Abstract
Background: Graves' disease is associated with thyrotropin receptor (TSHR) antibodies of variable bioactivity. Recently, antibodies have been characterized that bind to the cleavage region of the TSHR ectodomain (C-TSHR-Ab), and their ability to induce thyroid cell apoptosis in vitro via excessive cell stress involving multiple organelles was demonstrated. Methods: To investigate the in vivo effects of C-TSHR-Ab, first a murine monoclonal antibody (mAb) directed against residues 337 to 356 of the TSHR cleavage region was developed, and then it was injected into mice. Results: These injections caused reduced serum total triiodothyronine and thyroxine and increased TSH levels compared to control mAb-injected mice. The C-TSHR-mAb induced histological evidence of endoplasmic reticulum stress, mitochondrial stress, and apoptosis in the thyroid glands. C-TSHR-mAb-mediated apoptosis was associated with cellular infiltrates consisting mostly of macrophages, dendritic cells, and neutrophils, while T- and B-lymphocytes were scarce. In addition, in the treated mouse thyroid tissue, hyper-citrullination of histone H3 was also found. This is known to occur via peptidylarginine deiminase 4 and plays an important role in the formation of neutrophil extracellular traps, which are likely to be partly responsible for thyroid infiltration, as seen in many autoimmune diseases. Examination of thyroid tissue from patients with Graves' disease also showed increased stress and some thyrocyte apoptosis compared to normal thyroid tissues. Conclusions: The fact that the C-TSHR-mAb induced accumulation of macrophages, neutrophils, and dendritic cells indicates that innate immunity plays a central role in shaping the adaptive immune response to the TSHR. In addition, this study provides further evidence that the hinge region of the TSHR ectodomain is intimately involved in the immune response in autoimmune thyroid disease.
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