Prior to the 2005 studies, few people studying macular degeneration suspected a major role for the complement immune system, which helps to clear pathogens from the body. The link between the complement factor H gene, which is a major inhibitor of the complement immune system, and other genes to macular degeneration has allowed scientists to explore the pathology of the disease in greater molecular detail. Mice lacking the protein altogether develop kidney and eye problems. (Mice don’t have maculas, so it’s impossible to accurately mimic the disease in rodents.) Human cells expressing the mutated version of the protein have altered immune function.
Hageman, who has since left Optherion, is exploring the power of the protective protein in novel ways. Because most complement factor H protein is made in the liver, his team is examining macular degeneration in people who undergo liver transplants. “We have seen cases where people who received a liver from someone with the risk form of the protein have developed macular degeneration quickly,” he says. “And we have seen a couple of cases where someone had AMD and progression was halted after receiving a liver from someone with the protective form.” But he cautions that these cases are anecdotal; researchers need to examine many more patients to see if the effect is statistically significant.
While it’s not exactly clear how alterations in the complement factor H gene boost risk for macular degeneration, scientists theorize that the mutant protein can no longer adequately control the complement immune system, perhaps triggering it to attack healthy cells rather than the pathogens it was designed to fight. “Chronic activation of complement and chronic inability to control it probably helps to explain the age-relatedness of the disease,” says Hageman.
Anand Swaroop, a researcher at the National Eye Institute, in Bethesda, MD, points out that while the complement system is important in AMD, genome-wide association studies have implicated other genes and pathways as well. “We know that in addition to the complement system, there are three or four other pathways involved, as well as environmental factors,” says Swaroop. “Those variants are clearly as important and we have no idea what they do. I think the ultimate cure will come from targeting multiple pathways.”