Histological changes Among the early hallmarks of AMD are drusen, which are complex deposits of lipids, proteins, glycopro-teins, and glycosaminoglycans that accumulate in the extracellular and inner aspects of Bruch's membrane (Anderson et al., 2002). These subretinal deposits, accompanied by a diffuse thickening of Bruch's membrane, have been speculated to form a physical barrier between the RPE and choroid, obstructing the flow of nutrients from choroid to RPE, or possibly resulting in loss of cell-cell contact between RPE and Bruch's membrane and causing degeneration of retinal tissue. The RPE cells are responsible for phagocytosis and degradation of outer segment disks shed by photorecep-tors. As they age and undergo oxidative stress, lipofuscin accumulates in the lysosomal compartment and leads to cellular damage and further impaired function. Though the origin of drusen remains controversial, current opinions are beginning to favor the vasculature of the choriocapillaris as a primary source rather than an intracellular source from the RPE. It is possible that the presence of lipofuscin and cellular debris excites an immune reaction and leads to the formation of drusen. This is reflected by the presence of immune components in drusen (Anderson et al., 2002; see later).
Chorioretinal neovascularization (CNV) is the most common cause of vision loss in AMD. New vessels from the choriocapillaris grow through Bruch's membrane and branch horizontally through the RPE cell layer (termed classic CNV) or between the inner Bruch's membrane and RPE (termed occult CNV because it doesn't show up on angiography). Although the impetus for CNV has not been definitively determined, there are suggestions that imbalances in growth factors include pigment epithelial derived factor (PEDF, which inhibits vascular outgrowth) and vascular endothelial growth factor (VEGF, which stimulates vascular growth), possibly as a result of hypoxia and inflammation of the RPE. Even in the absence of CNV, the changes to the RPE Bruch's membrane and the outer plexiform layer of the retina result in scar formation at that level with concomitant damage to the neurosensory outer retina, termed geographic atrophy, which can also result in loss of central vision.
Composition of drusen and its implications Understanding the composition of drusen provides important clues to the molecular pathology of the disease. In addition to classical immunohistochemical techniques, several advanced proteome analysis tools have begun to provide detailed information about the nature and composition of drusen. Perhaps the most significant of the new findings is that drusen contain protein molecules that mediate inflammatory and immune processes. These include immunoglobulins, components of complement pathway, and modulators for complement activation (e.g., vitronectin, clusterin, membrane cofactor protein, and complement receptor-1), molecules involved in the acute-phase response to inflammation (e.g., amyloid P component, a1-antitrypsin, and apolipoprotein E), major histocompatibility complex class II antigens, and HLA-DR antigens (Crabb et al., 2002). Cellular components also have been identified in drusen, including RPE debris, lipofuscin, and melanin, as well as processes of choroidal dendritic cells, which are felt to contribute to the inflammatory response (Mullins et al., 2000).
In addition to immune components, a number of other proteins occur in drusen, some of them also found in atherosclerotic plaques and other age-related diseases in which protein deposits occur. The most common of these appear to be TIMP-3, clusterin, vitronectin, and serum albumin. Other proteins found in drusen include serum amyloid P component, apolipoprotein E, IgG, Factor X, and some complement proteins (Mullins et al., 2000). A number of proteins are found exclusively or in increased amounts in drusen associated with AMD than in drusen from individuals unaffected by AMD. These include some crystallins, EEFMP1, and amyloid-beta. In addition, the presence of immunoreactive proteins and oxidative modifications of many proteins found in drusen implicate both oxidation and immune functions in the pathogenesis of AMD.
Immune aspects These findings have led to the suggestion that immune complex-mediated inflammation damages RPE cells, and choroidal dendritic cells are activated and recruited by injured RPE, whereas RPE cells respond to control dendritic cell activation by secreting proteins that modulate the immune response. Shed or phagocytosed cell membranes of injured RPE or dendritic cells are postulated to function as cores for these secreted components to accumulate and form extracellular deposits.
Furthermore, the codistribution of IgG and terminal complement complexes in drusen implicates an immune response directed against retinal antigens, and the immune complex formation might be taking place at the site of drusen formation. This hypothesis is supported by the presence of putative anti-retinal autoantibodies in the sera of patients with ARMD. Anti-retinal autoantibodies previously have been reported in a number of ocular disorders, including retinitis pigmentosa, paraneoplastic retinopathies, and retinal vasculitis (Anderson et al., 2002). In addition, patients with membranoproliferative glomerulonephritis, in which complement activation and immune complex deposition cause glomerular injury, develop drusen deposits resembling those in ARMD in ultrastructure and composition including C5 and IgG. However, the role of antiretinal autoantibodies in the pathogenesis of ARMD has not been examined in detail. It remains unknown whether the initiation of chronic inflammation and subsequent drusen formation requires autoimmune-mediated events as a primary factor. To clarify the role of autoimmunity, immunogenic molecules for circulating antiretinal autoantibodies in patients need to be identified.
Oxidative aspects Oxidative damage is implicated in the pathogenesis of AMD by both theoretical considerations and experimental data (Roth, Bindewald, and Holz, 2004). The retina has a highly active metabolism with a resultant high oxygen demand, and is exposed to light and polyunsatu-rated fatty acids, all of which tend to increase its susceptibility to photo-oxidative damage. In a fashion somewhat analogous to that seen in the lens, as the retina ages its antioxidant defenses begin to decline, here including both antioxidant enzymes and antioxidants such as lutein, and macular pigment density. As the RPE age oxidation of lipids and other cellular components result in accumulation of nonmetabolizable material as lipofuscin in the lysosomes, leading to their enlargement and formation of lipofuscin granules. These closely parallel drusen formation in time and distribution in the retina. In addition, epidemiological correlation of AMD with light exposure, age, and light pigmentation as well as the prevention or delay of AMD by antioxidant vitamins in the AREDS trial also support an oxidative role in AMD.
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