Immunologic determinants of age-related macular degeneration

Icahn School Of Medicine At Mount Sinai, New York NY

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Abstract

? 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.