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August 2010, Issue 44

 

The Role of Inflammation in the Pathogenesis of Age-Related Macular Degeneration

 

Pouya Dayani, MD
David Boyer, MD

Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly in the United States, and the number of individuals affected is expected to increase by 50% by the year 2020.1  Although a hereditary component to the development of AMD has been identified, it is believed that AMD is a polygenic disease, with a number of genes affecting susceptibility of an individual.2  Other factors that may play a role in the development of AMD include age, race, gender, diet, smoking, and obesity.1  Systemic processes such as vascular disease, atherosclerosis and even infectious agents have also been implicated in the pathogenesis of AMD.3, 4

There has been increasing evidence over the years that inflammation plays a critical role in the development and the progression of AMD.5-7 8-10  Drusen are typically the earliest clinical findings of AMD.  There is evidence suggesting that drusen formation is the result of a localized inflammatory response following retinal pigment epithelium (RPE) injury that involves human leukocyte antigens (HLA) and the complement system.6-8  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.11  For example, amyloid, which is an acute phase reactant and a major inflammatory component of the plaques seen in Alzheimer disease, is observed in drusen.12  Other components of drusen include proteins involved in modulating the immune response, such as vitronectin, apolipoproteins B and E, and complement receptor 1.13  Furthermore, a wide spectrum of associations with the presence of drusen or RPE changes have been described including a history of arthritis, periodontal disease, oral steroid use, and cyclooxygenase 2-inhibitor use.16

A number of studies have also provided growing evidence that inflammation may play an important role in the formation of choroidal neovascularization (CNV).  Early monocyte activation has been noted in those with neovascular AMD, and chronic inflammatory cells have been identified on the outer surface of Bruch's membrane in eyes with neovascular AMD.17, 18  These inflammatory cells are thought to damage Bruch's membrane through the release of proteolytic enzymes, oxidants, and toxic oxygen compounds.16, 22  Inflammatory cells, such as neutrophils, have been implicated and have been shown to induce CNV in experimental models.  Abnormal macrophage recruitment is associated with production of vascular endothelial growth factor (VEGF) 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 laser-induced CNV.20, 21

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.13  Other reported changes include increased RPE lipofuscin content and increased lipid peroxidation.13  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.23   In addition, lipofuscin formation in RPE cells has been shown to be reduced by antioxidant therapy.24

A number of reports have demonstrated a strong association between the Y402H polymorphism in the complement factor H gene (CFH) and the risk of developing AMD.  This variant may account for up to 43% of AMD cases.25-27  The involved gene is on chromosome 1, in an area of multiple genes involved in complement regulation.28  The complement system is part of the immune system and helps protect host cells from invading pathogens, remove debris, and enhance cell-mediated immune responses.  There are 3 arms to the complement system: the classic arm, the lectin-mediated arm, and the alternative arm.  CFH 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, in turn, can lead to an elevated immune response, thereby adversely affecting healthy tissue.28  Interestingly, changes in markers of inflammation, such as C-reactive protein, have been reported in AMD patients with the CFH variant and may be the result of altered binding by CFH.29  Other studies have also found elevated levels of inflammatory biomarkers, such as interleukin-6 or high-sensitivity CRP, in patients with AMD.16, 30-32

An association between HLA class I and class II polymorphisms and AMD has also been reported, further supporting the role of the immune system and AMD pathogenesis.33  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.34  This 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.  Others have suggested that an infectious agent could cause an aberrant activation of the complement pathway, leading to the development of AMD.  For example, there is conflicting data regarding the association of C. pneumoniae and AMD.35-37

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, and then triggers the progression of AMD.  As our understanding of the role of inflammatory and immune mediated processes in AMD pathogenesis continues to grow, additional diagnostic and therapeutic interventions will hopefully be developed.  This may allow earlier intervention in the disease process, thereby slowing or arresting the development of the disease.

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sponsor

Ingrid U. Scott, MD, MPH,  Editor

Professor of Ophthalmology and
Public Health Sciences,
Penn State College of Medicine

 

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