Complement System and Age-Related Macular Degeneration/AMD

Complement System and Age-Related Macular Degeneration / AMD

Complement System and Age-Related Macular Degeneration / AMD Background

A particular polymorphism of FH (Y402H) is strongly associated with development of age-related macular degeneration / AMD, which is the first cause of blindness in the developed countries. The loss of central vision is associated with loss of photoreceptors and drusen formation in the retina. This is due to the constant exposure to light, smoking, the high-metabolic rate in the eye, and its particular sensibility to oxidative stress. Oxidized lipids and malondialdehyde are generated and if not properly handled by FH, they induce complement activation. FH binding to oxidized epitopes on altered or dying cells leads to inactivation of C3b to an anti-inflammatory fragment iC3b. Moreover, FH attenuates malondialdehyde-induced IL-8 production by macrophages and retinal pigment epithelial cells and decreases the expression of genes involved in macrophage infiltration, inflammation, and neovascularization in the eye. At risk, FH variant H402 has a weaker capacity to interact with oxidized lipids and malondialdehyde in the drusen, thus allowing constant background complement activation, leading to retinal epithelial cells damage and macrophages activation. These results explain the strong genetic association of the H402 with the risk of age-related macular degeneration / AMD. Increased risk for age-related macular degeneration / AMD is conferred also by polymorphisms in several other genes of the alternative complement pathway, including FI, C3, C2, FB, and C9.

Genetic analyses revealed that the deletion of CFHR1 and CFHR3, which is a polymorphism in the normal population with varying frequency depending on the ethnicity between 2 and 20%, is a protective factor against development of AMD. CFHR1 and CFHR3 are natural deregulators of FH, competing with it for cell surface binding. Therefore, their absence will increase the local binding of FH to oxidized surfaces, leading to a better protection, thus explaining the protective effect of this deletion in AMD.e disorders. Because of its functions, the complement system is an attractive therapeutic target for a wide range of diseases.

Complement System and Age-Related Macular Degeneration / AMD References

1. Edwards A O, et al. (2005). Complement factor H polymorphism and age-related macular degeneration. Science, 308(5720), 421-424.
2. Hageman G S, et al. (2005). A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proceedings of the National Academy of Sciences of the United States of America, 102(20), 7227-7232.
3. Haines J L, et al. (2005). Complement factor H variant increases the risk of age-related macular degeneration. Science, 308(5720), 419-421.

Complement System
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Complement Genetic Feature
Complement Activation Pathways
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Complement System and Diseases
Complement System and Cancer
Complement System and Rheumatic Diseases
Complement Receptor 1 / CR1 and Alzheimer's Disease / AD
Complement System and Autoimmune Diseases
Complement System and Age-Related Macular Degeneration/AMD
Complement System and Schizophrenia
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Complement System Structure
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