bee sting allergy could be a defense response gone haywire.pdf

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11/1/13 Bee sting allergy could be a defense response gone haywire

www.sciencedaily.com/releases/2013/10/131024121448.htm

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Oct. 24, 2013 For most people, a bee sting causestemporary pain and discomfort, but for thosew ith abee venom allergy, the consequences can bedevastating: They experience anaphylactic shock,

including a drop in blood pressure, itchy hives andbreathing problems, and may die ifnot prom ptlytreated.

New findings by Stanford UniversitySchool of Medicine scientists mayprovide an evolutionary explanation forsevere allergic reactions. In a paper tobe published online Oct. 24 in Immunity,the researchers show that mice injectedwith a small dose of bee venom werelater resistant to a potentially lethal doseof the same venom. The study is the firstexperimental evidence that the sameimmune response involved in allergiesmay have evolved to serve a protectiverole against toxins.

The study builds on earlier work by the researchers,characterizing the innate immune response to snake venom andhoneybee venom. Innate immune responses occur in subjectsexposed to a foreign substance, such as a pathogen or a toxicmaterial like venom, for the first time. Immune cells called mastcells, which reside in most of the body's tissues, are poised tounleash signals that turn on defense responses when a pathogenor toxin intrudes. In a previous study, the researchers found thatmast cells produce enzymes that can detoxify components ofsnake venom, and that mast cells can also enhance innateresistance to honeybee venom.

Such innate immune responses do not require priorimmunization or the development of specific antibodies. By

contrast, during an adaptive immune response, the immunesystem generates antibodies that recognize the invadingpathogen or toxin; this process makes it possible to vaccinateagainst infectious diseases. Adaptive immunity is usually afaster, more specific and more effective form of defense thaninnate immunity.

In allergic reactions, a type of antibody called IgE binds to thesurface of mast cells and prompts them to initiate an adaptiveimmune response when exposed to the antigen recognized bythat IgE. "The functions of IgE and mast cells are mostly knownin the context of allergies," said Thomas Marichal, DVM, PhD, apostdoctoral scholar and co-lead author of the study.

"It was kind of a dogma that most IgE-related responses aredetrimental," said postdoctoral scholar Philipp Starkl, PhD, theother lead author. "We and others speculated that there shouldbe some very positive evolutionary pressure to keep these cellsand these antibodies, because if they were just bad and

deleterious, they would have been eliminated."

The researchers hypothesized that IgE might be required forprotection against a lethal sting, and that allergies are anextreme, and maladaptive, example of this type of defense. Thisidea, known as the toxin hypothesis of allergy, was firstproposed by Margie Profet in 1991, but was largely ignored byimmunologists until recently.

To find out whether adaptive immune responses could help miceresist bee venom, Marichal and Starkl first injected mice with alow dose of venom equivalent to one or two stings. The micedeveloped more venom-specific immune cells, and higher levelsof IgE antibodies against the venom, than control mice injectedwith a salt solution.

Three weeks later, they injected both groups of mice with apotentially lethal dose of venom, similar to five bee stings. Theimmunized mice had less hypothermia and were three timesmore likely to survive than the control mice. Moreover, they did

Health & Medicine

Immune System

Allergy

Lymphoma

Plants & Animals

Mice

Frogs and Reptiles

Genetically Modified

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Immune system

Allergen

Natural killer cell

T cell

Bee sting

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Bumblebee. For most people, a bee sting causes

temporarypain and discomfort, but for those with abee venom allergy, the consequences can bedevastating: They experience anaphylactic shock,including a drop in blood pressure, itchy hives andbreathing problems, and may die if not promptlytreated. (Credit: tr3gi / Fotolia)

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Bee Sting Allergy Could Be a Defense Response Gone Haywire

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MLA

not develop the anaphylactic reactions characteristic of severeallergies.

To determine whether IgE antibodies were required for thisprotection, the team tested mice with three types of mutations:mice without IgE, mice without functional IgE receptors on theirmast cells, and mice without mast cells. The IgE-deficientmutant mice were previously developed by Hans Oettgen, MD,PhD, associate professor of pediatric immunology at HarvardMedical School and a co-author of the study.

In all three groups of mutant mice, pre-immunization with a lowdose of bee venom did not confer protection against a lethaldose, suggesting that the protection depends on IgE signalingand mast cell activation. "That was pretty exciting for us," said

Marichal. "It was the first time we could see a beneficial functionfor these IgE antibodies."

Pre-immunization with a low dose of venom from the Russell'sviper also protected mice from a higher dose of venom from thissnake, which is one of the "big four" species responsible formost snakebite deaths in India. So the researchers believe theresponse could be generalized to different types of toxic venoms.

"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 againstpotentially toxic amounts of venom, such as would happen if theanimal encountered a whole nest of bees, or in the event of asnakebite," said Stephen Galli, MD, professor and chair ofpathology and the co-senior author of the study. "Anaphylaxisprobably represents the extreme end of a spectrum of IgE-associated reactivity, which in some unfortunate individuals iseither poorly regulated or excessively robust, so the reactionitself can become dangerous to them."

Galli cautioned that it's not yet known whether IgE responsesalso protect humans from the toxic effects of arthropod or reptilevenom, but it would be unthinkable to test lethal doses of venomin humans. Reptile and arthropod venoms are complex chemicalcocktails. Some venom components have evolved to mimicchemicals made by the human body, such as endothelin-1,which causes blood vessels to constrict during bacterialinfections. At the same time, mammals have evolved immuneresponses to venom, which in some cases escalate intomaladaptive allergic react ions.

"We experience allergies in a much cleaner world, where wedon't have the same threats of venomous creatures andpotentially toxic food that existed for much of our evolutionaryhistory," said Galli. "And so we're left with this residual type ofreactivity that seems completely mysterious and pointless andharmful. This is the first evidence, that we know of, indicatingthat IgE-associated 'allergic-type' immune responses can

actually reduce the toxicity of naturally occurring venoms."

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The above story is based on materialsprovided by StanfordUniversity Medical Center. The original article was writtenby Molly Sharlach.

Note: Materials may be edited for content and length. Forfurther information, please contact the source cited above.

Journal Reference:

1. Thomas Marichal, Philipp Starkl, Laurent L. Reber, JanetKalesnikoff, Hans C. Oettgen, Mindy Tsai, Martin Metz,Stephen J. Galli. A Beneficial Role for Immunoglobulin Ein Host Defense against Honeybee Venom. Immunity, 24October 2013 DOI: 10.1016/j.immuni.2013.10.005

Need to cite this story in your essay, paper, or report? Useone of the following formats:

Stanford University Medical Center (2013,October 24). Bee sting allergy could be a defenseresponse gone haywire. ScienceDaily. RetrievedNovember 1, 2013, fromhttp://www.sciencedaily.com/releases/2013/10/131024121448.htm

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advancing our understanding of the properties ofvenom as a potential resource for drug development.... > read more

Venomous Catfish Described (Dec.4, 2009) In contrast to theexhaustive research into venomproduced by snakes and spiders,

venomous fish have been neglected and remainsomething of a mystery. Now, a study of 158catfish species has ... > read more

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