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Gene Tied to Out-of-Control Immune Response

septic shock



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A gene called auf1 seems to protect against septic shock in mice, a new study finds. Animals lacking the gene were more likely to undergo shock, suggesting that the gene helps keep the immune system's response to infections in check. Researchers hope to discover whether different forms of auf1 and related genes make people more likely to suffer autoimmune disease or life-threatening reactions to infections such as anthrax or flu.

Infectious organisms trip specialized immune cells in the body and cause them to pump out proteins called cytokines, which produce inflammation and other hallmarks of infection, such as chills and fever. The body must carefully regulate its cytokine response, however, because "if it isn't turned off it can lead to septic shock and rapid death," says microbiologist Robert Schneider of New York University. Septic shock, which causes 9 percent of deaths in the U.S. each year, occurs when the immune reaction to a bacterial infection grows out of control, shutting down organs and sending blood pressure plummeting. Researchers think similar effects contribute to death from anthrax and pandemic flu.

The auf1 gene had previously turned up as a player in cytokine regulation. To learn more about its role, Schneider and his colleagues bred mice that lacked the gene. The animals were five times as likely as regular mice to go into shock and die when exposed to bacterial cells, the group reports in the November 15 issue of Genes and Development. The engineered mice contained heightened quantities of RNA, the precursor of protein synthesis, for the cytokines interleukin-1 beta and tumor necrosis factor alpha. Loss of the AUF1 protein seems to make these RNA molecules more stable and more easily translated into cytokine proteins, Schneider says. How that happens remains unclear, but "we're beginning to understand how the cytokine response, the so-called cytokine storm, is regulated and controlled," he says.

An increasingly common idea, says Bruce Beutler of the Scripps Research Institute in La Jolla, Calif., holds that "aberrations in these pathways determine who's going to live and who's going to die" from infections. The next step is to figure out if people differ in their sensitivity to cytokines, he explains. "Probably some people are more capable of surviving the response. That's something that people have barely looked at."

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