Immunologic Determinants of Age-Related Macular Degeneration

 描述（由申请人提供）：视网膜相关性黄斑变性（AMD）是美国65岁以上人群视力受损和失明的主要原因，也是全球第三大致盲原因。几条证据表明免疫激活和炎症参与了AMD的发病机制，包括作为AMD风险因素的全身性炎症生物标志物、作为AMD风险因素的玻璃疣中补体沉积、补体因子和趋化因子遗传多态性以及AMD患者中循环活化的单核细胞。抗逆转录病毒（ART）治疗，免疫储备，艾滋病毒感染的患者加速/加剧衰老和缩短寿命由于年龄相关的疾病，如心血管疾病，中风和糖尿病。免疫恢复的HIV感染者具有与>70岁的HIV未感染者相似的免疫系统变化，称为免疫衰老。来自AIDS眼部并发症纵向研究（LSOCA）队列的入组数据显示，中期AMD的患病率（患病率约10%）是年龄匹配的未感染HIV队列的4倍。LSOCA已经招募了2092名患有AIDS的参与者，从招募和每6个月的随访访问开始，在标本库中保存了医疗和治疗数据、冷冻保存的血浆和血液白细胞标本，并且具有5年和10年随访视网膜照片的档案，这些照片将在阅读中心对事件AMD进行分级。将使用巢式病例对照设计评价冷冻保存的血液标本的炎症、免疫（特别是单核细胞）激活和免疫衰老标志物的证据，这些证据是流行性和偶发性AMD的风险因素。途径和标志物将是那些已知在接受抗逆转录病毒疗法治疗的艾滋病毒感染者和未感染艾滋病毒的老年人中起作用的途径和标志物。将在来自AMD相关眼病研究（AREDS）队列的冷冻保存标本中评价LSOCA队列中确定为与AMD相关的生物标志物和途径。这些研究将有助于我们更好地理解炎症、免疫激活和免疫衰老在AMD发病机制中的作用。

 DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the major cause of visual impairment and blindness in persons > 65 years in the United States and the 3rd leading cause of blindness worldwide. Several lines of evidence have implicated immune activation and inflammation in the pathogenesis of AMD, including biomarkers of systemic inflammation as risk factors for AMD, complement deposition in drusen, complement factor and chemokine genetic polymorphisms as risk factors for AMD, and circulating activated monocytes in patients with AMD. Antiretroviral (ART) -treated, immunorestored, HIV-infected patients have accelerated/accentuated aging and a shortened life span due to age-related diseases, such as cardiovascular disease, stroke, and diabetes. Immunorestored, HIV-infected persons have immune system changes similar to those of >70 year-old HIV- uninfected persons, known as immunosenescence. Enrollment data from the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) cohort show a ~4-fold greater prevalence (prevalence ~10%) of intermediate- stage AMD vs. that seen in an age-matched, HIV-uninfected cohort. LSOCA has enrolled 2092 participants with AIDS, has medical and treatment data, cryopreserved plasma and blood leukocyte specimens in a specimen repository from enrollment and every-6-month follow-up visits, and has an archive of 5- and 10-year follow-up retinal photographs, which will be graded at a Reading Center for incident AMD. Cryopreserved blood specimens will be evaluated for evidence of inflammation, immune (particularly monocyte) activation, and immunosenescence markers as risk factors for both prevalent and incident AMD, using a nested case-control design. Pathways and markers will be those known to be operative in both ART-treated, HIV infected persons, and in HIV-uninfected older persons. Biomarkers and pathways identified as relevant to AMD in the LSOCA cohort will be evaluated in cryopreserved specimens from the Age-Related Eye Disease Study (AREDS) cohort. These studies will lead to an improved understanding of the roles of inflammation, immune activation, and immunosenescence in the pathogenesis of AMD.