Researchers have discovered why some individuals experience itchiness after being exposed to allergens or mosquito bites, while others do not. Their study indicates that this mechanism could be a target for preventing allergic reactions in model systems prior to human trials.
What causes some people to itch after a mosquito bite or an allergic reaction to dust or pollen, while others remain unaffected? A recent investigation has uncovered the reasons for these variations, identifying the interplay between immune and nerve cells that results in itch sensations. The study, led by allergy and immunology experts at Massachusetts General Hospital, which is part of the Mass General Brigham healthcare network, successfully obstructed this pathway in preclinical research, revealing a potential new treatment for allergies. These findings were published in Nature.
“Our findings provide insight into why, in a world full of allergens, some individuals develop allergic reactions while others do not,” explained senior author Caroline Sokol, MD, PhD, who practices in the Allergy and Clinical Immunology Unit at MGH and is an assistant professor at Harvard Medical School. “By mapping out the pathway that influences allergen sensitivity, we have discovered a new cellular and molecular network that could be targeted to manage and prevent allergic responses, including itching. Our preclinical evidence suggests this might also be applicable to humans.”
While the immune system is essential for detecting bacteria and viruses and launching long-lasting immune responses, it plays a secondary role when it comes to allergens. In individuals who have not previously encountered allergens, sensory nerves respond directly to these allergens, causing itchiness and prompting local immune cells to trigger an allergic response. Those with chronic allergies may experience ongoing itch due to the immune system’s influence on these sensory nerves.
Prior research from Sokol’s team established that the sensory nervous system in the skin, particularly the neurons that trigger itch, can directly recognize allergens that possess protease activity, a common characteristic among various allergens. The researchers hypothesized that innate immune cells could set a “threshold” in sensory neurons for reacting to allergens, potentially affecting allergy susceptibility in different people.
The team conducted various cellular analyses and genetic sequencing to uncover the underlying mechanisms. They discovered a particular yet poorly understood type of immune cell in the skin, termed GD3 cells, which release a molecule called IL-3 in response to environmental stimuli such as the microbes typically found on the skin. IL-3 works directly on certain itch-responsive sensory neurons, enhancing their sensitivity to even minimal exposure to protease allergens, which originate from common sources like house dust mites, molds, and mosquitoes. Although IL-3 heightens the sensitivity of sensory nerves to allergens, it does not trigger itchiness on its own. The researchers found that this entire process involves a signaling pathway that increases the production of specific molecules, initiating an allergic reaction.
Further experiments in mouse models demonstrated that eliminating IL-3 or GD3 cells, or inhibiting downstream signaling pathways, rendered the mice resistant to allergic itch and the immune responses triggered by allergens.
Given that the immune cells in these mouse models share similarities with those in humans, the authors conclude that these findings may shed light on the pathway’s significance in human allergies.
“Our data indicate that this pathway likely exists in humans as well, suggesting that targeting the IL-3-related signaling pathway may lead to the development of new allergy prevention therapies,” stated Sokol. “Crucially, if we can identify the specific factors that activate GD3 cells and initiate the IL-3 signaling mechanism, we could intervene and not only comprehend but also prevent allergic sensitization.”
Disclosures: Sokol serves as a paid consultant for Bayer and Merck and receives research funding from GSK. Aderhold currently works for Werewolf Therapeutics. McAlpine is a paid consultant for Granite Bio. Woolf is associated with multiple organizations including Nocion Therapeutics, QurAlis, and BlackBox Bio and serves on the scientific advisory boards for several companies. Villani has a financial interest in 10X Genomics, which produces gene sequencing technology utilized in this research.
Funding: This study was supported by grant no. T32HL116275 and a Catalyst Research grant from the National Eczema Association, among other NIH grants and various scholarships.
