Single Genetic Glitch May Explain Most Allergies and Asthma

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Allergies are certainly the result of both genetic and environmental factors, but there is fresh evidence to suggest that at least one major genetic aberration could be behind everything from hay fever to food allergies to asthma.

Allergies — to dust, pet hair or peanuts — are essentially the product of misdirected immune systems, which start to see innocuous objects as potential threats and launch an intensive assault that can translate into sneezing, wheezing, and even potentially fatal seizures. For decades now, rates of allergies and other immune-related diseases such as asthma and eczema have been rising in the U.S., and the rapid increase suggests that it’s more than just genes, or just changes in lifestyle that made us too clean that are at work.

Now researchers studying the genetics behind the rare tissue disorders Marfan and Loeys-Dietz syndromes have discovered that there may be a common genetic driver behind almost all allergic diseases. Reporting in the journal Science Translational Medicine, scientists from Johns Hopkins Children’s Center and the Johns Hopkins Institute of Genetic Medicine say that they were surprised to find that the same mutation they found in the Marfan and Loeys-Dietz patients may also trigger the immune changes responsible for allergies; most of the patients with the two rare disorders also have higher than normal rates of allergies.

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The culprit, they say, is abnormal signaling by a protein called transforming growth factor-beta (TGF-beta). TGF-beta is responsible for regulating cell growth and communication, and in the Marfan and Loeys-Dietz patients, mutations in the TGF-beta gene, combined with other genetic aberrations, contribute to dangerous thinning of the blood vessels.

People with seasonal or food allergies are not more likely to develop the conditions, but improper functioning of this protein can also trigger other effects — most notably the cascade of events that are familiar to anyone who suffers from allergies — the release of histamines that trigger mucous and liquid production that can cause swelling and itching of the eyes and nose; the flood of inflammatory cells to the lungs that can cause shortness of breath; the dilation of blood vessels that can lead to a dangerous drop in blood pressure and even shock.

“Disruption in TGF-beta signaling does not simply nudge immune cells to misbehave but appears to singlehandedly unlock the very chain reaction that eventually leads to allergic disease,” said the study’s senior author Dr. Harry Dietz, a cardiologist at Johns Hopkins Children’s Center in a statement.

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The researchers came to their conclusion after studying 58 kids with Loeys-Dietz syndrome, all of whom had a history of allergies or related immune diseases, and high levels of T-cells, the cells that can both recognize and attack foreign agents that threaten the body.

While TGF-beta normally regulates T cell function, in the patients in the study, the T-cells were over-active, zealously attacking not just dangerous pathogens but harmless food proteins too. This cycle could explain how most allergies are triggered, the researchers say.

The results suggest that TGF-beta could be a useful target for new allergy treatments. “One of the hurdles in trying to develop new treatments for allergies is pinpointing the key signaling pathways we need to target,” Dr. Pamela Frischmeyer-Guerrerio, an immunologist at Hopkins and one of the study’s co-authors, said to HealthDay. “TGF-beta really seems to be central to one of the key pathways that underlie the development of all forms of allergic disease.” There is already a drug available that inhibits TGF-beta — a blood pressure medication called losartan (Cozaar) — that the study researchers are testing to see if it can relieve allergy symptoms in animals.

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