By Dina Fine Maron
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Millions of people suffer from hives or shortness of breath when they encounter everyday exposures such as pollens or peanuts. In their most favorable light you could think of your allergies as a really annoying super power, with telltale wheezing signaling your body senses the presence of something that you don't see or consciously smell. Despite decades of inquiry, however, scientists remain unable to pin down why allergies occur.
Because allergic reactions basically mirror the way our body responds to parasites such as worms, working to expel them through sneezes, vomiting or watery eyes, the prevailing belief among allergy experts is that allergies are just an unfortunate misdirected immune response. A pair of new studies, however, takes a fresh look at why allergies occur and provides the first evidence that those bodily responses may be no accident at all. Rather, they could be the body's way of protecting us against toxins in the environment.
This is not the first time the idea has been proposed, but these new works independently provide the first hard data to support it. By simulating honeybee stings and snakebites in mice, researchers found that exposure to these venoms can trigger a protective immune response in which the body creates specific antibodies to help neutralize the substances in future encounters. One study found that mice receiving a small dose of these venoms followed by a would-be fatal dose three weeks later had much higher survival rates than those given only the large dose. The researchers found evidence that mice receiving a small initial venom dose, akin to stings or bites, developed allergen-specific antibodies, which bind to cells throughout the body, priming them to quickly react to venoms. The papers, from researchers at the medical schools at Stanford University and Yale University are published in the November 14 issue of Immunity.
Knowing more about why venom allergies exist and tracing the molecular pathway of the immune response it elicits could have implications for understanding allergies to other things, too, the authors say. Itching, coughing or vomiting as a result of exposure to environmental irritants could signal that the body is ramping up a response to help you survive these substances in the future--or to predispose you to avoid them.
The studies fall short of settling the question once and for all of why we have allergies, however. For one, they do not provide any answers about why the immune system sometimes fatally overreacts with hypersensitive responses such as anaphylaxis, a potentially life-threatening allergic reaction that obstructs the airways and sparks a sudden drop in blood pressure. One theory, the authors posit, is these strong reactions are merely an evolutionary holdover: Anaphylaxis could just be the protective mechanism going into overdrive in a way that would have been worthwhile for our ancestors if the only other option was no protection for anyone against these toxins. The same principle may be at work with allergies as with sickle-cell anemia, says Stephen Galli, a pathologist from the Stanford team who focuses on immunology. With sickle-cell anemia, if you have two copies of the defective gene, you have a very serious disease but carrying just one copy helps protect individuals against malaria.
Generally, our immune systems have two modes for dealing with foreign substances. A type 1 response would kill an invader whereas a type 2 response would just expel it from the body. Pathogens such as bacteria and viruses, as well as infected human cells, trigger type 1, killing them. Parasites and other large external threats elicit a type 2 reaction--the expulsion strategy. Using a type 1 approach for something like allergens "would be like using a nuclear bomb to deal with street crime," says Ruslan Medzhitov, an immunobiologist at Yale who co-authored one of the papers. Because pollen and venom are not parasites, many allergists have supported the idea that the immune system's response to allergies is merely a glitch. This pair of studies, however, provides the first data suggesting why that response may be a deliberate action.
So then why do food allergies impact some 5 percent of all U.S. children when food is not directly harmful? The reasons still remain poorly understood, and these studies do not address them. Foods may have proteins that remind the body of other, harmful substances or are related to toxic plants. Thus, in the course of evolution our bodies may have unwittingly lumped them into the same category, Medzhitov says.
As for why allergies are seemingly on the rise, this work does nothing to dispel or support the so-called hygiene hypothesis, which links allergies to modern hyperclean environments. With the advent of clean water and childhoods devoid of consuming much dirt (and the millions of bacteria and viruses that come with them) the immune system does not receive the early training it needs to function correctly, the hypothesis says. A healthy exposure to those invaders leads the body to invest more in type 1 responses, including strong microbe defense, rather than type 2 reactions such as allergies.
The Stanford team simulated both bee stings and snakebites in two separate strains of mice to examine the extent to which genetics influences the immune response. They found that prior exposure to the venoms provided significant protections in both strains. When the mice were exposed to the bee venom and then reexposed three weeks later at least 80 percent survived; of the mice that were not similarly inoculated, under 30 percent managed to survive. Simulated snakebites among mice led to a similar death toll, with at least three quarters of venom-exposed mice surviving compared with only about a quarter of the control group. Moreover, in the case of honeybee venom this protection was transferable; unexposed mice injected with serum containing circulating bee-venom specific antibodies from the venom-injected mice experienced some protection when they encountered a near-lethal dose of venom 20 hours later.
The Yale team testing bee and snake venom exposures also found that after six weekly immunizations of an enzyme common across multiple venoms, mice reexposed to the enzyme after a week off were afforded better protection than their unimmunized brethren. In nature each venom may have slightly different impacts on the body in their whole form, but by focusing on this enzyme the investigators could study the molecular pathway that might trigger the body's development of antibodies to multiple venoms, potentially setting the stage for future therapies, the authors say. Not all venoms contain this particular enzyme, but the findings, coupled with Stanford's, provide new insights into allergen interactions with the body.
"It's really hard to say if this will change the way people with allergies are treated or manage it, but at least physicians can say it's not a total mystery why these allergies developed," Galli remarks. The point of these works was to figure out why allergies exist at all, so we are still far from providing therapies based on these findings, Medzhitov says. The line between protection and anaphylaxis with venom is still narrow and we still don't know what controls the transition from protective response to a deadly one, preventing any immediate treatments for now.