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Immune response to SARS sets up puzzling paradox

Scientists are baffled by how SARS, which claimed nearly 800 lives last year, affects the immune system. Credit: FEATURECHINA/WILSON WEN

Severe acute respiratory syndrome (SARS) rarely makes headlines these days, but immunologists are still chasing down why only a subset of people became severely ill and died from the disease. Popular hypotheses all suggest that an overactive or otherwise dysfunctional immune response may be to blame.

SARS last year claimed nearly 800 lives worldwide. Many researchers initially suggested that those who die have an overactive immune system that triggers a destructive inflammatory response.

The theory was supported by anecdotal reports that at a hospital in Guangzhou, the southern Chinese city where SARS originated, AIDS patients—who presumably have weak immune systems—were resistant to SARS infection.

Scientists were also intrigued that children, prime candidates for most respiratory illnesses, seemed to escape the brunt of the epidemic. “The whole mechanism of disease causation in SARS is quite an enigma,” says Malik Peiris, professor of microbiology at Hong Kong University.

The whole mechanism of disease causation in SARS is quite an enigma. Malik Peiris, Hong Kong University.

Several teams are now trying to solve the puzzle at a molecular level, but have had to rely on animal models and samples from previous outbreaks. “Everyone wants a glimpse of the immune response in SARS patients,” says David Kelvin, head of experimental therapeutics at University Health Network in Toronto.

Kelvin and his colleagues collected samples from 110 patients—35 of them within the first 24 hours after symptoms appeared—and followed them approximately every five days; 45 patients were tracked for more than a year. The researchers looked at gene expression profiles of various immune cells and markers to study both the immediate, or innate, immune response and the later adaptive immune response.

Based on their observations, Kelvin says, those who become severely ill are predisposed either by genetics or by their immune history to be particularly susceptible. “We think they're lacking an arm of the immune system,” he says. He declined to reveal further details because the data are unpublished. The researchers are also collaborating with a Taiwanese team to identify a genetic predisposition to SARS.

Others are still pursuing the idea of an overactive immune response. Haichao Wang and his colleagues are investigating the role of HMGB1, a late-stage cytokine that mediates lung injury and inflammation. Wang, chief of basic science research at the North Shore University Hospital in New York, is testing the effect of Chinese herbal recipes used as SARS treatments during the outbreaks. He has found preliminary evidence that some of the herbs can block HMGB1 and prevent the toxic inflammatory cascade seen in SARS.

Peiris is also following molecular leads on the immune response to SARS, but declined to reveal details. “We still don't have an exact idea of what the immune system is doing,” he says. “Maybe it's not functioning well or maybe it's functioning too well.”

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Mandavilli, A. Immune response to SARS sets up puzzling paradox. Nat Med 10, 1268 (2004).

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