Graves hyperthyroidism is caused by autoantibodies to the thyrotrophin receptor (TSHR) that mimic thyroid stimulation by TSH. The disease develops spontaneously in humans but not in animals and conventional immunization with purified TSHR protein and adjuvant fails to generate Graves-like antibodies that stimulate the thyroid. However, antibody-mediated hyperthyroidism can be induced in mice or hamsters by novel approaches involving multiple injections of cells expressing the TSHR or repeated immunization with TSHR-DNA in plasmid or adenoviral vectors.
The adenovirus model has provided unique insight into several critical aspects of Graves disease, particularly the role of TSHR cleavage and A-subunit shedding in initiating or enhancing immune responses leading to thyroid stimulating antibodies (TSAb) and, in association with increased antibody titers, epitope spreading away from TSAb and towards TSH blocking antibodies (as in rare hypothyroid patients). Moreover, the animal models opened the way to investigating antigen-presentation, including the role of B cells, analysis of TSHR epitopes recognized by T cells as well as the isolation of monoclonal TSAb. Environmental factors including iodine and infectious pathogens have been explored and the different outcomes of manipulating immunity towards Th1 or Th2 cytokines to enhance or suppress hyperthyroidism probably reflect heterogeneity in human disease.
Finally, the models are contributing to unraveling two major issues in human thyroid autoimmunity. First, the question of immune tolerance has been addressed using TSHR knockout mice, in which the TSHR is a foreign protein, as well as in mice in which the human A-subunit is a self protein because it is targeted transgenically to the thyroid gland. Second, genetic studies of induced hyperthyroidism emphasize the contribution of non-MHC and MHC genes, as in humans. The first whole genome scan demonstrates the potential of recombinant inbred mice for discriminating between immune-response genes and thyroid-function susceptibility genes in Graves disease.