The role of complement in AMD.
Age related macular degeneration (AMD) is a common form of blindness in the western world and genetic variations of several complement genes, including the complement regulator Factor H, the central complement component C3, Factor B, C2, and also Factor I confer a risk for the disease. However deletion of a chromosomal segment in the Factor H gene cluster on human chromosome 1, which results in the deficiency of the terminal pathway regulator CFHR1, and of the putative complement regulator CFHR3 has a protective effect for development of AMD. The Factor H gene encodes two proteins Factor H and FHL1 which are derived from alternatively processed transcripts. In particular a sequence variation at position 402 of both Factor H and FHL1 is associated with a risk for AMD. A tyrosine residue at position 402 represents the protective and a histidine residue the risk variant. AMD is considered a chronic inflammatory disease, which can be caused by defective and inappropriate regulation of the continuously activated alternative complement pathway. This activation generates complement effector products and inflammatory mediators that stimulate further inflammatory reactions. Defective regulation can lead to formation of immune deposits, drusen and ultimately translate into damage of retinal pigment epithelial cells, rupture of the interface between these epithelial cells and the Bruch's membrane and vision loss. Here we describe the role of complement in the retina and summarize the current concept how defective or inappropriate local complement control contributes to inflammation and the pathophysiology of AMD.
Zipfel
Peter F
PF
Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Beutenbergstrasse 11a, Jena, Germany. peter.zipfel@hki-jena.de
Lauer
Nadine
N
Skerka
Christine
C
D065766:Atypical Hemolytic Uremic Syndrome; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D003180:Complement C3b Inactivator Proteins; D017242:Complement Factor H / Q000235:genetics; D003170:Complement Pathway, Alternative / Q000235:genetics; D003165:Complement System Proteins / Q000235:genetics* / Q000378:metabolism*; D015432:Glomerulonephritis, Membranoproliferative / Q000235:genetics / Q000276:immunology; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics / Q000276:immunology; D006801:Humans; D055261:Immunogenetic Phenomena; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D008268:Macular Degeneration / Q000235:genetics* / Q000276:immunology*; D018448:Models, Immunological; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics
C514392:ARMS2 protein, human; C517621:CFHR1 protein, human; D003180:Complement C3b Inactivator Proteins; D011506:Proteins; D017242:Complement Factor H; D003165:Complement System Proteins