At a glance
Sensory neurons in mice retained a “memory” of a first allergen exposure that primed them to react more strongly the next time.
Primed neurons also reacted more strongly to different allergens that send the same type of danger signal, which may help to explain why one allergy often leads to others.
The neuronal memory faded over time, raising the possibility that it could one day be reset to lower allergy risk.
A new study in mice led by Harvard Medical School investigators at Massachusetts General Hospital offers a potential explanation for two long-standing questions in allergy: Why do allergies often emerge only after repeated exposure, and why do people with one allergy frequently develop others? The findings were published Sept. 22 in Immunity.
The team’s earlier work revealed that sensory neurons — the nerve cells that allow us to feel sensations such as itch and pain — can directly sense certain allergens and help start the allergic immune response. The new study shows that these neurons do not simply detect allergens in the moment but can retain a metabolically encoded record — or “memory” — of previous exposures that allows them to respond more strongly to later exposures, even after the original allergen is gone.
The findings suggest that sensory neurons, like certain immune cells, can hold a memory of past allergen encounters. That may help explain why allergies build over time and why one allergy often leads to others. It also points to these nerve cells as a possible new target for preventing allergies before they take hold.
“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,” said senior author Caroline Sokol, HMS assistant professor of medicine at Mass General and a physician-scientist in allergy and clinical immunology at Mass General Brigham. Sokol is also a member of the Ragon Institute of Mass General Brigham, MIT, and Harvard and a core member of the Gene Lay Institute of Immunology and Inflammation.
The study grew out of a familiar clinical observation — people tend to encounter the same pollen, pets, or foods repeatedly before developing an allergy. Drawing on her perspective as a clinician, scientist, and allergy sufferer, Sokol wondered whether the nervous system might help explain this delay.
“Neurons are known for their ability to form memories,” Sokol said. “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 test this idea, the researchers modeled repeated allergen exposure in mice and found that an initial exposure activates a specific signaling pathway in neurons. This pathway primes them to later respond to the same allergen, as the team hypothesized.
It also primes them to respond to other allergens that share the same enzymatic activity but have different molecular structures. This suggests that sensory neurons may remember a shared feature of allergens — the type of danger signal they produce — rather than their precise molecular identity. This cross-allergen response may help explain why developing sensitivity to one allergen can increase susceptibility to others.
Because the work was done in mice, more research is needed to learn whether the same process happens in humans. Notably, the neurons’ allergic memory faded over time in the mouse 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,” Sokol said.
Adapted from a Mass General Brigham news release.
Authorship, funding, disclosures
Xueping Zhu is first and co-corresponding author of the study. Additional authors are Haibo Yang, Haoting Zhan, Isabela J. Kernin, Dean R. Buttaci, Ngoc Le, Cai Han, Parth R. Naik, Peri R. Matatia, Sarah Zaghouani, Lillian R. Delacruz, Lukas M. Altenburger, Neal P. Smith, Elena Wu, Rebecca Londoner, Cameron H. Flayer, Zhengwang Sun, Alison E. Ringel, Alexandra-Chloe Villani, and Rod A. Rahimi.
This work was supported in part by the National Institutes of Health (R01AI202406, 1S10OD036287), the Food Allergy Science Initiative, a Massachusetts General Hospital Howard M. Goodman Fellowship, the Gene Lay Institute of Immunology and Inflammation, and a Gene Lay Institute of Immunology and Inflammation Fellowship.
Sokol is a paid consultant for Bayer, Merck, and Lilly; has received sponsored research support from GSK; and serves on the scientific advisory board for Granite Biosciences and the advisory board for Immunity. Additional author disclosures can be found in the paper.
