Wild Vs. Lab Rodent Comparison Supports Hygiene Hypothesis

The prevailing hypothesis concerning the development of allergy and probably autoimmune disease is the "hygiene hypothesis," which states that people in "hygienic" societies have higher rates of allergy and perhaps autoimmune disease because they -- and hence their immune systems -- have not been as challenged during everyday life by the host of microbes commonly found in the environment.

The study suggests that an overly hygienic environment could simultaneously increase the tendency to have allergic reactions and the tendency to acquire autoimmune disease, despite the fact that these two reactions represent two different types of immune responses.

The researchers added that their experimental model, which compares specific immune system responses of wild rodents to laboratory rodents, could open up a new approach to studying human disease and allergies that complements traditional scientific studies.

"Laboratory rodents live in a virtually germ- and parasite-free environment, and they receive extensive medical care -- conditions that are comparable to what humans living in Westernized, hygienic societies experience," said William Parker, Ph.D., an assistant professor of experimental surgery and senior member of the study team. "On the other hand, rodents living in the wild are exposed to a wide variety of microbes and parasites, much like humans living in societies without modern health care and where hygiene is harder to maintain."

The researchers published their results early on-line in the Scandinavian Journal of Immunology. The research was supported by the National Institutes of Health, the Duke University School of Medicine and the Fannie E. Rippel Foundation.

Up to 50 million Americans are estimated to suffer from allergies, and another 8 million have some form of autoimmune disorder, which occurs when an overactive immune system attacks tissues in the body. Examples of autoimmune disorders include lupus, insulin-dependant diabetes, rheumatoid arthritis and scleroderma.

"The most commonly accepted explanation for this high incidence of allergy and perhaps autoimmune disease is the hygiene hypothesis," Parker said. But this hypothesis has not been thoroughly tested in animal studies, he said, and the few studies conducted have focused on specific pathogens or parasites.

The Duke researchers decided to study the hypothesis by comparing the immune systems of wild house mice and common rats to laboratory mice and rats. The strength of this model, Parker said, is that it takes into account the totality of the animals living in their natural environment.

Specifically, the team focused the animals' production of various antibodies, known as immunoglobulins, either associated with autoimmune disease or associated with allergy. When an animal encounters a foreign invader, or antigen, its immune system kicks into action by producing antibodies that bind to the invader and destroy it.

Of the many classes of immunoglobulins (Ig), the IgG type is often involved in autoimmune disease, while the IgE type is likely a key defender against parasites and has been implicated in allergic reactions in humans, Parker said.

For their experiments, the researchers trapped wild rats in rural and urban settings in North Carolina and trapped wild mice in Wisconsin. They then measured the levels of antibodies in the blood of the wild rodents and compared the levels to those observed in mice and rats housed in Duke animal facilities.

All of the wild rodents had higher levels of IgG and IgE, with the IgE showing the most pronounced difference, Parker said. Additionally, the wild rodents had higher levels of a particular type of IgG called polyreactive, autoreactive IgG, which is associated with autoimmune disease in hygienic humans and rodents. However, the increased levels of these antibodies did not presumably cause untoward reactions in the wild rodents, Parker said.

That wild rodents had higher levels of IgE was not unexpected, he added, since wild rodents would likely have encountered parasites that activated the production of antibodies as protection. However, the production of polyreactive, autoreactive IgG by the wild rodents was unexpected: Polyreactive, autoreactive antibodies are always found to be a type of IgM, a different type of antibody than IgG, although all previous studies have focused on hygienic populations.

"These results appear to demonstrate that the environment has profound effects on the production of IgE and autoreactive IgG," Parker said. "While the production of these two antibody types lead to autoimmune disease and allergy, respectively, in the laboratory animals, their production seemed to represent a nonpathogenic, protective response to the environment by the wild rodents.

"We would expect that the targets of the autoreactive IgG and IgE in the 'hygienic' laboratory rodents would be substantially different from the targets of the same antibodies in the wild animals," he said.

In the wild animals, the autoreactive IgG likely bind to environmental antigens and therefore do not have deleterious effects, Parker said.

"However, autoreactive IgG in hygienic animals can bind avidly to the body's own cells, which can lead to autoimmune disease," he said. "In a parallel fashion, the IgE in the wild animals is protective because the antibodies bind to parasite antigens, while the same antibodies in laboratory animals would bind to abundant but harmless environmental antigens, leading to allergies to those antigens."

"These results are consistent with the idea that animals without access to modern medicine have high levels of autoimmune-like and allergic-like immune responses that represent appropriate responses to unknown factors in their environment," he said.

Although this study suggests that the environment plays an important role in how the immune systems in animals develop, genetics is likely to be involved as well, Parker said. He now is planning additional studies to help decipher the full role of genetics.

Also, his group is planning further studies of the hygiene hypothesis, using the new rodent model to examine other factors that may be contributing to the higher rates of allergy and autoimmune diseases of humans in industrialized societies, such as lack of exercise, increased mental stress and the consumption of processed food.

Duke members of the research team included Aditya Devalapalli, Aaron Lesher, Karl Shieh, Jonathan Solow, Mary Lou Everett and Arpana Edala. Other team members included Parker Whitt and Nolan Newton of the N.C. Department of Environmental and Natural Resources; and Renee Long of the U.S. Geological Survey's National Wildlife Health Center, in Madison, Wisc.