Conventional wisdom has held for some time that children who grow up in environments rich with biodiversity — farms, homes with pets, rural settings in general — are less likely to have allergies. The thing nobody has ever completely understood is why?

Yale researchers have now found an answer. It turns out that exposure to diverse microbes and proteins early in life creates broad immune memory and a specific antibody that helps block allergic reactions later in life. Rather than overreacting to harmless allergens (ragweed, cats, peanuts, etc.), researchers say, an experienced immune system responds in a balanced way.

The findings may inform better strategies for allergy prevention, encouraging early exposure to natural environments and new therapies that boost protective immune responses rather than just suppressing symptoms.

The all-Yale study is published in the journal Nature.

“We wanted to test this idea that living in a less clean environment protects you from allergies,” said Ruslan Medzhitov, the Sterling Professor of Immunobiology at Yale School of Medicine and first author of the study. “The main question we wanted to answer was what’s happening to the immune system when you’re in a natural environment and exposed to a lot of microbes?”

To find out, researchers compared two groups of mice. One group consisted of mice raised in microbe-rich environments — akin to mice living in a natural habitat. The other group consisted of laboratory mice raised in sterile conditions. Researchers exposed both groups to allergens and then measured allergic reactions, antibody production, and immune cell activity in the animals.

They stimulated the mice’s immune systems by exposing them to common infectious agents, as well as complex, real-world food allergens such as soy, peanut, and pea samples. Researchers also noted when allergies were most likely to develop by comparing early-life and adult exposures in the mice.

They found that mice raised in real-world environments were largely protected from severe allergic reactions compared to the lab mice. Natural mice had a type of immune memory that could handle allergens that the lab mice had never encountered before. This cross-reactive immune memory shifts responses away from allergy-driving antibodies (IgE) toward protective antibodies (IgG,) which don’t fuel allergic responses.

“The natural mice get all kinds of microbial exposures, but they’re not sick. They represent what is the normal state of the animal — and of humans up until about 100 years ago,” said Medzhitov. “Basically, we found that this normal exposure to microbes and other antigens builds up a very different state of the immune system compared to what we see in the clean mice, whose systems are clearly not normal.”

Very “clean” environments may leave the immune system undertrained and more likely to overreact, the researchers say. Allergies have risen dramatically in modern societies, and this study shows that environment, and not just genetics, plays a big role in determining who develops allergies.

“With industrialization and the use of antibiotics, sanitization, hygiene products, vaccinations, and so on, we’re increasingly protected against truly dangerous microbes, which is great,” said Medzhitov. “But the tradeoff is that our immune system is in this untrained, unprepared state, and otherwise harmless exposures trigger a pathological allergic response.”

The new findings indicate that exposure to allergens and the cultivation of IgG (Immunoglobulin G) antibodies, the most common antibody found in the blood, may cure existing allergies. They also shed light on the role that the environment may play in triggering autoimmune conditions, the researchers say.

Other study authors include associate research scientist Steven Erickson; postgraduate researcher Benjamin Lauring; and research associate Jaime Cullen, all in the Department of Immunobiology.