Susceptibility to autoimmune myocarditis is associated with intrinsic differences in CD4(+) T cells.

A.SW and B10.S mice share the same major histocompatibility complex (MHC) haplotype (H-2(s)). However, A.SW mice are susceptible to experimental autoimmune myocarditis (EAM) and develop severe disease after immunization with myosin, whereas B10.S mice are resistant. We found that naive A.SW mice have intrinsically increased total CD4(+) T cell counts and increased proportions of CD4(+) T cells in their spleens compared to B10.S mice. Among total CD4(+) T cells, naive A.SW mice have a lower relative frequency of forkhead box protein 3 (FoxP3(+))CD25(+) regulatory T cells (T(regs)). A.SW mice also had a higher proportion of CD4(+) T cells and a lower proportion of T(regs) in their hearts and spleen during EAM, with greater T cell activation and proliferation, compared to B10.S mice. These differences in the T cell compartment were not antigen-specific, as ovalbumin/complete Freund's adjuvant (OVA/CFA) or CFA immunization elicited the same differences in CD4(+) T cells and T(regs) between A.SW and B10.S mice. Moreover, A.SW mice had more T helper type 17 (Th17) cells and B10.S had more Th1 cells in their hearts. The higher percentage of CD4(+) T cells and their enhanced potential to differentiate towards the Th17 pathway was also observed in naive A.SW mice. Interleukin (IL)-6 is required for Th17 induction. Interestingly, IL-6Rα expression was greater on naive A.SW CD4(+) T cells, compared to B10.S CD4(+) T cells, indicating that this intrinsic difference, together with a relatively lower T(reg) proportion of CD4(+) T cells, might lead to heightened Th17 responses and greater susceptibility to autoimmunity in A.SW mice.

Iodination of murine thyroglobulin enhances autoimmune reactivity in the NOD.H2 mouse.

Autoimmune thyroiditis in humans has been linked to excess iodine intake. A causative relationship between dietary iodine and thyroiditis has been clearly established in animal models of thyroiditis, including the NOD.H2(h4) mouse strain, which develops enhanced thyroiditis spontaneously after supplementation of drinking water with sodium iodide. To assess the mechanisms by which iodine may contribute to disease pathogenesis, we have purified hypoiodinated thyroglobulin (Lo-I Tg) from the thyroids of mice fed methimazole and potassium perchlorate. This preparation contained only a trace of iodine and was poorly reactive to monoclonal antibody 42C3, which has been shown previously to distinguish hypoiodinated from normal Tg. A cloned T cell line 2D11 from a diseased NOD.H2(h4) mouse proliferated in response to normal Tg, but not to Lo-I Tg. Serum antibodies from NOD.H2(h4) mice with thyroiditis were poorly reactive to Lo-I Tg. To determine that these changes were due specifically to iodine content, Lo-I Tg was reiodinated in vitro. Reiodination of Lo-I Tg partially re-established the reactivity of NOD.H2(h4) serum antibodies. The data demonstrate that the reactivity of thyroglobulin-specific antibodies and certain T cells are dependent on the iodine content of thyroglobulin. These findings suggest that iodine contributes to autoimmune thyroiditis in the NOD.H2(h4) mouse by directly enhancing the antigenicity of thyroglobulin.