Human reactions to bee venom can be categorised as local or systemic, and systemic responses can be anaphylactic or toxic. All elicit either Type 1 or Type 2 responses from the immune system. Science writer Dave Black explains how each of those present on humans and how beekeepers might be at greater likelihood to react severely, but how more stings might just be the best medicine…
It goes without saying that beekeepers have an occupationally high probability of being stung, and a far greater exposure to bee-related antigens than the general population. They have a greater risk of allergy and anaphylaxis, and yet there are plenty of beekeepers who tolerate stings daily, and who have worked for decades with no ill-effects. How do we assess the risk? Are beekeepers born or made? Are they the peculiar group of self-selected individuals we think they are, or can anyone learn to put up with irregular doses of bee venom?
Answering questions like this is difficult, and despite all we know it’s still not possible to predict with any certainty individuals who will either develop a progressive tolerance, or who could be tipped into a sudden and possibly fatal allergy. Lots of things make this a tricky topic to study. Bee venom has been examined pretty thoroughly and there are many constituents that someone might be sensitive to, either individually or in combination; it challenges the entire immune system. Some constituents may not be allergenic but are actually toxic to various degrees.
Honeybee venom is different, but similar, to other hymenopteran (the order of insects which includes bees, wasps and ants) venoms, and varies with bee age, species, season, locale, forage, and so on. No two stings are ever the same. Human immune systems also differ, are not particularly well understood, and researchers find testing people with potentially life-threatening allergens um… challenging. Public Health statistics are a bit vague, beset with misreporting, diagnostic uncertainty, methodological differences and disagreement about nomenclature. A lot of myth and anecdote.
When we are stung, on average, 140–150μg of venom is delivered in the first 20 to 30 seconds (ie. 95% of it) and the median lethal dose (LD50) of whole bee venom is known to be between 2.8 and 3.5mg of venom per kg of human body weight. Someone weighing 60–70kg has a 50% chance of death upon being stung by 1,000–1,500 bees, even without any allergy, and it can be much less. The severity of the effects that result from the ‘envenomation’ is determined mostly by victim age, body weight, number of stings, and individual characteristics of the victim like pre-exiting diseases and allergies.
Two Types of Response
Immune systems are often thought of in terms of two basic types, based on the kind of pathogen they can deal with. Type 1 immunity specialises in micro-organisms by recognising them and providing ways to directly neutralise them. In contrast, Type 2 immunity is not particularly specific, but focused on macro-organisms (intestinal worms for example) and various kinds of ‘contaminants’ (like venom) that threaten the host. We are all able to deploy both to a greater or lesser extent. Type 2 responses tend to create defences that block the irritant, or facilitate its expulsion, so producing lots of mucus and getting a runny nose would be considered a Type 2 immune response. Whereas a Type 1 response would destroy the virus, if there is one, or the cells that contain it.
Local versus Systemic
The reaction to insect stings can be also be classified as either local responses or systemic responses. Local inflammatory reactions are characterized by pain, swelling and itching at the sting site. These reactions are experienced by most non-allergic individuals and are normally resolved within 24h. Some people (about 30%) develop a large local reaction, which involves a slow swelling more than 10 cm in diameter and lasting more than 24h, and which intensifies and reaches its largest size after 24-48h. The swelling may be accompanied by fever or headache, or an inflammatory reaction along the lymphatic vessels, but this improves slowly and gradually over several days. Large local reactions may be life-threatening if the swelling restricts your airway, but the risk of a systemic reaction is not significantly increased in the case of subsequent stings.
Anaphylactic versus Toxic Reactions
Systemic (anaphylactic) reactions, and systemic (toxic) reactions are generalised, ‘hypersensitive’, responses to either allergens or toxins in the venom that affect the whole body, not just the part that has been stung. Hypersensitve individuals show a reaction within five to ten minutes. Toxic reactions are ‘dose-dependant’ (lots of stings); anaphylactic reactions are not. Anaphylactic immune reactions are extreme Type 2 responses and are considered a bit of a puzzle. There is no obvious reason why sometimes the body should initiate a Type 2 response with such extreme urgency, within minutes of exposure, to tiny amounts of venom.
Allergic hypersensitivity can develop against a huge variety of allergens that have little in common in terms of their structure or origin, and clearly, most allergens do not have any similarity with the immunogenic activities of macro-parasites. Pollen, bee venom, shellfish, peanuts, latex, and penicillin are all possible allergens for some people, but they do not have any chemical or physical characteristics in common that would explain why they might be considered noxious.
For many years ‘hypersensitive’ (anaphylactic) Type 2 immune responses have been thought of as extreme cases of ‘misdirection’, an unintended and unlucky side-effect of a mostly functioning immune system. That idea is now being reassessed. A hypersensitivity to allergens may have evolved to ensure we avoid unfavourable environments in future, while allergic reactions themselves (mucus overproduction, sneezing, itching, etc.) are engaged in the present to reduce exposure and promote expulsion of unwanted environmental substances.
Why does this sensitivity vary so much? One possibility is luck, but it may be a consequence of our individual physiologies. For example, if protection from a noxious foreign substance can be conferred by both a thicker membrane and detoxification, the individual that has enhanced detoxification capacity need not resource a strong barrier.
The Confounded Beekeeper
Various surveys in EU and the USA in the 1980s and 1990s have reported systemic reactions to bee stings in 1–4% of the general population. In the more exposed population of beekeepers 14–32% report systemic reactions[i] [ii] [iii] [iv]. As a group, beekeepers confound the results of nearly all the studies so far. Risk factors derived from studying the general public don’t seem to apply[v]. Sensitization to bee or wasp venom occurs frequently in tests, with studies reporting 27.1% to 40.7% of the general population having detectable specific antibodies to Hymenoptera venom[vi]. Based on previous work, it is known that positive results of diagnostic allergy tests, including skin tests and venom-specific immunoglobulin assays, are found in 30–60% of beekeepers.
Beekeepers have elevated levels of a venom-specific antibody called IgE (immunoglobulin ‘E’) known to be associated with allergic hypersensitivity. Yet, like beekeepers, many people who develop IgE-dependent Type 2 immune responses to honeybee venom do not exhibit anaphylactic reactivity despite having these specific IgE antibodies. It is also known that a different honeybee venom specific antibody, IgG4 (part of a Type 1 response), is particularly high in the beekeepers’ group. Moreover, the higher the number of stings in the beekeepers, the higher the concentration of specific IgG4 antibodies (sIgG4). These seem to be a feature of an acquired tolerance to honeybee venom in the beekeepers.
In the general population increasing age is a risk factor for venom hypersensitivity, but among beekeepers clinical symptoms after bee stings were less severe with the increasing age of the beekeepers. This correlation may be due to the fact that older beekeepers have higher sIgG4 levels that provide better protection. Systemic reactions were observed in 45% of beekeepers with fewer than 15 stings annually, but in none of those with more than 200 annual stings (so about one every other day). The older beekeepers have been exposed to bee venom allergens for longer than the younger ones, which somehow causes a natural desensitization. Infrequently stung beekeepers are at the highest risk.
Of Mice and Men
In recent years studies in experimental animals have produced a growing body of evidence that indicates it’s the same IgE-dependant pathways that enhance the resistance of mice to poisons from snakes, scorpions, and honeybees, in subsequent exposures[vii]. Mice with a previous Type 2 response to a normal dose of bee venom have better survival rates to potentially lethal doses of venom on a later occasion, and mice who lack IgE (due to a genetic abnormality) missed out on this protective effect[viii]. It’s proposed that a form of Type 1 immune interaction with Type 2 immune responses reduces the pathology associated with these responses, while maintaining an ability to learn about protecting us from a good dose of toxic venom[ix].
The 19th century German philosopher Friedrich Nietzsche observed “Was mich nicht umbringt, macht mich stärker”, translated to the often misused “What doesn’t kill me, makes me stronger”. There’s no reason to think he had honeybees in mind, but it seems particularly apt here.
Dave Black is a commercial-beekeeper-turned-hobbyist, now working in the kiwifruit industry. He is a regular science writer providing commentary on “what the books don't tell you”, via his Substack Beyond Bee Books, to which you can subscribe here.
References
[i]Ulrich R. Muller, Bee venom allergy in beekeepers and their family members. Current Opinion in Allergy and Clinical Immunology 2005, 5:343–347
[ii]K Münstedt M Hellner, D Winter, R von Georgi, Allergy to Bee Venom in Beekeepers in Germany, J Investig Allergol Clin Immunol 2008; Vol. 18(2): 100-105 PMID:18447138
[iii]Alex G. Richter, Peter Nightingale, Aarnoud P. Huissoon, and Mamidipudi T. Krishna, Risk factors for systemic reactions to bee venom in British beekeepers, Ann Allergy Asthma Immunol. 2011;106:159 –163. doi:10.1016/j.anai.2010.11.005
[iv]Bousquet J, Menardo JL, Aznar R, Robinet-Levy M, Michel FB. Clinical and immunologic survey in beekeepers in relation to their sensitization. J Allergy Clin Immunol. 1984;73:332-40
[v]Matysiak J, Matysiak J, Bręborowicz A, Kycler Z, Dereziński P, Kokot ZJ. Immune and clinical response to honeybee venom in beekeepers. Ann Agric Environ Med. 2016; 23(1): 120–124. doi: 10.5604/12321966.1196866
[vi]Gunter J. Sturm, Bettina Kranzelbinder, Christian Schuster, Eva M. Sturm, Danijela Bokanovic, Jutta Vollmann, Karl Crailsheim, Wolfgang Hemmer, and Werner Aberer, Sensitization to Hymenoptera venoms is common, but systemic sting reactions are rare. 2013 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaci.2013.10.046
[vii]Marichal & Starkl et al, A Beneficial Role for Immunoglobulin E in Host Defense against Honeybee Venom, Immunity 39, 963–975, November 14, 2013, http://dx.doi.org/10.1016/j.immuni.2013.10.005
[viii]Marichal, T., Starkl, P., Reber, L.L., Kalesnikoff, J., Oettgen, H.C., Tsai, M., Metz, M., Galli, S.J., 2013. A Beneficial Role for Immunoglobulin E in Host Defense against Honeybee Venom. Immunity 39, 963–975. https://doi.org/10.1016/j.immuni.2013.10.005
[ix]Stephen J. Gallia, Martin Metz, Philipp Starkl, Thomas Marichal, Mindy Tsai, Mast cells and IgE in defense against lethality of venoms: Possible “benefit” of allergy, AllergoJInt. 2020 March ; 29(2): 46–62. doi:10.1007/s40629-020-00118-6.
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