Apparently, there's yet another reason to be nostalgic about the good old days: parasite infections. Or if not the parasites themselves, then at least the immune system's reaction to and regulation by them.
"Historically, when people lived more rural lifestyles, parasite infections were common," David Artis told BioWorld Today. Indeed, in much of the world, they still are: An estimated 2 billion people worldwide are infected with parasitic worms. However, the elimination of those worms appears to come at a price - as parasitic infections decrease in a population, allergies and asthma increase.
There is a long-standing hypothesis that an idle immune system is the devil's workshop: Allergies and asthma are caused by a so-called type 2 immune response, which is the type of adaptive immune response that normally occurs in reaction to parasite infections. (In contrast, the adaptive immune system mounts a type 1 response to viruses and bacteria.)
In the April 2006 issue of the Journal of Experimental Medicine, Artis and his colleagues at the University of Pennsylvania; Schering-Plough Biopharma in Palo Alto, Calif.; and the UK's University of Edinburgh reported on research that might show an additional connection between type 2 immunity and the severe inflammation that characterizes asthma and allergies, as well as a host of other diseases.
They showed that besides giving the type 2 immune system a steady job, parasite infections also appear to lead to the production of cytokines that combat inflammation. So as hygienic conditions improve, "the [type 2] immune system not only has no worms to fight, but has also lost that regulatory response that the worms induce," Artis said. And as a result, a type 2 immune response that is both misdirected and uninhibited now is causing "fairly debilitating and sometimes lethal" diseases at an increasing frequency.
Artis, an assistant professor of pathobiology at Penn, said that while the pathway driving the type 1 immune responses is reasonably well understood, factors driving type 2 responses have remained "elusive."
In their JEM paper, the scientists wanted to identify such factors. Based on previous experiments, their working hypothesis was that the cytokine interleukin-25 would turn out to be a critical driver of type 2 immune responses.
"But," Artis said, "the great thing about science is that you are allowed to prove yourself wrong."
The other great thing is that sometimes when you're wrong, the results are more interesting than if you had been right. In this case, Artis and his team found that contrary to their initial hypothesis, interleukin-25 is not absolutely necessary for the induction of type 2 immune responses. But they made some unexpected discoveries about IL-25 that could have big payoffs in the treatment of autoimmunity.
Artis and his colleagues first infected a highly susceptible mouse strain with a parasitic worm; the mice were able to clear the worm infection when they were treated with recombinant IL-25.
The researchers next made mice with no gene for IL-25. In response to a worm infection, the knockouts generated less of a gastrointestinal type 2 immune response and more of a type 1 response than their wild-type cousins. However, blocking the type 1 response led to a type 2 response even in interleukin-25 knockouts, showing that "under normal conditions, IL-25 is critical for driving type 2 responses. But it is not essential," Artis said.
In the course of the experiments, though, the scientists made another observation: In addition to the fact that IL-25-deficient mice were unable to overcome worm infections, they developed a severe inflammatory response to those chronic infections. That severe inflammation went along with higher levels of interleukin-17.
Artis explained that IL-17 producing helper T cells are a recently discovered cell type that is "found in pretty severe inflammatory diseases like multiple sclerosis, inflammatory bowel disease and arthritis. And this population could be what is driving tissue destruction in those diseases." Unsurprisingly, there also is considerable pharmaceutical interest finding an off switch for IL-17. Schering-Plough and Johnson & Johnson have research programs in IL-17, as does South San Francisco-based Genentech Inc.
In the JEM paper, Artis and his team do not provide direct evidence about the nature of the interaction between IL-25 and IL-17. But possibly, the heightened levels of IL-17 in the knockouts are caused by there being no IL-25 to inhibit IL-17 production, a possibility that the scientists are investigating experimentally.
Artis is interested in seeing his research have an impact in the clinic. "You want your basic science to be relevant to humanity," he said. But he does not expect that he himself will be involved in that part of the work. "I'm not a physician, and I don't have an M.B.A.," he said. "What we do well is the basic research."