Allergy to the venom in bee stings may be an immune response that prepares the body to withstand a potentially fatal dose of the poison, according to new research from Stanford University School of Medicine.
For most people, a bee sting results in some temporary pain and discomfort. But a small minority have a severe allergic reaction known as anaphylactic shock, which includes a drop in blood pressure, itchy hives and breathing problems, and can cause death if not treated straight away.
Now a new study from Stanford researchers published in an online issue of Immunity provides the first experimental evidence to support the idea that allergic reactions evolved to protect the body against toxins.
They injected mice with a small dose of bee venom and showed this made them resistant to a potentially lethal dose administered later.
The study suggests that for most people, the allergic reaction does the job of priming the immune system against a bigger dose of the same venom and is not life-threatening. But for those whose reaction is severe and potentially fatal, it appears the protective mechanism has gone awry, say the researchers.
The toxin hypothesis of allergy
In earlier work the team had looked at how the innate system responds to snake venom and bee venom.
The innate immune system is the part that first engages with a toxic substance like venom that the body has not come across before.
On meeting the substance, immune cells called "mast" cells, which are found in nearly all tissues in the body, release signals that switch on certain defense mechanisms to deal with the intruder.
In their work on snake venom, the team found the mast cells produce enzymes that disarm the toxic parts and that these same cells can enhance innate resistance to honey bee venom as well.
Although the adapative immune system is much faster, the innate immune system does not need to be primed ahead of the encounter with specific antibodies (it is the adaptive immune system that makes vaccination possible).
But in allergic reactions, a type of antibody called IgE attaches to the surface of mast cells and triggers them to start an adaptive immune response.
The idea that allergies might be extreme and maladaptive examples of this type of defense was first proposed over 20 years ago but has been largely ignored by immunologists until recently.
The Stanford researchers have revived this theory, known as the toxin hypothesis of allergy, and suggest IgE might be required for protection against a lethal dose of venom.
Co-senior author Stephen Galli, professor and chair of pathology, says:
"Our findings support the hypothesis that this kind of venom-specific, IgE-associated, adaptive immune response developed, at least in evolutionary terms, to protect the host against potentially toxic amounts of venom, such as would happen if the animal encountered a whole nest of bees, or in the event of a snakebite."
IgE signaling and mast cell activation
To investigate the adaptive immune response to bee venom, the team first injected one group of mice with a low dose equivalent to one or two stings, and another control group with salt solution.
The venom group of mice developed more venom-specific immune cells and higher levels of IgE antibodies against the venom than the controls.
Then three weeks later, they injected both groups of mice with a potentially lethal dose of venom, equivalent to about five bee stings. The venom-primed group were three times more likely to survive than the controls, developed less hypothermia and did not show any anaphylactic reactions.
The team proved it was IgE antibodies at work by testing three groups of genetically altered mice - one lacking IgE, another lacking mast cells and mice whose mast cells did not have receptors capable of allowing IgE to bind to them.
They then repeated their previous pre-immunization experiment - they injected all three groups with a low dose of bee venom, and then tested if this protected them against a lethal dose. But this did not work, suggesting that protection depends on IgE signaling and mast cell activation.
The researchers also got similar results, again in mice, using venom from the Russell's viper (which is responsible for most deaths from snakebite in India) leading them to conclude the response could be generalized to different types of toxic venoms.
For obvious reasons, these experiments cannot be carried out in humans, so it is not possible to say if IgE also protects humans from the toxic effects of reptile and arthropod venoms.
Also, these venoms are complex and some have evolved ways of imitating chemicals in the human body. At the same time, mammals have evolved immune responses to venom, which in some cases may go awry.
Prof. Galli explains:
"Anaphylaxis probably represents the extreme end of a spectrum of IgE-associated reactivity, which in some unfortunate individuals is either poorly regulated or excessively robust, so the reaction itself can become dangerous to them."
Funds from the German 1 Research Foundation, the National Institutes of Health, the Max Kade Foundation, the Austrian Academy of Sciences, the Austrian Science Fund and a Marie Curie International fellowship helped finance the study.
Earlier this year, researchers writing in Antiviral Therapy described how they discovered that bee venom destroys HIV and spares surrounding cells.
Written by Catharine Paddock PhD
