TSH receptor-adenovirus-induced Graves’ hyperthyroidism is attenuated in both interferon-γand interleukin-4 knockout mice; implications for the Th1/Th2 paradigm

Abstract

SUMMARYThe role of the Th1/Th2 balance in the pathogenesis of murine Graves' hyperthyroidism is controversial. In BALB/c mice injected with adenovirus expressing TSH receptor (TSHR-adeno model), we found that suppression of TSHR-specific Th1 immune responses by exogenous interleukin-4 (IL-4), agalactosylceramide or helminth ( Schistosoma mansoni ) infection was associated with inhibition of hyperthyroidism, indicating the critical role for Th1 cytokines. In contrast, BALB/c IL-4 knockout (KO), but not interferon-g (IFN-g ) KO mice failed to develop Graves' hyperthyroidism when injected with TSHR-expressing M12 B lymphoma cells (TSHR-M12 model), suggesting the importance of Th2 cytokine IL-4. To reconcile differences in these two models, we used IL-4 KO and IFN-g KO BALB/c mice in the TSHR-adeno model. Unlike wild-type (wt) BALB/c mice in which 60% developed hyperthyroidism, only 13 and 7% of IL-4 KO and IFN-g KO mice, respectively, became hyperthyroid. Thyroid stimulating antibodies were positive in most hyperthyroid mice. TSHR antibody titres determined by TSH binding inhibition and ELISA were comparable in all three groups. IgG1 and IgG2a TSHR antibody titres were similar in IFN-g KO and wt mice, whereas IgG1 TSHR antibody titres and TSHRspecific splenocyte IFN-g secretion were lower in IL-4 KO than in IFN-g KO and wt mice, respectively. Our results clearly implicate both IFN-g and IL-4 in development of hyperthyroidism in the TSHRadeno model. These data, together with the previous report, also indicate different cytokine requirements in these two Graves' models, with IFN-g being more important in the TSHR-adeno than the TSHR-M12 model. Moreover, our previous and present observations indicate a difference in the role of exogenous versus endogenous IL-4 in TSHR-adenovirus induced Graves' hyperthyroidism.

Interleukin 10 deficiency attenuates induction of anti-TSH receptor antibodies and hyperthyroidism in a mouse Graves' model

“…For example, mice genetically deficient for a certain cytokine are useful for this purpose. Indeed the experiments with mice deficient for IFN-g (a Th1 cytokine) or IL17 (a Th17 cytokine) have revealed a critical role played by IFN-g, but not IL17, in developing experimental Graves' hyperthyroidism in a susceptible BALB/c mice (Nagayama et al 2004a, Horie et al 2010. This study identified IL10 as another important cytokine for the pathogenesis of Graves' disease in mice.…”

“…Although the reason(s) for this difference is unclear, it is not surprising that the pharmacological levels of exogenous IL10 and the physiological levels of endogenous IL10 have distinct functions, as we have previously shown for IL4 (Nagayama et al , 2004a.…”

“…In these models, an in vitro T cell recall assay demonstrates the antigen-specific secretions of interferon (IFN)-g and interleukin (IL) 10 from splenocytes of immunized BALB/c mice (Nagayama et al 2004b, Saitoh et al 2007, suggesting the importance of these two cytokines in the disease pathogenesis. Indeed our previous study clearly demonstrates the resistance of IFN-g deficient BALB/c mice to induction of Graves' hyperthyroidism (Nagayama et al 2004a). This finding indicates that Graves' hyperthyroidism is an autoantibody-dependent but T helper type 1 (Th1)-mediated autoimmune disease.…”

Association between Helicobacter pylori Infection and Graves’ Disease: A Meta-Analysis

“…Moreover, the background of H. pylori prevalence influences the positive predictive value (PPV) of this method, as discussed in the study by Soveid in Iran. [15][16][17][18][19][20][21][22] We found no significant association between H. pylori seropositivity and Graves' disease in this subgroup, as shown by the pooled OR of 3 studies using serology method, and moderate heterogeneity. In contrary, the association was statistically significant in the non-serology method subgroup with 0% of heterogeneity.…”

Thyroid Status and Its Correlation With the Functional Activity of Immunocytes

“…В результате эксперимента было также доказано, что доста-точно кратковременное изменение уровня ТГ со-провождается дисбалансом в концентрации ос-новных предикторов амплификации иммунного ответа. Зафиксированная динамика может сви-детельствовать о ключевой роли ТГ в сохранении баланса Th1-/Th2-и Тreg-цитокинов, т. к. сдвиг уровня сывороточных оппозитных цитокинов был ответом на изменение тиреоидного статуса, что не противоречит результатам предшествую-щих исследований [14].…”