Immunologic Determinants of Age-Related Macular Degeneration (AMD)

项目摘要 视网膜相关性黄斑变性（AMD）是导致视力损害和失明的主要原因 在美国，65岁以上的人群中，是第三大致盲原因 国际吧有几条证据表明，免疫激活和炎症在 AMD的发病机制，包括全身性炎症的生物标志物作为AMD的危险因素， AMD，玻璃疣中的补体沉积，补体和趋化因子遗传多态性， AMD患者中AMD和循环活化单核细胞的危险因素。抗病毒 接受抗逆转录病毒疗法（ART）治疗、免疫力恢复的艾滋病毒感染者的死亡率 衰老，由于年龄相关疾病而导致的年龄调整寿命缩短，以及免疫系统 与70岁以上未感染艾滋病毒的人（免疫衰老）相似的变化。 来自艾滋病眼部并发症纵向研究（LSOCA）队列的数据显示， 中期AMD的患病率增加约4倍，发病率增加1.75倍 vs.在未感染艾滋病毒的人群中所见。LSOCA的初步数据表明，单核细胞 活化和全身炎症是AMD的危险因素。冻存血液标本 将评估来自LSOCA的炎症生物标志物和趋化因子作为 AMD，采用巢式病例对照设计和时间更新分析。血液生物标志物和 评价的趋化因子是那些已知在ART治疗的HIV感染者中有效的趋化因子 以及未感染艾滋病毒的老年人，重点关注与单核细胞活化有关的问题。 在LSOCA队列中鉴定为与AMD相关的生物标志物将在HIV-1中进行评价。 未感染者使用来自眼科相关眼病研究的冷冻保存标本 （AREDS）队列。生物标志物和趋化因子水平将与AMD风险基因相关 两个队列中的多态性。将使用基于发现的方法来识别血浆 LSOCA和AREDS队列中AMD的蛋白质组学风险因素。这些研究将导致 更好地理解炎症、免疫激活和免疫- 衰老在AMD发病机制和衰老生物学中的作用。

PROJECT SUMMARY Age-related macular degeneration (AMD) is the major cause of visual impairment and blindness in persons >65 years of age in the United States and the 3rd leading cause of blindness worldwide. Several lines of evidence implicate immune activation and inflammation in the pathogenesis of AMD, including biomarkers of systemic inflammation as risk factors for AMD, complement deposition in drusen, complement and chemokine genetic polymorphisms as risk factors for AMD and circulating activated monocytes in patients with AMD. Antiretroviral (ART)-treated, immune-restored, HIV-infected persons have accentuated and accelerated aging, an age-adjusted shortened lifespan due to age-related diseases, and immune system changes similar to those seen in >70 year-old HIV-uninfected persons (immunosenescence). Data from the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) cohort show an ~4-fold increased prevalence and a 1.75-fold increased incidence of intermediate-stage AMD vs. that seen in HIV-uninfected cohorts. Preliminary data from LSOCA suggest that monocyte activation and systemic inflammation are risk factors for AMD. Cryopreserved blood specimens from LSOCA will be evaluated for inflammatory biomarkers and chemokines as risk factors for AMD, using nested case-control design and time-updated analyses. Blood biomarkers and chemokines evaluated will be those known to be operative in ART-treated, HIV-infected persons and in HIV-uninfected older persons focusing on those related to monocyte activation. Biomarkers identified as relevant to AMD in the LSOCA cohort will be evaluated in HIV- uninfected persons using cryopreserved specimens from the Age-Related Eye Disease Study (AREDS) cohort. Levels of biomarkers and chemokines will be correlated with AMD risk gene polymorphisms in both cohorts. A discovery-based approach will be used to identify plasma proteomic risk factors for AMD in both the LSOCA and AREDS cohorts. These studies will lead to an improved understanding of the roles of inflammation, immune activation, and immune- senescence in the pathogenesis of AMD and of the biology of aging.