The Membrane Attack Complex in Aging Human Choriocapillaris

Abstract

Age-related macular degeneration (AMD) is a common disease that can result in severe visual impairment. Abnormal regulation of the complement system has been implicated in its pathogenesis, and CFH polymorphisms contribute substantially to risk. How these polymorphisms exert their effects is poorly understood. We performed enzyme-linked immunosorbent assay (ELISA) analysis on young, aged, and AMD choroids to determine the abundance of the membrane attack complex (MAC) and performed immunofluorescence studies on eyes from 117 donors to evaluate the MAC in aging, early AMD, and advanced AMD. Morphometric studies were performed on eyes with high- or low-risk CFH genotypes. ELISA confirmed that MAC increases significantly with aging and with AMD. MAC was localized to Bruch's membrane and the choriocapillaris and was detectable at low levels as early as 5 years of age. Hard drusen were labeled with anti-MAC antibody, but large or confluent drusen and basal deposits were generally unlabeled. Labeling of retinal pigment epithelium was observed in some cases of advanced AMD, but not in early disease. Eyes homozygous for the high-risk CFH genotype had thinner choroids than low-risk homozygotes (P < 0.05). These findings suggest that increased complement activation in AMD and in high-risk genotypes can lead to loss of endothelial cells in early AMD. Treatments to protect the choriocapillaris in early AMD are needed.

Age-Related Macular Degeneration: A Complementopathy?

“…Analysis of human donor eyes has shown that complement activation in the choroidocapillary region already starts early in life and is associated with choroidal thinning and the development of AMD [43]. In this study, it was shown that choroidal deposition of the MAC sC5b-9 in humans is already evident at the age of 5 years and that it increases during a lifetime.…”

Lutein and Factor D: Two intriguing players in the field of age-related macular degeneration

“…Drusen are located on the RPE side of Bruch's membrane and complement is not only involved here but as shown recently also at the chorio-capillaris side [52]. Complement activation at the chorio-capillaris already starts early in life and is associated with choroidal thinning and development of AMD [54]. These authors showed that choroidal deposition of the membrane attack complex (sC5b-9) in humans was already evident at 5 years of age and that it increases markedly during life and with the presence of AMD.…”

“…Quantitative analysis of sC5b-9 in retinal samples by ELISA showed that young donors had relatively low levels of sC5b-9. Retinal samples from AMD patients had variable but significantly higher sC5b-9 levels as compared to the age-matched control eyes [55]. Further support for a role of the complement system in AMD came from several genetic studies (see Table 2) that revealed that variants in complement system genes alter an individual's risk of developing AMD [56,57].…”

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

“…Similarly, numerous clinical trials focused on targeting complement factors to prevent GA spread but were ultimately found ineffective. The biological relevance of CFH polymorphisms in and AMD context (Haines et al 2005;Edwards et al 2005;Klein et al 2005) remains elusive; Cfh mutant mice show only a marginal phenotype (Coffey et al 2007), and many individuals exhibiting complement deposition in the RPE never present with AMD (Anderson et al 2010;Mullins et al 2014). Thus, the field may be missing the biological understanding of AMD needed to create effective therapeutics.…”