Application of HLA Class II Transgenic Mice to Study Autoimmune Regulation

In the past decade, we participated in the increased use of HLA class II transgenic mice to delineate genetic control in autoimmune diseases. Our studies began with individual class II transgenes to determine permissiveness for experimental autoimmune thyroiditis (EAT), first in resistant strains and then in the absence of endogenous H2 class II molecules. Polymorphism for HLA-DRB1 was observed, as DR3, but not DR2 or DR4, molecules serve as a determinant for EAT induction with either mouse thyroglobulin (mTg) or human thyroglobulin (hTg). This delineation enabled identification of pathogenic Tg peptides, based on DR3-binding motifs. HLA-DQ polymorphism was also detectable; hTg induced moderate EAT in DQ8+, but not DQ6+, mice. Coexpressing permissive and nonpermissive alleles, DR3+ mice showed reduced EAT severity in the presence of DQ8, but not DQ6, DR2, or DR4. Determining the regulatory T cell (Treg) influences showed that Treg depletion increased thyroiditis incidence and severity without altering the...