Singh Amardeep
Department of Ophthalmology, Copenhagen University Hospital Roskilde, Køgevej 7-13, 4000 Roskilde, Denmark.
Dan Med J. 2014 Jun;61(6):B4872.
Age-related macular degeneration (AMD) is a leading cause of visual impairment in the aged population worldwide. The mechanisms underlying this multifactorial and heterogenic disease are complex and incompletely understood. There is increasing evidence to suggest that regulatory differences in the immune system are involved in the development of the various subtypes of AMD. The purpose of this thesis was to identify some of these potential differences in patients with early or late (wet, dry, or fibrotic) AMD. Specifically, we sought to determine differences in 1) expression of regulators of the complement pathway (CD46, CD55, and CD59) on circulating leukocytes; 2) expression of microglia-inhibitory proteins (CD200 and CD200R) on circulating leukocytes; and 3) plasma concentrations of 25-hydroxyvitamin D, a factor known to inhibit angiogenesis, fibrosis, inflammation, and oxidation. All participants underwent a semi-structured interview and detailed retinal imaging. Fresh venous blood was obtained and the frequency of cells expressing the proteins in question was determined using flow cytometry. Plasma 25-hydroxyvitamin D was measured using liquid chromatography-tandem mass spectrometry. Also, genotyping as performed in order to determine the frequency of certain single-nucleotide polymorphisms in the vitamin D metabolism. Patients with wet AMD were found to have statistically significant lower frequencies of CD46 and CD59 on CD14+monocytes and higher frequencies of CD200 on CD11b+ monocytes compared to control individuals without AMD (p = 0.0070 and p = 0.047, respectively). Moreover, we found a lower frequency of CD46 on CD45+lymphocytes in patients with wet AMD and subretinal fibrosis compared to patients with wet AMD without fibrosis (p = 0.010). Vitamin D status was not different across AMD subgroups; however, the presence of subretinal fibrosis in patients with wet AMD was associated with a statistically significant lower concentration of 25-hydroxyvitamin D (p < 0.001). Our results suggest that inadequate systemic immune modulation is an important pathogenic mechanism in the aetiology of AMD. Moreover, some differences in protein expression and vitamin D status appear to be related to the phenotypical diversity of AMD, proposing that different mechanisms may underlie the different subtypes of AMD.
年龄相关性黄斑变性（AMD）是全球老年人群视力损害的主要原因。这种多因素且异质性疾病的潜在机制复杂，尚未完全明确。越来越多的证据表明，免疫系统的调节差异参与了AMD不同亚型的发生发展。本论文的目的是确定早期或晚期（湿性、干性或纤维化型）AMD患者中一些潜在的差异。具体而言，我们试图确定：1）循环白细胞上补体途径调节因子（CD46、CD55和CD59）的表达差异；2）循环白细胞上小胶质细胞抑制蛋白（CD200和CD200R）的表达差异；3）25-羟基维生素D的血浆浓度差异，25-羟基维生素D是一种已知可抑制血管生成、纤维化、炎症和氧化的因子。所有参与者均接受了半结构化访谈和详细的视网膜成像检查。采集新鲜静脉血，使用流式细胞术确定表达相关蛋白的细胞频率。采用液相色谱-串联质谱法测定血浆25-羟基维生素D。此外，进行基因分型以确定维生素D代谢中某些单核苷酸多态性的频率。与无AMD的对照个体相比，湿性AMD患者CD14+单核细胞上CD46和CD59的频率在统计学上显著降低，而CD11b+单核细胞上CD200的频率更高（分别为p = 0.0070和p = 0.047）。此外，与无纤维化的湿性AMD患者相比，伴有视网膜下纤维化的湿性AMD患者CD45+淋巴细胞上CD46的频率更低（p = 0.010）。AMD各亚组的维生素D状态无差异；然而，湿性AMD患者视网膜下纤维化的存在与25-羟基维生素D浓度在统计学上显著降低相关（p < 0.001）。我们的结果表明，全身免疫调节不足是AMD病因中的一个重要致病机制。此外，蛋白表达和维生素D状态的一些差异似乎与AMD的表型多样性有关，提示不同的机制可能是AMD不同亚型的基础。
