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 characterized by a sharp drop in body temperature and blood pressure, as well as difficulty breathing. This anaphylactic shock is usually attributed to the immune system going into overdrive. But a new study in mice points to an additional culprit: the nervous system.

The findings, reported today in Science Immunology, “are consistent with what people thought but no one could prove,” said Sebastien Talbot, a neuroimmunologist at Queen’s University who was not involved in the study. The work, he says, could open new targets for treating severe allergic reactions in humans.

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

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

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

But what tells the mice to overheat in the first place? The researchers focused on a series of neurons in the spinal cord that seemed especially active during anaphylaxis. When the team manipulated receptors on the neurons to effectively turn them off, the animals did not cool down during anaphylaxis. Activating the neurons, on the other hand, created the symptoms of anaphylaxis even without exposure to an allergen.

During actual anaphylaxis, mast cells appear to be key to this phenomenon. The team found that in addition to histamine, the cells release a compound called chymase, which interacts with neurons that connect to brain regions 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.

Immunologists have long thought histamine was the main player in anaphylaxis, Talbot says, so it was surprising to him that chymase — and the nervous system — also seem to play a big role. “It was cool to find a new mediator that actually caused a crosstalk between the neurons and the neurons [immune] cells.”

The study may provide new targets for the treatment of anaphylaxis in humans. Individuals suffering 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 were lacking.

Drugs that block communication between immune cells and neurons by targeting chymase, or the receptors it activates on neurons, may be one way to help individuals suffering from severe allergic reactions, says Evangeline Bao, an immunologist at Duke and co-author of the new study. Since these would address the cause of the reaction, rather than just relieving the symptoms like the EpiPen does, this could be a better strategy — and a more preventative one, she says.

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

Such applications are still a long way off, Talbot warns. Still, he says, “The study will certainly spark a lot of research in the field.”

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