Exposure to seasonal flu weakened armour against H1N1

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Exposure to seasonal flu weakened armour against H1N1

Faulty antibodies from previous infections boosted severity of swine flu in the

middle-aged. 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 today in Nature Medicine1, began with a hunch that

antibodies from past encounters with pathogens might have determined the

severity of H1N1 cases.

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, paediatrician Polack of Vanderbilt

University in Nashville, Tennessee, 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 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 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. "

References

Monsalvo, A. C. et al. Nature Medicine doi:10.1038/nm.2262 (2010).

http://www.nature.com/news/2010/101205/full/news.2010.649.html