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By KRISTA CONGER A novel gene family that appears critical to the development of asthma in mice has been identified by researchers at Lucile Packard Children’s Hospital. The finding may revolutionize treatment and diagnosis of the 15 million people in the United States who suffer from asthma. It may also explain why incidence rates have climbed rapidly in industrialized countries in the past 20 years, say researchers. Asthma has a genetic component, but efforts to identify suspects have been stymied because the disease involves more than a dozen independently acting genes. When the Stanford researchers used a special technique to look at the effects of only small stretches of DNA at a time, however, they pinpointed as culprits a previously unknown group of genes called the Tim family.
"It was only by using this mouse model that we could identify a locus and some potential candidate genes that could be inducing this phenomenon," said Rosemarie DeKruyff, PhD, senior author of the study, published in the December issue of Nature Immunology. "It was especially interesting when we found that the gene we homed in on encoded the hepatitis A receptor gene." Family member Tim1 encodes a protein used by the hepatitis A virus to latch on to human cells. The newly discovered link between the Tim family and the virus may help to explain why infection with hepatitis A appears to protect against asthma. The researchers speculate that binding of the virus to the protein interferes with disease development in infected individuals. If so, their finding may provide a clue as to why asthma rates are increasing in regions where hepatitis A infection is dropping. "It may be that when hepatitis A binds to this receptor it somehow brings about a deletion of those cells that bias the immune response toward asthma," said DeKruyff, a professor of pediatrics at Packard. "But there are also other possibilities," she added. To carry out the research, Jennifer McIntire, an MD/PhD student working in DeKruyff’s lab in collaboration with Dale Umetsu, MD, PhD, chief of the division of allergy and immunology, bred together two sets of mice. One set develops airway hyperreactivity, or AHR, after being exposed to an allergen, and another is resistant to AHR, which causes the shortness of breath, chest tightening, wheezing and coughing that are hallmarks of human asthma attacks. Using a technique known as backcrossing, McIntire and her colleagues generated mice that were genetically identical to the susceptible mice, other than for small segments of DNA from the resistant group. They then looked for mice in the group that did not develop AHR when exposed to an allergen. They found that mice containing a small segment of DNA similar to an asthma susceptibility region on human chromosome 5 were significantly less likely to develop AHR than the susceptible group, even though the two groups shared the rest of their genomes. The region on human chromosome 5 contained some likely candidate genes, including several encoding proteins called cytokines that regulate the immune response leading to asthma. Many researchers had assumed that these cytokine genes were responsible for the increased asthma susceptibility conferred by the region. However, when McIntire and her colleagues analyzed the stretch of DNA more closely, they found that the development of AHR was actually linked to a nearby group of genes, which they named the Tim family. The three-member gene family encodes a group of protein receptors found on stimulated T cells – the immune cells that modulate the airway’s response to inhaled allergens. Genetic variations in two of the family members, Tim1 and Tim3, correlated with the development of AHR, whereas the DNA sequences of the previously suspect cytokine genes did not. The researchers are now investigating whether similar variations, or polymorphisms, are also linked to the development of asthma in humans. "Identifying the gene can help in diagnosing asthma, particularly if it turns out that one polymorphism is associated with it versus another. Perhaps if you have that particular allele, you’re more likely to develop asthma. We may also one day be able to alter the immune response or block the activation of receptors that leads to asthma," said DeKruyff. Other medical center participants in the study include undergraduate Sarah Umetsu and Omid Akbari, PhD, in the division of allergy and immunology; and Gregory Barsh, MD, PhD, in the departments of pediatrics and genetics.
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Exposure to workplace inhalants increases risk of lung diseases |
Stanford Report, December 5, 2001
