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Differential Requirement of Signal Transducer and Activator of Transcription-4 (Stat4) and Stat6 in a Thyrotropin Receptor-289-Adenovirus-Induced Model of Graves’ Hyperthyroidism

Department of Biochemistry and Molecular Biology, Indiana University School of Medicine (K.J.L., P.G., G.S.S.), Evansville, Indiana 47712; and Department of Microbiology and Immunology, Walther Oncology Center, Indiana University School of Medicine (M.H.K.), Indianapolis, Indiana 46202

Address all correspondence and requests for reprints to: Dr. Gattadahalli S. Seetharamaiah, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 8600 University Boulevard, Evansville, Indiana 47712. E-mail: seethara{at}iupui.edu.

T helper type 1 (Th1) and Th2 cells have critical roles in the development of cell-mediated and humoral immune responses, respectively. This division of function predicts that Th1 cells mediate inflammatory diseases and Th2 cells promote antibody (Ab)-mediated autoimmunity. Our previous studies using HEK-293 cells expressing the extracellular domain of the TSH receptor (TSHR) showed that Stat4^–/– mice, which lack Th1 cells, are susceptible, whereas Stat6^–/– mice, which lack Th2 cells, are resistant to the induction of Graves’ hyperthyroidism. To investigate the role of Stat4 and Stat6 genes in other murine models of hyperthyroidism, we injected wild-type BALB/c, Stat4^–/–, and Stat6^–/– mice with an adenovirus expressing amino acid residues 1–289 of TSHR (TSHR-289-ad or 289-ad). The viral system induces a much stronger immune response with much more rapid onset of disease. Our results showed that 56% of wild-type, 75% of Stat4^–/–, and 39% of Stat6^–/– mice developed hyperthyroidism. Hyperthyroid mice exhibited thyroid stimulatory Abs. The Stat4^–/– mice developed a higher incidence and greater severity of hyperthyroidism compared with wild-type and Stat6^–/– mice. BALB/c and Stat4^–/– mice showed significantly higher TSHR Abs of the IgG1 subclass and IL-4 compared with Stat6^–/– mice. In contrast, Stat6^–/– mice had predominantly the IgG2a subclass of TSHR Ab and produced significantly higher amounts of IFN- than BALB/c and Stat4^–/– mice. All hyperthyroid mice showed enlarged thyroid glands with hyperactivity. These results suggest that in the TSHR-289-ad model, the Th2 cells are more efficient in mediating disease, but in the absence of Th2 cells, Th1 cells may still initiate a reduced incidence of Graves’ hyperthyroidism.

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