The Role of Inflammation in AMD
Research is revealing many possible links between AMD and the inflammatory response
Pouya N. Dayani, MD • David S. Boyer, MD
The number of individuals affected by age-related macular degeneration is expected to increase by 50% by the year 2020.1 Although a hereditary component to the development of AMD has been identified, AMD is believed to be a polygenic disease (Figure 1), with a number of genes affecting the susceptibility of an individual.2,3 Some of the factors reported to play a role in the development of AMD include age, race, sex, diet, smoking and obesity.1 Systemic processes, such as vascular disease, atherosclerosis and even infectious etiologies have also been implicated in the pathogenesis of AMD.4,5
Figure 1. AMD is believed to be a polygenic disease, with a number of genes affecting the susceptibility of an individual.
EVIDENCE OF INFLAMMATION
Of the above factors, there has been increasing support in recent years that inflammation plays a critical role in the development and progression of AMD.6-8,9-11 Drusen formation (Figure 2), which is the earliest clinical finding and the hallmark of AMD, has been shown to result from a localized inflammatory response.7-9 Support for this concept comes from the observation that several components of complement and other proteins involved with immune-mediated processes and inflammation are present in drusen.12
Figure 2. The drusen pathway may sometimes be linked to inflammatory processes. COURTESY OF MORTON E. SMITH, MD
For example, amyloid, which is an acute phase reactant and a major inflammatory component of the plaques seen in Alzheimer's disease, is also observed in drusen.13 Other components of drusen include proteins involved in modulating the immune response, such as vitronectin, apolipoproteins B and E, and complement receptor 1.14 Furthermore, a number of inflammatory associations with the presence of drusen or retinal pigment epithelium changes have been described, including a history of arthritis, periodontal disease, oral steroid use and cyclo-oxygenase 2–inhibitor use.15
A number of studies have also provided growing evidence that inflammation plays an important role in the formation of choroidal neovascularization. For example, early monocyte activation and the presence of chronic inflammatory cells on the outer surface of Bruch's membrane have been described in eyes with neovascular AMD.16,17 These inflammatory cells are thought to damage Bruch's membrane through the release of proteolytic enzymes, oxidants, and toxic oxygen compounds.15,18
Further support for this association comes from experimental models in which inflammatory cells, such as neutrophils, have been shown to induce CNV. Abnormal macrophage recruitment has been associated with vascular endothelial growth factor production by the RPE and may be involved in stimulating aberrant angiogenesis.19 Additional support for the role of macrophages in the development of CNV comes from data showing that depletion of macrophages is associated with a reduction in the size and leakage of experimental, laser-induced CNV.20,21
THE ROLE OF OXIDATIVE STRESS
Advanced age is a known risk factor for the development of AMD. Studies have shown that a number of changes take place with age that may predispose the RPE and choriocapillaris to oxidative damage. These changes include a decrease in plasma levels of glutathione, vitamin C, and vitamin E, as well as a decrease in RPE-cell vitamin E levels and catalase activity.14 Other reported changes include increased RPE lipofuscin content and increase lipid peroxidation.14
This increased oxidative stress and the resulting RPE (and likely choroidal) injury may elicit an inflammatory response in Bruch's membrane and the choroid. An abnormal extracellular matrix (ECM), largely derived from the RPE and photoreceptors, is then produced, altering the diffusion of nutrients to the retina and choroid, causing further damage to these structures. The results of the Age-Related Eye Disease Study showed that antioxidant supplementation could mitigate some of this oxidative damage and decrease the progression of AMD.22 In addition, lipofuscin formation in RPE cells has been shown to be reduced by antioxidant therapy.23
THE COMPLEMENT CASCADE
A number of recent reports have strongly implicated variants in the complement cascade that modify the risk of AMD, with the most consistent evidence concerning the complement factor H (CFH), complement factor B/complement component 2, and complement component 3 genes.24-31 The most significant association has been between the Y402H polymorphism in CFH, which may account for up to 59% of AMD cases.24-26,32 The involved gene is on chromosome 1, in an area of multiple genes involved in complement regulation.33
The complement system, which is part of the innate immune system, helps to protect host cells from invading pathogens, to remove debris, and to enhance cell-mediated immune responses. There are three arms to the complement system: the classic arm, the lectin-mediated arm and the alternative arm. Complement factor H is a powerful inhibitor of the complement system and is a regulatory molecule in the alternative and classic complement systems. It has been suggested that a CFH dysfunction, such as that caused by the Y402H polymorphism, could disrupt the normal complement cascade. This process, in return, can lead to an elevated immune response, thereby adversely affecting healthy tissue.33
C-reactive protein, a general marker of systemic inflammation, has been associated with AMD and its progression and has been shown to have a synergistic relationship with the CFH variant (possibly as a result of altered binding by factor H).3,34-43 Elevated levels of other inflammatory biomarkers, such as interleukin-6, have also been observed in AMD patients.35
Genome-wide association studies have identified a number of genetic loci associated with AMD. A recent large meta-analysis of genome-wide association studies by Yu et al. confirmed associations for 10 previously published advanced AMD loci and reported two novel associations near FRK/COL10A1 and VEGFA.3 The authors concluded that the genetic loci associated with AMD suggest that the disease process is partly mediated by dysregulation of the alternate complement pathway (CFH, C2, CFB, C3, CF1), HDL cholesterol metabolism (LIPC, CETP, ABCA1), angiogenesis (VEGFA), and degradation of the extracellular matrix (COL10A1, COL8A1, FRK, TIMP3 and possibly ARMS2).3
Another genome-wide association study observed a protective effect from a SKIV2L variant, a gene near the complement component 2/complement factor B locus, further establishing the link between inflammatory and oxidative stress pathways and AMD.50 This study also identified a protective effect at MYRIP, a gene involved in RPE melanosome trafficking. The authors propose that the protective effect of MYRIP may be a result of minimizing RPE exposure to reactive oxygen species, thereby preventing or delaying declines in RPE function.50
A COMPARATIVE MODEL OF CHOLESTEROL
It has been suggested that cardiovascular disease can provide a comparative model for the role of cholesterol in the pathogenesis of AMD.51 Cardiovascular disease and AMD share a number of the same risk factors, including hypertension, high body mass index, a history of smoking, elevated plasma fibrinogen, homocysteine, C-reactive protein and other cytokines.34,35,52-54 Moreover, aspirin (an anti-inflammatory drug) and statin therapy (which decreases CRP) are associated with decreased rates of CNV in AMD patients.56,57
Plaques in carotid bifurcation and lower extremity arterial disease have also been associated with AMD.55 The presence of cholesterol, apolipoprotein B and apolipoprotein E in drusen and basal linear deposits of RPE cells links AMD with lipoproteins involved in the pathogenesis of atheroscelrosis.58 To date, however, the association between serum lipid and AMD has been inconsistent.59-62
As mentioned above, genome-wide association studies have recently shown an association between AMD and hepatic lipase (LIPC), a gene located at chromosome 15q22.63-65 This new variant encodes the hepatic lipase enzyme and affects serum HDL cholesterol levels.66
A study by Reynolds et al. reported on the associations of the LIPC gene with lipid biomarkers and AMD.64 They found that the HDL-raising allele of the LIPC gene was associated with a reduced risk of AMD. Higher total cholesterol and LDL levels were associated with an increased risk of AMD, whereas higher HDL levels reduced the risk of advanced AMD.
Associations between human leukocyte antigens (HLA) class 2 and class 2 polymorphisms and AMD have also been reported, further supporting the role of the immune system and AMD pathogenesis.67 Moreover, immunological mimicry between host and microbial glycoproteins has been suggested as a possible source of local immune response and inflammation.
For example, the retinal S-antigen, a photoreceptor cell protein, has immunological similarities with streptococcal M protein.68 This similarity is consistent with the observation that patients with certain ocular diseases can have circulating antibodies to retinal proteins and implicates the possibility of an autoimmune process in AMD pathogenesis. Other researchers have suggested that an infectious agent could cause aberrant activation of the compliment pathway, leading to the development of AMD. For example, there are conflicting data regarding the association of C. pneumoniae and AMD.69-71
In summary, there is substantial evidence that AMD is associated with local and systemic inflammatory processes. It is possible that inflammation triggers a process that is subsequently perpetuated, leading to clinically evident AMD. It is also possible that inflammation results from already existing changes, which then trigger the progression of AMD.
As our current understanding of the role of inflammatory and immune-mediated processes in AMD pathogenesis continues to grow, additional diagnostic and thera peutic interventions (such as those targeting the complement pathway) will hopefully be developed to target these factors. In addition, patients at high risk for disease progression may be recognized by assessing known risk factors, such as demographic, environmental and macular characteristics, as well as the multiple genetic loci identified in recent studies.72 This process may allow earlier intervention in the disease process, thereby slowing or arresting the development of the disease. RP
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|Pouya N. Dayani, MD, and David S. Boyer, MD, practice with Retina-Vitreous Associates Medical Group in Los Angeles. Neither author reports any financial interest in the products mentioned in this article. Dr. Dayani can be reached via e-mail at firstname.lastname@example.org.|