Whether it’s to pollen or peanuts, dander, dust mites or mould, the chances are that you, or someone you know, has an allergy. Nut-free schools are now common, and teachers are often trained in how to administer adrenaline in the case of a pupil suffering a severe allergic reaction. According to figures from the European Academy of Allergy and Clinical Immunology, diagnoses of food allergy have doubled in the past decade, while the number of hospitalisations caused by severe allergic reactions has risen seven-fold. It estimates that, within ten years, more than half of Europeans will be affected by allergy.
Figures such as these have prompted many to conclude that we’re in the midst of an allergy epidemic. The reality may be slightly more complex: the prevalence of some allergies, particularly to food, may have been overestimated, while the incidence of others, such as asthma and eczema, may have plateaued, or even slightly declined.1 But allergies are certainly more prevalent than they were 50–100 years ago, and they also seem to be a peculiarly Western phenomenon
Why should this be? One popular theory is that the rise in allergies is the price we must pay for increased cleanliness and fewer childhood infections. This so-called ‘hygiene hypothesis’ of allergic disease was first proposed in 1989, but subsequent studies have refuted the idea that reduced exposure to pathogens is the cause. More likely, it’s a lack of exposure to the myriad of microorganisms and parasites that were present in hunter-gatherer times when our immune systems were evolving that might be prompting them to overreact.
The good news is that a better understanding of how the immune system regulates itself – and how organisms such as parasites subvert this system – is spurring the development of new treatments for allergy, and even raising the prospect of a cure.
The advantages of old friends
Some of the strongest evidence for this ‘old friends mechanism’ comes from studies of people infected with parasitic worms, like hookworm. Severe hookworm infection is a major cause of anaemia and malnutrition in developing countries, and because this adversely affects school attendance and educational attainment, many have initiated deworming programmes. Professor Alison Elliott, who directs the Co-Infections Programme at the Medical Research Council’s Uganda unit, has been investigating the impact of deworming on women and their children living on the shores of Lake Victoria. “We’ve found that if the mother had an infection – particularly hookworm – during pregnancy, then her baby was less likely to develop eczema,” Elliott says. What’s more, treating women with the deworming drug albendazole during pregnancy significantly increased the chances that their baby would have eczema.2
There’s supporting evidence from developed countries too. For instance, allergies seem to be more prevalent in city-dwellers compared to people who live in the countryside. One recent study by Professor Ilkka Hanski at the University of Helsinki in Finland found that people living near farms and forests had far more diversity in the types of bacteria living on their skin – including the presence of a genus called Acinetobacter , which seem to encourage immune cells to secrete an anti-inflammatory substance called IL-10.3 Other studies have suggested that exposure to a cowshed during the first six months of life reduces allergy risk – probably for similar reasons.
What is happening here? Allergic reactions are a normal immune response to foreign invaders, occurring in an inappropriate context. Their purpose is to expel the foreign particles – be they a bacterium, parasite, or piece of pollen – from the body, which is why airborne allergies make us sneezy, snotty and weepy, while allergies to food often trigger diarrhoea. In the case of harmful organisms, this makes perfect sense. But most of the proteins that trigger allergic reactions – called allergens – are quite harmless. What’s interesting about them though, is how much they have in common with the few proteins that distinguish our own tissue from that of parasitic worms. Increasingly, immunologists suspect that the reason we have allergies could be because the immune system evolved to recognise these proteins and react to them.
“I can’t think of any evolutionary advantage to having allergies, but there were advantages to getting rid of worms – or at least keeping their numbers down to a modest level,” says Elliott. Because of this, parasites have themselves evolved strategies to dampen down the immune system. For most of human history then, ‘old friends’ like worms have lived in a kind of equilibrium with the human immune system, to the point where our immune cells expect them to be there. In their absence, these immune cells could become overactive.
Admittedly, this is unlikely to be the only factor contributing to the rise in allergies in recent decades. A citizen science project called #BritainBreathing from the British Society for Immunology, University of Manchester and Royal Society of Biology is currently gathering symptom data from large sections of the allergic population via a mobile app to try to unpick some of these factors. For instance, in the case of hay fever, pollution has been shown to modify the structure of pollen proteins to make them more allergenic, and the intensification of agriculture has increased the likelihood of vast clouds of allergenic pollen forming in localised areas. We’re also being exposed to new pollens, such as ragweed, thanks to the introduction of foreign plant species from abroad.
Even so, increasing the diversity of microbes that we and our children are exposed to may be a simple way to reduce the chances of our immune systems developing a reaction against them in the first place. This doesn’t mean not washing our hands – the sorts of microbes that cause food poisoning or other illnesses don’t seem to be the ones that have a protective function. Instead, it means breastfeeding our babies, avoiding unnecessary use of antibiotics that deplete our microbes, and spending more time in the countryside where many of these benefi cial bugs are thought to be found.
What about people with established allergies? To date, there’s little evidence that boosting our exposure to a broad repertoire of microbes can cure allergies. Attempts to curb symptoms of hay fever or asthma by deliberately infecting people with parasites such as hookworm and whipworm, for instance, have so far yielded variable results. Infecting people with live worms is also far from ideal, since they can make some people very ill.
However, work is underway to better understand what parasites are doing to the immune system, in the hope of replicating, or even improving on it. One such group is headed by Professor Rick Maizels at the University of Glasgow. He has been collecting some of the molecular fl ak that parasites such as the intestinal roundworm, Heligmosomoides polygyrus, (which infects mice) release in order to suppress the immune system of their hosts. Of particular interest is a protein called allergic response inhibitor (ARI), which seems to interfere with signalling by an immune system protein called IL33. “IL33 is like an alarm signal given out by the host’s cells,” says Maizels. “It seems to be the spark that initiates the allergic response.” Indeed, when Maizels and his team purifi ed ARI and injected it into mice, it protected them against the development of allergies in the same way that infecting them with whole parasites would. They are now testing whether the same protein can reverse established allergy.
Although H. polygyrus is a mouse parasite, and ARI is therefore intended to suppress the immune systems of mice, the gene for IL33 has also been implicated in human allergies – particularly asthma. Pharmaceutical companies are now trying to develop monoclonal antibodies to IL33 for the treatment of asthma. However, “we think what the parasite is doing is a bit cleverer because it is starting upstream of IL33, at the very beginning of the signalling pathway,” Maizels says. This could potentially make it more effective: bolting the stable door, rather than trying to catch the horse once it has already bolted. But ARI is less effective in human cells, so its structure may need to be tweaked if it is ever to be used in people.
Re-education of immune cells
Both ARI and existing allergy treatments, such as antihistamines, work by suppressing the immune response. But what about trying to re-educate immune cells so that they no longer mistake these proteins for enemies? That’s the idea of desensitisation therapy: currently the closest thing we have to a cure for allergy. Here, immune cells in the lymph nodes are exposed to increasing doses of the problematic allergen – either through regular injections, or drops or tablets under the tongue. Though the precise mechanism remains unclear, this exposure prompts the development of regulatory T cells, which act as a brake on immune responses, ultimately resulting in tolerance of the antigen.
Desensitising immunotherapy is time-consuming and expensive, so for now it’s only used for those with severe allergies – although researchers are investigating new ways of delivering allergens, which could make it practical for a larger number of people. It also carries a risk of anaphylaxis, a severe allergic reaction which involves the whole body and can be life-threatening. Finding new ways to stimulate the body’s natural mechanisms of reining in wayward immune responses and inducing tolerance is therefore a major objective for many immunologists. Maizels is investigating another parasitic protein that seems to directly mimic a signalling molecule the body uses to stimulate the production of regulatory T cells, which are specialised immune cells that can shut down infl ammation. Other researchers, meanwhile, are focusing their efforts on the allergens that initiate allergic responses in the first place.
A two-step process
The development of allergies is a two-step process. The fi rst stage occurs the fi rst time an allergy-prone person is exposed to a substance such as pollen or pet dander, and involves the presentation of fragments of allergen to helper T cells, which then stimulate B cells to produce IgE antibodies against it. These circulate until they encounter another type of immune cell called a mast cell. These loiter in barrier sites of the body, such as the skin and lungs, and then grab onto the antibodies that pass by and keep hold of them. The next time you encounter that allergen – even if it’s not for months or years later – those primed mast cells will bind to it and become activated.
“Mast cells are packed with chemical weapons like histamine, and once they’re activated they immediately start spewing out these chemicals,” says Dr Sheena Cruickshank, who studies the initiation of immune responses at the University of Manchester. These chemical payloads help to recruit more immune cells to the site, make the blood vessels leaky (so these immune cells can get into the tissue), and help to produce mucus; the result is swelling, the secretion of fluid to try and fl ush the invader away, and the triggering of explosive responses like sneezing. “Mast cells are very good at protecting against infections, so they are important cells, but unfortunately in allergy they are bad,” says Cruickshank.
Context is everything
As well as helping B cells to produce antibodies, T cells are also involved in infl uencing the behaviour of mast cells and other cells involved in mounting an immune response. But the context in which the T cell sees the allergen is extremely important: if IgE antibodies on mast cells have bound to the allergen and triggered infl ammation, T cells will amplify that response. If the T cell encounters the allergen in the absence of infl ammation, it will encourage the development of regulatory T cells, ultimately resulting in tolerance. “We think T cells are what really create and sustain the allergic response,” says Mark Larché at McMaster University in Ontario, Canada.
Crucially, T cells respond to fragments of allergens, whereas mast cells need to see the whole thing in order to become activated. So Larché is searching for short stretches of amino acids within allergens that have the properties enabling T cells to see them. “The idea is that we get rid of all the elements that trigger allergic responses, whilst retaining the important stuff that can be used to target T cells,” he says.
So far, his team has identifi ed a number of short peptide sequences from cat dander, grass pollen and house dust mite, which are currently in phase 2 and 3 clinical trials. In one such trial, volunteers who were injected with the cat dander peptides four times over the course of three months, reported a 3.9-point improvement in their allergic symptoms. This compares with an average 1.1-point improvement for traditional immunotherapy, which involves regular injections over several years. They also reported fewer adverse events with peptide therapy compared to traditional immunotherapy.4 Further studies are ongoing.
While it’s too early to say whether such approaches will truly yield a cure for allergy, these insights into the crosstalk between immune cells and the delicate balance it maintains between suppression and infl ammation are at least grounds for optimism. At the moment, you’d be hard pushed to find a classroom without at least one allergy sufferer in it; perhaps in another 50 years this debilitating condition will once again be viewed as an anomaly rather than the norm.
This article was written by Linda Geddes as part of the BSI's report '60 years of immunology: past, present and future'. This article is licensed under Creative Commons Attribution-NoDerivative Licence (CC BY-ND 4.0). Additional permissions may need to be sort from image licence owners.
- House of Lords 2007 The extent and burden of allergy in the United Kingdom. Chapter 4 in: Select Committee on Science and Technology – Sixth Report
- Mpairwe et al. 2011 Pediatric Allergy and Immunology 22 305–312
- Hanski et al. 2012 Proceedings of the National Academy of Sciences 109 8334–8339
- Patel et al. 2013 Journal of Allergy and Clinical Immunology 131 103–109