Immune Gene Evolution May Be Driven By Parasites

by Kayt Sukel

July 22, 2009

Soon after I brought my newborn son home from the hospital, my grandmother admonished me not to bathe him too often. If babies are too clean, they are more likely to get sick, she said. Now researchers are finding there may be something to that folk wisdom. A population genetics study published in the June 8 issue of the Journal of Experimental Medicine suggests that parasites have helped shape the human immune system—and that a lack of exposure to helminthes, or worms, may account for rising rates of autoimmune disorders such as irritable bowel disease (IBD), Type 1 diabetes and celiac disease.

The hygiene hypothesis

For nearly two decades, researchers have put forward the so-called hygiene hypothesis: the argument that raising children in extremely clean conditions negatively impacts immune development, predisposing them to autoimmune disease in later life. It’s somewhat counterintuitive. Cleanliness, after all, is known to directly prevent the spread of communicable diseases; for example, both the Centers for Disease Control and Prevention and the World Health Organization advising frequent hand-washing as a useful deterrent against the H1N1 pandemic flu strain.

But what concerns researchers in the field isn’t simply the prevalence of autoimmune diseases but where they are occurring. “Autoimmune diseases have become extremely prominent in the West. You don’t see these diseases in developing countries. But in developed countries, these diseases seem to have come out of nowhere and keep increasing in frequency,” says David Elliott, a gastroenterologist and immunologist at the University of Iowa. “Our proposal is that this is an environmental change, not a genetic one, and it is one that has occurred in the last couple of generations.”

Elliott and colleagues examined the differences between developing countries and developed ones, looking for key differences. And one thing kept popping up—exposure to helminthes, or parasitic worms.

“It became clear that where helminthes are geographically, diseases like IBD are absent. And where IBD is present, helminthes are absent,” he says. “Historically, it fits. IBD started appearing when we started to eradicate helminthes. It just kind of clicked.”

Anne Cooke, a pathologist at the University of Cambridge, saw a similar effect in mouse models of Type 1 diabetes when moving into her laboratory nearly two decades ago. A pin worm infection en route inhibited the development of the disease.

“We know diabetes is under both genetic and environmental control,” she says. “As a disease, it’s increasing dramatically in the developed world and vanishing in the developing world.

“Something has altered in the environment that is maybe precipitating the development of the disease in those with genetically susceptible backgrounds. And parasites are a fascinating possibility. We used to get all manner of parasitic infections like pin worms. They live within you for some time and they’ve developed strategies to evade host immune systems. It’s likely they are mediating some kind of response.”

Co-evolving immune system

But what might this have to do with our genes? Quite a bit. Mateo Fumagalli, a population genetics researcher at the Scientific Institute IRCCS Eugenio Medea in Italy, and his colleagues have found evidence that helminthes have played a role in the evolution of the human immune system. Looking at the geographical distribution of single nucleotide polymorphisms (SNPs), mutations that shape genetic variability, the group found that genetic variability was correlated with the diversity of an area’s parasites.

“Genetic variation is particularly important in the immune system, and genes in the immune system seem to be more polymorphic [variable] than genes with other functions,” says Manuela Sironi, one of Fumagalli’s colleagues. “It’s thought that pathogens have a strong selection pressure on the genes in our immune system. And with these correlations, we’ve found that helminthes have a very strong selective pressure on the evolution of our immune system.”

Sironi and Fumagalli’s data suggest that our immune systems have co-evolved with parasitic worms—living alongside helminthes for millions of years has shaped the way our immune systems react to pathogens, through a greater genetic diversity in our immune-related genes. In turn, helminthes have evolved the ability to mitigate the human immune response to their own advantage, as many worms need their human host healthy in order to propagate and survive.

Fumagalli’s research group then analyzed five interleukin genes, which encode for proteins involved in mediating the immune system’s response to disease. These genes have evolved to deal with a variety of different pathogens, including viruses, bacteria, fungi and worms.

“These genes are very involved with many autoimmune diseases like Crohn’s and multiple sclerosis,” Cooke says. “And these genes have evolved to deal with a lot of diverse pathogens.  But when you take someone out of the environment where there is that diversity, all those different pathogens, it may result in an imbalance: an overactive response to pathogens and, ultimately, autoimmune disease.”

The work provides evidence that the human immune system likely co-evolved with helminthes. That makes perfect sense, Cooke says.

“A worm needs its host, and it’s important that they are able to harness our immune system in order to survive,” she says. “It’s happened over millions of years, but in evolving alongside us, these organisms have used our immune systems to facilitate their life cycle and in doing so have induced all kinds of regulation and fine-tuning that we’re only beginning to understand.”

Worms as medicine?

Given this co-evolution, is it possible that bringing back some pathogen diversity may help treat those suffering from autoimmune disorders? Elliott, of the University of Iowa, has shown some success in treating people suffering from ulcerative colitis with the ova from Trichuris suis, or pig whip worms.

“The group did show improvement in their disease scores,” he says. “And it is being developed as a treatment by a company in Germany that is gearing up for clinical studies this fall.”

Both Elliott and Cooke caution that there is still much more to understand about this technique, known as helminthic immunomodulation, before it could be used as a standard treatment for autoimmune disorders.

“We still don’t know the actual mechanism helminthes utilize to reduce inflammatory response,” Elliott says. “I suspect that there are multiple mechanisms at work, since it is such a robust effect. It is a very complex relationship between helminthes and the mammalian immune system that we’re trying to better understand. But we do postulate that, for some, helminthes offer a more symbiotic than parasitic relationship.”

Until scientists understand more about these mechanisms, though, Elliott recommends not trying helminthic therapies at home.

“This is something that has to be approached clinically and scientifically, and we just don’t know enough yet,” he says. “I think this is something that is capturing the public mindset. Until we know more, it’s just not safe to go out and try to find your own helminthes.”