Some people just can't stop scratching after they're bitten by a mosquito — but not everyone gets itchy after a bug bite or similar allergy-triggering encounter. Now, new research in mice pinpoints differences in immune system activity that may determine whether you end up itchy.
The skin is densely populated with sensory neurons, which are nerve cells that detect changes in the environment and then trigger sensations, such as pain, in response. When a person encounters a potential allergen, like mosquito saliva, these neurons detect it and may trigger an itchy sensation in response. They also help activate nearby immune cells, which kick off an inflammatory reaction featuring swelling and redness.
Some people who are repeatedly exposed to an allergen can develop chronic allergic inflammation, which fundamentally changes the tissues where that inflammation is raging. For instance, the immune cells that respond to allergens can change the nerves' sensitivity, making them more or less likely to react to a substance.
"We all have sensory neurons, so we can all feel itchy — but not all of us get allergies, even though we're surrounded by the same allergens," senior study author Dr. Caroline Sokol, a professor of allergy and immunology at Harvard Medical School and Massachusetts General Hospital, told Live Science. "So what defines whose sensory neurons fire in response to allergens and whose don't?"
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To find out, Sokol and colleagues exposed mice to a chemical called papain, which causes an itchy sensation that makes mice scratch their skin. The different groups of lab mice in the study were missing different immune cells. The research, published Wednesday (Sept. 4) in the journal Nature, found that mice that lacked a specific type of T cell didn't scratch when they were exposed to papain.
The researchers wanted to find out how these cells, dubbed GD3 cells, drove sensory nerve responses. They grew GD3 cells in the lab and treated them with a chemical to make them release signaling molecules called cytokines. Then, they injected mice with normal immune systems with the cytokine-containing liquid the cells were grown in.
This treatment didn't trigger itchiness on its own. However, it did intensify the mice's scratching responses to a variety of allergens, including mosquito spit. This suggested that something released by GD3 cells hiked up the nerve-induced itching.
By comparing the chemicals secreted by GD3 cells with those from other immune cells in the central layer of the skin, the researchers discovered that only one factor was unique to the GD3 cells: interleukin 3 (IL-3), which is known to help regulate inflammation.
Only some sensory neurons responded to IL-3. Those that did respond became more likely to trigger an itch — a sign that the cytokine "primes" neurons to react to allergens.
In contrast, when the researchers removed the genes for IL-3 or its receptors — or removed the GD3 cells entirely — the mice could not initiate an allergic response. With further experiments, the researchers concluded that IL-3 activates two separate signals: one that promotes the nerve-driven itching and another that controls the immune side of the allergic response.
By releasing IL-3, the GD3 cells were "absolutely essential" for setting the threshold at which a sensory nerve would react to an allergen, Sokol said. This chain reaction involving IL-3 "may give us a new pathway to treat patients with chronic itch disorders," she added.
However, so far, the research has been conducted only in mice, so the researchers can't be certain that human cells will behave the exact same way. Although the mouse immune cells in the study have very similar genes and proteins as their human equivalents, Sokol emphasized that it's important to understand whether and how human T cells react to IL-3. That data is needed to translate the finding into itch treatments or ways to predict who might be at risk of allergies.
"We all have that friend who doesn't react to mosquito bites and the friend who looks horrific after a day outside," Sokol said. "We believe [the IL-3 pathway] is determining that in real time, because when we look at mosquito bite-induced itch — and the allergic immune response that follows — we see that it is completely dependent on the cells in this pathway."
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