Study of Genetic Condition May Yield Clues to Cause of Allergies07/24/13
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
TGFbgene 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
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,
"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.
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