KeywordsAllergy Symptom Positive Selection Pressure Honeybee Venom Bronchial Constriction Darwinian Medicine
An excessive pathological reaction of the immune system towards environmental substances, such as foods and pollens, that are tolerated by the immune system of nonallergic individuals.
Allergies have become increasingly prevalent over recent decades, particularly in the West. As a consequence, interest has grown regarding why such a phenomenon exists in the first place, especially given the risk of experiencing a potentially fatal allergic reaction called anaphylaxis (Gross 2015). Early explanations typically viewed allergies as merely immunological errors. However, the evolutionary persistence of allergic capability suggests that it has an adaptive value for the host, of which exerted a strong enough positive selection pressure to outweigh the physiological costs and risk of fatality. Margie Profet became a notable theorist for why allergies evolved with her controversial hypothesis regarding what this benefit of allergies may have been.
The Toxin Hypothesis
In her paper published in 1991, Profet proposed the “toxin hypothesis” which argues that allergies evolved as a defense mechanism against toxins. Toxins are unfortunately ubiquitous in the natural world and cause acute bodily damage to a host. Many are also secondarily mutagenic or carcinogenic, resulting in cumulative damage by inducing mutations or cancer, respectively. While the body has other defenses against toxins, Profet suggested that allergies provide an adaptive last line of defense against those which have previously proven able to bypass the host’s primary antitoxin defense mechanisms. Given the high prevalence and danger of toxins, if allergic capability does indeed provide protection then the phenomenon may have conferred a net advantage across mammalian history, thus explaining its evolutionary retention.
To support her hypothesis, Profet described how substances which tend to trigger allergic reactions (allergens) are commonly toxic, despite this characteristic being previously overlooked and underappreciated. It appeared to her that it was no coincidence that allergenic potential is often in line with toxicity, whether in terms of acute toxicity, mutagenicity, or carcinogenicity. As she pointed out, the four most strongly allergenic metals from the natural environment (arsenic, beryllium, chromium, and nickel) are known to be unambiguously carcinogenic. She also acknowledged that some allergens do not actually appear toxic themselves but noted that in these cases they commonly act as carrier proteins for low-molecular-weight toxins, thus ultimately aiding in toxin-induced damage.
Profet argued that the manifestation of allergies shows adaptive design for protecting the body from toxins before they, and any contained or adhering mutagens, can cause damage. She reasoned that symptoms like sneezing, coughing, vomiting, and diarrhea are consistent with serving a purpose of aiding the physical expulsion of toxic allergens from the nasal passages, lungs, stomach, and intestines, respectively. Meanwhile, she suggested that other symptoms like bronchial constriction, swollen sinuses, and a drop in blood pressure are suited to help block or slow the dissemination of toxins around the body. Interestingly, the benefit of these allergy symptoms may be twofold in that they might facilitate the conditioning of avoidance behavior which reduces future toxin exposure.
Profet also described how less salient features of allergies show good design for the toxin hypothesis but contrastingly poor design for an alternative idea known as the helminth hypothesis. This hypothesis purports that allergies evolved to protect against helminths (parasitic worms) rather than toxins and consequently views allergies towards the diverse range of nonhelminth allergens as a by-product of pathogen defense. One example feature suggested by Profet as consistent with the toxin, but not helminth, hypothesis is the urgent and risky nature of allergies. Allergic reactions operate with a rapidity and severity that seems to imply design for countering threats that are able to cause serious harm within minutes or hours. Unlike toxins though, helminths do not impose serious harm in such a short time frame upon parasitizing a host. Profet reasoned that, in addition to other features, it would appear dysfunctional for allergies to have evolved this way if serving a purpose of protecting against helminths.
The toxin hypothesis received great interest from media and the general public with its novel and relatively radical view on the evolution of allergies. However, the hypothesis faced skepticism from the scientific community. Some criticism focused on Profet’s educational background, but the predominant concern was the limited evidence demonstrating that allergic capability actually helps to protect against toxins. As interest in allergies has grown within the last decade, an increasing amount of evidence for the hypothesis has emerged. Support largely comes from two major sources, including research on the association between allergies and risk of cancer and research on the protective effect of allergic capability towards venom.
Allergies and Cancer
One line of evidence commonly used for the toxin hypothesis is the observation that individuals with a history of allergies tend to have a lower risk of developing cancer. Since the early research described by Profet (1991), various meta-analyses and literature reviews have suggested that evidence for this inverse allergy-cancer correlation is substantial, most notably for the risk of glioma (e.g., Amirian et al. 2016). It is reasoned that the lower risk of cancer in allergic individuals reflects the fact that allergies protect the body from toxins, of which many are carcinogenic. However, many researchers consider that this relationship may have arisen rather fortuitously. The immunosurveillance hypothesis, for example, suggests that it occurs simply because allergies are a side effect of a hyperactive immune system that is more efficient at identifying and attacking both foreign allergens and domestic precancerous cells (Il’yasova et al. 2009). Unlike the toxin hypothesis, this suggests that it is not allergies that are reducing the risk of cancer, but the hypervigilant immune system instead. As a result, it is uncertain whether the inverse allergy-cancer correlation is appropriate to use as evidence for the toxin hypothesis.
Nevertheless, the literature on allergies and cancer can be argued as more consistent with the toxin hypothesis. For example, the toxin hypothesis predicts that the inverse allergy-cancer association should occur specifically for cancers of tissues and organ systems that are directly exposed to carcinogens from the external environment and from which the toxic substances can be expelled by allergy symptoms. Conversely, the immunosurveillance hypothesis predicts that the inverse association should be present for cancers of all tissues and organ systems. A comprehensive review of the literature conducted by Sherman et al. (2008) indicated that research findings are more often consistent with the former prediction, suggesting that the allergy-cancer association may in fact provide suitable, albeit merely correlational, evidence for Profet’s toxin hypothesis.
Allergies and Protection Against Venom
Within recent years, a line of experimental evidence has emerged that demonstrates a protective value of allergic capability. These experiments have particularly utilized venoms as they consist of highly toxic components that can cause severe and life-threatening tissue damage and, perhaps unsurprisingly, also have a high allergenic propensity. For example, Marichal et al. (2013) conducted a study in which they injected a group of mice with small doses of honeybee venom (simulating one or two stings), triggering production of venom-specific immunoglobulin E (IgE) antibodies. IgE antibodies are a critical component of the allergic response as they precipitate the release of chemicals, such as histamine, that cause the typical allergy symptoms. The research found that the mice had significantly better outcomes when challenged three weeks later with near-lethal doses of the venom compared to a naïve control group of mice. Specifically, they were three times more likely to survive, had less severe sublethal reactions, and experienced a lower risk of anaphylactic shock. Further, mice who were genetically lacking IgE or the IgE receptor, FcεRI, did not experience this acquired protective immunity against venom. The authors concluded that key elements of allergic reactivity (IgE-related responses) are critical for enhancing host resistance to harmful venoms, thus supporting the toxin hypothesis.
Profet’s hypothesis that allergies are an adaptation to protect against toxins provided a rather provocative explanation for why they exist. The idea may have initially generated criticism, but it has been increasingly advocated by the scientific community, as encouraged by the growing amount of supporting evidence. The hypothesis certainly requires more testing though and it may be worthwhile for researchers to investigate the potential benefit of allergies for a wider range of toxins, in line with the diversity of allergens. Regardless of the outcome, the hypothesis has provided a refreshing viewpoint on allergies and has stimulated novel questions for allergy research. Ultimately, it is hoped that improving the functional understanding of allergies will pave the way for some concrete developments in the prevention, diagnosis, and treatment of this growing phenomenon.
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