The nervous system may play a role in severe allergic reactions | Science

Peanuts have a dark side. In some people, they can cause a dangerous and sometimes fatal allergic reaction marked by a sharp drop in body temperature and blood pressure, as well as difficulty breathing. This anaphylactic shock has generally been blamed on the overworked immune system. But a new study in mice identifies an additional culprit: the nervous system.

The findings, published today in Sciences Immunology, “agree with what people thought, but no one has been able to demonstrate it,” says Sébastien Talbot, a neuroimmunologist at Queen’s University who was not involved in the study. The work, he says, could open up new targets for treating severe allergic reactions in people.

Anaphylaxis strikes approximately one in 50 people in the United States each year. Besides peanuts, bee stings and certain medications are common triggers. These allergens cause mast cells of the immune system to release a barrage of histamine and other molecules that spread throughout the body, dilating blood vessels and narrowing the airways. Body temperature can also drop, making people cold and clammy, but why this happens is less clear.

The mice also suffer from anaphylaxis. When exposed to an allergen, they lie on their stomachs and stretch. Such behaviors are controlled by the central nervous system, leading Duke University immunologist Soman Abraham to suspect that nerves may also play a role in severe allergic reactions.

To find out, he and his colleagues gave mice ovalbumin — the main protein found in egg whites and a known trigger of anaphylaxis — and used electrodes and microscopy to record and measure the neuron activity. As in humans, the rodents’ body temperature dropped by about 10°C. But the mice’s brains didn’t register this as a sudden freeze; instead, areas of the brain that typically respond to heat had higher levels of activity. This false sensation of warmth explains why animals stretch as if they are too hot even as their body temperature drops.

But what tells mice they are overheating in the first place? The researchers focused on a set of neurons in the spinal cord that seemed particularly active during anaphylaxis. When the team manipulated receptors on neurons to effectively turn them off, the animals did not cool down during anaphylaxis. Activation of neurons, on the other hand, recreated the symptoms of anaphylaxis even without allergen exposure.

During actual anaphylaxis, mast cells seem to be the key to this phenomenon. The team found that in addition to histamines, the cells release a compound called chymase, which interacts with neurons that connect to areas of the brain that regulate body temperature. When the team blocked the release of chymase, the animals no longer lowered their body temperature in response to an allergen.

Histamine has long been thought by immunologists to be the main player in anaphylaxis, Talbot says, so it was surprising to him that chymase — and the nervous system — also seemed to play a major role. “It was cool to find a new mediator that actually triggered crosstalk between neurons and the [immune] cells.”

The study could provide new targets for treating anaphylaxis in humans. People who suffer from severe allergic reactions often need to carry an EpiPen, which delivers a shot of adrenaline to stop the reaction once it has started. But preventive treatments have been lacking.

Drugs that block this communication between immune cells and neurons by targeting chymase or the receptors it activates on neurons could be a way to help people with severe allergic reactions, says Evangeline Bao, an immunologist at Duke and co-author new study. Because these would target the root cause of the reaction, instead of just relieving symptoms like the EpiPen does, it might be a better and more preventative strategy, she says.

Crosstalk between the immune and nervous systems could also play a role in other severe reactions, Bao says. She and her colleagues are now studying how this communication plays out in sepsis, the body’s overreaction to an infection. As with anaphylaxis, sepsis is an overreaction to an insult; in this case, immune cells release inflammatory molecules that can damage organs, leading to death in some cases.

Such applications are still a long way off, warns Talbot. Still, he says, “the study will definitely spur a lot of research in the area.”

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