Drusen associated with aging and age‐related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease

Abstract

Age‐related macular degeneration (AMD), a blinding disorder that compromises central vision, is characterized by the accumulation of extracellular deposits, termed drusen, between the retinal pigmented epithelium and the choroid. Recent studies in this laboratory revealed that vitronectin is a major component of drusen. Because vitronectin is also a constituent of abnormal deposits associated with a variety of diseases, drusen from human donor eyes were examined for compositional similarities with other extracellular disease deposits. Thirty‐four antibodies to 29 different proteins or protein complexes were tested for immunoreactivity with hard and soft drusen phenotypes. These analyses provide a partial profile of the molecular composition of drusen. Serum amyloid P component, apolipoprotein E, immunoglobulin light chains, Factor X, and complement proteins (C5 and C5b‐9 complex) were identified in all drusen phenotypes. Transcripts encoding some of these molecules were also found to be synthesized by the retina, retinal pigmented epithelium, and/or choroid. The compositional similarity between drusen and other disease deposits may be significant in view of the recently established correlation between AMD and atherosclerosis. This study suggests that similar pathways may be involved in the etiologies of AMD and other age‐related diseases.—Mullins, R. F., Russell, S. R., Anderson, D. H., Hageman, G. S. Drusen associated with aging and age‐related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J. 14, 835–846 (2000)

Vascular endothelial growth factor in eye disease

“…Complement factors 3 and 5 (Mullins et al, 2000;Johnson et al, 2000), as well as fragments C3a and C5a, have been reported as important in AMD and in laser-induced CNV (Nozaki et al, 2006). C3a and C5a caused upregulation of VEGF in RPE in vitro and in vivo (Nozaki et al, 2006).…”

Common coding variants in the HLA-DQB1 region confer susceptibility to age-related macular degeneration

“…[5][6][7][8][9][10][11] The human leukocyte antigen (HLA) region on chromosome 6p21.31 encodes gene products that regulate immune response. Drusen, a pathologic hallmark of AMD, contain HLA class II antigens, 12 and increased HLA class II immunoreactivity has been associated with drusen formation, 13 suggesting that HLA may influence the development of AMD. Although a few small candidate gene studies found that certain HLA class I and class II polymorphisms were associated with a predisposition to AMD, 14,15 the largest genome-wide association study (GWAS) meta-analysis conducted by the AMD Gene Consortium, which included more than 77 000 subjects, did not identify any HLA polymorphisms that were independently associated with the risk of AMD.…”

The complement system and age-related macular degeneration

“…[4][5][6] Immune mechanism and cellular interactions in AMD are similar to those seen in other diseases characterised by the accumulation of extracellular deposits such as atherosclerosis and Alzheimer's disease. 7 Evidence is growing that the complement system may play a significant role in the pathogenesis of AMD. Inflammatory and immune-mediated events involving complement proteins have been implicated in the biogenesis of drusen.…”