New Research Explains Why Allergies Worsen Over Time and Lead to New Sensitivities

A new study led by researchers at Mass General Brigham may help explain two longstanding mysteries surrounding allergies: why people can encounter a substance repeatedly before developing an allergy, and why those who develop one allergy sometimes become sensitive to others. Published in the journal Immunity, the preclinical research suggests that sensory nerves do more than simply detect allergens. They may also develop a kind of biological memory that makes the immune system respond more strongly to future exposures.

Previous research by the team showed that sensory neurons—the nerve cells responsible for sensations such as pain and itching—can directly detect certain allergens and help trigger an immune response. The new study takes that discovery a step further, showing that these neurons can retain a memory of earlier encounters through lasting changes in how they use energy. This memory primes them to react more strongly when exposed again, even after the original allergen has disappeared.

The investigation was inspired by a familiar pattern: people often encounter pollen, animal dander, or certain foods many times before developing allergic symptoms. Senior author Caroline Sokol, MD, PhD, a physician-scientist and allergy sufferer herself, wondered whether the nervous system might help explain why. “Neurons are known for their ability to form memories,” said Sokol. “We asked whether an initial allergen exposure might leave a trace – not enough on its own to trigger a full allergic response, but enough to prime the neurons to respond more strongly the next time.”

To investigate, researchers repeatedly exposed mice to allergens and identified a cellular signaling pathway called mTORC1 that helps establish this memory. The pathway changes the activity of mitochondria—the structures inside cells that produce energy—leaving sensory neurons primed for future encounters. When the mice encountered an allergen again, these neurons responded more strongly, amplifying the immune activity associated with allergic sensitization. Importantly, researchers found that interfering with mTORC1 signaling or mitochondrial function could prevent this heightened response without substantially disrupting the initial response.

Perhaps even more intriguing, the neuronal memory was not limited to the original allergen. Researchers found that exposure to one allergen could make sensory neurons more responsive to different allergens that shared similar biological activity. The experiments focused on protease allergens, which contain enzymes that break down proteins. For example, neurons initially exposed to papain, an enzyme found in papaya, subsequently responded more strongly to allergens associated with house dust mites and Alternaria mold. This suggests that nerve cells may remember certain characteristics of an allergen rather than its exact identity, potentially helping explain how sensitivity to one substance can contribute to sensitivity to others. Whether this mechanism also plays a role in food allergies or other allergic conditions in humans remains to be determined.

The findings could eventually lead to new approaches for preventing allergies before they become established. “Now that we know what may cause people to become allergic and pick up more sensitivities, we can design ways to stop it from happening,” explained Sokol. “What is especially encouraging is that allergic memory in neurons faded with time in our models. We are now investigating whether we can deliberately reset this memory, which could ultimately offer a way to reduce the risk of developing allergies.” In the experimental models, the heightened neuronal response persisted for approximately three weeks before fading, suggesting that this memory may be reversible rather than permanent.

The research adds to growing evidence that allergies involve a close partnership between the nervous and immune systems, rather than being driven by immune cells alone. Scientists at Mass General Brigham, the Ragon Institute, and the Gene Lay Institute are now exploring whether interrupting or resetting this neuronal memory could help prevent allergic sensitization. Although the findings are limited to preclinical models and have not yet been demonstrated in humans, they identify a promising new target for future allergy-prevention therapies.