First experimental proof supporting the toxin hypothesis

To verify the potential protective effect of IgE against honeybee venom, the researchers repeated the experiment with three types of transgenic mice: those incapable of synthesising IgE, those deficient in IgE receptors and those deficient in mast cells.  “In all three cases, protection against honeybee venom had disappeared”, Thomas Marichal reveals. “This shows that IgE, known for being noxious and considered as being the product of an immune dysfunction, can have a beneficial effect in the host’s response to a well-known allergen in humans”. These tests were also done with venom from a specie of viper and the same results – the same protective effects -, were observed.

This is the first experimental proof of a controversial hypothesis that was already suggested in 1991 by Margie Profet, i.e. the toxin hypothesis. “Margie Profet suggested that allergic reactions were immunological defense mechanisms against toxins”, explains Thomas Marichal. “This hypothesis was largely ignored by the scientific community. It was already known that the Th2 response could have a beneficial effect in defense against macroparasites such as intestinal worms. Consequently, many scientists believed that all allergies were the price to pay for defense against these parasites", the researcher continues. “But we have clearly demonstrated here that IgE help to protect against toxins!”

The scientists suggest a mechanism by which IgE exert their protective effect against the two types of venom tested. During a second exposure to these venoms, the mast cells may be rapidly activated by the IgE and may release substances (especially proteases) capable of degrading and neutralizing the toxins present in these venoms. Hence, a decrease in toxicity and, consequently, an increase in the survival of the animals.

Changing our conception of IgE

According to the authors of this study, published in the journal Immunity(1), acute and potentially fatal allergic reactions may be just a very small part of a spectrum of reactions mediated by IgE. In the case of allergies to venoms, a dysfunction of the immune system is indeed involved but, for the majority of people, after an initial exposure to the venom, the IgE might be able to produce a beneficial effect against toxic substances in the case of further exposure to them. This notion is supported by clinical observations showing that only a minority of people having developed IgE against honeybee venom develop acute and potentially fatal reactions when exposed to the venom again. Scientists would like to identify which factors determine whether the IgE are more likely to induce a harmful or protective reaction.

“From a fundamental point of view, this discovery answers a basic question associated with the usefulness and conservation of IgE and allergic responses over the course of evolution. It is the first direct evidence of the beneficial and protective role of IgE against toxins. This will certainly modify the way scientists think about allergies and, in the future, could lead to the development of vaccines in order to protect us against toxins and other environmental threats", Thomas Marichal concludes.

(1) Marichal Thomas*, Starkl Philipp* (* co-first authors), Reber Laurent L., Kalesnikoff Janet, Oettgen Hans C, Tsai Mindy, Metz Martin**, Galli Stephen J** (** co-corresponding authors). A beneficial role for Immunoglobulin E in Host Defense Against Honeybee Venom, Immunity (2013), http://dx.doi.org/10.1016/j.immuni.2013.10.005.