Study of Genetic Condition May Yield Clues to Cause of Allergies

Results from kids with Loeys-Dietz syndrome might help guide treatment of all allergic diseases, researchers say

Wednesday, July 24, 2013

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WEDNESDAY, July 24 (HealthDay News) -- A disorder that affects connective tissue could provide vital clues to the genetic origin of nearly all human allergies and allergic diseases, say the authors of a new study of children.
People who have Loeys-Dietz syndrome tend to also suffer disproportionately from allergic diseases, researchers at Johns Hopkins Children's Center and the Johns Hopkins Institute of Genetic Medicine in Baltimore found when looking at a group of 58 children aged 7 to 20 who have the syndrome.
"We found that these patients had a very high risk of developing not just one allergy, but all forms of allergic disease," said study author and immunologist Dr. Pamela Frischmeyer-Guerrerio.
In their paper, published July 24 in Science Translational Medicine, the researchers contend that the genetic mutation that causes Loeys-Dietz syndrome appears to be closely tied to allergies -- so much so that it might explain why certain people suffer from allergic reactions.
However, other allergists are skeptical, saying the genetic link could just be a coincidence.
Loeys-Dietz syndrome is caused by the mutation of a gene called TGFb, and the researchers wondered if this mutation also might create a greater susceptibility to allergies and allergic diseases like eczema and asthma.
They found that the Loeys-Dietz syndrome patients had elevated levels of the signaling molecule produced by the gene, a protein called transforming growth factor-beta or TGF-beta.
TGF-beta serves many roles in the human body. It controls how cells grow in various organs, which is why mutation of the TGFb gene can lead to Loeys-Dietz syndrome, in which blood vessels develop into twisted shapes and physical abnormalities occur like cleft palate and clubfoot.
TGF-beta also is known to play a part in regulating the immune system, spurring the body to fight against foreign microbes while suppressing reactions against foreign bodies like food and pollen.
In Loeys-Dietz, the elevated TGF-beta signaling seems to prompt an immune response to innocuous substances, in effect causing the development of allergic diseases like asthma and eczema, Frischmeyer-Guerrerio said.
"We found the body's regulatory cells were actually producing inflammatory mediators themselves," she said. "Instead of doing their job of suppressing allergic molecules, they're actually producing those allergic molecules themselves and promoting inflammation." She added that researchers found the same sort of immune system misbehavior in allergic children who do not have Loeys-Dietz Syndrome.
Taking it a step further, researchers took undifferentiated immune cells -- cells that haven't yet transformed into more specialized cells -- from Loeys-Dietz syndrome patients and immersed those cells in TGF-beta. The cells quickly changed into allergy-promoting immune cells capable of attacking both microbes and allergens like food or pollen.
All this suggests that changes in TGF-beta signaling could strongly predispose some people toward developing allergies and allergic diseases, Frischmeyer-Guerrerio said.
"One of the hurdles in trying to develop new treatments for allergies is pinpointing the key signaling pathways we need to target," she said. "TGF-beta really seems to be central to one of the key pathways that underlie the development of all forms of allergic disease."
However, the case may not be as cut-and-dried as that, said Dr. Mitchell Grayson, an associate professor of pediatrics, medicine, microbiology and molecular genetics in the division of allergy and clinical immunology at the Medical College of Wisconsin. He was not involved with the new study.
"What this study does tell us is we need to pay more attention to TGF-beta receptors in allergic disease, but it doesn't tell us that we've found a single pathway. I didn't see here the tie that shows these defects are related to TGF-beta receptor signaling," said Grayson, also co-director of the infection, inflammation and immunity research unit at the Children's Research Institute of the Children's Hospital of Wisconsin.
Noting the similar immune response that researchers found in children with and without Loeys-Dietz syndrome, he said, "The problem with that is you don't know if that's related to the same type of TGF-beta receptor defects. It may just be if you're allergic, that's what you do."
If TGF-beta does end up being the culprit behind allergies, there are already-approved drugs on the market that are aimed at reducing TGF-beta signaling, study author Frischmeyer-Guerrerio said. One is the blood pressure medication losartan, which did reduce signaling in syndrome patients.
"Now, the next step will be for us to look at ways to inhibit this pathway," she said.

SOURCES: Pamela Frischmeyer-Guerrerio, M.D., Ph.D., immunologist, Johns Hopkins Children's Center, Baltimore; Mitchell H. Grayson, M.D., associate professor, pediatrics, medicine, microbiology and molecular genetics, division of allergy and clinical immunology, Medical College of Wisconsin, and co-director, infection, inflammation and immunity research unit, Children's Research Institute, Children's Hospital of Wisconsin; July 24, 2013, Science Translational Medicine

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