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Scientists discover a genetic glitch at the root of allergies

Ashthma inhaler

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Scientists have long known that asthma and allergies, which are on the rise in children in the developed world, are caused by a combination of genetic and environmental factors.

What has stumped them, though, is which genes are responsible.

Now, in what is thought to be a scientific first, researchers at Johns Hopkins Children's Center and the Johns Hopkins Institute of Genetic Medicine in Maryland have identified a genetic glitch they believe is at the root of a range of allergic disorders, from peanuts to pollen to bee stings.

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As a result, the team is now investigating whether common drugs already widely prescribed for other conditions can halt or reverse allergic symptoms, including asthma, in animals.

"This is a really huge breakthrough because we are finally getting at the root causes of these diseases," lead investigator Dr. Pamela Frischmeyer-Guerrerio, an immunologist at Johns Hopkins Children's Center, said in an interview. "That gives us a huge handle on how to develop new treatments."

According to researchers, the culprit is aberrant signalling – abnormal communication between cells – in a protein called transforming growth factor-beta. The protein, also known as TGF-beta, has widespread effects on the body, including the maturation of infants' stomachs in a way that develops tolerances to common foods that might otherwise induce an allergic reaction, and prevents allergies in later life.

"Disruptions in TGF-beta signalling does not simply nudge immune cells to misbehave, but appears to single-handedly unlock the very chain reaction that eventually leads to allergic disease," said Dr. Harry Dietz, a cardiologist at Johns Hopkins Children's Center and senior investigator for the study.

The findings were published Wednesday in Science Translational Medicine.

Researchers became curious about the effects of TGF-beta over several years after noticing that patients with Loeys-Dietz Syndrome (named in part after the Johns Hopkins cardiologist) were more prone to allergies than most people. Loeys-Dietz is a rare condition marked by flimsy blood vessels and a dangerous stretching of the aorta that is caused in part by abnormal TGF-beta signalling.

Their study involved 58 children with Loeys-Dietz between the ages of seven and 20 with a history of allergies such as food allergies, rhinitis, eczema, asthma and gastrointestinal and esophageal allergic disease.

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Because TGF-beta is known to control immune cell maturation, researchers focused on patients' regulatory T-cells, a type of suppressor cell that normally works to keep immune cells from becoming inflamed.

What they found was that in these patients, the regulatory T-cells were doing the opposite and secreting allergy-promoting molecules. Even more interesting to researchers, though, was the discovery that regulatory T-cells later obtained from patients with allergies but not Loeys-Dietz were misbehaving in the same way.

Ronald Cohn, head of the Division of Clinical and Metabolic Genetics at the Hospital for Sick Children in Toronto, who coincidentally trained for years under Dr. Dietz at Johns Hopkins, called the findings "very exciting" and a prime example of how research on rare diseases can lead to solutions to larger public health problems.

"As a person who has allergies himself, I'm hopeful for myself and for my children, who have severe allergies," Cohn said. "How nice would it be to prevent that?"

Roughly 2.5 million Canadians, or one in 13, suffer from a significant food allergy, according to a 2010 nationwide study published in the Journal of Allergy and Clinical Immunology. About three million Canadians have asthma, according to the Asthma Society of Canada.

Frischmeyer-Guerrerio said researchers are now looking into whether several drugs that are already approved by the U.S. Food and Drug Administration can mitigate allergies in mice, and she is hopeful that trials on humans can begin in the next couple of years.

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One drug that the team is focusing on is losartan, which is commonly used to treat high blood pressure. Losartan targets a molecule that affects blood vessel tone and TGF-beta signalling, and has been shown to halt ballooning of the aorta in Loeys-Dietz sufferers.

"We're very hopeful that this will lead to a lot of new therapeutic trials," she added.

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