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1. Old eyes = blind eyes?

2. The inflamed eye

3. Unwanted blood vessels

4. Treatment ahead?

The macula, site of central vision, has no large blood vessels. It does have by far the densest concentration of light-sensitive cells in the retina. Courtesy New England Eye Center, Boston, MA

 

Meet the savage macrophage
Photograph of the red interior of an eyeball, showing the optic nerve and cloudy macula.Why do things go so tragically awry in age-related macular degeneration? Could the light-sensitive neurons be destroyed as a result of an immune system run amok? Five years ago, AMD was not considered an inflammatory disease. The illness did not, for example, start with an immune response, unlike such inflammatory diseases as rheumatoid arthritis and juvenile diabetes.

Now, however, it seems that early in AMD, an activation of the immune system sets the stage for a self-destructive process that eventually kills the photoreceptor (light-sensitive) cells. The apparent role for the immune system in AMD follows closely the realization that inflammation plays a key role in such other age-related woes as Alzheimer's disease and atherosclerosis.

Under the old view of atherosclerosis, fat simply accumulated in the arteries until it broke off and formed a clot. The new view involves inflammation. "We now know that the lipid [fat] sticks to the vessel wall, but it's not toxic until a macrophage [a kind of immune cell] ingests it and becomes activated and releases growth factors," says Scott Cousins, who researches AMD at the Bascom Palmer Eye Institute at the University of Miami. "Atherosclerosis is now considered an inflammatory disease, it's not simply a result of cholesterol."

Meet the macrophages
Macrophages (loosely speaking, the name means "big-mouth") are large white-blood cells that are central to many immune processes. Macrophages may come in several flavors, depending on what genetic program they happen to be running.

Scavenging macrophage simply eat up cellular debris. They're as necessary as a vacuum cleaner, but considerably less obnoxious.

Reparative macrophages are partly activated. They release growth hormones and factors that cause blood vessel growth, but are implicated in athersclerosis and rheumatoid arthritis.

Activated macrophages release a mess of growth factors and nasties like tumor necrosis factor, a cell-whacking molecule that we'd liken to Arnold Schwarzenegger -- a useful ally, perhaps -- but dangerous in the wrong circumstances.

Photograph of the inside of an eyeball, showing yellow spots labeled drusen and thin  red lines labeled dry retinal changes. Drusen and other retinal changes signify the presence of dry AMD. Courtesy New England Eye Center, Boston, MA

A second component of AMD is the drusen, an abnormal deposit found under the retina at the start of the disease. Each morning, the bottom 10 percent of each rod and cone drops away, having become exhausted from converting photons of light into nerve signals.

See the trash strike
Each day, a typical RPE cell (that's the retinal pigment epithelium - jargon we would love to avoid...) gobbles about 20,000 chunks of rods and cones. But if RPE cells tire with age (sound familiar?), trash removal breaks down, leaving drusen -- the dregs of unprocessed rods and cones. As Martin Friedlander, chief of the retina service at the Scripps Research Institute, puts it, "When the garbage system quits, the city starts smelling."

Cousins says this accumulation of garbage -- the drusen -- are probably the first stimulus of the inflammatory response in AMD.

Cousins, who says some scientists have been pointing to a role for macrophages in AMD for 15 years, says new images of eyes with AMD show macrophages linking to drusen. They may be trying to digest the drusen, or stimulating an inflammation, or both. (Kinda reminds us of dumpster-diving immune cells gobbling sub-retinal trash).

By the time wet AMD appears, Cousins adds, the inflammation is obvious, since lab studies show "abundant macrophages, releasing scarring factor and other chemicals." Furthermore, when Cousins experimentally damages the eye of a research animal with a laser, he can watch new blood vessels being created, and macrophages "crawling into the retina."

Top: microscopic image of healthy tissue, a column of white cells surrounded by pink and purple stained cells. Bottom: Inflamed tissue, a row of white cells thickly lined with lots of pink and purple stained cells.A classic example of the inflammation conflagration. When normal tissue is damaged or injured, a cascade of immune cells come to the rescue. National Institute of General Medical Sciences.

"Macrophages are an important contributor to neovascular formation," he says, using jargon for the formation of new blood vessels. In other words, macrophages seem to be releasing chemicals that stimulate growth of new blood vessels, a process (forgive yet more jargon) that's called angiogenesis.

But macrophages aren't always harmful - they also play that essential "sanitation-worker" role in removing cellular trash. Why don't these macrophage simply eat and run, without releasing a nasty chemical soup? Why, in other words, are they so excited? There are many possibilities, including genetic predisposition or the after-effects of a long-ago infection. When the Cousins lab checked for antibodies to various infective agents, they found that more people with wet AMD had been exposed to cytomegalovirus, which infects the young and lingers, dormant, for decades.

These data are preliminary.

Got any idea where these new blood vessels originate?

 

 

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