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Abstract：
UNASSIGNED: A single-nucleotide polymorphism in HTRA1 has been linked to age-related macular degeneration (AMD). Here we investigated the potential links between age-related retinal changes, elastin turnover, elastin autoantibody production, and complement C3 deposition in a mouse model with RPE-specific human HTRA1 overexpression.
UNASSIGNED: HTRA1 transgenic mice and age-matched CD1 wild-type mice were analyzed at 6 weeks and 4, 6, and 12 to 14 months of age using in vivo retinal imaging by optical coherence tomography (OCT) and fundus photography, as well as molecular readouts, focusing on elastin and elastin-derived peptide quantification, antielastin autoantibody, and total Ig antibody measurements and immunohistochemistry to examine elastin, IgG, and C3 protein levels in retinal sections.
UNASSIGNED: OCT imaging indicated thinning of inner nuclear layer as an early phenotype in HTRA1 mice, followed by age and age/genotype-related thinning of the photoreceptor layer, RPE, and total retina. HTRA1 mice exhibited reduced elastin protein levels in the RPE/choroid and increased elastin breakdown products in the retina and serum. A corresponding age-dependent increase of serum antielastin IgG and IgM autoantibodies and total Ig antibody levels was observed. In the RPE/choroid, these changes were associated with an age-related increase of IgG and C3 deposition.
UNASSIGNED: Our results confirm that RPE-specific overexpression of human HTRA1 induces certain AMD-like phenotypes in mice. This includes altered elastin turnover, immune response, and complement deposition in the RPE/choroid in addition to age-related outer retinal and photoreceptor layer thinning. The identification of elastin-derived peptides and corresponding antielastin autoantibodies, together with increased C3 deposition in the RPE/choroid, provides a rationale for an overactive complement system in AMD irrespective of the underlying genetic risk.
UNASSIGNED: HTRA1 transgenic mice and age-matched CD1 wild-type mice were analyzed at 6 weeks and 4, 6, and 12 to 14 months of age using in vivo retinal imaging by optical coherence tomography (OCT) and fundus photography, as well as molecular readouts, focusing on elastin and elastin-derived peptide quantification, antielastin autoantibody, and total Ig antibody measurements and immunohistochemistry to examine elastin, IgG, and C3 protein levels in retinal sections.
UNASSIGNED: OCT imaging indicated thinning of inner nuclear layer as an early phenotype in HTRA1 mice, followed by age and age/genotype-related thinning of the photoreceptor layer, RPE, and total retina. HTRA1 mice exhibited reduced elastin protein levels in the RPE/choroid and increased elastin breakdown products in the retina and serum. A corresponding age-dependent increase of serum antielastin IgG and IgM autoantibodies and total Ig antibody levels was observed. In the RPE/choroid, these changes were associated with an age-related increase of IgG and C3 deposition.
UNASSIGNED: Our results confirm that RPE-specific overexpression of human HTRA1 induces certain AMD-like phenotypes in mice. This includes altered elastin turnover, immune response, and complement deposition in the RPE/choroid in addition to age-related outer retinal and photoreceptor layer thinning. The identification of elastin-derived peptides and corresponding antielastin autoantibodies, together with increased C3 deposition in the RPE/choroid, provides a rationale for an overactive complement system in AMD irrespective of the underlying genetic risk.
摘要：
■HTRA1的单核苷酸多态性与年龄相关性黄斑变性（AMD）有关。在这里，我们调查了与年龄相关的视网膜变化之间的潜在联系，弹性蛋白周转率,弹性蛋白自身抗体生产，在具有RPE特异性人HTRA1过表达的小鼠模型中和补体C3沉积。
■HTRA1转基因小鼠和年龄匹配的CD1野生型小鼠在6周龄和4、6和12至14月龄时使用光学相干断层扫描（OCT）和眼底摄影进行体内视网膜成像分析，以及分子读数，专注于弹性蛋白和弹性蛋白衍生的肽定量，抗弹性蛋白自身抗体，和总Ig抗体测量和免疫组织化学检查弹性蛋白，IgG,视网膜切片中的C3蛋白水平。
■OCT成像显示内核层变薄是HTRA1小鼠的早期表型，其次是年龄和年龄/基因型相关的感光层变薄，RPE,和总视网膜。HTRA1小鼠显示RPE/脉络膜中弹性蛋白水平降低，视网膜和血清中弹性蛋白分解产物增加。观察到血清抗弹性蛋白IgG和IgM自身抗体以及总Ig抗体水平的相应年龄依赖性增加。在RPE/脉络膜中，这些变化与年龄相关的IgG和C3沉积增加相关.
■我们的结果证实人HTRA1的RPE特异性过表达在小鼠中诱导某些AMD样表型。这包括改变的弹性蛋白周转，免疫反应，RPE/脉络膜中的补体沉积以及与年龄相关的外视网膜和感光层变薄。弹性蛋白衍生肽和相应的抗弹性蛋白自身抗体的鉴定，随着RPE/脉络膜中C3沉积的增加，无论潜在的遗传风险如何，都提供了AMD中补体系统过度活跃的理由。
■HTRA1转基因小鼠和年龄匹配的CD1野生型小鼠在6周龄和4、6和12至14月龄时使用光学相干断层扫描（OCT）和眼底摄影进行体内视网膜成像分析，以及分子读数，专注于弹性蛋白和弹性蛋白衍生的肽定量，抗弹性蛋白自身抗体，和总Ig抗体测量和免疫组织化学检查弹性蛋白，IgG,视网膜切片中的C3蛋白水平。
■OCT成像显示内核层变薄是HTRA1小鼠的早期表型，其次是年龄和年龄/基因型相关的感光层变薄，RPE,和总视网膜。HTRA1小鼠显示RPE/脉络膜中弹性蛋白水平降低，视网膜和血清中弹性蛋白分解产物增加。观察到血清抗弹性蛋白IgG和IgM自身抗体以及总Ig抗体水平的相应年龄依赖性增加。在RPE/脉络膜中，这些变化与年龄相关的IgG和C3沉积增加相关.
■我们的结果证实人HTRA1的RPE特异性过表达在小鼠中诱导某些AMD样表型。这包括改变的弹性蛋白周转，免疫反应，RPE/脉络膜中的补体沉积以及与年龄相关的外视网膜和感光层变薄。弹性蛋白衍生肽和相应的抗弹性蛋白自身抗体的鉴定，随着RPE/脉络膜中C3沉积的增加，无论潜在的遗传风险如何，都提供了AMD中补体系统过度活跃的理由。
