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System backfired. Some adult victims of severe H1N1 had lungs full of a protein called C4d (orange, left). C4d usually helps destroy viruses, but researchers think that when it met the 2009 virus, it helped kill the host instead.

Fernando Polack

How Swine Flu Killed the Healthy

The H1N1 pandemic virus that took the world by storm in 2009 may have had an unexpected accomplice. Some of the thousands who died may have been victims of their own immune systems, suggests a paper appearing in Nature Medicine today. The study provides a possible answer to one of the most baffling questions since the virus appeared in the spring of last year: Why did the virus cause most damage in 20- to 50-year-olds—who are generally the healthiest—while sparing the very young and the very old?

Influenza pandemics occur when a totally new strain of the virus emerges, against which nobody's immune system is fully prepared; that's why both the healthy and the weak are vulnerable. But that doesn't explain why senior citizens, with generally weaker immune systems, and young children, with no immunity to influenza whatsoever, tended to get cases of H1N1 that were milder than their healthier counterparts. "In a middle-aged population, we saw a lot of people getting very, very ill," says pediatrician Fernando Polack of Vanderbilt University in Nashville, Tennessee.

The reason, according to Polack, is that their immune systems' programming backfired. After looking at lung samples from 75 young and middle-aged adult victims of the 2009 pandemic, they found an uncanny amount of a protein called C4d, a molecule that normally binds to antibodies to form virus-fighting immune complexes.

When antibodies fight a virus under normal conditions, Polack says, they call in C4d, a compound that can destroy viruses. In the case of flu, most people had antibodies to seasonally circulating influenza strains, but these antibodies were a poor match to the pandemic virus. Although they recognized the virus and latched on to it, they weren't able to stop it from replicating, says Polack. When the antibodies and the C4d formed the immune complexes, Polack speculates that the system spiraled out of control. Instead of punching holes in the viruses, the immune complexes punched holes in the victims' veins and flooded their lungs with water and plasma. "The immune system gets fooled into activating this particular immune defense, and it causes harm," says Niranjan Bhat, an infectious disease physician at Johns Hopkins Children's Center in Baltimore, Maryland, who was not part of the research.

This was less likely to happen in young children and infants, with few or no antibodies against seasonal flu strains, says Polack. And elderly people had antibodies to the H1N1 strain that circulated in the United States until 1957—a descendant of the Spanish flu pandemic of 1918—which are known to be a much better match to the 2009 H1N1 strain; so the flood of C4d generally didn't occur in them. When the team looked at lung samples from victims of the seasonal flu, they found only trace amounts of C4d, which seemed to confirm their suspicions.

Not everyone is convinced. "There's no doubt that those immune complexes are there," says virologist Ron Fouchier of the Erasmus Medical Center in Rotterdam, the Netherlands. "The question is, are those antibody complexes there because there's another problem, or are those antibodies there causing the problem?"

But epidemiologist Thomas Reichert of the Entropy Research Institute in Lincoln, Massachusetts, finds Polack's hypothesis completely plausible. There's not much that could cause this kind of lung damage except an invasion of T lymphocytes (the immune system's "warrior cells"), he says, and Polack found no evidence of that. The immune system's overreaction, says Reichert, is "kind of a last-ditch way of handling something. ... If we can't identify you specifically enough, but we know there's a lot of you, we're just going to blow the whole damn place up."