Depletion of CD4+CD25+ regulatory T cells exacerbates sodium iodide-induced experimental autoimmune thyroiditis in human leucocyte antigen DR3 (DRB1*0301) transgenic class II-knock-out non-obese diabetic mice

Abstract

Both genetic and environmental factors contribute to autoimmune disease development. Previously, we evaluated genetic factors in a humanized mouse model of Hashimoto's thyroiditis (HT) by immunizing human leucocyte antigen DR3 (HLA-DR3) and HLA-DQ8 transgenic class II-knock-out non-obese diabetic (NOD) mice. DR3+ mice were susceptible to experimental autoimmune thyroiditis (EAT) induction by both mouse thyroglobulin (mTg) and human (h) Tg, while DQ8+ mice were weakly susceptible only to hTg. As one environmental factor associated with HT and tested in non-transgenic models is increased sodium iodide (NaI) intake, we examined the susceptibility of DR3+ and/or DQ8+ mice to NaI-induced disease. Mice were treated for 8 weeks with NaI in the drinking water. At 0 x 05% NaI, 23% of DR3+, 0% of DQ8+ and 20% of DR3+DQ8+ mice had thyroid destruction. No spleen cell proliferation to mTg was observed. Most mice had undetectable anti-mTg antibodies, but those with low antibody levels usually had thyroiditis. At 0.3% NaI, a higher percentage of DR3+ and DR3+DQ8+ mice developed destructive thyroiditis, but it was not statistically significant. However, when DR3+ mice had been depleted of CD4+CD25+ regulatory T cells prior to NaI treatment, destructive thyroiditis (68%) and serum anti-mTg antibodies were exacerbated further. The presence of DQ8 molecules does not alter the susceptibility of DR3+DQ8+ mice to NaI-induced thyroiditis, similar to earlier findings with mTg-induced EAT. Susceptibility of DR3+ mice to NaI-induced EAT, in both the presence and absence of regulatory T cells, demonstrates the usefulness of HLA class II transgenic mice in evaluating the roles of environmental factors and immune dysregulation in autoimmune thyroid disease.

T Helper Type 17 Immune Response Plays an Indispensable Role for Development of Iodine-Induced Autoimmune Thyroiditis in Nonobese Diabetic-H2h4 Mice

“…This is presumably due to extremely low frequency of Tg-specific T eff in NOD-H2 h4 mice, although anti-Tg autoantibodies were readily detected as demonstrated above, but not due to a matter of antigenicity of Tg, although iodination of Tg has been reported to enhance its antigenicity (30). Fynn et al (31) also observed no T cell proliferation to Tg in DR3 transgenic class II-knockout NOD mice. Furthermore, similar data have been reported in NOD mice; detection of insulin-specific T cell response has been reported to be difficult in the mice, despite clear elevation of antiinsulin autoantibodies in their sera (32).…”

CD4+CD25+ naturally occurring regulatory T cells and not lymphopenia play a role in the pathogenesis of iodide-induced autoimmune thyroiditis in NOD-H2h4 mice

“…Consequently, as we predicted, the timing of depletion prior to increased dietary iodide appears to be a critical factor for CD4 þ CD25 þ Treg to exert their suppressor function. While we nearly completed the present study, Flynn et al [27] published an article showing exacerbation of iodide-induced thyroiditis in a different mice (human DR3 transgenic class II-knock out NOD mice) by injecting anti-CD25 antibody 2 and 1.5 weeks before starting NaI water (the shorter time lapse than that in the study of Yu et al [18]). …”

Risk factors and pathogenesis of Hashimoto’s thyroiditis

“…Tai patvirtina nuomonę, kad HLA-DRB1 polimorfizmas lemia jautrumą autoimuniniam tiroiditui. Be to, šio gyvūno modelio metu pastebėta, kad padidintas jodo kiekis maiste paspartina skydliaukės ligos susiformavimą, o CD4+, CD25+ T ląstelių stygius sunkina jodo sukeltą tiroidito eigą (10). Dar vieno naujo tyrimo metu tyrėjai pastebėjo, kad nekrotizavusios skydliaukės folikulų epitelinės ląstelės gali sukelti dendritinių ląstelių subrendimą in vitro, po to šias dendritines ląsteles sušvirkštus atgal autologinėms pelėms, sukeliamas eksperimentinis autoimuninis tiroiditas, kurio metu būna limfocitinė skydliaukės infiltracija ir nustatoma tiroglobulinui specifinių imunoglobulinų G (11).…”