For two weeks, mice were exposed to barn dust every second day; the dust was daubed on their nostrils. Then they were exposed to a notorious trigger of asthma: house dust mite poo. The untreated mice duly had an asthma attack.
The barn dust snorters did not. What was the magic ingredient in the cow barn dust? But how, exactly, was exposure to endotoxin preventing the mouse immune system over-reacting to the presence of dust mite poo? The immune system operates like an army.
And like all armies it relies on sentries — a collection of cells known as the innate immune system. They are the first responders and they brief the command centres on the nature of the assault. Do the invaders like to hide inside cells — like viruses and some bacteria? Or are they like tiny helminth worms — a type of parasite — that proliferate openly in the bloodstream?
Different invaders require a different response. Like sending troops to fight within a town, the immune forces must carefully go from house to house to check for hidden combatants. At birth, the human immune system seems to be set to a TH2 default state. During the first years of life, as it is exposed to the environment, it learns to rebalance towards TH1. In asthmatics, the immune system seems to have adapted badly: they remain more inclined towards the carpet bombing of a TH2 response.
Endotoxin may be one of the environmental triggers that helps usher the immune system from TH2 to TH1. How does endotoxin achieve this? Endotoxin is known to activate receptors on sentry cells. But what was the next signal? The researchers suspected it might be the product of a gene called A To prove A20 was the crucial go-between, the Ghent team eliminated it from mice. They found the protective effect of endotoxin and farm dust was greatly diminished, confirming the importance of A It was not only the sentry cells that relayed the A20 signal to the immune system.
The cells that line the airways and provide a barrier against microbes — so-called epithelial cells — also played this role. What about humans? To find out, the researchers took swabs of epithelial cells from the airways of normal and asthmatic patients and grew these cells in dishes. They were exposed to endotoxin every second day for one week, and then sprinkled with house dust mites.
However, just as in the mice, the cells pre-treated with endotoxin showed far lower levels of these chemicals.
A Holistic Approach
Interestingly, the cells from asthmatic people produced less A20 than those of non-asthmatics — a finding consistent with the notion that their immune armies had been poorly trained because they carry a defective form of this gene. These findings tally well with studies of children living on farms. For instance the GABRIELA study of 1, rural children aged six to 12 from four European countries including Germany , found that those children most susceptible to asthma carried a defective form of the A20 gene.
Starting from the womb, infants are exposed to farm dust which carries endotoxin among other things.
It triggers the release of A20, which signals the assembly of a better functioning immune army. He suspects the protective element is connected to cows and hay.
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But he does not rule out a type of vaccine in the future that, like endotoxin, could be used to train the human system. Alternatively, knowing the crucial signalling role of A20 points to a new target for developing drugs that raise its activity. But childhood exposure may not be enough to recruit a healthy immune army for life.
A study in Silesia, Poland showed that once people in traditional villages stopped keeping animals they lost much of their protection against allergies. In , their rates of allergy were about a third that of people in the nearby towns. But in , Poland joined the European Union and many villagers, rather than conforming to costly new husbandry standards and the requirement to pasteurise their milk, jettisoned their animals. The result was that their allergy levels rose to match the level of the people in the towns.
First they develop allergies to wheat flour; after several months their allergic response is followed by asthma. Drinking unpasteurised milk carries the risk of being infected with dangerous bacteria including listeria, salmonella and enterohaemorrhagic E. Also in Cosmos : Read the second of our two-part series on asthma.
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This article appeared in Cosmos 66 - Dec-Jan under the headline "Solving the asthma riddle". Astronomers have solved the mystery at the heart of the beautiful Rosette nebula. Digital Issues Buy a back issue. Renew my subscription Give a Gift Manage my subscription. Features Biology 23 November Solving the asthma riddle.
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Elizabeth Finkel reports. The remainder of this article is exclusive to Cosmos subscribers To continue reading this article, please subscribe for unlimited access or log in. Elizabeth Finkel is editor-at-large of Cosmos. Looking for more science? First, Don has published in a broad range of journals, specifically targeting nematologists with papers in the Journal of Nematolology , Nematologica and International Journal of Parasitolology , and the entire scientific community with papers in Nature , PNAS and Science.
Second, a remarkable number of Dr. In particular, as of December , his book has received more than literature citations. Significantly, four of his peer-review publications have been cited more than times, and 13 peer-review publications and three book chapters have each been cited more than times. This is a truly remarkable achievement. The theme running through Dr. The ability of nematodes to modulate their development via dauer entry and exit is a fundamental strategy used by parasitic and free-living species alike.
Biology and the Riddle of Life
In , Dr. Although this pathway has been subsequently expanded by Dr. During the s, Dr.
The developmental effects of the pheromone were characterized, and in particular he showed that certain mutants defective in formation of dauer larvae exhibit pleiotropic defects in sensory behavior and possess ultrastructural abnormalities in the dendritic processes of chemosensory neurons. The cloning of genes in the dauer pathway during the s revealed that the same machinery is shared with other animals, including humans.
To use but one example, two dauer genes daf-1 and daf-4 encode transmembrane receptor protein kinases. Numerous other receptors in this family have been found subsequently, including mammalian receptors for activin, bone morphogenetic proteins and transforming growth factor- b. These ligands are cytokines that have profound effects on cell differentiation in vertebrate development.
Other daf genes correspond to members of the insulin pathway in mammals, and certain daf genes control life-span and aging in animals. Collectively, these studies have revealed much about the basic biology of nematodes, and of animals in general. But much more than that, Dr. Riddle has actively engaged researchers studying important parasitic nematodes.