Interferon-gamma (IFN-γ)-mediated retinal ganglion cell death in human tyrosinase T cell receptor transgenic mouse.
Interferon-gamma (IFN-γ)-mediated retinal ganglion cell death in human tyrosinase T cell receptor transgenic mouse.
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DOI：
10.1371/journal.pone.0089392
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Mehrotra S
中科院分区：
文献类型：
--
作者：
Husain S;Abdul Y;Webster C;Chatterjee S;Kesarwani P;Mehrotra S
我们最近展示了带有 h3T-A2 转基因小鼠模型的人酪氨酸酶 TCR 的特征，该模型表现出自发性自身免疫性白癜风和视网膜功能障碍。当前研究的目的是利用该模型确定 T 细胞和 IFN-γ 在视网膜功能障碍和视网膜神经节细胞 (RGC) 死亡中的作用。 RGC 功能通过图案视网膜电图 (ERG) 来测量，以响应图案化视觉刺激的对比度反转。通过荧光金逆行标记使 RGC 可视化。通过免疫组织化学和蛋白质印迹法测量 CD3、IFN-γ、GFAP 和半胱天冬酶的表达。所有功能和结构变化均在 12 个月大的 h3T-A2 小鼠中进行测量，并与年龄匹配的 HLA-A2 野生型小鼠进行比较。与野生型小鼠相比，h3T-A2 小鼠的模式 ERG（42%，p = 0.03）和 RGC 数量（37%，p = 0.0001）均减少。 h3T-A2 小鼠中 CD3 表达水平增加（h3T-A2：174±27% vs. HLA-A2：100%；p = 0.04）。 h3T-A2 小鼠中效应细胞因子 IFN-γ 的水平也显着增加（h3T-A2：189±11% vs. HLA-A2：100%；p = 0.023）。 h3T-A2 小鼠的神经纤维 (NF) 和 RGC 层中 CD3 和 IFN-γ 免疫染色均增加。此外，我们还发现 h3T-A2 小鼠中 GFAP 染色显着增加（主要位于 NF 层），而 IFN-γ (-/-) 敲除 h3T-A2 小鼠中 GFAP 染色显着减少。我们还发现 h3T-A2 小鼠中 caspase-3 和 -9 上调。根据我们的数据，我们得出结论，h3T-A2 转基因小鼠表现出的视觉缺陷主要与视网膜内层和 RGC 功能有关。这种新型 h3T-A2 转基因小鼠模型提供了了解 RGC 病理学和测试拯救 RGC 的神经保护策略的机会。
We have recently demonstrated the characterization of human tyrosinase TCR bearing h3T-A2 transgenic mouse model, which exhibits spontaneous autoimmune vitiligo and retinal dysfunction. The purpose of current study was to determine the role of T cells and IFN-γ in retina dysfunction and retinal ganglion cell (RGC) death using this model. RGC function was measured by pattern electroretinograms (ERGs) in response to contrast reversal of patterned visual stimuli. RGCs were visualized by fluorogold retrograde-labeling. Expression of CD3, IFN-γ, GFAP, and caspases was measured by immunohistochemistry and Western blotting. All functional and structural changes were measured in 12-month-old h3T-A2 mice and compared with age-matched HLA-A2 wild-type mice. Both pattern-ERGs (42%, p = 0.03) and RGC numbers (37%, p = 0.0001) were reduced in h3T-A2 mice when compared with wild-type mice. The level of CD3 expression was increased in h3T-A2 mice (h3T-A2: 174±27% vs. HLA-A2: 100%; p = 0.04). The levels of effector cytokine IFN-γ were also increased significantly in h3T-A2 mice (h3T-A2: 189±11% vs. HLA-A2: 100%; p = 0.023). Both CD3 and IFN-γ immunostaining were increased in nerve fiber (NF) and RGC layers of h3T-A2 mice. In addition, we have seen a robust increase in GFAP staining in h3T-A2 mice (mainly localized to NF layer), which was substantially reduced in IFN-γ (-/-) knockout h3T-A2 mice. We also have seen an up-regulation of caspase-3 and -9 in h3T-A2 mice. Based on our data we conclude that h3T-A2 transgenic mice exhibit visual defects that are mostly associated with the inner retinal layers and RGC function. This novel h3T-A2 transgenic mouse model provides opportunity to understand RGC pathology and test neuroprotective strategies to rescue RGCs.
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