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Common link — a glucose-guzzling immune cell — involved in coronary artery disease and rheumatoid arthritis

Rheumatoid arthritis and coronary artery disease share a common culprit: an important type of immune cell, called a macrophage, that has gone haywire. Stanford investigators have zeroed in on a molecular defect in macrophages' metabolic process that drives both disorders.

If you could see what the top of my desk looks like right now, you might understand why I'm just getting around to blogging about a study that was published close to two months ago. (I found out about it only two or three weeks ago, and I didn't actually read it until just the other day.)

The study, which appeared in BMJ (formerly the British Medical Journal), didn't draw much media attention. But I think it's important. Stanford immunologist Connie Weyand, MD, and her colleagues have found a crucial common element linking the world's number-one cause of death, coronary artery disease, and what is probably the world's most-common autoimmune disease, rheumatoid arthritis.

It's known that people with rheumatoid arthritis are particularly susceptible to coronary artery disease, but nobody's understood why.

While we usually think of CAD as a plumbing problem arising from the build-up of fatty plaque inside major arteries -- and it is! -- it's increasingly viewed as stemming from underlying inflammatory processes that have only recently begun to be fully revealed.

RA, meanwhile, is generally seen as an autoimmune condition in which a person's joints come under attack by his or her own aberrant immune system. And it is! What clogged arteries and burning, swollen joints have in common is far from obvious.

But, it turns out, both of these seemingly disparate disorders are driven by the same thing: hyperactivity on the part of certain wayward immune cells, known as macrophages, that are plagued with a defect turning them into what you could call "glucoholics."

A macrophage (its name derives from the Greek words for "big eater") exists mainly to do three good things: gobble up nasty microbial pathogens and nascent tumor cells, call for help from other warrior cells of the body's immune army, and clean up cellular debris and dying cells in the wake of an injury.

But in people with CAD and RA, some macrophages go haywire and make trouble instead of solving problems. As I wrote in another blog entry a year ago about these cells' involvement in CAD:

[T]his [defective] macrophage is predisposed to go haywire because it's got a sweet tooth: Coronary artery disease patients' macrophages tend to suck up far more glucose from the blood stream than they should. Anyone who's ever raised little children probably knows what that means: These glucose-guzzling macrophages are in a constant state of excitement. Their revved-up sugar metabolism generates tons of dangerous free radicals, leading to the production and secretion of inflammatory substances that promote arterial plaque buildup and breakup.

Note: This happens not because there's too much sugar in a person's blood, but because the morphed macrophages start scooping up all the sugar they can suck out of our serum.

In the new study, Weyand and her colleagues showed that rampaging sugar-crazed macrophages loom large in RA, too, effectively sitting around in patients' joints and calling in squads of other immune-cell types.

Not only that, but the investigators dug deep into the whirling wheels and gears of glucose-guzzling macrophages' metabolism, and unearthed some pathological processes whose effect was to send these macrophages into a state of chronic overdrive. In particular, they zeroed in on a single enzyme in macrophages' sugar-digesting pathway whose malfunction morphs macrophages into M&M-munching monsters (OK, admittedly there is no vending machine involved: glucose-gobbling). The enzyme, GSK3b, is well known, but its role in CAD and RA wasn't.

The really good news here is that isolating GSK3b as a culprit gives drug developers a brand-new target to shoot at in the service of downing both coronary artery disease and rheumatoid arthritis. I suppose there’s still a long way from this discovery to a side-effect-free GSK3b-fixing drug that has succeeded in Phase 3 trials, but one can dream...

Photo by Alexas_Fotos

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