Allergy sufferers, rejoice. Two new studies suggest that your sneezing and wheezing may actually protect you. Researchers report that mice that develop an allergic response to the venom in honey bee stings are more likely to survive potentially lethal doses of the same venom later on. The findings show that allergy can be beneficial and reveal some of the molecular machinery at work, but experts say the implications for humans are still unclear.
In humans and other mammals, the immune system fends off unfamiliar and potentially harmful substances, such as viruses or toxins, in one of two ways. The so-called “type 1” reaction responds to viruses, bacteria, and other microbes by destroying them, while the “type 2” reaction uses an array of symptoms—including sneezing, coughing, and diarrhea—to expel allergens from the body.
Because the type 2 response and the antibody it produces, immunoglobulin E (IgE), have been associated with resistance to worm infections, many scientists think that they evolved to protect against parasites (as opposed to microbes) but that they have no modern-day protective purpose. In the parasite-free developed world, they run rampant, reacting to benign substances such as pollen or peanuts with annoying or, in the case of anaphylactic shock (an extreme allergic reaction that can cause severe swelling and difficulty breathing), life-threatening consequences. Or so the prevailing theory goes.
But pathologist Stephen Galli of the Stanford University School of Medicine in Palo Alto, California, thought type 2 responses had gotten a bad rap. To explore the effects—and tease out potential benefits—of type 2 reactions, he and his colleagues exposed mice to a common allergen: honey bee venom. They administered a dose of the venom—about as much as found in one or two bee stings—to two strains of mice: a type 1 response-prone strain and a type 2 response-prone strain. Two control groups of the same strains received no injections.
Regardless of their predisposition to type 1 or 2 reactions, both of the “stung” mouse groups showed a type 2 response, ramping up their production of IgE antibodies specific to the venom. Then, 3 weeks later, the researchers gave all the mice a potentially lethal dose of the venom and waited to see what would happen.
“It was an answer an allergist wouldn’t expect,” Galli says. “The second time around, the mice were protected.”
Eighty-six percent of the type 1-prone mice that had had an allergic reaction survived the dose, versus only 7% of the mice that weren’t allergic. Among the type 2-prone mice, 80% of the allergic mice survived, whereas only 28% of the nonallergic mice did. The scientists saw a similar protective effect when they repeated the experiment using snake venom, which contains some of the same allergens found in bee venom.
The antibodies protected the mice even when the rodents hadn’t produced them. Injecting IgE-deficient mice with venom-specific IgE-rich blood serum was sufficient to confer protection, Galli says. And repeating the experiment in mice lacking IgE or the ability to respond to it showed no protective effect.
The results suggest that type 2 responses may have evolved to protect against venoms as well as parasites and that they’re still serving this function, the team reports today in the journal Immunity.
The defense mechanism might have helped humans survive in the challenging conditions in which we evolved, Galli says. “We spent a long time encountering venomous insects and reptiles, and it’s likely that this defense mechanism made that possible.”
In a separate study also published today in Immunity, immunologist Ruslan Medzhitov of the Yale University School of Medicine and colleagues confirm that mice with a previous type 2 response to bee venom have a greater resistance to potentially lethal doses of the stuff later on and that IgE-lacking mice miss out on this protective effect. What’s more, the team tracked down the venom ingredient that triggers the allergy—an enzyme called PLA2 that damages cell membranes and is found in the venoms of snakes, spiders, and many other creatures. The researchers worked out each step in the chain of events that leads to the type 2 reaction. The immune system sends out a surge of chemical messengers called cytokines to repair the damage done by PLA2, and that activates the type 2 response, Medzhitov says.
“As far as I know, this is the first direct evidence that IgE-mediated responses can be protective and beneficial,” Medzhitov says. “It’s like the sensation of pain: It’s very unpleasant, but very important for our protection.”
“These are very compelling, excellent studies,” says immunogeneticist Kathleen Barnes of Johns Hopkins University in Baltimore, Maryland, who was not involved in either study, “but we need to exercise caution in applying these findings in humans.” Human type 2 responses pose a number of mysteries, she says. It is unclear, for example, whether people with strong type 2 responses, who are prone to allergies, enjoy stronger resistance to venoms than the rest of us, or why type 2 response can cause life-threatening symptoms in certain individuals. The studies offer important new information, but leave these questions unanswered, she says.
Immunologist Fred Finkelman of the University of Cincinnati College of Medicine in Ohio agrees. “Together, these studies round out our understanding of the evolution of the allergic response,” he says. “But this is more the beginning of the story than the end of it.”