Science Editor

Editor's note: This is part two of a two-part series on immune cells that are directly under the control of neurons. Part one ran in Friday's issue.

Most stroke victims are probably not too worried about developing an infection. But, unfortunately, their doctors are – for good reason.

Those who have suffered a stroke become much more susceptible to infections, which, in fact, are a major cause of death for stroke victims. Pneumonia ultimately kills more than 10 percent of all stroke victims – partly because they are more likely to aspirate food and other particles into their lungs, but partly because they are immunosuppressed.

That increased risk is "almost immediate," Paul Kubes, critical care researcher at the University of Calgary, told BioWorld Today. "It's like the immune system just shuts down."

That shutdown makes a certain amount of sense: It is the brain's way of trying to prevent a massive inflammatory response that can damage the brain more severely than the original lack of blood flow does.

But it comes at a price.

Just how the brain shuts down the immune system following a stroke had been unclear. But one clue came from the speed with which the process goes ahead.

"In the body, there are very few things that work within minutes," Kubes noted. But one of those exceptions is a hybrid immune system cell that lives in the liver: the invariant natural killer T, or iNKT cell.

Most T-cell types respond to antigens presented to them by dendritic cells, and so their activation occurs a few days after infection – enough time for dendritic cells to gobble up bacteria or viruses and present them to T cells, and for those T cells to expand.

In contrast, iNKT cells live mainly in the liver, and can respond to lipids, which allows them to be activated much more quickly. "Although it has the markers of a T cell, [an iNKT cell] will respond to stimuli within minutes," Kubes said.

In the Sept. 15, 2011, issue of Sciencexpress, Kubes and his colleagues showed that when a stroke occurs, NKT signals are the first immune system cells to know about it. During a stroke, the brain releases the transmitter norepinephrine into the liver. Norepinephrine's claim to fame is that it sets off the fight-or-flight response when an organism is in danger. But, ironically, iNKT cells exposed to the transmitter have more or less the opposite of a fight-or-flight response.

The transmitter essentially functions as a stop sign for iNKT cells in the liver. They, in turn, influence other T cells in a way that favors the development of inhibitor T cells, making animals more susceptible to infection. In the experimental setup used by Kubes and his team, the animals died after their experimental strokes at a rate similar to that in human stroke victims.

Kubes and his team tested whether directly activating the iNKT cells after a stroke could prevent their norepinephrine-induced shutdown. They found that mice treated with an iNKT cell activator after a stroke had no more brain tissue damage than controls. But they had higher levels of interferon-gamma, and fewer signs of pneumonia – the most frequent infection after a stroke – than control animals.

Much like the work of Kevin Tracey and his team at the Feinstein Institute for Mecical Research, published in the same issue of Sciencexpress, the paper showed that the brain's control over the immune system may be more direct than is currently appreciated. Kubes said that they also identify iNKT cells as "master regulators. . . . They really decide which way the immune system is going to go." (See BioWorld Today, Sept. 16, 2011.)

Kubes called the two papers "complementary." The work of Tracey's group could explain "how beta adrenergic signaling may help modulate cytokines in tissues such as spleen where fewer NKT cells are found – thus providing a mechanism of suppressing or modulating other sites of potent cytokine production."

Practically, the work of Kubes and his group offers "a real potential to think about the way to treat stroke," and in particular, prevent the infections that stroke victims are prone to.

Kubes said prophylactic antibodies are sometimes discussed as another way to protect stroke patients. But in his opinion, that approach is "a nonstarter." The reason, he said, is the ever-increasing resistance of hospital bugs such as Staphylococcus aureus to antibiotics. Such resistance, Kubes said, is "already a huge problem, and it's only going to get worse" – and it will get worse faster the more prophylactic antibiotics are used: "We really have to get away from that kind of treatment approach."