Schistosoma mansoni and α-Galactosylceramide: Prophylactic Effect of Th1 Immune Suppression in a Mouse Model of Graves’ Hyperthyroidism

Abstract

Graves’ hyperthyroidism, an organ-specific autoimmune disease mediated by stimulatory thyrotropin receptor (TSHR) autoantibodies, has been considered a Th2-dominant disease. However, recent data with mouse Graves’ models are conflicting. For example, we recently demonstrated that injection of BALB/c mice with adenovirus coding the TSHR induced Graves’ hyperthyroidism characterized by mixed Th1 and Th2 immune responses against the TSHR, and that transient coexpression of the Th2 cytokine IL-4 by adenovirus skewed Ag-specific immune response toward Th2 and suppressed disease induction. To gain further insight into the relationship between immune polarization and Graves’ disease, we evaluated the effect of Th2 immune polarization by helminth Schistosoma mansoni infection and α-galactosylceramide (α-GalCer), both known to bias the systemic immune response to Th2, on Graves’ disease. S. mansoni infection first induced mixed Th1 and Th2 immune responses to soluble worm Ags, followed by a Th2 response to soluble egg Ags. Prior infection with S. mansoni suppressed the Th1-type anti-TSHR immune response, as demonstrated by impaired Ag-specific IFN-γ secretion of splenocytes and decreased titers of IgG2a subclass anti-TSHR Abs, and also prevented disease development. Similarly, α-GalCer suppressed Ag-specific splenocyte secretion of IFN-γ and prevented disease induction. However, once the anti-TSHR immune response was fully induced, S. mansoni or α-GalCer was ineffective in curing disease. These data support the Th1 theory in Graves’ disease and indicate that suppression of the Th1-type immune response at the time of Ag priming may be crucial for inhibiting the pathogenic anti-TSHR immune response.

Graves’ disease and Hashimoto’s thyroiditis in monozygotic twins: case study as well as transcriptomic and immunohistological analysis of thyroid tissues

“…This chemokine, together with CCL21, enables migration of T-cells into secondary lymphoid tissues or, as in the case of thyroid tissue, into ectopic follicles. Moreover, we have confirmed recent data demonstrating higher expression of (27)). Moreover, older studies have investigated cytokine cDNAs in thyroids using RT-PCR, which enables detection of traces of cytokine mRNAs (28 -31).…”

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

“…This finding indicates that Graves' hyperthyroidism is an autoantibody-dependent but T helper type 1 (Th1)-mediated autoimmune disease. Our other studies, showing suppression of development of Graves' disease by Th2 polarization induced by parasite infection or IL4, support this notion (Nagayama et al , 2004b.…”

“…BALB/c) by repetitive immunizations with recombinant adenovirus expressing the human full-length TSHR or its A-subunit (Nagayama et al 2002, Chen et al 2003. 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).…”

Inhibition of type 1 diabetes in filaria‐infected non‐obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3+ regulatory T cells

“…Indeed, animal models of arthritis, 22 type I diabetes, [12][13][14]21,24 Graves hyperthyroidism, 25 experimental autoimmune encephalitis 15,26 and colitis [16][17][18] have all been inhibited or ameliorated by infections with helminth parasites or parasite-derived products. In this study, we found that infection with filarial helminths also protects against autoimmunity.…”