Reason Behind Itching: How Allergens Activate Sensory Neurons

The immune system is mainly responsible for identifying germs and viruses and initiating long-lasting immune responses against them. On the other hand, the sensory nervous system takes priority over the immune system when dealing with allergens. Why do some people experience itching following a mosquito bite or contact with an allergen such as dust or pollen, while others do not? A recent study has identified the mechanism through which immune and nerve cells interact to cause itching, explaining these differences.

Role of Sensory Neurons in Allergic Reactions

When someone is exposed to an allergen for the first time, their sensory nerves react to the allergen immediately, causing itching and triggering an allergic reaction in the immune cells in the area. Individuals with chronic allergies may experience persistent itching due to the immune system interfering with these sensory neurons.

The researchers, led by allergy and immunology specialists at Massachusetts General Hospital, a founding member of the Mass General Brigham healthcare system, then inhibited this pathway in preclinical trials, pointing to a new method for allergy therapy. The findings have been published in the journal Nature(1^✔ ✔Trusted Source
A ℽ∂ T cell IL-3 axis controls allergic responses through sensory neurons

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In a world full of allergens, the findings provide one reason why some people may be more susceptible than others to experiencing an allergic reaction. The discovery of a new cellular and molecular circuit that can be targeted to treat and prevent allergic responses, including itching, offers hope for the development of human-translatable strategies based on preclinical evidence.

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 hypothesized 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.

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Role of GD3 Cells and IL-3 in Allergen Sensitivity

The researchers performed different cellular analyses and genetic sequencing to try and identify the involved mechanisms. They found that a poorly understood specific immune cell type in the skin, that 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 like house dust mites, environmental molds, and mosquitos.

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IL-3 makes sensory nerves more reactive to allergens by priming them without directly causing itchiness. The researchers found that this process involves a signaling pathway that boosts the production of certain molecules, leading to the start of an allergic reaction .

Then, they performed additional experiments in mouse models and found the removal of IL-3 or GD3 cells, as well as blocking its downstream signaling pathways, made the mice resistant to the itch and immune-activating ability of allergens.

Since the type of immune cells in the mouse model is similar to that of humans, the authors conclude these findings may explain the pathway’s role in human allergies.

“Our data suggest that this pathway is also present in humans, which raises the possibility that by targeting the IL-3-mediated signaling pathway, we can generate novel therapeutics for preventing an allergy,” said Sokol.

“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 sensitization but prevent it.”

Reference:

1. A γδ T cell–IL-3 axis controls allergic responses through sensory neurons- (https:www.nature.com/articles/s41586-024-07869-0)

Source-Eurekalert