.initials: EF
authors.lastname: Gillespie
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Gianoukakis
authors.forename: Barbra S
authors.initials: BS
authors.lastname: Miller
authors.forename: Paul G
authors.initials: PG
authors.lastname: Gauger
authors.forename: Gerard M
authors.initials: GM
authors.lastname: Doherty
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Douglas
mesh_terms: D000328:Adult; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006111:Graves Disease / Q000235:genetics / Q000378:metabolism* / Q000601:surgery; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009915:Orbit / Q000378:metabolism*; D011989:Receptors, Thyrotropin / Q000235:genetics / Q000378:metabolism*; D013961:Thyroid Gland / Q000378:metabolism* / Q000601:surgery; D013965:Thyroidectomy
chemical_list: D015850:Interleukin-6; D016209:Interleukin-8; D011989:Receptors, Thyrotropin