When good cells go bad, allergic asthma can develop

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When good immune cells go rogue, the consequence can be allergic asthma.

It's already known that up to 50 percent of those who repeatedly are infected with a common virus early in life develop allergic asthma later in life. Now a team led by the University of Pittsburgh School of Medicine has explained in a mouse model the complex process that causes regulatory immune cells to change character and act like bad immune cells that attack harmless allergens, resulting in inflammation and restricted airways.

They have explained how the respiratory syncytial virus, or RSV, alters the immune system to cause allergic asthma.

"We know that recurrent infections of RSV that require hospitalization in early life increase the risk for asthma in adult life," said Anuradha Ray, who along with Prabir Ray is a Pitt doctor of medicine and immunology. They are co-senior authors of the study. "But until now, it hasn't been clear why this happens."

PG graphic: Cells gone wild
(Click image for larger version)

The study has been published online in Nature Medicine, and the lead author is Nandini Krishnamoorthy, a postdoctoral associate in the medical school's Division of Pulmonary, Allergy and Critical Care Medicine. The team included other researchers from Pitt and other universities.

Using newborn mice, they determined that mother's milk not only includes allergens but also biological molecules that suppress the immune system to prevent it from attacking harmless allergens in the newborn. In that way, breast milk prevents development of allergies to pollen, dust, tree sap, among other allergens, and represents "an important mechanism of protection from diseases such as asthma," the study says.

But that tolerance for allergens also "renders newborns more vulnerable to infections by pathogens" such as RSV, which, as the study explains, can target the workings of regulatory immune cells in early life "with an effect on subsequent disease development."

Understanding how RSV leads to asthma involves understanding the role of immune cells.

Good immune cells, known as regulatory T cells or "Tregs," determine which immune cells are created. In normal people, Tregs suppress unnecessary immune responses unless such responses are required to fight infections. For example, TH1 cells help to fight bacterial infections, while TH2 cells protect from worm infections.

TH2 cells can also emerge to attack harmless allergens. However, key ingredients in mother's milk, combined with the regulatory cells, suppress the TH2 and prevent the infant from developing allergies.

But repeated RSV infections transform the regulatory cells by altering receptors on their surface and cause them to function more like TH2 cells -- "those bad immune cells that cause allergies," Dr. Krishnamoorthy said. Once the transformation occurs, the Treg cells no longer serve the protective function and begin secreting compounds that normally TH2 cells secrete, causing inflammation and airway restrictions characteristic of asthma.

The study determined that the virus used multiple mechanisms to cause an allergic response leading to asthma. The result is impairment of good immune cells, prompting them to cause a breach in the "robust form of maternally transferred tolerance" for inhaled allergens.

Previous studies have shown that in 40 to 50 percent of the cases involving repeated RSV infections in newborns, the person eventually develops allergic asthma later in life. But Andy Nish, a fellow with the American Academy of Allergy Asthma and Immunology and an allergist in Gainesville, Ga., said the study is important in showing for the first time that the previously unexplained association between RSV and allergic asthma actually is a causal one.

"The study is very interesting and gives us a proposed mechanism" for RSV causing the asthma, he said. "They can prove that Treg cells are responsible and in a very elegant way they demonstrated that. In the future we should have asthma and allergies well controlled with current hope and thought that there should be more therapy options coming down the road.

"This study is one step in that direction."

Tina Hartert, director of the Vanderbilt University's Center for Asthma Research, said 70 percent of infants are infected with RSV in the first year of life, with 100 percent infected by age 2. In infants and the elderly, RSV -- which occurs during the same season as influenza -- causes cold-like and flu-like symptoms. Other ages often don't show any symptoms. Babies born in the spring and summer develop their immune systems in time to help fight off the virus more readily than those born just before or during winter months.

There's been controversy about the influence of breast feeding in RSV infections, but Dr. Hartert said "what's not controversial is the myriad benefits of breast feeding."

A vaccine against RSV has yet to be developed. The Pitt research could help guide the development of a method to block the virus' ability to diminish Treg cells so they induce allergic asthma. Of all children with asthma, 80 to 85 percent have allergic asthma or an allergic component to the asthma, Dr. Hartert said.

"What's exciting about this study is having another level of evidence to move toward primary prevention in asthma," said Dr. Hartert, who's familiar with the Pitt team. "I think they are a terrific group that really is working on the cutting edge of this field."

health

David Templeton: dtempleton@post-gazette.com or 412-263-1578.


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