Vitamin D Deficiency Modulates Graves’ Hyperthyroidism Induced in BALB/c Mice by Thyrotropin Receptor Immunization

TSH receptor (TSHR) antibodies and hyperthyroidism are induced by immunizing mice with adenovirus encoding the TSHR or its A-subunit. Depleting regulatory T cells (Treg) exacerbates thyrotoxicosis in susceptible BALB/c mice and induces hyperthyroidism in normally resistant C57BL/6 mice. Vitamin D plays an important role in immunity; high dietary vitamin D intake suppresses (and low intake enhances) adaptive immune responses. Vitamin D-induced immunosuppression may enhance Treg. Therefore, we hypothesized that decreased vitamin D intake would mimic Treg depletion and enhance hyperthyroidism induced by A-subunit adenovirus immunization. BALB/c mice had a reduced ability vs. C57BL/6 mice to generate the active metabolite of vitamin D (1,25-dihydroxyvitamin D3). Vitamin D deficiency induced subtle immune changes in BALB/c (not C57BL/6) mice. Compared with mice fed regular chow, vitamin D-deprived BALB/c mice had fewer splenic B cells and decreased interferon-γ responses to mitogen and lacked memory T-cell responses to A-subunit protein. However, vitamin D deficiency did not alter TSHR antibody responses measured by ELISA, TSH binding inhibition, or cAMP generation from TSHR-expressing cells. Unexpectedly, compared with vitamin D-sufficient mice, vitamin D-deficient BALB/c mice had lower preimmunization T4 levels and developed persistent hyperthyroidism. This difference was unrelated to the immunological changes between vitamin D-deficient or -sufficient animals. Previously, we found that different chromosomes or loci confer susceptibility to TSHR antibody induction vs. thyroid function. Our present studies provide evidence that an environmental factor, vitamin D, has only minor effects on induced immunity to the TSHR but directly affects thyroid function in mice. Vitamin D deficiency in BALB/c mice reduces baseline thyroid function and prolongs hyperthyroidism induced by thyrotropin receptor-adenovirus immunization, but surprisingly has only minor effects on immune responses.