June 19, 2000 St. Louis, June 16, 2000 -- Challenging an important dogma, immunologists have discovered a new way the body distinguishes its cells from foreign cells so it can destroy microbes without harming itself. The findings suggest a new approach to autoimmune disease and ovarian cancer. They are reported in the June 16 issue of Science.
Like military personnel, cells that kill harmful bacteria and parasites must recognize invaders so they don't destroy their colleagues with friendly fire. Until now, scientists thought that only immune cells called natural killer cells were equipped for the job. These cells scan other cells for a security badge called MHC class I. If this badge if missing or altered, the offending cell is destroyed.
But researchers at Washington University School of Medicine in St. Louis have discovered that cells called macrophages, which eat microbes and damaged cells, also can distinguish self from other. Instead of relying on MHC class I, they recognize a cell-surface protein called CD47.
"The beauty of the CD47 system is that a macrophage with a single receptor can discriminate between self and foreign. If it sees a particle with CD47, it knows all is well. If it sees a particle without CD47, it knows the particle is foreign and potentially dangerous," says Per-Arne Oldenborg, Ph.D., lead author of the Science paper.
Oldenborg is a postdoctoral fellow in the laboratory of Frederik P. Lindberg, M.D., Ph.D., an assistant professor of medicine in the Division of Infectious Diseases and an assistant professor of molecular microbiology.
"Until now, our understanding of how the immune system tells the difference between self and foreign has been based on the dogma that only the interaction between natural killer cells and MHC class I is important," Lindberg says. "Our finding challenges that dogma by showing that the body's own cells can be represented by CD47 and that the macrophage, a much more basic component of the body's defense system, can make the distinction."
In 1998, Lindberg's group injected white blood cells that lacked CD47 into normal mice and found that the cells quickly disappeared. After Oldenborg joined the group in 1999, he obtained the same result with red blood cells that lacked CD47. By injecting stained cells and examining slices of various organs under the microscope, he found the cells in the spleen. They were in a region called the red pulp, whose many macrophages cleanse blood of damaged cells and foreign particles.
Because the injected red blood cells differed from normal red blood cells only in their lack of CD47, the researchers concluded that macrophages must recognize this cell-surface protein. "CD47 tells macrophages to leave them alone," Oldenborg says. "Because bacteria and other foreign particles in the blood do not express CD47, they get eaten up."
Macrophages roam the body, congregating in places such as the lungs, gut and spleen where pathogens are likely to enter. Therefore, people have wondered how these front-line cells could possibly recognize all the different types of microbes that infect humans. Borrowing an analogy, Oldenborg says that foreign submarines were thought to be surfacing around the Swedish archipelago during the 1980s. The Swedish navy distributed a map of submarine silhouettes so residents could report which ones they saw. Of course, most of the reported vessels turned out to be Swedish. The navy therefore distributed a new map showing only the three types of Swedish submarines. They asked residents to call only if the silhouette they saw was not on that map. "The Swedish researcher Klas Kärre used this analogy to explain natural killer cell function, but it also is apt for CD47," Oldenborg says. "Recognizing a single molecular tag, CD47, is much easier than having to recognize a large number of unknown tags."
Lindberg's group obtained the cells without CD47 from mice whose CD47 gene had been inactivated. Lindberg derived these mice when he was a postdoctoral fellow in the Washington University laboratory of Eric J. Brown, M.D., who now is at the University of California, San Francisco.
The mice are much more sensitive to certain autoimmune diseases, particularly hemolytic anemia, in which the body destroys its own red blood cells. Therefore abnormally low levels of CD47 might contribute to this condition in humans. In fact, researchers previously discovered that red blood cells of people with a disorder called Rh null, which involves mild hemolytic anemia, have less than 25 percent of the usual level of CD47.
In contrast, certain ovarian tumors display too much CD47. "That might be a way for tumor cells to turn off macrophages and therefore escape destruction," Oldenborg says. "So it will be important to investigate the role of CD47 in specific diseases."
Oldenborg P-A, Zheleznyak A, Fang Y-F, Lagenaur CF, Gresham HD, Lindberg FP. Role of CD47 as a marker of self on red blood cells. Science, June 16, 2000.
Funding from the National Institute of General Medical Sciences, the American Diabetes Association, the Washington University-Monsanto Research Agreement, the Medical Research Service of the Department of Veterans Affairs, the Swedish Medical Research Council and the Howard Hughes Medical Institute supported this research.
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