Exceptional hyperthyroidism and a role for both major histocompatibility class I and class II genes in a murine model of Graves' disease

PLoS One. 2011;6(6):e21378. doi: 10.1371/journal.pone.0021378. Epub 2011 Jun 27.


Autoimmune hyperthyroidism, Graves' disease, can be induced by immunizing susceptible strains of mice with adenovirus encoding the human thyrotropin receptor (TSHR) or its A-subunit. Studies in two small families of recombinant inbred strains showed that susceptibility to developing TSHR antibodies (measured by TSH binding inhibition, TBI) was linked to the MHC region whereas genes on different chromosomes contributed to hyperthyroidism. We have now investigated TSHR antibody production and hyperthyroidism induced by TSHR A-subunit adenovirus immunization of a larger family of strains (26 of the AXB and BXA strains). Analysis of the combined AXB and BXA families provided unexpected insight into several aspects of Graves' disease. First, extreme thyroid hyperplasia and hyperthyroidism in one remarkable strain, BXA13, reflected an inability to generate non-functional TSHR antibodies measured by ELISA. Although neutral TSHR antibodies have been detected in Graves' sera, pathogenic, functional TSHR antibodies in Graves' patients are undetectable by ELISA. Therefore, this strain immunized with A-subunit-adenovirus that generates only functional TSHR antibodies may provide an improved model for studies of induced Graves' disease. Second, our combined analysis of linkage data from this and previous work strengthens the evidence that gene variants in the immunoglobulin heavy chain V region contribute to generating thyroid stimulating antibodies. Third, a broad region that encompasses the MHC region on mouse chromosome 17 is linked to the development of TSHR antibodies (measured by TBI). Most importantly, unlike other strains, TBI linkage in the AXB and BXA families to MHC class I and class II genes provides an explanation for the unresolved class I/class II difference in humans.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Female
  • Genetic Linkage / genetics
  • Graves Disease / genetics
  • Graves Disease / immunology*
  • Graves Disease / metabolism*
  • Hyperthyroidism / genetics*
  • Hyperthyroidism / immunology*
  • Immunoglobulins, Thyroid-Stimulating / immunology*
  • Major Histocompatibility Complex / genetics
  • Major Histocompatibility Complex / physiology*
  • Mice
  • Quantitative Trait Loci / genetics
  • Receptors, Thyrotropin / genetics
  • Receptors, Thyrotropin / immunology*
  • Receptors, Thyrotropin / metabolism*


  • Immunoglobulins, Thyroid-Stimulating
  • Receptors, Thyrotropin