Immunization with the extracellular domain of TSH receptor (TSHR) led to the development of hyperthyroxinemia in BALB/cJ, but not C57BL/6J, SJL/J, and B10.BR, mice. Earlier, human studies had shown that thyroid-stimulating antibodies are predominantly of the immunoglobulin G1 (IgG1) subclass with a narrow specificity to TSHR, and antibodies that block thyroid function could be of any subclass with a brooder specificity. Therefore, antibody responses in susceptible (BALB/cJ) and resistant (SJL/J) mice were characterized. There were no significant differences in the titers, relative affinities, or isotypes of antibodies against the TSHR. BALB/cJ and SJL/J sera reacted with 2 and 7 of 26 overlapping peptides from the extracellular domain of the TSHR. The ability of sera from BALB/cJ and SJL/J mice to block TSH binding to TSHR was reversed by 1 and 6 of the reactive peptides, respectively. BALB/cJ mice showed predominantly an IgG1 response against the TSHR and peptides, whereas SJL/J mice showed varying levels of all IgG subclasses. Although SJL/J sera reacted with peptides to which blocking antibodies bind, they did not show hypothyroidism, suggesting that their sera contained a mixture of blocking and stimulating antibodies that negated the effects of each other. In contrast, some TSHR-specific antibodies in BALB/cJ probably represented stimulating antibodies.
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