By Janelle Weaver

One of the puzzles of last year's H1N1 "swine flu" pandemic--which caused thousands of deaths worldwide--was that seemingly healthy middle-aged adults were hit hardest. A study has now shown that previous infection with other, seasonal, influenza strains primed patients' immune systems to harm their bodies rather than to mobilize against the new threat.

The study, published online December 5 in Nature Medicine, began with a hunch that antibodies from past encounters with pathogens might have determined the severity of H1N1 cases. (Scientific American is part of Nature Publishing Group.)

Exposure to viruses causes the body to produce antibodies that fight off infection. These proteins continue to circulate in the bloodstream and can recognize new invaders that resemble past pathogens. For example, the 2009 H1N1 episode spared many elderly people because they had already encountered a related H1N1 strain more than half a century ago, which had armed them with defensive antibodies. But curiously, young children infected with H1N1 who had little or no prior infection with influenza showed milder symptoms than did middle-aged adults.

After observing these phenomena, pediatrician Fernando Polack of Vanderbilt University in Nashville, Tenn., and his team explored past exposure to pathogens. They found that pre-existing antibodies in infected middle-aged people recognized the 2009 H1N1 virus, but attacked organ tissue rather than defending against the invader.

"Nobody really had a good explanation for why middle-aged people seemed to have more severe disease than would have been expected," says Richard Scheuermann, an immunologist at the University of Texas Southwestern Medical Center in Dallas. "This explanation is the first one that I've seen that actually makes sense."

Renegade weapons

The researchers took samples of blood and respiratory-tract fluid from people infected with H1N1 in Argentina last year. Individuals with severe symptoms had low numbers of white blood cells called lymphocytes, and those who died showed signs of swelling, blood loss and adverse immune responses in their lungs.

They found that middle-aged patients had antibodies that bound less effectively to this H1N1 strain than did the antibodies of elderly people, and therefore did not protect against it. And the antibodies of extremely ill individuals also bound less well to the virus than did those of mildly sick patients. These dysfunctional antibodies attached to the flu pathogens and formed complexes that infiltrated the lungs and triggered a biochemical pathway that promotes inflammation and can cause cell membranes to rupture. It was this process that damaged tissue in the patients who died.

The team had also analyzed lung sections from people who had died in a 1957 pandemic involving the H2N2 strain of flu. They found evidence of similar complexes in the tissue. The finding implies that deaths from that pandemic were also caused by pre-existing antibodies that were maladapted to fighting off the new infection.

"This is the first paper that has examined this idea of immune complexes as a potential cause for severity of illness," says David Kelvin, an immunologist at the University Health Network in Toronto, Canada. But the authors will have to perform experiments in animals to confirm that the faulty antibodies and harmful complexes are responsible for severe illness, he adds.

Polack explains that intense reactions to H1N1 were provoked by antibodies that probably arose from prior contact with a seasonal flu strain known as H3N2, or with H1N1 strains present in the community before the pandemic. Although these antibodies may have helped to combat seasonal flu strains, the new virus was different enough not to produce the appropriate immune response. Because abnormal complexes were a factor in cases of both 2009 H1N1 and 1957 H2N2, the proposed mechanism could underlie excessive immune responses in a range of diseases, he says.

For instance, previous exposure to measles, dengue fever and respiratory syncytial virus worsens some people's reactions to subsequent strains of those diseases, says Polack. But he adds that other factors, such as secondary bacterial infections, also contribute to the severity of illness.

In light of the findings, Scheuermann cautions against attempts to develop universal vaccines that work against different strains of flu viruses year after year, because they could generate destructive antibodies. Instead, the results may prompt doctors to treat middle-aged flu patients with drugs that inhibit the formation of antibody-pathogen complexes, he says, adding, "Now that we have an understanding of the mechanism of severe disease, we'll be in a much better position to treat infected people and prevent them from dying."