Autoimmune Responses and Immune Mediators Induced by Cytosolic DNA Fragments in Graves’ Disease

Abstract

Graves’ hyperthyroidism is caused by autoantibodies against the thyroid-stimulating hormone receptor (TSHR) that mimic the action of thyroid-stimulating hormone. The establishment of Graves’ hyperthyroidism in experimental animals is an important approach for investigating the mechanisms of self-tolerance breakdown that lead to the production of thyroid-stimulating TSHR autoantibodies. Shimojo’s model was the first successful Graves’ animal model, generated using AKR/N (H-2^k) mice. This model highlights the importance of coincident major histocompatibility complex (MHC) class II expression in TSHR-expressing cells in the development of Graves’ hyperthyroidism. We found that cytosolic self-genomic DNA fragments obtained from sterile injured cells can induce abnormal MHC class II expression as well as the production of numerous inflammatory cytokines and chemokines in thyrocytes in vitro, implying that severe cell injury can initiate immune responses related to thyroid autoimmunity and mediated by cytosolic DNA signalling. In vivo and in vitro studies suggest that induction of antigen-processing and -presenting genes, including MHC molecules, could be evoked, at least in part, by the type I interferon (IFN) or IFN-\(\gamma\) signaling pathway. Furthermore, successful Graves’ animal models have been established primarily by immunizing mice with TSHR-expressing plasmids or adenoviruses. In these models, double-stranded DNA vaccines presumably exert similar immune-activating effects in cells at the inoculation site. This chapter focuses on evidence suggesting that cell injury-derived self-DNA fragments act as a trigger of Graves’ disease and discusses the potential molecular mechanisms by which cytosolic dsDNA can induce MHC molecules.