C-reactive protein and complement factor H in aged human eyes and eyes with age-related macular degeneration

Abstract

Background There is increasing evidence that inflammation and immune-mediated processes (complement activation) play an important role in age-related macular degeneration (AMD) pathogenesis. A genetic variation in the complement factor H (CFH) gene and plasma levels of C-reactive protein (CRP), a systemic marker of subclinical inflammation, have been consistently shown to be associated with an increased risk for AMD. In the present study, we examined the immunolocalization of CRP and CFH in aged control human donor eyes (n=10; mean age 79 yrs) and eyes with AMD (n=18; mean age 83 yrs). Methods Alkaline phosphatase immunohistochemistry was performed using polyclonal antibodies against CRP and CFH on cryopreserved tissue sections from disc/macular blocks. Three independent masked observers scored the reaction product (0-8). Results In aged control eyes, the retinal pigment epithelium/Bruch’s membrane/choriocapillaris (RPE/BrM/CC) complex including intercapillary septa (ICS) had the most prominent immunostaining for CRP and CFH. CRP was significantly higher than controls in BrM/CC/ICS and choroidal stroma in early and wet AMD eyes (p<0.05). In contrast, CFH was significantly lower in BrM/CC/ICS complex of AMD choroids than in controls (p<0.05). Interestingly, CRP and CFH were significantly reduced in BrM/CC/ICS complex in atrophic area of macula in geographic atrophy (GA)(p<0.05). Drusen and basal laminar deposits were intensely positive for CRP and CFH. Conclusion These immunohistochemical findings show that changes in distribution and relative levels of CRP and CFH were evident in early and late AMD eyes. This suggests that high levels of CRP and insufficient CFH at the retina/choroid interface may lead to uncontrolled complement activation with associated cell and tissue damage. This study supports the hypothesis that inflammation and immune-mediated mechanisms are involved in the pathogenesis of AMD.

Aqueous Humor Cytokine Levels in Patients with Polypoidal Choroidal Vasculopathy and Neovascular Age-Related Macular Degeneration

“…In the current study, the aqueous humor CRP level was significantly higher in eyes with neovascular AMD or PCV compared with control eyes. In an immunohistochemical study, Bhutto et al [17] reported that CRP is significantly higher than in controls in Bruch's membrane, choriocapillaris and choroidal stroma in human donor eyes with early or advanced AMD. In the current study, higher levels of CRP in the aqueous humor in eyes with neovascular AMD and PCV might reflect inflammation in the choroid in these eyes.…”

Pharmacogenomics & its Application in Ophthalmology

“…In addition, changes in relative levels of CFH and CRP may also contribute to uncontrolled complement activation that may result in cell and tissue damage. 31 The complement system is a key component in the pathogenesis of ARMD and therefore it may play a major role in developing new therapeutic interventions. 32 The combination of antioxidants and zinc studied by the Age-Related Eye Disease Study (AREDS) was reported to reduce disease progression and visual loss in certain patients with non-exudative AMD.…”

Risk Factors for Age-related Macular Degeneration

“…157 One study found people with rheumatoid arthritis had less prevalence of AMD and suggested anti-inflammatory agents, commonly used to manage the symptoms of rheumatoid arthritis, provide a protective effect against development of ARMD, 243 since there is some evidence that inflammation may play a role in the development of ARMD. 244 However, environmental and genetic factors may also be relevant as rheumatoid arthritis is commonly a disease of the young and ARMD is more apparent over 50 years of age. 245 …”