Studies on multiple thyroid cell membrane-directed antibodies in Graves' disease

Immunoglobulin G was obtained from the serum of a woman who had given birth to three children with a delayed onset of hyperthyroidism; the clinical events were due to the coexistence of thyroid-stimulating antibody (TSAb) and an inhibitor of TSAb in the maternal serum. The current studies explore the possible existence of additional thyroid membrane-directed antibodies. Human thyroid slices, cells in monolayer culture, and functioning rat thyroid cells (FRTL5), with measurement of cyclic AMP concentration, were used for TSAb assays. Assays of the inhibition of binding of 125I-thyrotropin (TSH) to its receptor used human thyroid and FRTL5 cells, and human thyroid and guinea pig fat cell membranes as receptors. All activities were associated with IgG kappa. Fractions of IgG kappa obtained by adsorption to and the desorption from human thyroid and guinea pig fat cell preparations and F(ab')2 and Fab fragments of the parent IgG were tested. Results indicated that there were three activities in the IgG, namely, TSAb; an inhibitor of TSH-binding that was active in all species and preparations tested, and was effective as Fab and F(ab')2 on both particulate and solubilized thyroid membranes; and an enhancer of TSH-binding (e.g., approximately equal to 220% increase in binding) that was relatively specific for human thyroid membranes only in particulate form, was not adsorbed by fat, and was active as F(ab')2, but minimally as Fab. The concept is developed that dilution of the total IgG, experimentally in vitro or by metabolic clearance in vivo in neonates, determines the effect on either thyroid stimulation or TSH-binding. The incidence of such multiple antibodies and their interaction remains to be determined.