FOR researchers trying to untangle the roots of the current epidemic
of asthma, one observation is especially intriguing: Children who grow
up on dairy farms are much less likely than the average child to develop
the respiratory disease.
Now, a European team studying mice has homed in on a possible
explanation: Bits of bacteria found in farm dust trigger an inflammatory
response in the animals’ lungs that later protects them from asthma. An
enzyme involved in this defense is sometimes disabled in people with
asthma, suggesting that treatments inspired by this molecule could ward
off the condition in people.
The study, published on page 1106, offers new support for the
so-called hygiene hypothesis, a 26-year-old idea that posits that our
modern zeal for cleanliness and widespread use of antibiotics have
purged the environment of microorganisms that once taught a child’s
developing immune system not to overreact to foreign substances.
“This gives us a tantalizing molecular mechanism for understanding
the epidemiological evidence,” says pediatric immunologist Stuart Turvey
of the University of British Columbia in Vancouver, Canada, who was not
involved with the new work. But others caution that the finding is
probably far from the only explanation for why early exposure to
microbes can make kids less allergy-prone.
About 20 studies in Europe and elsewhere have found that children
raised on farms have relatively low rates of allergies and asthma. Some
researchers suspect a key reason is that the kids breathe in air full of
molecules from the cell wall of certain bacteria, called
lipopolysaccharides for their fat-sugar structure. Also known as
endotoxins, these fragments—from dying bacteria in cow manure and
fodder—cause a temporary low state of inflammation in the lungs that
somehow dampens the immune system’s response to allergens, the thinking
goes.
Pulmonologist Bart Lambrecht and immunologist Hamida Hammad of Ghent
University and Flanders Institute for Biotechnology in Belgium and their
collaborators wanted to probe the mechanism for endotoxins’ protective
effect.
They first showed that injecting the molecules into the noses of six-
to 12-week-old mice every other day for two weeks protects the rodents
from developing asthma later, in response to dust mites. In the
endotoxin-exposed mice, the epithelial cells lining the lungs made lower
levels of proinflammatory molecules called cytokines when they
encountered the dust mites; the mice also had fewer dendritic cells, the
immune sentinels activated by cytokines.
An enzyme made by the epithelial cells, called A20, seemed to play a
role in reducing these inflammatory responses. In mice engineered to
lack the gene for A20 in their lung epithelial cells, endotoxins did not
protect the animals from asthma. The team got similar results when they
repeated the mouse experiments with farm dust, which includes not just
endotoxins but other potentially inflammatory fragments from bacteria,
fungi, and plants as well.
The Ghent team then tested bronchial cells from healthy people and
found that exposure to endotoxins lowers the levels of the same
inflammatory molecules studied in the mice. The levels didn’t drop as
much in cells from people with asthma, and their cells also made less
A20 protein. Finally, the researchers found that among nearly 500 farm
children, those carrying a mutation that lowers A20 activity were five
times more likely to develop asthma.
Until now, Lambrecht says, most explanations for the hygiene
hypothesis assumed it acts directly on the immune system’s T cells. The
new finding shows that with endotoxins, “it’s not happening in the
immune system. It’s in the structural cells of the airway,” Lambrecht
says. “We need this environmental exposure to cool down the epithelium
so it knows what’s dangerous and not dangerous.”
He points out that A20 plays a similar restraining role in the gut of
a newborn, helping it tolerate the beneficial microbes that contribute
to digesting food. The new study suggests that a drug that boosts A20’s
activity could help protect children with a family history of asthma
from developing the disease, Lambrecht says. (Dosing children with
endotoxins is risky because the mechanism is apparently finely tuned;
large exposures promote asthma.)
Others who study the hygiene hypothesis caution that the newly
uncovered mechanism does not entirely explain the protective effect of
dairy farm life. Drinking unprocessed milk also seems to ward off asthma
in kids, points out Gary Huffnagle of the University of Michigan, Ann
Arbor—and that effect is unlikely to involve the lung epithelium. What’s
more, endotoxin levels are not that much higher on farms than in
cities, suggesting “it’s too simple an answer,” says asthma genetics
researcher William Cookson of Imperial College London, who thinks
changes in living microbial communities in the lungs and gut may be just
as important.
Harvard University immunologist, Richard Blumberg, would also like to
see the Ghent team show that the protective response lasts from birth
into adulthood—
experiments that Lambrecht’s group is now planning. For now, says
Blumberg, the new study is “another important layer of our community’s
search to understand the biology behind the hygiene hypothesis.”
VIA: GUARDIANNG
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