Induction of autoimmune thyroiditis by unique human thyroglobulin epitopes in H2E transgenic mice

Experimental autoimmune thyroiditis (EAT), a model for Hashimoto's thyroiditis, can be induced by injecting either mouse (M) or human (H) thyroglobulin (Tg) into genetically susceptible mice. EAT susceptibility is linked to H2A class II genes; k & s haplotypes are susceptible, while b & f are resistant. The introduction of H2A ^k or HLA-DRB1 *0301 (DR3) transgene into resistant B10.M (H2 ^f) or class II knock-out Ab ⁰ mice led to severe thyroid infiltration. These transgenic strains responded to EAT induction with both MTg and HTg. Here, we introduced H2Ea transgene into resistant B10 (H2 ^b) or Ab ⁰ mice, resulting in surface Eβ ^b expression. To our surprise, both transgenic strains showed severe inflammation only after HTg, but not MTg, immunization. In proliferative assays, HTg-primed cells did not respond to MTg, and stimulation with HTg was blocked by anti-Eβ ^b. We also tested three primary hormonogenic site 12mer peptides, 100% identical between MTg and HTg. Although two can activate T cells for thyroiditis transfer and cytotoxicity, none stimulated HTg-primed cells. Previous cross-activation and cross-tolerance studies with MTg and HTg suggested that MTg had both conserved and unique T cell epitopes. This is the first demonstration of HTg-unique epitopes.