To reflect human autoimmune thyroiditis, thyroid peroxidase (not thyroglobulin) antibodies should be measured in female (not sex-independent) NOD.H2h4 mice

Abstract

NOD.H2 h4 mice are the most commonly used model for human autoimmune thyroiditis. Because thyroid autoimmunity develops slowly (over months), NOD.H2 h4 mice are usually exposed to excess dietary iodide to accelerate and amplify the process. However, unlike the female bias in human thyroid autoimmunity, autoantibodies to thyroglobulin (TgAb) are reported to be similar in male and female NOD.H2 h4 . We sought evidence for sexual dimorphism in other parameters in this strain maintained on regular or iodized water. Without iodide, TgAb levels are higher in males than in females, the reverse of human disease. In humans, autoantibodies to thyroid peroxidase (TPOAb) are a better marker of disease than TgAb. In NOD.H2 h4 mice TPOAb develop more slowly than TgAb, being detectable at 6 months of age versus 4 months for the latter. Remarkably, unlike TgAb, TPOAb levels are higher in female than male NOD.H2 h4 mice on both regular and iodized water. As previously observed, serum T4 levels are similar in both sexes. However, thyroid-stimulating hormone (TSH) levels are significantly higher in males than females with or without iodide exposure. TSH levels correlate with TgAb levels in male NOD.H2 h4 mice, suggesting a possible role for TSH in TgAb development. However, there is no correlation between TSH and TPOAb levels, the latter more important than TgAb in human disease. In conclusion, if the goal of an animal model is to closely reflect human disease, TPOAb rather than TgAb should be measured in older female NOD.H2 h4 mice, an approach requiring patience and the use of mouse TPO protein.

Nanoparticles Bearing TSH Receptor Protein and a Tolerogenic Molecule Do Not Induce Immune Tolerance but Exacerbate Thyroid Autoimmunity in hTSHR/NOD.H2h4 Mice

“…than TgAb, which are usually detected at age 16 wk after iodide exposure for 8 wk [for example (12,13,15,19)]. In the current study, following np-TSH-ITE injection, both pathogenic and nonpathogenic TSHRAb are detectable in transgenic hTSHR/NOD.…”

“…TgAb were measured by ELISA and data reported as the OD 490 nm (mean + SE). TgAb levels do not differ between males and females on iodide (12)(13)(14)19) and therefore data are shown for males and females combined. The numbers of mice are indicated in parentheses.…”

“…1A), the time at which TSHRAb are usually measured (11). Because of relatively small numbers, data for male and female mice are not shown separately for TPOAb despite our recent findings that such an approach is preferred (19). TgAb were detectable at lower levels at the earlier time point (16 wk old mice) (Supplemental Fig.…”

The NOD Mouse Beyond Autoimmune Diabetes

“…In contrast to the low ~5% to ~15% incidence of SAT in NOD mice, 50%-70% of NOD.H2 h4 congenic mice develop SAT (21,26,28). Moreover, subjecting the mice to an iodine-rich diet enhances the severity and the incidence of thyroid lesions in both NOD and NOD.H2 h4 congenic mice, which can reach an incidence of nearly 100% in both strains (21,22,24,(28)(29)(30).…”

“…In NOD mice, the cumulative incidence at one year ranges from ~5% to ~15% (20,21). In both humans and mice, an iodine-rich diet accelerates the development of the disease (21,22). The iodide excess is toxic for thyroid cells by a mechanism involving oxidative stress (23).…”