Differential Susceptibility of BALB/c and BALB/cBy mice to Graves' hyperthyroidism

BALB/c mice are susceptible to the induction of Graves' hyperthyroidism. To investigate the susceptibility of BALB/c substrains of mice to the induction of hyperthyroidism, we immunized BALB/cJ and BALB/cByJ mice with an adenovirus expressing amino acid residues 1-289 of thyrotropin receptor (TSHR). The data presented in this article showed that 17 of 26 (65%) BALB/c and only 4 of 30 (13%) BALB/cBy mice developed hyperthyroidism. Hyperthyroid mice displayed characteristics of Graves' disease, such as thyroid-stimulating antibodies and enlarged thyroid glands. To explore the differences in the susceptibility of these substrains for hyperthyroidism, we examined the TSHR antibodies in three different assays. The TSHR antibodies determined in a radioreceptor assay (TSH binding inhibitory immunoglobulins) were similar in both of these BALB/c substrains. The TSHR antibody titers of total IgG, IgG1, and IgG2a were measured by an enzyme-linked immunosorbent assay and were found to be similar in these mice. There were no significant differences between these two groups of mice in the thyroid-stimulating antibody activity. However, BALB/cBy mice had significantly higher TSH-blocking antibody activity compared to BALB/c mice. TSHR-specific proliferation of splenocytes and secretion of cytokines interferon-gamma and interleukin-4 by spleen cells were comparable in both the groups. BALB/cJ and BALB/cByJ mice both belong to same MHC haplotype, H-2(d), but differ in the Qa-2 region of class Ib molecule. This report shows the importance of other genes, such as Qa-2 region of class Ib molecule in addition to MHC class II, in the susceptibility of Graves' hyperthyroidism.