Abstract
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 chomosome 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.
Highlights
Susceptibility to Graves’ disease has long been associated with genes of the major histocompatibility complex (MHC; HLA in humans)(reviewed in [1])
Response of recombinant AXBXA strains to A-subunit adenovirus immunization
The rank order for TSHR antibodies measured by ELISA differed from that for TSH binding (TBI)
Summary
Susceptibility to Graves’ disease has long been associated with genes of the major histocompatibility complex (MHC; HLA in humans)(reviewed in [1]). A similar mechanism would be expected to play a role in MHC class II binding for peptides of the thyrotropin receptor (TSHR), the autoantigen in Graves’ disease. Consistent with this possibility, MHC class II region genes were most tightly linked to susceptibility in a genome-wide association scan in thyroid autoimmune disease, which included an expanded cohort of Graves’ patients [5]. Besides MHC class I and II, a recent study found ‘‘a novel and major association of HLA-C in Graves’ disease that eclipses the classical HLA-DRB1 effect’’ [7]
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