Allergies such as peanut allergy and hay fever make millions of us miserable, but scientists aren’t even sure why they exist. Carl Zimmer talks to a master immunologist with a controversial answer for Mosaic

For me, it was hornets.

One summer afternoon when I was 12, I ran into an overgrown field near a friend’s house and kicked a hornet nest the size of a football. An angry squadron of insects clamped on to my leg; their stings felt like scorching needles. I swatted the hornets away and ran for help, but within minutes I realized something else was happening. A constellation of pink stars appeared around the stings. The hives swelled, and new ones began appearing farther up my legs. I was having an allergic reaction.

My friend’s mother gave me antihistamines and loaded me into her van. We set out for the county hospital, my dread growing as we drove. I was vaguely aware of the horrible things that can happen when allergies run amok. I imagined the hives reaching my throat and sealing it shut.

I lived to tell the tale: my hives subsided at the hospital, leaving behind a lingering fear of hornets. But an allergy test confirmed that I was sensitive to the insects. Not to honey bees or wasps or yellow jackets—just the particular type of hornet that had stung me. The emergency room doctor said I might not be so fortunate the next time I encountered a nest of them. She handed me an EpiPen and told me to ram the syringe into my thigh if I was stung again. The epinephrine would raise my blood pressure, open my airway, and perhaps save my life. I’ve been lucky: that afternoon was 35 years ago, and I haven’t encountered a hornet’s nest since. I lost track of that EpiPen years ago.

Anyone with an allergy has their origin story, a tale of how they discovered that their immune system goes haywire when some arbitrary particular molecule gets into their body. There are hundreds of millions of these stories. In the USA alone, an estimated 18 million people suffer from hay fever, and food allergies affect millions of American children. The prevalence of allergies in many other countries is rising. The list of allergens includes—but is not limited to—latex, gold, pollen (ragweed, cockleweed, and pigweed are especially bad), penicillin, insect venom, peanuts, papayas, jellyfish stings, perfume, eggs, the feces of house mites, pecans, salmon, beef, and nickel.

Once these substances trigger an allergy, the symptoms can run the gamut from annoying to deadly. Hives appear, lips swell. Hay fever brings sniffles and stinging eyes; allergies to food can cause vomiting and diarrhea. For an unlucky minority, allergies can trigger a potentially fatal whole-body reaction known as anaphylactic shock.

The collective burden of these woes is tremendous, yet the treatment options are limited. EpiPens save lives, but the available long-term treatments offer mixed results to those exhausted by an allergy to mold or the annual release of pollen. Antihistamines can often reduce sufferers’ symptoms, but these drugs also cause drowsiness as do some other treatments.

We might have more effective treatments if scientists understood allergies, but a maddening web of causes underlies allergic reactions. Cells are aroused, chemicals released, signals relayed. Scientists have only partially mapped the process. And there’s an even bigger mystery underlying this biochemical web: why do we even get allergies at all?

“That is exactly the problem I love,” Ruslan Medzhitov told me recently. “It’s very big, it’s very fundamental, and completely unknown.”

Medzhitov and I were wandering through his laboratory, which is located on the top floor of the Anlyan Center for Medical Research and Education at the Yale School of Medicine. His team of postdocs and graduate students were wedged tight among man-sized tanks of oxygen and incubators full of immune cells. “It’s a mess, but a productive mess,” he said with a shrug. Medzhitov has a boxer’s face—massive, circular, with a broad, flat nose—but he spoke with a soft elegance.

Medzhitov’s mess has been exceptionally productive. Over the past 20 years, he has made fundamental discoveries about the immune system, for which he has been awarded a string of major prizes. Last year he was the first recipient of the €4 million ($4,395,520) Else Kröner Fresenius Award. And though Medzhitov hasn’t won a Nobel, many of his peers think he should have: in 2011, 26 leading immunologists wrote to Nature protesting that Medzhitov’s research had been overlooked for the prize.

Medzhitov is currently turning his attention to a question that could change immunology yet again: why do we get allergies? No one has a firm answer, but what is arguably the leading theory suggests that allergies are a misfiring of a defense against parasitic worms. In the industrialized world, where such infections are rare, this system reacts in an exaggerated fashion to harmless targets, making us miserable in the process.

Medzhitov thinks that’s wrong. Allergies are not simply a biological blunder. Instead, they’re an essential defense against noxious chemicals—a defense that has served our ancestors for tens of millions of years and continues to do so today. It’s a controversial theory, Medzhitov acknowledges. But he’s also confident that history will prove him right. “I think the field will go around in that stage where there’s a lot of resistance to the idea,” he told me. “Until everybody says, ‘Oh yeah, it’s obvious. Of course it works that way.’”



Plant fever to IgE

The physicians of the ancient world knew about allergies. Three thousand years ago, Chinese doctors described a “plant fever” that caused runny noses in autumn. There is evidence that the Egyptian pharaoh Menes died from the sting of a wasp in 2641 BCE. Two and a half millennia later, the Roman philosopher Lucretius wrote, “What is food to one is to others bitter poison.”

But it was a little more than a century ago when scientists realized that these diverse symptoms are different heads on the same hydra. By then researchers discovered that many diseases are caused by bacteria and other pathogens and that we fight these invaders with an immune system—an army of cells that can unleash deadly chemicals and precisely targeted antibodies. They soon realized that the immune system can also cause harm. In the early 1900s, the French scientists Charles Richet and Paul Portier were studying how toxins affect the body. They injected small doses of poison from sea anemones into dogs, then waited a week or so before delivering an even smaller dose. Within minutes, the dogs went into shock and died. Instead of protecting the animals from harm, the immune system appeared to make them more susceptible.

Other researchers observed that some medical drugs caused hives and other symptoms. And this sensitivity increased with exposure—the opposite of the protection that antibodies provided against infectious diseases. The Austrian doctor Clemens von Pirquet wondered how it was that substances entering the body could change the way the body reacted. To describe this response, he coined the word ‘allergy,’ from the Greek words allos (‘other’) and ergon (‘work’).

In the decades that followed, scientists discovered that the molecular stages of these reactions were remarkably similar. The process begins when an allergen lands on one of the body’s surfaces—skin, eye, nasal passage, mouth, airway, or gut. These surfaces are loaded with immune cells that act as border sentries. When a sentry encounters an allergen, it first engulfs and demolishes the invader, then decorates its outer surface with fragments of the substance. Next the cell locates some lymph tissue. There it passes on the fragments to other immune cells, which produce a distinctive fork-shaped antibody, known as immunoglobulin E, or IgE.

These antibodies will trigger a response if they encounter the allergen again. The reaction begins when an antibody activates a component of the immune system known as a mast cell, which then blasts out a barrage of chemicals. Some of these chemicals latch on to nerves, triggering itchiness and coughing. Sometimes mucus is produced. Airway muscles can contract, making it hard to breathe.

This picture, built up in labs over the past century, answered the ‘how?’ part of the allergies mystery. Left unanswered, however, was ‘why?’ And that’s surprising, because the question had a pretty clear answer for most parts of the immune system. Our ancestors faced a constant assault of pathogens. Natural selection favored mutations that helped them fend off these attacks, and those mutations accumulated to produce the sophisticated defenses we have today.

It was harder to see how natural selection could have produced allergies. Reacting to harmless things with a huge immune response probably wouldn’t have aided the survival of our ancestors. Allergies are also strangely selective. Only some people have allergies, and only some substances are allergens. Sometimes people develop allergies relatively late in life; sometimes childhood allergies disappear. And for decades, nobody could even figure out what IgE was for. It showed no ability to stop any virus or bacteria. It was as if we evolved one special kind of antibody just to make us miserable.

One early clue came in 1964. A parasitologist named Bridget Ogilvie was investigating how the immune system repelled parasitic worms, and she noticed that rats infected with worms produced large amounts of what would later be called IgE. Subsequent studies revealed that the antibodies signaled the immune system to unleash a damaging assault on the worms.

Parasitic worms represent a serious threat not just to rats, but to humans, too. Hookworms can drain off blood from the gut. Liver flukes can damage liver tissue and cause cancer. Tapeworms can cause cysts in the brain. More than 20 percent of all people on Earth carry such an infection, most of them in low-income countries. Before modern public health and food safety systems, our ancestors faced a lifelong struggle against these worms, as well as ticks and other parasitic animals.

During the 1980s, several scientists argued forcefully for a link between these parasites and allergies. Perhaps our ancestors evolved an ability to recognize the proteins on the surface of worms and to respond with IgE antibodies. The antibodies primed immune system cells in the skin and gut to quickly repel any parasite trying to push its way in. “You’ve got about an hour to react very dramatically in order to reduce the chance of these parasites surviving,” said David Dunne, a parasitologist at the University of Cambridge.

According to the worm theory, the proteins of parasitic worms are similar in shape to other molecules we regularly encounter in our lives. If we encounter those molecules, we mount a pointless defense. “Allergy is just an unfortunate side-effect of defense against parasitic worms,” says Dunne.

Listing image by Flickr user: rapturedmind