CONTEXT: 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.
DESIGN/SETTING/PARTICIPANTS: Patients undergoing surgical thyroidectomy at two 
academic medical centers were recruited to the study.
MAIN OUTCOME MEASURES: 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.