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Autoimmune Disease Unit (C.-R.C., H.A., P.N.P., S.M.M., B.R.), Cedars-Sinai Research Institute and University of California, Los Angeles, School of Medicine, Los Angeles, California 90048; and Department of Medical Gene Technology (Y.N.), Nagasaki University School of Biomedical Sciences, Nagasaki 852-8523, Japan
Address all correspondence and requests for reprints to: Dr. Basil Rapoport, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite B-131, Los Angeles, California 90048. E-mail: rapoportb{at}cshs.org.
We investigated why TSH receptor (TSHR) adenovirus immunization induces hyperthyroidism more commonly in BALB/c than in C57BL/6 mice. Recent modifications of the adenovirus model suggested that using adenovirus expressing the TSHR A subunit (A-subunit-Ad), rather than the full-length TSHR, and injecting fewer viral particles would increase the frequency of hyperthyroidism in C57BL/6 mice. This hypothesis was not fulfilled; 65% of BALB/c but only 5% of C57BL/6 mice developed hyperthyroidism. TSH binding inhibitory antibody titers were similar in each strain. Functional TSHR antibody measurements provided a better indication for this strain difference. Whereas thyroid-stimulating antibody activity was higher in C57BL/6 than BALB/c mice, TSH blocking antibody activity was more potent in hyperthyroid-resistant C57BL/6 mice. F1 hybrids (BALB/c x C57BL/6) responded to A-subunit-Ad immunization with hyperthyroidism and TSHR antibody profiles similar to those of the hyperthyroid-susceptible parental BALB/c strain. In contrast, ELISA of TSHR antibodies revealed that the IgG subclass distribution in the F1 mice resembled the disease-resistant C57BL/6 parental strain. Because the IgG subclass distribution is dependent on the T helper 1/T helper 2 cytokine balance, this paradigm can likely be excluded as an explanation for susceptibility to hyperthyroidism. In summary, our data for BALB/c, C57BL/6, and F1 strains suggest that BALB/c mice carry a dominant gene(s) for susceptibility to induction of a thyroid-stimulating antibody/TSH blocking antibody balance that results in hyperthyroidism. Study of this genetic influence will provide useful information on potential candidate genes in human Graves’ disease.
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