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Jul 24, 2013

Shared Genetic Aberration Links Connective Tissue Disorders to Common Allergies

  • Peanuts, pollen, shellfish, and bee stings—aberrant TGF-beta signaling may be behind immune responses to these and other allergens, scientists at Johns Hopkins’ Children’s Center and Institute of Genetic Medicine report today.

    Writing in Science Translational Medicine, the team links a faulty genetic pathway already known for its role in two connective tissue disorders with several allergy types.

    While environmental factors most often trigger allergic reactions, researchers have long sought to determine the extent to which genetics play a role in these immune responses. Such a desire was reignited in the minds of Johns Hopkins researchers who, when studying patients with Loeys-Dietz syndrome last year, found that affected individuals showed higher than normal rates of allergies.

    Aware that mutations in genes leading to abnormal TGF-beta signaling are central to both Loeys-Dietz and Marfan syndromes (two genetic conditions marked by blood vessel laxity and stretching of the aorta), the researchers began to examine the pathway more closely.

    Studying 58 children with Loeys-Dietz, most of whom had either a history of allergic disease—like allergic rhinitis, eczema, or food allergies, among other things—or active allergies, the researchers found that these patients also had abnormally high levels of several traditional markers of allergic disease, including IgE, plus more eosinophils—white blood cells involved in allergic reactions.

    Zeroing in on these patients’ T cells, of which they had unusually high number, the researchers found that rather than taming inflammation, the regulatory cells were secreting allergy-promoting cytokines. Next, the researchers exposed naïve immune cells from the Loeys-Dietz patients to TGF-beta, finding that they swiftly transformed into allergy-promoting immune cells that recognized and attacked pathogens, but also otherwise innocent substances, like food proteins.

    "We have evidence that the same glitch in TGF-beta that is responsible for some of the clinical manifestations seen in Marfan and Loeys-Dietz diseases also lies behind the cascade of events that culminates in the development of conditions like asthma, food allergies and eczema," Pamela Frischmeyer-Guerrerio, M.D., Ph.D., an immunologist at Johns Hopkins Children's Center, said in a statement.

    Dr. Frischmeyer-Guerrerio’s colleague, study co-author and cardiologist Harry Dietz, M.D. continued: “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.”

    Drs. Frischmeyer-Guerrerio and Dietz et al. took their investigation a final step further, showing that Loeys-Dietz syndrome patients administered the blood-pressure medication losartan—which is known for its taming effect on TGF-beta signaling—showed reduced levels of the protein SMAD, whereas those we were untreated showed abnormally high levels of the protein, a known transmitter of TGF-beta signaling. The researchers point to losartan as a potential treatment for allergies, and in their statement note they are currently investigating the FDA-approved blood pressure drug for this purpose in preclinical studies.

    “TGF-beta receptor mutations impose a strong predisposition for human allergic disease” appeared online in Science Translational Medicine July 24.


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