TSH receptor antibodies as measured in the thyroid stimulating immunoglobulin (TSI) reporter bioassay Thyretain are not detected in patients with euthyroid Graves' disease

Background: The ophthalmopathy associated with Graves’ hyperthyroidism is most likely a T-cell mediated disorder, although most investigators believe that auto antibodies directed against the TSH Receptor (TSH-R) expressed on the surface of the orbital fibroblasts and pre-adipocytes are the main driver of the orbital reactions. Cases of ophthalmopathy without TSH-R binding antibodies and not closely associated with Thyroid Stimulating Immunoglobulin’s (TSI), challenge the notion that ophthalmopathy is perpetrated by TSI circulating in peripheral blood and TSI producing plasma cells resident in the orbital tissues. One way to address a possible role of TSH-R antibodies in the development of ophthalmopathy is to study patients with so-called “Euthyroid Graves’ eye Disease (EGD)”, who have the same eye disorder but with normal thyroid function and no features of thyroid autoimmunity during long term follow up. Methods: The cell-based reporter bioassay Thyretain™ was used to assess TSI in serum of the patients (n=50) and control subjects (n=20); The patient groups; EGD (n=13), of whom 6 were first tested early in the course of their eye disorder (<6 months) and 7 tested ≥ 6 months after the onset of eye symptoms, Graves’ disease with (n=13), and without (n=12), ophthalmopathy and euthyroid relatives from a previously studied family having a high prevalence of thyroid autoimmunity and ophthalmopathy (WH-Fam n=12). Thyretain™-TSI results were expressed as per cent of the sample to reference ratio (SRR %), a positive test being taken as an SRR% of > 140%. Results: Only 3 of 13 (23 %) patients initially diagnosed with EGD tested TSI positive in one or more serum samples, and all 3 became hyperthyroid at the time of the positive test or soon after. Among the remaining 10 EGD patients who tested TSI negative, none developed thyroid autoimmunity during follow up visits 6 months to 10 years after initial diagnosis. Normal subjects and euthyroid relatives from WH-Fam all tested TSI negative whereas 9 out of 12 (75%) Graves’ Hyperthyroidism (GH) and 11 out of 13 (86%) Graves’ Ophthalmopathy (GO) patients tested TSI positive. Conclusion: These findings of positive TSI among patients with GH and GO, but not among patients with EGD with the exception of the 3 patients who developed Graves’ hyperthyroidism, strongly suggests that TSH-R antibodies cannot play a major role in the pathogenesis of what is best called endocrine or auto immuneophthalmopathy.