Thyrotrophin receptor blocking antibodies: incidence, characterization and in-vitro synthesis

The prevalence and characteristics of TSH receptor blocking activity were examined in patients with different thyroid disorders. Studies were also performed on the in-vitro synthesis and immunoregulation of the blocking antibody. Blocking activity was tested by measuring the inhibition of TSH-stimulated cAMP production of cultured human thyroid cells by patient immunoglobulin (Ig) preparations. The following patients were investigated (number of cases in parentheses): Hashimoto's thyroiditis (33); primary myxoedema (17); euthyroid ophthalmopathy (8); active Graves' disease (19); cold nodule (5); non-toxic goitre (14); toxic adenoma (8); toxic multinodular goitre (9) and 22 normal controls. TSH receptor blocking activity was only detected in primary hypothyroidism with the following characteristics: (i) Such activity was present in only 16% of the patients (both goitrous, i.e. Hashimoto's thyroiditis, and non-goitrous, i.e. primary myxoedema), and in three patients with previously active Graves' hyperthyroidism who had become hypothyroid. (ii) Blocking activity seems to be associated with the Ig fraction of serum as indicated by protein A adsorption. (iii) The block-positive samples did not bind 125I-TSH, which seems to rule out an antibody directed against TSH. (iv) The specificity of the blocking activity seems to be directed towards the TSH-(thyroid stimulating immunoglobulin, TSI) receptor-mediated cAMP response since no inhibition of prostaglandin E1-stimulated cAMP production was found. Moreover, all cases in which an inhibitory effect was demonstrated towards TSH also exhibited blocking of TSI-stimulated cAMP, with a high correlation between the degree of inhibition of the TSH to that of the TSI response (r = 0.89, P less than 0.001, n = 11). The blocking activity may contribute to the pathogenesis of some cases of primary hypothyroid autoimmune thyroiditis, both goitrous and non-goitrous, as well as in the evolution of hyper- to hypothyroidism. By culturing peripheral blood lymphocytes, as well as B/T lymphocyte co-cultures isolated from three patients with blocking activity present in serum, the in-vitro synthesis of the blocking antibody was demonstrated for the first time. Moreover, in-vitro secretion of the antibody by patients B lymphocytes, as well as T cell regulation of autoantibody production, were also shown.