The Role of Complement Factor H in Age-related Macular Degeneration: A Review

Abstract 

Factor H is a 155kDa sialic acid containing glycoprotein that plays an integral role in the regulation of the complement-mediated immune system that is involved in microbial defense, immune complex processing, and programmed cell death. These events take place primarily in fluid phase and on the cell surface and are particularly important in the context of distinguishing self from non-self. Activation of the complement system occurs within seconds and results in a proteolytic cascade eventually forming the membrane attack complex leading to cell lysis. Factor H protects host cells from injury resulting from unrestrained complement activation. Mutations and SNPs (single nucleotide polymorphisms) in Factor H have been implicated in a variety of human conditions including age-related macular degeneration (AMD), atypical hemolytic uremic syndrome, and membranoproliferative glomuleronephritis type II or dense deposit disease. It should not be surprising that these seemingly unrelated diseases involving mutations in Factor H may share common features. Because the immune process involves, in part, an inflammatory response and common or similar surface antigens, it is also not unexpected to observe features of inflammation, including deposition of bioactive complement fragments such as C3a and C5a, a cellular influx of immune related cells such as lymphocytes, and the potential for multiple organ involvement. We review recent developments in molecular genetics; SNPs, including Y402H; the three-dimensional structure; and mass spectroscopy of Factor H as it relates to the pathogenesis of eye disease. In addition, we discuss the concepts of molecular mimicry, sequestered or hidden antigens, and antigenic cross reactivity, and propose that AMD should not simply be considered to be an eye disease, but rather a systemic vascular disease where the eye has the ability to self regulate a local immune response. Identification of the initial event or inciting antigen has yet to be determined and will significantly advance the understanding of the pathogenesis of AMD.

Key words: abdominal aortic aneurysm (AAA), adaptive optics, age-related macular degeneration, alternative and classic pathway, alternative splicing, Alzheimer disease, ARMS2, atherosclerosis, complement control proteins (CCP), dense deposit disease (DDD), drusen, Factor H, hemolytic uremic syndrome (HUS), HIV, HTRA1, inflammation, innate and acquired immune system, liver, LOC387715/ARMS2, mass spectrometry, membanoproliferative glomerulonephritis (MPGHII), molecular mimicry, multifocal choroiditis, neutrophils, polyanions, relapsing polychondritis, retinal pigment epithelium (RPE), risk factors, S-antigen, short consensus repeats (SCR), Streptococcus M protein, transplantation, trilateral retinoblastoma, vascular disease, Y402H polymorphism