Pharma & drug development

Answers from dust

Children who grow up on farms have a far lower risk of asthma and other respiratory allergies, and recently researchers found out why. Study author Martijn Schuijs explains how the discovery could pave the way for a vaccine against asthma.

Might living on a farm protect a child from allergies, hayfever and asthma? On the surface, this sounds like a strange question, but in fact the link is well-established. Children who have grown up on farms – dairy farms in particular – benefit from a far lower incidence of respiratory allergies, with folk wisdom borne out by a number of studies.

When Poland became part of the EU, for instance, many people moved from rural settings, where they had worked on farms, into cities. This precipitated a documented spike in the incidence of asthma.

Various researchers have asked why this might be, generally looking for some variant on the ‘hygiene hypothesis’. This hypothesis, often invoked to explain high rates of asthma in the developed world, suggests that children who grow up in too-clean household environments lack the necessary germ exposure to ‘educate’ their maturing immune system. This in turn may contribute to the development of asthma.

If children living on farms are exposed to a wider range of microbes during their development (as one 2011 paper confirmed) then this could go some way towards explaining their low risk of allergies.

However, the hygiene hypothesis taken alone doesn’t provide a very comprehensive explanation. Only recently have scientists found true evidence of a causal mechanism linking farms with immunity to asthma.

According to researchers from Ghent University and the Flemish Institute for Biotechnology, who published their findings in the journal Science in September, the secret may lie in dust. It appears that bacteria in farm dust and manure trigger a specific immune response in young children, with a protein in the lung tissue, A20, playing a key role in regulating this reaction.

Endotoxins and allergies

The researchers’ first steps involved mice. Every other day, for two weeks, they exposed mice to a low dose of lipopolysaccharides (LPS), otherwise known as endotoxins, which are molecules found in the outer membrane of certain bacteria. After the two weeks were up, they exposed the mice to house dust mites, to see whether or not this triggered an allergic reaction. While the control group did indeed show signs of allergy, the mice that had been exposed to endotoxins did not.

“We found that mice treated with LPS were protected from the development of asthma. Since farm dust also contains LPS, amongst other things, we also investigated the possible protective role of farm dust in our model. Like LPS, farm dust was able to protect the mice from asthma in a similar way,” says study author Martijn Schuijs, of the VIB Inflammation Research Center at the University of Ghent.

After dissecting the results more closely, the researchers found the regulatory protein A20 was more highly produced in LPS-treated mice than in the controls.

To confirm this was the case, the researched created genetically modified mice that could not express the A20 protein in their lungs. When these mice were exposed to farm dust, followed by house dust mites, the farm dust had no protective effect and the mucous membrane was unable to reduce the allergic reaction.

“Genetically deleting the A20 molecule ensures the immune response and the production of pro-inflammatory cytokines will be dampened much more slowly, resulting in an elevated immune response,” explains Schuijs. “Normally after farm dust treatment, the mice expressed much higher levels of this A20 molecule, which could explain why farm dust can protect them from mounting an overactive immune response to house dust mites, leading to allergies and asthma.”

From mouse to man

The researchers then went on to test their hypothesis in cell samples from humans, taken from lung biopsies. Here, they found exactly the same effect in action – human bronchio-epithelial cells were protected against the development of asthma when pre-treated with LPS or farm dust. They also checked A20 levels in asthmatic subjects versus controls, and discovered that the asthma patients had a lower expression of the molecule than the non-asthmatic cohort.

Finally, they looked at data from 1,700 children who had grown up on farms. Despite the protective effects of farm dust, some of these children had gone on to develop asthma and other respiratory allergies. It turned out these children had a certain genetic variant that caused the A20 protein to malfunction.

“We have shown that farm dust can protect mice against house dust mite-induced asthma, via a mechanism of A20 induction in airway epithelial cells,” recaps Schuijs. “Following these observations, we would like to know which specific component in the farm dust is responsible for the observed protection and if it is the A20 alone which is necessary for protection. Answering these questions would bring the development of a more targeted drug or vaccine much closer.”

While this will not happen any time soon, their ultimate goal will be to develop a drug that parents can give to young children, which has the same protective effects as farm dust. While people who already have respiratory allergies don’t benefit from dust exposure, there appears to be a critical window in which endotoxins can induce immunity to common allergens.

“Our ultimate goal will always be helping patients by developing either a better more specific drug or even a vaccine for asthma,” says Schuijs. “So far we suspect that part of the answer lies in the endotoxins and the exposure of people to endotoxins in the environment. But there are undoubtedly more substances in farm dust that can play a role in the observed protection, which we definitely should look into. Discovering how farm dust provides this type of protection has certainly put us on the right track towards developing a vaccine.”

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