Allergies and Why We Have Them

I never really thought too much about allergies. I’m one of the lucky people who doesn’t suffer from them. It wasn’t until I got married to a guy who is allergic to half the world (he’d probably be ok at sea as long as he didn’t eat any sea creatures) that I really started thinking about it.

What exactly is an allergic reaction? What is actually happening inside the body to cause the sneezing, runny nose, hives, and especially life-threatening reactions like anaphylaxis? Even more confusing is why. Why would evolution give us mammals allergies?

Mammals produce special antibodies called Immunoglobulin E (IgE) antibodies, which are antibodies that are different than the normal IgM and IgG antibodies that are active when you get a viral or bacterial infection or get a vaccine. You’ve probably heard of IgM and IgG in the context of COVID. IgE antibodies are much less prevalent; there are 0.001% fewer IgE antibodies than IgG antibodies circulating in the blood[1].

During an allergic reaction, antigens (anything that provokes an immune response) from pollen, foods, or whatever you’re allergic to bind to IgE antibodies that were produced the first time you were exposed to the antigen and have since been hanging around waiting for the pollen or peanuts to attack again.

These antibodies are either floating around the blood stream or, much more often, already bound to mast cells[2], which are a type of immune cell located in humans in mucosal and epithelial tissue in areas of likely antigen entry into the body[3], for example respiratory and digestive tracts[4] where they wait for you to inhale or eat something that needs to be vanquished.

Once activated by a bound antigen, the mast cells go through a degranulation process- a process in which they release the inflammatory chemicals (like histamines) they have ready inside them all the time. This causes inflammation in the tissue affected and recruits other immune cells called eosinophils and basophils to amplify the immune response[2] even more.

The site of antigen entry into the body determines what kind of allergic reaction will occur. Inhaling pollen for example irritates the upper respiratory tract causing sneezing, congestion, and a sore throat in people with pollen allergies. When an allergen reaches the bloodstream, it can cause systemic anaphylaxis where the throat constricts so that breathing is difficult and blood pressure drops suddenly. Being injected with a medicine you’re allergic to can lead to anaphylaxis and so can bee stings in people who are allergic to bee venom. Some allergens, like peanuts, can cause systemic anaphylaxis if ingested by being quickly absorbed into the bloodstream[2]. In short, anaphylaxis does not sound fun and should probably be avoided as much as possible.

IgE antibodies evolved pretty early in mammals, before we even split into the 3 mammalian branches (monotremes, marsupials, and placental mammals) that exist today. This split occurred around 200 million years ago, so as you can imagine, these antibodies are quite old. Mast cells and basophils are found in birds and reptiles as well[5] and are therefore even older.

So why did we even evolve these overzealous immune mechanisms if all they do is make us miserable and potentially even kill us? Well, they do have some function aside from giving us the sniffles. They have also been found to protect us against helminths (parasitic worms) like hookworm. Interestingly, in communities with high rates of helminth infections, studies have found lower rates of allergies and asthma[6] as if, just like certain working dogs, the immune system needs a task, otherwise it causes chaos.

The parasitologist David Dunne’s theory is that IgE antibodies developed to quickly mount an immune response against worms, which can be incredibly destructive to the body. The faster the response, the better the chance of fighting them off.

Unfortunately for us, there is a very wide range of allergenic worm proteins that induce an IgE and mast cell response. Even more unfortunately for us, many common proteins are similarly shaped to these worm proteins and induce a similar immune response[7].

The “Hygiene Hypothesis,” proposed in 1989, theorizes that the reason the frequency of allergies has increased so dramatically since the 1950’s is because of increased hygiene levels of the modern world. Our body is not exposed to enough dirt and pathogens when we’re children and our immune system therefore overreacts to things that are not pathogens.

The early exposure to pathogens trains our body to produce more T helper 1 cells (a type of adaptive immune cell) and fewer Th2 cells which are associated more with allergies and asthma[8]. However, helminth infections are also known to increase Th2 levels, even though helminth infections lower the risk of developing allergies.

However, long term helminth infections have also been found to increase an anti-inflammatory molecule called interleukin-10 which suppresses allergic reactions[9] and inflammation so perhaps even though helminth infections lead to higher Th2 levels, they can also suppress allergic reactions as a side effect.

The “Hygiene Hypothesis” is based on the observation that industrialized and industrializing countries have much higher incidence of allergies and asthma. They also found that the children of immigrants that had moved from countries with low incidence of allergies and asthma to countries with high incidence also had rates of allergies and asthma[10] consistent with the rates of the country that their parents moved to.

Another hypothesis is that allergies evolved to keep us safe from toxins and damaging allergens. Many of the symptoms of allergies actually act as a way of expelling things from the body- sneezing, runny noses, itching, vomiting, diarrhea, etc. So perhaps it’s the body’s way of getting rid of irritating or dangerous materials that have entered the body from our external environment.

Two groups came up with a similar hypothesis that allergies are nature’s way of protecting us from unsavory environmental characters. Stephen Galli’s group injected mice with a small amount of bee venom (the amount of one or two stings from a bee), which induces degranulation in mast cells.

They then reinjected the mice with a much larger dose, potentially enough to kill them. The mice that had been exposed to a small amount of venom first had a higher likelihood of survival than those that didn’t. They even transferred just the IgE antibodies from the mice that had been exposed to bee venom to mice that had not, and even just the antibodies gave similar protection to the mice when injected with a large dose of venom.

Ruslan Medzhitov’s group performed a similar experiment with purified PLA2, the protein in bee venom that causes an allergic reaction[7]. However, PLA2 only induced an allergic reaction in its active form.

Its active form shears off certain molecules from the membrane, leading to the production of various other molecules, including one that can rupture the cell membrane, killing the cell. If you didn’t follow that- PLA2, a component in many types of venoms, leads to the production of molecules that can kill cells.

When they denatured the protein to inactivate it, it did not cause an allergic reaction or give any protection against larger doses of venom later on[11]. So in short, this hypothesis posits that allergies developed in order to protect the body by either expelling or attacking the environmental toxins, from plants or animals.

So why is there suddenly such an increase in allergies these past 50 years? Medzhitov’s theory is that in this day and age, we have created so many potentially toxic compounds and chemicals that our bodies are trying very hard to protect us from all of them[7].

Obviously, none of these hypotheses answers all the questions or has presented enough evidence to be able to decide either way. And none of these theories can explain why some of us are more prone than others to allergies. Why does my husband suffer from allergies when I, on the other hand, can eat, breathe, and touch whatever I like without a second thought? Why should he have all the bad luck and I get off so easy? Perhaps there’s a genetic component. Perhaps it’s wholly a product of the immune system’s early education. Perhaps allergies are really just a side effect of some other important immune mechanism and not a product of selective advantage. Either way, more research needs to be done to prove or disprove any of these theories.

Sources:

1. Burton, O. T., and Oettgen, H. C. (2011). Beyond immediate hypersensitivity: evolving roles for IgE antibodies in immune homeostasis and allergic diseases. Immunol. Rev. 242, 128–143.

2. Charles A Janeway, J., Travers, P., Walport, M., and Shlomchik, M. J. (2001). Effector mechanisms in allergic reactions.

3. Krystel-Whittemore, M., Dileepan, K. N., and Wood, J. G. (2015). Mast Cell: A Multi-Functional Master Cell. Front. Immunol. 6, 620.

4. Basophil, Eosinophil & Mast Cell Disorders in Allergic Disease | World Allergy Organization Available at: https://www.worldallergy.org/disease-focus/basophil-eosinophil-mast-cell-disorders-in-allergic-disease [Accessed October 1, 2022].

5. Pritchard, D. I., Falcone, F. H., and Mitchell, P. D. (2021). The evolution of IgE-mediated type I hypersensitivity and its immunological value. Allergy 76, 1024–1040.

6. Fitzsimmons, C. M., Falcone, F. H., and Dunne, D. W. (2014). Helminth Allergens, Parasite-Specific IgE, and Its Protective Role in Human Immunity. Front. Immunol. 5, 61.

7. A controversial theory may explain the real reason humans have allergies Available at: https://qz.com/689806/a-controversial-theory-may-explain-the-real-reason-humans-have-allergies [Accessed November 6, 2022].

8. Pfefferle, P. I., Keber, C. U., Cohen, R. M., and Garn, H. (2021). The Hygiene Hypothesis — Learning From but Not Living in the Past. Front. Immunol. 12, 635935.

9. Scudellari, M. (2017). News Feature: Cleaning up the hygiene hypothesis. Proc. Natl. Acad. Sci. USA 114, 1433–1436.

10. Okada, H., Kuhn, C., Feillet, H., and Bach, J. F. (2010). The “hygiene hypothesis” for autoimmune and allergic diseases: an update. Clin. Exp. Immunol. 160, 1–9.

11. Palm, N. W., Rosenstein, R. K., Yu, S., Schenten, D. D., Florsheim, E., and Medzhitov, R. (2013). Bee venom phospholipase A2 induces a primary type 2 response that is dependent on the receptor ST2 and confers protective immunity. Immunity 39, 976–985.