CD40 plays an important role in the pathogenesis of Graves' disease (GD). Inhibition of CD40 expression may be a promising treatment for GD. In this study, we used an animal model to investigate whether lentivirus expressing siRNA for CD40 (LV-CD40-siRNA) could be useful for the therapy of GD. BALB/c mice were injected with PBS alone (PBS group), negative lentivirus (control siRNA group), or LV-CD40-siRNA (CD40 siRNA group), 3 days before being treated with adenovirus expressing human TSHR A subunit (Ad-TSHR289) three times at 3-week intervals to induce GD model. Sera thyroxine (T4) levels were assayed by RIA. The expression of CD40 was detected at the mRNA level by real-time PCR and protein level by flow cytometry. The expression of CD40, CD80, and CD86 was significantly decreased in the CD40 siRNA group (P<0.05), while FOXP3 expression was increased compared to the control siRNA group (P=0.05). Mean T4 levels were decreased 14% in the CD40 siRNA group compared to the control siRNA group. The rate of disease induction was similar among the three groups injected with Ad-TSHR289. LV-CD40-siRNA is a useful tool to inhibit the expression of CD40 in vivo, but it cannot decrease the incidence of hyperthyroidism in a limited period of time.
Feng Ye, Bingyin Shi, Xiaoyan Wu, Peng Hou, Lei Gao, Xiaodan Ma, Li Xu and Liping Wu
Y Wang, L P Wu, J Fu, H J Lv, X Y Guan, L Xu, P Chen, C Q Gao, P Hou, M J Ji and B Y Shi
Graves' disease (GD) is a common organ-specific autoimmune disease with the prevalence between 0.5 and 2% in women. Several lines of evidence indicate that the shed A-subunit rather than the full-length thyrotropin receptor (TSHR) is the autoantigen that triggers autoimmunity and leads to hyperthyroidism. We have for the first time induced GD in female rhesus monkeys, which exhibit greater similarity to patients with GD than previous rodent models. After final immunization, the monkeys injected with adenovirus expressing the A-subunit of TSHR (A-sub-Ad) showed some characteristics of GD. When compared with controls, all the test monkeys had significantly higher TSHR antibody levels, half of them had increased total thyroxine (T4) and free T4, and 50% developed goiter. To better understand the underlying mechanisms, quantitative studies on subpopulations of CD4+T helper cells were carried out. The data indicated that this GD model involved a mixed Th1 and Th2 response. Declined Treg proportions and increased Th17:Treg ratio are also observed. Our rhesus monkey model successfully mimicked GD in humans in many aspects. It would be a useful tool for furthering our understanding of the pathogenesis of GD and would potentially shorten the distance toward the prevention and treatment of this disease in human.
Sisi Luan, Wenkai Bi, Shulong Shi, Li Peng, Zhanbin Li, Jie Jiang, Ling Gao, Yifeng Du, Xu Hou, Zhao He and Jiajun Zhao
Subclinical hyperthyroidism, a condition characterized by decreased thyroid-stimulating hormone (TSH) and normal concentration of thyroid hormone, is associated with an elevated risk for cognitive impairment. TSH is the major endogenous ligand of the TSH receptor (TSHR) and its role is dependent on signal transduction of TSHR. It has not, however, been established whether TSHR signaling is involved in the regulation of cognition. Here, we utilized Tshr knockout mice and found that Tshr deletion led to significantly compromised performance in learning and memory tests. Reduced dendritic spine density and excitatory synaptic density as well as altered synaptic structure in CA1 subfield of the hippocampus were also noted. Furthermore, the synapse-related gene expression was altered in the hippocampus of Tshr -/- mice. These findings suggest that TSHR signaling deficiency impairs spatial learning and memory, which discloses a novel role of TSHR signaling in brain function.