Gene expression profiles differ markedly in mouse strains that are (or are not) susceptible to hyperthyroidism induced using thyrotropin receptor-expressing adenovirus

Abstract

BALB/c mice are susceptible and C57BL/6 mice are resistant to Graves' hyperthyroidism induced by immunization with adenovirus encoding the thyrotropin receptor (TSHR) A-subunit. Both strains develop comparable levels of TSHR antibodies, but potent TSH blocking antibody activity in C57BL/6 mice likely blocks development of hyperthyroidism. We used microarrays to compare gene expression in spleens of mice immunized with A-subunit adenovirus (TSHR-Ad) or control adenovirus (Con-Ad). To preclude the effects of variable thyroxine (T(4)) levels, mice were studied when euthyroid as follows: BALB/c mice immunized three times with TSHR-Ad or Con-Ad and C57BL/6 mice immunized three times with TSHR-Ad or Con-Ad. Among the 14,000 expressed probe sets, there were no statistically significant differences in gene expression in BALB/c mice immunized with TSHR-Ad versus Con-Ad. In contrast, expression of 57 transcripts (representing 40 genes) changed in response to TSHR-Ad in C57BL/6 mice. Diverse genes were identified, including proteins involved in immune responses, inflammation, and cell cycling as well as heat-shock proteins and proteases. Down-regulation of chitinase 3- and-4 gene expression likely reflects cytokines produced by T-helper 2 (Th2) type cells. Indeed, the immunoglobulin (IgG) subclass for TSHR antibodies reflects a deviation away from Th2 cytokines and toward Th1 in C57BL/6 mice. In conclusion, TSHR-Ad immunization altered gene expression profiles in C57BL/6, but not in BALB/c, mice. This response primarily involved reduced gene expression. In C57BL/6 mice, decreased expression of genes such as cathelicidin, calgranulins, and lipocalin following TSHR A-subunit adenovirus immunization suggests the importance of innate immunity in this response.