Mutation to Neutrophil Gene Eases Lung Infections in Cystic Fibrosis

Researchers have found that a mutation in the IFRD1 (Interferon-related developmental regulator 1) gene modulates the degree of severity of lung disease in sufferers of cystic fibrosis, an inherited chronic disease that affects the lungs and digestive system. Cystic fibrosis, which affects about 70,000 people worldwide, results from a mutation in the CFTR gene. This defects causes the body to produce unusually thick, sticky mucus that clogs the lungs and leads to life-threatening respiratory infection.

Investigators at Children's Hospital Medical Center (Cincinnati, OH, USA) analyzed the genetic makeup of nearly 3,000 cystic fibrosis patients, and found that small genetic differences in the IFRD1 gene correlated with lung disease severity. IFRD1 is a histone-deacetylase-dependent transcriptional co-regulator expressed during terminal neutrophil differentiation.

To determine the role of IFRD1 in the disease process, the investigators genetically engineered a line of mice lacking the gene. They reported in the February 25, 2009, online edition of the journal Nature that the IFRD1 deficiency caused delayed bacterial clearance from the airway, but also less inflammation and disease.

The protein encoded by IFRD1 is particularly abundant in neutrophils, and to some extent regulates their function. Mutations to IFRD1 were also found to have an effect on neutrophils from normal individuals as well those from cystic fibrosis patients.

"Neutrophils appear to be particularly bad actors in cystic fibrosis," said senior author Dr. Christopher Karp, professor of molecular immunology at Children's Hospital Medical Center. "They are important to the immune system's response to bacterial infection. In cystic fibrosis, however, neutrophilic airway inflammation is dysregulated, eventually destroying the lung."

"It is possible that IFRD1 itself could become a target for treatment, but right now it is a signpost to pathways for further study," Dr. Karp said. "We want to find out what other genes and proteins IFRD1 interacts with, and how this is connected to inflammation in cystic fibrosis lung disease."

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