The prevalence and clinical significance of blocking thyrotropin receptor antibodies in untreated hyperthyroid Graves' disease

The goal of this study was to evaluate the clinical significance of the blo cking thyrotropin receptor antibodies (TSHRAb) in Graves' disease. The amou nt of blocking and stimulating TSHRAb were measured in 200 patients with un treated hyperthyroid Graves' disease using several cell lines carrying diff erent TSHR chimera. Stimulating TSHRAb were measured in Chinese hamster ova ry (CHO) cells with wild-type human TSHR (CHO-hTSHR) or a TSHR chimera with residues 90-165 (Mc2) or 8-165 (Mcl+2) substituted by equivalent residues of rat luteinizing hormone/chorionic gonadotrophin (LH/CG) receptor or in F RTL-5 cells. Blocking TSHRAb were measured in Mc2 cells. The activities of different TSHRAb were assessed and clinical features were compared to patie nts who were positive or negative for blocking TSHRAb antibodies. Blocking TSHRAbs were detected in 18.5% of patients (37/200) with hyperthyroid Grave s' disease. Patients with blocking antibodies had significantly lower mean stimulating TSHRAb activities than those without blocking antibodies in wil d-type CHO-hTSHR cells (301 +/- 179 vs. 446% +/- 537%, p = 0.005). Mean sti mulating TSHRAb activities measured by FRTL-5, Mcl+2, or Mc2 cells and mean thyrotropin receptor inhibitor immunoglobulin (TBII) activities were not d ifferent between the two groups. The patients with blocking antibodies were not different from those without blocking antibodies in age, gender ratio, initial serum free thyroxine (T-4) levels, or goiter size. However, the pr evalence of exophthalmos was higher (35.1% vs. 17.5%, p = 0.024) in the pat ients with blocking antibodies than those without. In summary, the presence of blocking TSHRAb is not rare in patients with hyperthyroid Graves' disea se when measured with chimeric receptor expressing cells, Blocking TSHRAb i n Graves' sera do not strongly antagonize the action of stimulating TSHRAb in vivo, but could be a major factor responsible for underestimation of sti mulating TSHRAb activities measured by CHO-hTSHR. The association of blocki ng TSHRAb with ophthalmopathy suggests that the TSHRAb repertoire of Graves ' patients is different in those who do and who do not have ophthalmopathy.