Peanuts have a dark side. In some people, they can cause a dangerous and sometimes deadly allergic reaction marked by a sharp drop in body temperature and blood pressure, as well as difficulty breathing. This anaphylactic shock has typically been blamed on the immune system going into overdrive. But a new study in mice pegs an additional culprit: the nervous system.
The findings, reported today in Science Immunology, “are line with what people thought but no one was actually able to demonstrate,” says Sebastien Talbot, a neuroimmunologist at Queen’s University who was not involved in the study. The work, he says, could open up new targets to treat severe allergic reactions in people.
Anaphylaxis strikes about one in 50 individuals in the United States every year. Besides peanuts, bee stings and some medicines 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 narrowing airways. Body temperature can also drop, making people feel cold and clammy, though why this happens has been less clear.
Mice experience anaphylaxis, too. When exposed to an allergen, they lie on their bellies and stretch out. Such behaviors are controlled by the central nervous system, which made Soman Abraham, an immunologist at Duke University, suspect nerves may also play a role in severe allergic reactions.
To find out, he and colleagues gave the mice ovalbumin—the main protein found in egg whites and a known trigger of anaphylaxis—and used electrodes and microscopy to record and measure neuron activity. 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 areas that typically respond to heat had higher levels of activity. This false feeling of warmth explains why the animals stretch out as if they’re overheating even as their body temperature drops.
But what’s telling the mice that they’re overheating in the first place? The researchers homed in on a set of neurons in the spinal cord that appeared especially active during anaphylaxis. When the team manipulated receptors on the neurons to effectively turn them off, the animals didn’t cool down during anaphylaxis. Activating the neurons, on the other hand, re-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 histamines, the cells release a compound called chymase, which interacts with neurons that connect to brain areas 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 major role. “It was cool find a new mediator that actually triggered a crosstalk between the neurons and the [immune] cells.”
The study could provide new targets to treat anaphylaxis in humans. Individuals who suffer from severe allergic reactions often have to carry an EpiPen, which delivers a shot of adrenaline to stop the reaction once it has begun. But preventative treatments have been lacking.
Drugs that block that communication between the immune cells and the neurons by targeting chymase or the receptors it activates on neurons could be a way to help individuals that suffer from severe allergy reactions, says Evangeline Bao, an immunologist at Duke and co-author on the new study. Because these would target the root cause of the reaction, instead of just alleviating the symptoms like the EpiPen does, this might be a better strategy—and a more preventive one, 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 looking at 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 way off, Talbot cautions. Still, he says, “The study is definitely going to spark a lot of research in the field.”