REGULATION OF INTERCELLULAR-ADHESION MOLECULE-1 EXPRESSION IN HUMAN THYROID-CELLS IN-VITRO AND HUMAN THYROID-TISSUE TRANSPLANTED TO THE NUDE-MOUSE IN-VIVO - ROLE OF GRAVES IMMUNOGLOBULINS AND HUMAN THYROTROPINRECEPTOR

To further explore a potential role for the human TSH receptor (hTSHR) in the propagation of thyroid autoimmune disease, we examined immunom odulatory effects in response to its stimulation by Graves' Igs both i n human thyroid tissue transplanted to the nude mouse and in primary c ultures of human thyrocytes. We injected nude mice bearing transplants derived from normal human thyroid with protein A-Sepharose-purified G raves' IgGs (0.05-1 mg) on 2 days and assessed, in addition to functio nal stimulation, the expression of intercellular adhesion molecule-1 ( ICAM-1) by transplant thyrocytes. In parallel to functional stimulatio n, as demonstrated by thyroid follicular cell hypertrophy in the trans plants and increased T-4 production, Graves' IgGs induced a marked dos e-dependent expression of ICAM-1 by transplanted thyrocytes, which exc eeded that of a continuous interferon-gamma infusion (200 IU/24 h) for 2 days. Normal IgGs were ineffective. Bovine TSH (bTSH) had little ef fect by itself, but did enhance interferon-gamma-induced ICAM-1 expres sion. To assess the specificity of their effects, experiments with Gra ves' IgGs were conducted in the presence and absence of a selective hT SHR antagonist (asialoagalacto-hCG). Asialoagalacto-hCG nearly complet ely abolished the stimulatory effect of Graves' IgGs on ICAM-1 express ion and significantly reduced the combined bTSH/interferon-gamma effec t. It failed, however, to affect interferon-gamma action. In vitro stu dies using human thyroid cells in primary culture confirmed the in viv o observations; treatment with saline resulted in 14% of cells express ing ICAM-1, with pooled normal IgGs (500 mg/L) in 18% and with Graves' IgGs (patient A, 448 mg/L; patient B, 260 mg/L) in 78% and 51%, respe ctively. Upon exposure to Graves' IgGs (90 mg/L) plus asialo-hCG (350 mg/L), 25% of the cells stained positively for ICAM-1, 29% to bTSH (10 IU/L), 31% to recombinant human TSH (10 IU/L), and 84% to interferon- gamma (10 IU/mL). In conclusion, stimulation of human thyroid cells, e ither transplanted to the nude mouse in vivo or studied under in vitro conditions, with Igs derived from patients with Graves' disease incre ased the expression of ICAM-1 on the surface of the cells. The action appears to be specific and mediated by the hTSHR. This particular prop erty of TSHR autoantibodies may be of pathophysiological relevance in Graves' disease, as it may assist in targeting the autoimmune attack a nd in promoting lymphocyte recruitment to the thyroid gland.