Immunologic Determinants of Age-Related Macular Degeneration (AMD)

项目总结 老年性黄斑变性(AMD)是导致视力损害和失明的主要原因 在美国，65岁的人是导致失明的第三大原因 全世界。有几条证据表明，免疫激活和炎症在 AMD的发病机制，包括全身炎症的生物标志物作为AMD的危险因素 老年性黄斑变性、补体沉积、补体和趋化因子的遗传多态性 AMD患者中AMD和循环活化单核细胞的危险因素。抗逆转录病毒 (抗逆转录病毒治疗)治疗、免疫恢复、艾滋病毒感染者的病情加重和加速 衰老，由年龄相关疾病引起的经年龄调整的寿命缩短，以及免疫系统 这种变化类似于70岁未感染艾滋病毒的人(免疫衰老)。 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患病率增加4倍，发病率增加1.75倍 而不是在未感染艾滋病毒的人群中看到的情况。来自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。超低温保存血液标本 LSOCA的炎症生物标志物和趋化因子将被评估为 AMD，采用嵌套病例对照设计和时间更新分析。血液生物标记物和 被评估的趋化因子将是那些已知对接受抗逆转录病毒治疗的艾滋病毒感染者有效的趋化因子。 而在未感染艾滋病毒的老年人中，重点是与单核细胞激活有关的那些。 在LSOCA队列中被确定为与AMD相关的生物标记物将在HIV- 使用来自年龄相关性眼病研究的冷冻标本的未感染者 (AREDS)队列。生物标记物和趋化因子水平与AMD风险基因相关 两组人群中均存在多态现象。一种基于发现的方法将被用于识别等离子体 LSOCA和AREDS队列中AMD的蛋白质组学危险因素。这些研究将导致 为了更好地理解炎症、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.