INDUCTION OF THYROIDITIS IN MICE WITH THYROTROPIN RECEPTOR LACKING SEROLOGICALLY DOMINANT REGIONS

Grave's disease (GD) is characterized by pathogenic autoantibodies to the human thyrotropin receptor (hTSH-R), and is frequently associated with a lymphocytic infiltrate of the thyroid gland. In attempts to est ablish a murine model of GD, we and others have previously shown that immunization of mice with recombinant preparations of the hTSH-R ectod omain induces high titres of specific antibodies, which, however, are not pathogenic, nor is the response accompanied by the development of thyroiditis. Since earlier reports identified the serological immunodo minant determinants within the N- and C-terminal regions of hTSH-R ect odomain, we reasoned that immunization of mice with truncated fragment s of ectodomain lacking these dominant regions might result in skewing of the response to other determinants of the molecule, with consequen t induction of immunopathological features present in GD. We show here that multiple challenge of BALB/c mice with an amino acid fragment of residues 43-282 generates antibodies directed at hTSH-R peptides 37-5 6, 157-176, 217-236 and 232-251. This reactivity pattern is distinct f rom that induced previously with the whole ectodomain of hTSH-R in BAL B/c animals. Thyroid function remained unaffected in these mice, sugge sting that pathogenic antibodies were not being induced. Interestingly , some animals developed lymphocytic infiltration oi the thyroid gland , clearly indicating the presence of pathogenic T cell determinants wi thin the 43-282 fragment. Challenge with the related fragment 43-316 p roduced the same pattern of serological response to the synthetic pept ides as fragment 43-282, but was not accompanied by thyroiditis. The r esults demonstrate: (i) the presence of thyroiditogenic determinants w ithin hTSH-R, and (ii) that these pathogenic determinants are likely t o be cryptic, as their effect is exhibited only when the hierarchy of immunodominance within hTSH-R is drastically altered.