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Allergies May Have Evolved to Protect Against Toxins
NIAID-funded Studies Suggest a Positive Role for Allergic Responses

A honeybee extracts nectar from a flower
A honeybee extracts nectar from a flower. Credit: Wikimedia Commons (User: John Severns)

Two NIAID-funded studies in mice provide new evidence that allergic responses can protect against toxins such as bee and snake venoms. The findings were published online ahead of the November 14, 2013, print issue of Immunity.

Background

Allergies, which affect millions of people worldwide, occur when the immune system responds to harmless substances. Allergic responses involve a type of antibody called immunoglobulin E (IgE). When an allergy-prone person first encounters an allergen, the immune system produces IgE antibodies that specifically recognize the substance. These IgE molecules attach to receptors on the surface of specialized immune cells called mast cells. When the person is again exposed to the allergen, the IgE antibodies signal the mast cells to release inflammatory chemicals, such as histamine. These chemicals cause allergy symptoms such as a runny nose and itching and, in some cases, can trigger life-threatening anaphylaxis.

Many people have an allergic reaction to the venom found in bee stings or snake bites. Previously, researchers led by Stephen Galli, M.D., at the Stanford School of Medicine found in mice that mast cells can also release enzymes that break down the venoms, making the animals more resistant to venom-induced death.

Results of Studies

Extending their previous work, Dr. Galli and his team found that mice given a small dose of honeybee venom, followed three weeks later by a potentially lethal dose, were more likely to survive than animals who received only the massive dose. After receiving the initial immunizing dose—about as much venom as is found in one or two bee stings—the mice began to produce venom-specific IgE antibodies.

The scientists showed that IgE production and the antibody’s ability to attach to mast cells were essential for the protective response. Immunization did not protect mice that lack the ability to produce IgE from a large dose of venom. However, when the IgE-deficient mice were given IgE-containing serum from normal mice exposed to bee venom, they acquired resistance to the venom. In a separate experiment, the investigators also found that mice lacking IgE receptors on mast cell surfaces did not develop a protective response against honeybee venom.

The second study, led by Ruslan Medzhitov, Ph.D., at the Yale School of Medicine, focused on the major allergen in bee venom—phospholipase A2 (PLA2), an enzyme that damages cell membranes and also is a component of snake and spider venoms. The scientists found that giving mice small doses of PLA2 from bee venom elicited IgE production. Six weekly immunizations with PLA2 protected mice against a lethal dose of the enzyme. Mice lacking mast cell IgE receptors did not acquire this protection.

To determine whether other types of venom can generate similar immune responses, the Yale and Stanford teams exposed mice to various snake venoms. Giving mice small doses of venoms or PLA2 from venomous snakes efficiently induced IgE-mediated protective responses. The Stanford team found that mice immunized with a small amount of venom from a Russell’s viper, a poisonous snake common in Asia, were protected against a lethal dose of the venom.

Significance

These two studies provide the first clear experimental evidence that IgE antibody production can have a beneficial effect. The finding that IgE-mediated immune responses can protect against venom supports the theory that allergic reactions may have evolved as a defense mechanism against environmental toxins. However, the question of what determines whether the IgE response leads to protection or life-threatening anaphylaxis in humans remains unanswered.

Next Steps

Future studies will focus on identifying the various genetic and environmental factors that determine whether an IgE response to venom leads to protective immunity or anaphylaxis.

References

Marichal T, Starkl P, Reber LL, Kalesnikoff J, Oettgen HC, Tsai M, Metz M, Galli SJ. A beneficial role for immunoglobulin E in host defense against honeybee venom. Immunity (2013)

Palm NW, Rosenstein RK, Yu S, Schenten DD, Florsheim E, Medzhitov R. Bee venom phospholipase A2 induces a primary type 2 response that is dependent on the receptor ST2 and confers protective immunity. Immunity (2013)

Last Updated December 11, 2013

Last Reviewed December 11, 2013