The Thyrotropin Receptor in Thyroid Eye Disease

Thyroid eye disease (TED) has an autoimmune etiology, but the nature of the autoantigen that is the target of the initiating event remains unknown. A number of candidates have been proposed based on Western blotting, library screening, and deduction from sequence similarity. A strong favorite is the thyrotropin receptor (TSHR), which is the target of the thyroid stimulating antibodies (TSAB) of Graves' disease (GD). We have recently demonstrated TSHR transcripts in orbital adipose tissue from a patient with TED by Northern blot, transcripts in normal adipose tissue being at the limit of detection. We have shown that the transcripts are translated into protein by immunohistochemical analysis using two monoclonal antibodies to the TSHR generated by genetic immunization. TSHR immunoreactivity is associated with elongated cells with the appearance of a fibroblast, often adjacent to clusters of adipocytes, in orbital biopsies from patients with TED but not in strabismus or pseudotumor biopsies. In animal studies, we have transferred thyroiditis to naive BALBc and NOD mice, using T cells primed to the human TSHR, either using the receptor expressed as a bacterial fusion protein or by genetic immunization. The BALBc develop a Th2-type response to the receptor, but the NOD a Th1-type with thyrocyte destruction. Orbital pathology, edema, infiltration by mast cells and lymphocytes, and adipose accumulation was also induced in 68% of the BALBc but none of the NOD mice. Together these data indicate that the preadipocyte expresses the TSHR and that a Th2 autoimmune response to the receptor may be an initiating event in TED.