New revelations in susceptibility to autoimmune thyroiditis by the use of H2 and HLA class II transgenic models

H2 and HLA transgenes were utilized to clarify the role of class II genes in susceptibility to experimental autoimmune thyroiditis (EAT), a model for Hashimoto's thyroiditis (HT). Susceptibility was transferred by H2 class II transgenes to a resistant haplotype and by HLA-DRA/DRBI*0301 (DR3) transgene into class II-negative Ab⁰ mice. Mice with a HLA-DRBI*1502 (DR2) transgene remain resistant to mouse thyroglobulin (mTg)-induced EAT, illustrating the role of HLA-DRB1 polymorphism. A role for HLA-DQ polymorphism was shown with hTg-induced EAT in HLA-DQ*0301/DQBI*0302 (DQS), but not HLA-DQ*0103/DQBI*0601 (DQ6), transgenic mice. Yet, both DQ8⁺ and DQ6⁺ mice were unresponsive to mTg. Single transgenes obviate the problems from DR/DQ linkage disequilibrium and may distinguish the degree of susceptibility and the response to shared or specific epitopes. The introduction of conserved Ed^k transgene into Ab⁰ mice reveals a new role for H2E molecules in EAT. Without H2A molecules, EαEβ^b molecules and T cells respond to hTg or pTg with severe thyroiditis, but not to mTg, thus distinguishing self from nonself. However, IA^b genes in resistant mice ameliorate Ea^k transgene-mediated thyroiditis, similar to the effect of Ed^k transgene on IA^s-mediated EAT. Studies in HLA DQ/DR double transgenic mice simulating human haplotypes could reveal HLA class II gene interactions in HT.