Why do some people itch after a mosquito bite or exposure to an allergen such as dust or pollen, while others do not? A new study has identified the reason for these differences, finding the pathway by which immune and nerve cells interact and cause itching. The researchers, led by allergy and immunology specialists at Massachusetts General Hospital, a founding member of the Mass General Brigham health care system, blocked this pathway in preclinical studies, suggesting a new treatment approach for allergies. The findings are published in Nature.
“Our research provides an explanation for why, in a world full of allergens, one person may be more likely to develop an allergic response than another,” said senior and corresponding author Caroline Sokol, MD, PhD, an attending physician in the Allergy and Clinical Immunology Unit at MGH, and an adjunct professor of medicine at Harvard Medical School. “By establishing a pathway that controls the response to allergens, we have identified a new cellular and molecular circuit that can be used to treat and prevent allergic responses, including itch. Our preclinical data suggest that this may be a translatable approach to humans.”
When it comes to detecting bacteria and viruses, the immune system is primarily responsible for detecting pathogens and initiating long-lasting immune responses against them. However, in the case of allergens, the immune system takes a backseat to the sensory nervous system. In people who have not been exposed to allergens before, their sensory nerves react directly to these allergens, causing itching and triggering local immune cells to initiate an allergic reaction. In people with chronic allergies, the immune system can affect these sensory nerves, leading to persistent itching.
Previous research by Sokol and colleagues showed that the skin’s sensory nervous system—specifically, the neurons that trigger itch—directly detects allergens through protease activity, a process driven by enzymes that are shared by many allergens. Thinking about why some people are more likely to develop allergies and chronic itch symptoms than others, the researchers hypothesized that innate immune cells might be able to set a “threshold” in sensory neurons for allergen reactivity, and that the activity of these cells might define which people are more likely to develop allergies.
The researchers performed different cellular analyses and genetic sequencing to try to identify the mechanisms involved. They found that a specific, poorly understood type of immune cell in the skin, which they called GD3 cells, produces a molecule called IL-3 in response to environmental triggers that include the microbes that normally live on the skin. IL-3 acts directly on a subset of itch-inducing sensory neurons to prime their responsiveness to even low levels of protease allergens from common sources such as house dust mites, environmental mold, and mosquitoes. IL-3 makes sensory nerves more reactive to allergens by priming them without directly causing itch. The researchers found that this process involves a signaling pathway that stimulates the production of certain molecules, leading to the initiation of an allergic reaction.
They then performed additional experiments in mouse models and found that removing IL-3 or GD3 cells, as well as blocking their downstream signaling pathways, rendered the mice resistant to the itch and immune-activating capabilities of allergens.
Since the type of immune cells in the mouse model is similar to that in humans, the authors conclude that these findings may explain the role of the pathway in human allergies.
“Our data suggest that this pathway is also present in humans, raising the possibility that by targeting the IL-3-mediated signaling pathway, we may be able to generate new treatments to prevent allergy,” Sokol said. “More importantly, if we can determine the specific factors that activate GD3 cells and create this IL-3-mediated circuit, we may be able to target those factors and not only understand allergic sensitization, but also prevent it.”
Disclosures: Sokol is a paid consultant to Bayer and Merck and receives sponsored research support from GSK. Aderhold is a current employee of Werewolf Therapeutics. McAlpine is a paid consultant to Granite Bio. Woolf is a founder of Nocion Therapeutics, QurAlis, and BlackBox Bio, and serves on the scientific advisory boards of Lundbeck Pharma, Axonis, and Tafalgie Therapeutics. Villani has a financial interest in 10X Genomics, a company that designs and manufactures genetic sequencing technology for use in research, and that technology is being used in this research.
Funds: This work was supported by Grant #T32HL116275 and a Catalyst Research Grant from the National Eczema Association, Grants K99/R00 HL151750, R01 HL158534, R01 AG082185 from the National Institutes of Health (NIH), and Grants #R35 HL135752, NIH R35 NS105076-01, and R01 AT011447 from the Cure Alzheimer’s Fund, Grants #DP2CA247831, R01AI15116 from the AAAAI Foundation, and the DYM Leung/JACI Editors Faculty Development Award, the Food Allergy Science Initiative, the Massachusetts General Hospital Howard Goodman Fellowship, and the Broad Institute Next Generation Scholar Award and the Massachusetts General Hospital Transformative Scholar Award. Sokol receives additional support for sponsored research from GlaxoSmithKline.