Together with two of his students, Noah Palm and Rachel Rosenstein, Medzhitov published his theory in Nature in 2012. Then he began testing it. First he checked for a link between damage and allergies. He and colleagues injected mice with PLA2, an allergen that’s found in honey-bee venom and tears apart cell membranes. As Medzhitov had predicted, the animals’ immune systems didn’t respond to PLA2 itself. Only when PLA2 ripped open cells did the immune system produce IgE antibodies.
Another prediction of Medzhitov’s theory was that these antibodies would protect the mice, rather than just make them ill. To test this, Medzhitov and his colleagues followed their initial injection of PLA2 with a second, much bigger dose. If the animals had not previously been exposed to PLA2, the dose sent their body temperature plunging, sometimes fatally. But the mice that had been exposed marshaled an allergic reaction that, for reasons that aren’t yet clear, lessened the impact of the PLA2.
Medzhitov didn’t know it, but on the other side of the country another scientist was running an experiment that would provide even stronger support for his theory. Stephen Galli, chair of the Pathology Department at Stanford University School of Medicine, had spent years studying mast cells, the enigmatic immune cells that can kill people during allergic reactions. He suspected mast cells may actually help the body. In 2006, for example, Galli and colleagues found that mast cells destroy a toxin found in viper venom. That discovery led Galli to wonder, like Medzhitov, whether allergies might be protective.
To find out, Galli and colleagues injected one to two stings’ worth of honey-bee venom into mice, prompting an allergic reaction. Then they injected the same animals with a potentially lethal dose, to see if the reaction improved the animal’s chance of survival. It did. What’s more, when Galli’s team injected the IgE antibodies into mice that had never been exposed to the venom, those animals were also protected against a potentially lethal dose.
Medzhitov was delighted to discover Galli’s paper in the same issue of Immunity that carried his own. “It was good to see that somebody got the same results using a very different model. That’s always reassuring,” Medzhitov told me.
Allergies as Alarm System
Still, the experiments left a lot unanswered. How precisely did the damage caused by the bee venom lead to an IgE response? And how did IgE protect the mice? These are the kinds of questions that Medzhitov’s team is now investigating. He showed me some of the experiments when I visited again last month. We sidled past a hulking new freezer blocking a corridor to slip into a room where Jaime Cullen, a researcher associate in the lab, spends much of her time. She put a flask of pink syrup under a microscope and invited me to look. I could see a flotilla of melon-shaped objects.
“These are the cells that cause all the problems,” said Medzhitov. I was looking at mast cells, the key agents of allergic reactions. Cullen is studying how IgE antibodies latch onto mast cells and prime them to become sensitive – or, in some cases, oversensitive – to allergens.
Medzhitov predicts that these experiments will show that allergen detection is like a home-alarm system. “You can detect a burglar, not by recognizing his face, but by a broken window,” he said. The damage caused by an allergen rouses the immune system, which gathers up molecules in the vicinity and makes antibodies to them. Now the criminal has been identified and can be more easily apprehended next time he tries to break in.
Allergies make a lot more sense in terms of evolution when seen as a home-alarm system, argues Medzhitov. Toxic chemicals, whether from venomous animals or plants, have long threatened human health. Allergies would have protected our ancestors by flushing out these chemicals. And the discomfort our ancestors felt when exposed to these allergens might have led them to move to safer parts of their environment.
Like many adaptations, allergies weren’t perfect. They lowered the odds of dying from toxins but didn’t eliminate the risk. Sometimes the immune system overreacts dangerously, as Richet and Protier discovered when the second dose of anemone allergen killed the dogs they were experimenting on. And the immune system might sometimes round up a harmless molecular bystander when it responded to an allergy alarm. But overall, Medzhitov argues, the benefits of allergies outstripped their drawbacks.
That balance shifted with the rise of modern Western life, he adds. As we created more synthetic chemicals, we exposed ourselves to a wider range of compounds, each of which could potentially cause damage and trigger an allergic reaction. Our ancestors could avoid allergens by moving to the other side of the forest, but we can’t escape so easily. “In this particular case, the environment we’d have to avoid is living indoors,” said Medzhitov.
Scientists are taking this theory very seriously. “Ruslan is one of the most distinguished immunologists in the world,” said Galli. “If he thinks there’s validity to this idea, I think it gets a lot of traction.”
Dunne, on the other hand, is skeptical about the idea that Medzhitov’s theory explains all allergies. Medzhitov is underestimating the huge diversity of proteins that Dunne and others are finding on the surface of worms – proteins that could be mimicked by a huge range of allergens in the modern world. “My money’s more on the worm one,” he said.
Life Without Allergies
Over the next few years, Medzhitov hopes to persuade skeptics with another experiment. It’s unlikely to end the debate, but positive results would bring many more people over to his way of thinking. And that might eventually lead to a revolution in the way we treat allergies.
Sitting on Cullen’s lab bench is a plastic box that houses a pair of mice. There are dozens more of these boxes in the basement of their building. Some of the mice are ordinary, but others are not: using genetic engineering techniques, Medzhitov’s team has removed the animals’ ability to make IgE. They can’t get allergies.
Medzhitov and Cullen will be observing these allergy-free mice for the next couple of years. The animals may be spared the misery of hay fever caused by the ragweed pollen that will inevitably drift into their box on currents of air. But Medzhitov predicts they will be worse off for it. Unable to fight the pollen and other allergens, they will let these toxic molecules pass into their bodies, where they will damage organs and tissues.
“It’s never been done before, so we don’t know what the consequences will be,” says Medzhitov. But if his theory is right, the experiment will reveal the invisible shield that allergies provide us.
Even if the experiment works out just as he predicts, Medzhitov doesn’t think his ideas about allergies will win out as quickly as his ideas about toll-like receptors. The idea that allergic reactions are bad is ingrained in the minds of physicians. “There’s going to be more inertia,” he said.
But understanding the purpose of allergies could lead to dramatic changes in how they’re treated. “One implication of our view is that any attempt to completely block allergic defenses would be a bad idea,” he said. Instead, allergists should be learning why a minority of people turn a protective response into a hypersensitive one. “It’s the same as with pain,” said Medzhitov. “No pain at all is deadly; normal pain is good; too much pain is bad.”
For now, however, Medzhitov would just be happy to get people to stop seeing allergies as a disease, despite the misery they cause. “You’re sneezing to protect yourself. The fact that you don’t like the sneezing, that’s tough luck,” he said, with a slight shrug. “Evolution doesn’t care how you feel.”
This story first appeared on Mosaic and is republished here under a Creative Commons license.