Key Points
- Professor Scott Cousins examines the various likely environmental and systemic contributors to the formation of drusen, and
discusses the potential implications for the treatment of geographic atrophy.
Drusen development: the four theories
Currently, there are four key theories for explaining drusen formation. These are:
- diminished choroidal blood flow subsequently diminishes oxygen delivery, leading to injury and deposit build-up on the macula;
- abnormal phagolysosomal degradation of the photoreceptors may lead to a build-up of undigested material, which in turn becomes
drusen;
- fat build-up within Bruch's membrane may form a barrier that prevents nutrient exchange;
- retinal pigment epithelial (RPE) cells may be the target of various injurious stimuli, such as oxidants, or maybe even immune
molecules.
"Traditionally, we have believed that free radicals and reactive oxidants have played a role in drusen pathogenesis. While
that is clearly true, more recently we've learned that there are other factors to take into account; dietary fat intake, for
example, is also important, and it is the type, as well as the quantity, of fat consumed that is relevant," Professor Cousins
explained. "We have found, for instance, that the consumption of polyunsaturated fatty acid, omega 6 (the major fatty acid
in red meat), is a contributor to drusen, whereas the intake of omega 3 fatty acid (the fatty acid content of deep-water fish)
is, conversely, protective against drusen formation." The role of inflammation
Our understanding of the disease has evolved rapidly in recent years. "I think that the greatest breakthrough in understanding
the pathogenesis of drusen that we have had in the last five to seven years is this idea that inflammation, in various forms,
is a major contributor to the disease; that the innate immune system plays a major role," asserted Professor Cousins. "In
the last three years, there has been a lot of data published that show that the genetic impetus of AMD is found among the
complement inhibitors in the complement system; specifically, Complement Factor H is the most important susceptibility gene.
"My laboratory, among others, has also looked at the role of one of the circulating white cells: the monocyte. We already
know that its tissue equivalent, the macrophage, has a major role to play in wet AMD, but we're now learning it plays a role
in dry AMD as well, and so we're exploring what this may mean for the development of the disease," Professor Cousins explained.
"The most recent breakthrough in our understanding was published in a New England Journal of Medicine article,"1 Professor Cousins continued. As previously reported by Ophthalmology Times Europe,2 this study examined the role of a mutation of the toll-like receptor 3 (TLR3) gene. TLR3 is a protein that alerts the immune
system to infections, and a mutated form of the TLR3 gene, expressing leucine instead of phenylalanine, was shown to be protective
against geographic atrophy, most likely by suppressing the death of RPE cells.
