Mouse Models of Graves' Disease

Graves' disease is characterized by overstimulation of the thyroid gland with agonistic autoantibodies against the thyrotropin (TSH) receptor, leading to hyperthyroidism and diffuse hyperplasia of the thyroid gland. Our and other laboratories have recently established several animal models of Graves' hyperthyroidism with novel immunization approaches, i.e., in vivo expression of the TSH receptor by injection of syngeneic living cells co-expressing the TSH receptor and major histocompatibility complex (MHC) class II or genetic immunization using plasmid or adenovirus vector coding the TSH receptor. This breakthrough has provided important insights into our understanding of the pathogenesis of Graves' disease. New findings obtained include that (i) professional antigen-presenting dendritic cells appear to be crucial for disease initiation, (ii) the free A subunit of the receptor is likely the main autoantigen for stimulating antibodies, (iii) non-MHC genes as well as MHC genes albeit less significant may be linked to disease susceptibility, (vi) certain infectious pathogens may have a negative impact on disease development, and (v) Graves' disease is not simplistically a T helper type 2 (Th2)-dominant autoimmune disease as previously considered; indeed TSH receptor-specific Th1 immune response appears to be critical for disease pathogenesis. Further studies with these models will hopefully lead to not only better understanding of the pathogenesis of Graves' disease but also the development of new approaches for treatment and ultimately prevention of Graves' disease in the future