Susceptibility rather than resistance to hyperthyroidism is dominant in a thyrotropin receptor adenovirus-induced animal model of Graves' disease as revealed by BALB/c-C57BL/6 hybrid mice.
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. F(1) 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 F(1) 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 F(1) 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.
Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite B-131, Los Angeles, California 90048, USA. rapoportb@cshs.org
Chun-Rong
CR
Chen
H
H
Aliesky
P N
PN
Pichurin
Y
Y
Nagayama
S M
SM
McLachlan
B
B
Rapoport
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000097:blood; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D018014:Gene Transfer Techniques; D006111:Graves Disease / Q000453:epidemiology / Q000276:immunology* / Q000503:physiopathology*; D015994:Incidence; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011989:Receptors, Thyrotropin / Q000235:genetics* / Q000276:immunology*; D013045:Species Specificity; D013972:Thyrotropin / Q000378:metabolism
D000906:Antibodies; D011989:Receptors, Thyrotropin; D013972:Thyrotropin