Age-related macular degeneration and the role of the complement system

• The alternative complement pathway plays a major role in AMD pathogenesis.
• Variants in genes including CFH, CFHRs, CFI, CFB and C3 modify AMD risk.
• MAC accumulates in the choriocapillaris and Bruch's membrane during ageing.
• The truncated version of FH, FHL-1 protects Bruch's membrane from complement activation.

Age-related macular degeneration (AMD) is a leading cause of visual impairment. It is characterised by damage to a tissue complex composed of the retinal pigment epithelium, Bruch's membrane and choriocapillaris. In early AMD extracellular debris including drusen accumulates in Bruch's membrane and then in late AMD geographic atrophy and/or neovascularisation develop. Variants in genes encoding components of the alternative pathway of the complement cascade have a major influence on AMD risk, especially at the RCA locus on chromosome 1, which contains CFH and the CFHR genes. Immunohistochemical studies have demonstrated complement components in unaffected and AMD macular tissue. Whilst other factors, including oxidative stress, play important roles in AMD pathogenesis, evidence for the central role played by complement dysregulation is discussed in this review.