Bisretinoids of RPE lipofuscin: trigger for complement activation in age-related macular degeneration

Genetic association studies and investigations of the constituents of subretinal deposits (drusen) have implicated complement dysregulation as one factor predisposing individuals to increased risk of age-related macular degeneration (AMD). Here we review evidence that molecular fragments released by photooxidation of the bisretinoids of retinal pigment epithelial lipofuscin, can activate complement. Complement activation by this mechanism is dependent on the alternative pathway. The diretinal conjugates comprising RPE lipofuscin accumulate in the cells throughout the lifetime of an individual. As such, these photooxidative processes, in a setting of complement dysregulation could contribute to chronic inflammation underlying AMD pathogenesis.