UNALTERED THYROID-FUNCTION IN MICE RESPONDING TO A HIGHLY IMMUNOGENICTHYROTROPIN RECEPTOR - IMPLICATIONS FOR THE ESTABLISHMENT OF A MOUSE MODEL FOR GRAVES-DISEASE

Grave's disease (GD) is a common disorder characterized by the presenc e of autoantibodies to the thyrotropin receptor. In the past, the exce edingly low expression of the thyrotropin receptor on thyrocytes has n ot allowed its purification in quantities sufficient to investigate th e establishment of an animal model for this disease. In this study, we have purified the 398-amino acid, extracellular region of the human t hyrotropin receptor (TSH-R.E) from insect cells using recombinant bacu lovirus, and explored its immunopathogenic properties in H-2(b,d,q,k,s ) strains of mice. The receptor preparation was highly immunogenic sin ce it elicited strong specific proliferative T cell responses as well as IgG responses in all strains tested. In addition, hyperimmunization with TSH-R.E induced (i) serum antibodies that blocked the binding of I-125-TSH to its receptor, a common feature of GD autoantibodies; and (ii) Ige that reacted with a synthetic peptide (residues 32-54) from the N-terminus of the receptor, a region implicated in the binding of thyroid stimulating antibodies. In SJL animals only, a weak antibody r esponse to two other thyroid antigens, thyroglobulin and thyroid perox idase, was also observed. The presence of these antibodies, however, w as not accompanied by a detectable alteration in thyroid function as a ssessed by the measurement of serum TSH, T4 and iodine levels. Also mo nonuclear infiltration of the thyroid gland or morphological changes c ompatible with an activation state of thyrocytes were not apparent in TSH-R-challenged mice. In contrast, mice treated with the anti-oxidant aminotriazole showed a dramatic increase in serum TSH levels and an a ctivated follicular epithelium. These data demonstrate that a highly i mmunogenic TSH-R.E in mice does not necessarily provide a proper stimu lus for the induction of a hyper- or hypothyroid status as defined by hormonal or histological criteria. Main reasons for the inability to i nduce receptor-specific antibodies that affect thyroid function such a s those generated in GD are likely to be the inappropriate folding of the recombinant extracellular domain of the receptor, or the xenogenei c nature of the autoantigen.