Researchers will determine whether asthma and related diseases are associated with mutations in a molecule that ordinarily keeps levels of certain immune white blood cells (called “eosinophils”) low, and instead allows them to accumulate in inflamed airways.
Levels of immune eosinophils in the blood are normally quite low, but excess levels are found in tissues in a number of human diseases, including asthma and esophagitis. Therapies that could control or reduce eosinophil levels, therefore, might prevent permanent tissue damage. The researchers have identified a molecule that is selectively found on the surface of eosinophils, called “Siglec-8.” Based on animal studies, they hypothesize that Siglec-8 molecules ordinarily bind to certain sugar-based molecules in tissues, which eventually leads to the death of the eosinophils. They further hypothesize that in asthma and esophagitis, genetic mutations occur in the signaling or binding abilities of the Siglec-8 molecules. The eosinophils, therefore, do not die, but instead build up in inflamed airway tissues. Mutations or “polymorphisms” in the Siglec gene are very common and the mutation could provide a pathway to either increased resistance or susceptibility to asthma.
The Johns Hopkins and Cincinnati Children’s Hospital Medical Center investigators will, in the aggregate, study human tissues from 500 patients with asthma, 500 patients with esophagitis, and 1,000 healthy study participants. The Cincinnati collaborators will conduct the genetic analyses to try to identify the gene mutation(s) that are involved, and the markers for these mutations that could be used for diagnosis.
Significance: The findings may result in the development of new diagnostic tests to identify patients with mutations, and also lead to new approaches to treating asthma, esophagitis, and other immune eosinophil-related diseases.