From compliment to insult: genetics of the complement system in physiology and disease in the human retina

Abstract

Age-related macular degeneration (AMD) is a major cause of visual impairment that affects the central retina. Genome wide association studies and candidate gene screens have identified members of the complement pathway as contributing to the risk of AMD. In this review, we discuss the complement system, its importance in retinal development and normal physiology, how its dysregulation may contribute to disease, and how it might be targeted to prevent damage to the aging choriocapillaris in AMD.

Figure 1

Simplified summary of complement activation pathways. Genes with described polymorphisms associated with AMD are indicated by asterisks. While there are numerous fluid phase and cell surface complement inhibitors, deposition of the membrane attack complex (MAC) on the choriocapillaris is a consequence of normal aging but is much more striking in AMD and in patients with the high risk CFH genotype.

Figure 2

Age-related macular degeneration. Top panel, fundus appearance of a 65-year-old patient with AMD. Note the presence of drusen and pigment abnormalities in the macula. Lower panel, localization of the membrane attack complex (green) to domains surrounding the human choriocapillaris in an eye with AMD. Choroidal endothelial cells are labeled with UEA-I lectin (red) and nuclei appear blue (DAPI). The retinal pigment epithelium autofluoresces yellow in the preparation.