How influenza drives asthma

Viral respiratory infection causes severe asthma attacks in almost all patients with asthma -- a reaction classically attributed to T cells of the adaptive immune system. Now, scientists have identified a pathway in mice by which a subset of innate immune cells, found in mammalian lungs for the first time, orchestrate influenza-induced asthma.

Influenza A virus Source: CDC

The discovery, published online today in Nature Immunology, suggests the innate immune system, and not just the adaptive immune system, triggers asthma attacks after viral infections. The cells, plus a newly identified pathway by which the cells are activated, could provide novel targets for therapies to control viral-induced asthma attacks, which fail to respond to conventional asthma medications, the authors write.

The research is "fresh and engaging," said Gary Anderson, who studies lung disease at the University of Melbourne in Australia and wasn't involved in the research, in an email. But, he warns, its medical relevance is unclear as drugs targeting the pathway identified have not succeeded in clinical trials of asthma.

At Children's Hospital at Harvard Medical School, immunologist Dale Umetsu and colleagues examined a mouse model of asthma induced with influenza virus, and were surprised to see an asthma reaction within five days. "Normally, the adaptive immune response takes 10 to 14 days," said Umetsu. "But with influenza, the responses occurred so fast that it couldn't really involve adaptive immunity and T cells."

They then challenged mice lacking T and B cells -- both involved in adaptive immunity -- with influenza virus, and still recorded an asthmatic reaction, confirming the attacks were not caused by an adaptive immune response. Measuring the cytokine secretions in the lungs of infected mice -- molecules that signal immune cells to the site of an infection --the team identified two that were being secreted in large quantities and contributing to the lung inflammation, interleukin 33 and interleukin 13.

The cytokines led the team to a population of innate immune cells activated by interleukin 33, called natural helper cells, which then secrete large amounts of interleukin 13. These cells are known to be essential in immune response to helminth infection in the intestines, but "this is the first study to find and characterize this substrate in the lungs," said first author Ya-Jen Chang.

New therapies are greatly needed for patients with viral-induced asthma attacks, who often end up in the hospital, said Umetsu. "Now that we've found these innate lymphocytes involved in asthma, we think they can be a good target for therapeutic applications," added Chang. Yet drugs targeting the interleukin 13 pathway have essentially failed in clinical trials of asthma, said Anderson. This, however, may reinforce the idea that multiple pathways cause asthma, and even if researchers find a drug that successfully targets one pathway, effective treatments may require a combination of therapies.

Y. Chang, et al., "Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity," Nat Immun, doi: 10.1038/ni.2045, 2011.


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