St. Louis, Jan. 29, 2001 — Scientists have obtained further evidence for a revolutionary way of viewing the prevalent respiratory disease, asthma. Combining complementary findings from mice and humans, they propose a modern scheme for the development of the disease. The study is presented in the Feb. 5 issue of Journal of Experimental Medicine.
Traditionally, experts believe that an asthmatic attack results from an increased allergic response combined with a decrease in the usual type of response to respiratory viruses. But Michael J. Holtzman, M.D., disagrees. "I would argue that, while the allergic response may increase, the antiviral response also increases," he explains. "Together, the two cause more inflammation and more disease."
Holtzman, the Selma and Herman Seldin Professor of Medicine and a professor of cell biology and physiology at Washington University School of Medicine in St. Louis, led this study in collaboration with Michael J. Walter, M.D., assistant professor of Medicine and Mario Castro, M.D., assistant professor of Medicine. Holtzman believes that the cells lining the airway, called epithelial cells, play an integral role in the asthmatic response.
They are known to host respiratory viruses, but Holtzman proposes that they also contain a special genetic program for fighting off viruses. If the setting is just right, a viral infection can scramble this program, altering the epithelial cells’ response to future viruses. The result is a mutated antiviral program that instigates an inflammatory response and asthmatic attack. Holtzman and colleagues set out to identify the set of genes in the antiviral program.
The current paper focuses on an interleukin gene called IL-12 p40, previously thought to be active only in the immune system. The researchers found that the gene also is selectively active in airway epithelial cells. And they showed that it becomes more active when mice get viral bronchitis and is overactive in people with asthma.
Therefore production of IL-12 p40 protein might be a key step in airway inflammation. "The fact that IL-12 p40 can be made outside of the traditional immune system gives more weight to the idea that epithelial cells may be important in immune defense and immune diseases," says Holtzman. He did not expect to find the IL-12 p40 gene in airway epithelium, but the fact that these cells produce a known anti-viral agent in response to viruses and that the gene also is active in asthmatic patients supports his scheme.
Holtzman and colleagues also discovered a slightly different form of the gene product, IL-12 p80. Though unsure of its complete role, they demonstrate that this variant is necessary for recruiting a specific set of immune cells called macrophages.
But if a viral infection can mutate a genetic program in epithelial cells, permitting asthma to develop, when does this infection occur? Holtzman and colleagues believe that reprogramming may occur during an infection very early in life, possibly in infancy. They are in the process of determining whether epithelial cells can harbor viruses for prolonged periods.
"The idea is that you develop an infection early in life, which causes abnormal programming in airway epithelial cells. If you have the right virus in the cell with the right genetic background, you would then develop an important part of asthma. Once we understand how the virus alters the program, we can begin to design treatment strategies."
Walter MJ, Kajiwara N, Karanja P, Castro M, Holtzman MJ. Interleukin 12 p40 production by barrier epithelial cells during airway inflammation. Journal of Experimental Medicine, 193:3, 1-14, Feb. 5, 2001. Funding from the National Institutes of Health, American Lung Association, Martin Schaeffer Fund and Alan A. and Edith L. Wolff Charitable Trust supported this research.
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