Evidence supporting the identity in Graves' disease of thyroid-stimulating antibody and thyroid growth-promoting immunoglobulin G as assayed in FRTL5 cells.

Abstract

This paper addresses the question: in Graves' disease is there a thyroid-growth stimulating IgG (TGI) separate from thyroidstimulating antibody (TSAb)? Using the functioning rat thyroid line (FRTL5) cells for TGI (incorporation of 13H1-thymidine into DNA) and TSAb (increase in cAMP concentration) assays, we tested IgG from 30 Graves' patients.Positive TGI assay occurred only if cAMP increased in the cells and responses correlated, i.e., r = 0.95, P < 0.001. With one very potent TSAb-IgG we showed that Fab was active as TGI and TSAb, IgG with pI of 8.5-9.0 was the most potent fraction in both systems and an inhibitory IgG prevented the action of both TSAb-IgG and TSH in both the TSAb and TGI assays. In the last example, the action was on the cell membrane and not on the TSH or IgG. These data are entirely compatible with the view that in Graves' disease, at least as tested in FRTL5 cells, the same IgG is active in stimulating both growth and adenylate cyclase.

Unlike thyrotropin, thyroid-stimulating antibodies do not activate phospholipase C in human thyroid slices.

“…This effect was thus related to the thyroid sample studied and not to any differential characteristics of the normal and Graves' IgG. The lack of effect of TSAb on inositol phosphates generation was not related to a negative interaction of Graves' IgG with receptor activated phospholipase C, since TSH-induced InsP3 responses were not inhibited by Graves' sera (3 experiments using sera 9,11,14). Fig.…”

“…However, claims have appeared for the existence of a growth-stimulating immunoglobulin (thyroid growth-stimulating antibodies or TGSAb), separate from TSAb, that might cause thyroid growth in Graves' disease and some euthyroid goiters through a pathway distinct from adenylate cyclase (10)(11)(12)(13). These results were in contradiction with the findings ofZakarija et al who showed a strict parallelism between growth and cyclic AMP accumulation-stimulating activities in Graves' immunoglobulins (14). These in vitro studies on human thyroid slices were initiated to determine whether Graves' disease immunoglobulins reproduced one or both of the primary metabolic effects of TSH (adenylate cyclase and phospholipase C activation) that might be relevant to the increased function ofthe gland and essential for the development of thyrotoxicosis.…”

“…However, these results were sometimes based on inadequate methodologies (29,30) and the experiments were never obtained with human thyroid cells or tissue. It has since been shown that cyclic AMP is the mediator of TSH mitogenic action in the FRTL5 cell line (31) and besides, that the growth promoting action ofGraves' sera parallel their action on cyclic AMP accumulation in these cells (14).…”

Insulin-Like Growth Factor-I Regulation of Immune Function: A Potential Therapeutic Target in Autoimmune Diseases?

“…Central to promoting the hyperthyroid state and thyroid enlargement in this disease are activating antibodies directed against the thyroidstimulating hormone receptor (thyrotropin receptor or TSHR) (Zakarija et al, 1988). These antibodies, termed thyroid-stimulating immunoglobulins, override the trophic control of thyroid function normally imposed by the hypothalamic/anterior pituitary axis through its elaboration by thyrotrophs of TSH.…”

Growth stimulating antibody, as another predisposing factor of Graves’ disease (GD): analysis using monoclonal TSH receptor antibodies derived from patients with GD

“…Those observations suggest that there exist thyrocyte growth stimulating antibody other than TSAb. On the contrary, Zakarija et al and Dumont et al reported that both activities were simultaneously detected and growth stimulating antibody and TSAb are identical [20,21]. However, the IgG fractions employed in those previous studies were polyclonal, and the GSA of monoclonal TRAb has not been clarified in detail.…”