Investigating How the Nervous System and Immune System Work Together to Trigger Allergic Reactions

Caroline L. Sokol, MD, PhD, FAAAAI

The skin is more than a barrier—it’s an active communication hub between the nervous and immune systems. In her laboratory, Caroline L. Sokol, MD, PhD, FAAAAI, is exploring how these systems interact to sense allergens and set allergic responses in motion, offering new insight into why allergic disease develops in some individuals and not others.

“We discovered that protease allergens are directly sensed in the skin by a subset of TRPV1+ itch-inducing sensory neurons, which transmit this information to T helper 2 (Th2)-skewing dendritic cells (DCs) via the neuropeptide Substance P. This interaction promotes DC migration to the draining lymph nodes, where they initiate allergic immune responses,” Dr. Sokol explained.

Because allergen exposure is common but allergic sensitization occurs only in some individuals, Dr. Sokol wanted to push deeper to understand what sets the threshold for neuronal allergen detection. “In recent work, we identified a group of cells in the skin, called γ/δ T cells that homeostatically produces IL-3. IL-3 affects peptidergic sensory neurons, which are involved with itching and immune responses,” she explained. “IL-3 increases neuropeptide production by sensory neurons, which leads to enhanced DC migration and Th2 differentiation, thereby tuning the neuroimmune set point for allergic responses. Together, these findings reveal a novel neuroimmune circuit that controls the initiation of allergic immunity.”

Dr. Sokol is excited about how this research is already benefiting other researchers and those in practice. “By identifying specific neuroimmune interactions we have provided new molecular and cellular targets for those studying allergic diseases, sensory biology and immune regulation,” she said. “Our findings also directly impact clinicians, informing hypotheses about early-life interventions and patient risk stratification.”

In 2019, Dr. Sokol was the recipient of the AAAAI Foundation & Dr. Donald Y. M. Leung/JACI Editors Faculty Development Award for her project, Innate Immune Control of Th2 Differentiation. Since 2020, Dr. Sokol’s lab has published 15 peer-reviewed articles and reviews related to their neuroimmunology work and Dr. Sokol has delivered more than 45 lectures and presentations at major academic institutions, national and international conferences and global symposia.

Like many investigators across the country, Dr. Sokol has been impacted by recent cuts in federal funding. “I’ve had to make the difficult decision to reduce the size of my lab and wind down promising projects that lost support,” she said. "These changes reflect a broader crisis in American science: even high-performing labs are facing increasingly unstable funding environments. That said, I remain deeply committed to advancing our research mission and continue to seek support through alternative funding mechanisms, including foundations and strategic partnerships, to ensure our work moves forward.”

When asked about next steps in her research, Dr. Sokol explained how she is focusing on understanding how repeated allergen exposure changes sensory neurons – both in how they detect allergens and how they communicate with immune cells. “We are investigating whether these nerves undergo long-term adaptations that make them more reactive over time, potentially driving the development of chronic allergic disease. In parallel, we are working to define how IL-3-producing epidermal γ/δ T cells are regulated in the skin, and how their activity shapes neuronal and immune responses to allergens. Finally, we are extending our research beyond environmental allergens to explore whether similar neuroimmune circuits influence the body’s response to food allergens, with the goal of identifying early events that lead to allergic sensitization.”

Dr. Sokol is hopeful that these new insights can support broader public health efforts. “By identifying early events in the allergic cascade, our work helps to inform prevention strategies and guide future funding priorities for government agencies,” she said. “Our ultimate goal is to stop allergic diseases before they start by uncovering how the nervous system helps trigger immune responses. With allergy rates continuing to rise, there’s an urgent need for new approaches. Philanthropic support allows us to move quickly, take bold risks and train the next generation of scientists – bringing us closer to a future where allergic diseases can be prevented.”