Finding and blocking the mechanism behind allergic itching

US researchers have discovered the pathway by which immune and nerve cells interact and lead to itching, explaining why some people feel itchy after a mosquito bite or exposure to an allergen while others do not. The team then blocked this pathway in preclinical studies, suggesting a new treatment approach for allergies. Their findings have been published in the journal Nature.

“Our research provides one explanation for why, in a world full of allergens, one person may be more likely to develop an allergic response than another,” said senior author Dr Caroline Sokol, an attending physician at Massachusetts General Hospital and assistant professor at Harvard Medical School.

The immune system plays a key part in detecting pathogens and initiating long-lived immune responses against them; however, for allergens, the immune system takes a backseat to the sensory nervous system. In people who haven’t been exposed to allergens before, their sensory nerves react directly to these allergens, causing itchiness and triggering local immune cells to start an allergic reaction. In those with chronic allergies, the immune system can affect these sensory nerves, leading to persistent itchiness.

Previous research from Sokol and colleagues showed that the skin’s sensory nervous system — specifically the neurons that lead to itch — directly detects allergens with protease activity, an enzyme-driven process shared by many allergens. When thinking about why some people are more likely to develop allergies and chronic itch symptoms than others, the researchers hypothesised that innate immune cells might be able to establish 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 and identify the involved mechanisms. They found that a poorly understood immune cell type in the skin, which they called a GD3 cell, 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 like house dust mites, environmental moulds and mosquitos. It makes sensory nerves more reactive to allergens by priming them without directly causing itchiness; this process involves a signalling pathway that boosts the production of certain molecules, leading to the start of an allergic reaction. Performing experiments in mouse models, the team found that removal of IL-3 or GD3 cells, as well as blocking their downstream signalling pathways, made the mice resistant to the itch and immune-activating ability of allergens.

“Our data suggest that this pathway is also present in humans, which raises the possibility that by targeting the IL-3-mediated signalling pathway, we can generate novel therapeutics for preventing an allergy,” Sokol said. “Even more importantly, if we can determine the specific factors that activate GD3 cells and create this IL-3-mediated circuit, we might be able to intervene in those factors and not only understand allergic sensitisation but prevent it.”

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