The Immune System's Hardened Truth
By Sarah C.P. Williams
ScienceNOW Daily News
13 April 2007

Call it an immune system double-cross. The same proteins that fight germs may also help fat and cholesterol clog our arteries, new research shows. Understanding this deadly duality could eventually lead to new drugs to ward off heart disease.

We all know that a diet high in fat and cholesterol is a bad thing. When these molecules circulate in the blood, they build up on blood vessel walls and increase the risk of atherosclerosis, a dangerous hardening of the arteries. Since the dawn of atherosclerosis research almost a hundred years ago, scientists have found white blood cells in the fatty plaques on artery walls, suggesting a link between the immune system and atherosclerosis. Researchers have been unable to pinpoint the molecular basis for the link, however, or explain the observation by many doctors that diseases such as lupus, inflammatory bowel syndrome, and hepatitis--all marked by chronic inflammation--increase the risk of high fat and cholesterol levels in patients, which in turn increases the risk of atherosclerosis.

A team of biochemists at the University of Chicago looked for new insights by pushing this relationship to extremes. They bred mice with an excess of immune cell molecules called LIGHT, which had been previously implicated in liver function. They found that even when fed a normal diet, mice with lots of LIGHT developed cholesterol and fat levels higher than normal mice on high-fat diets. When fed a high-fat, high-cholesterol diet, these effects were even worse, the team reports today in Science. The researchers then created a way to block LIGHT from activating any inflammatory pathways in the mice. Several weeks later, mice on the therapy showed marked reduction in cholesterol and a kind of fat called triglycerides, with levels returning close to normal. The researchers suspect that LIGHT stops the liver from digesting the fatty molecules, forcing them into the bloodstream.

Pathologist Yang-Xin Fu, a senior author on the paper, thinks targeting the same pathway in humans could reduce risk of atherosclerosis. It would be novel; the therapy would work through a different mechanism than current statin drugs. "Any patient who can't bring down their lipid levels through diet and common medication could potentially be helped by such a treatment," he says.

"This is certainly a very important step forward," says Klaus Ley, a cardiovascular researcher at the University of Virginia in Charlottesville. But he and others would like to see more data on the LIGHT pathway before they dub these results conclusive. Fiddling with LIGHT has such broad consequences on development and health that the lipid effects may simply be a by-product of these drastic alterations, not a direct link, says immunologist Luc Teyton of the Scripps Research Institute in San Diego, California. "At this stage I still want to be very cautious."