IMMUNOGLOBULIN HEAVY CHAIN VARIABLE REGION GENES CONTRIBUTE TO THE INDUCTION OF THYROID STIMULATING ANTIBODIES IN RECOMBINANT INBRED MICE

Graves’ hyperthyroidism is an autoimmune disease occurring spontaneously in humans caused by autoantibodies that stimulate the thyrotropin-receptor. In mice, inducing Graves’-like hyperthyroidism requires in vivo expression of the thyrotropin-receptor using plasmid or adenovirus vectors. However, mice with different genetic backgrounds vary markedly in their susceptibility to induced hyperthyroidism. Further, in some strains major disparities exist between the induction of hyperthyroidism and detection of thyroid-stimulating antibodies. To break tolerance, all Graves’ mouse models involve immunization with human thyrotropin-receptor DNA and the standard thyroid-stimulating antibodies bioassay utilizes cells expressing the human thyrotropin-receptor. We hypothesized, and now report, that disparities between hyperthyroidism and thyroid-stimulating antibody bioactivity are explained, at least in part, by differential antibody recognition of the human versus the mouse thyrotropin-receptor. The genetic basis for these species differences was explored using genotyped, recombinant-inbred mouse strains. We report that loci in the immunoglobulin heavy chain variable region as well as in the MHC region contribute in a strain-specific manner to the development of antibodies specific for the human or the mouse thyrotropin-receptor. The novel finding of a role for immunoglobulin heavy chain variable region gene involvement in thyroid-stimulating antibody epitopic specificity provides potential insight into genetic susceptibility in human Graves’ disease.