‘Ancient, funny’ cells are to blame for itchy mosquito bites

Allergens are everywhere, but our physiological responses to them are anything but simple. Pollen or dust mites can trigger coughing, sneezing, or a sore throat like colds caused by viruses do. Some people feel itchy from mosquito bites, while others barely notice them–and scientists are trying to find out why there is such a wide range of reactions.

“It doesn’t make sense for us to have responses against allergens,” Massachusetts General Hospital clinical allergist Dr. Caroline Sokol tells Popular Science. “They’re not infectious, so they shouldn’t bother us.”

Yet they still really bother us, with at least 1 in 4 American adults affected by seasonal allergies.

To find out why, Sokol and other allergists are researching how dust mites, cat and dog dander, or pollen are detected by the body. They found a molecular pathway where the interaction between immune and nerve cells leads to itching. Importantly, they were able to physically block this pathway in preclinical studies using mice. The findings are detailed in a study published September 4 in the journal Nature and could potentially lead to new allergy treatments in the future.

Scratching the itch

While the immune system is the first line of defense against viruses and bacteria, it generally takes a backseat to the sensory nervous system when detected allergens. However, the immune system can also control and interact with the sensory nervous system.

For some people who haven’t been previously exposed to allergens, the sensory nerves can react directly to these allergens. This causes the itchiness we feel and triggers local immune cells to begin an allergic reaction. This includes itching or hives on the skin. Those with chronic allergies have immune systems that can make sensory nerves more active, which leads to persistent itchiness.

Earlier studies found that the neurons that lead to itching directly detect allergens that have protease activity. Protease allergens are environmental proteins found in numerous sources including pollens, dust mites, some insect venoms, and more that can trigger allergic inflammation.

“We don’t fully know what it is within the mosquito saliva that makes us itchy,” says Sokol. “We certainly know mosquito saliva has a bunch of enzymes or chemicals and some of those enzymes are proteases that break up proteins and are really similar to a lot of pollen molecules.”

Sokol and her colleagues hypothesized that some innate immune cells might be able to establish a “threshold” in sensory neurons for allergen reactivity. The activity of these cells, in turn, may define which people are more likely to develop allergies.

An allergic domino effect

In the new study, the team performed different cellular analyses and genetic sequencing to try and pinpoint which molecular mechanisms are at play during allergic itching when exposed to various protease allergens.

They found that a poorly understood and specific immune cell in the skin called GD3 is involved. In turn, GD3 cells produce a molecule called IL-3 in response to environmental triggers, which are usually present on the skin. The IL-3 molecules then act directly on some itch-inducing sensory neurons to get their responses ready, even if only low-level allergens from common sources like mosquitos are present.

“These weird, very ancient but funny cell types make it absolutely essential for this mosquito induced itch,” says Sokol. “It’s also essential for the downstream allergic immune response to it. So depending on how many of these GD3 cells you have, depending on how much IL3 you have, that’s likely going to define how you react to mosquitoes.”

The team found that this process involves a signaling pathway that works like a line of dominoes to boost the production of certain molecules and starts an allergic reaction.

“Some of those early responses, some of that early inflammation, is the nervous system waking up,” says Sokol

Using this pathway as a guide, they performed additional experiments in mice. They found that the physical removal of the IL-3 molecule or GD3 cell from mice skin samples and blocking its downstream signaling pathways, made the mice resistant to the itchiness and immune-activating ability of certain allergens.

Some new clues

According to the team, because these types of immune cells in mice are similar to ours, these findings may help explain the role that the pathway plays in humans.

“What’s cool about this study is that now we have a pathway. We can tell you exactly what pathway to look for and can think of ways to intervene and to break this pathway,” says Sokol. “But the problem is we don’t know why these cells are warped in some people and not in other people.”

The team got some early clues to why some people have more virulent allergic reactions, but there is still more work to be done to fully understand this mechanism. The number of GD3 cells and their activity levels is age dependent. The makeup of the skin microbiota also plays a role in these reactions and GD3 cells are also sensitive to environmental changes like drier air.

“Allergies are increasing in number and it’s not just that we’re better at diagnosing them,” says Sokol. “We really need to get to the bottom of why and there are a lot of questions, but that’s what makes it a fun area of science and medicine to be in.”

The co-authors listed the following disclosures in the study. Caroline Sokol is a paid consultant for Bayer and Merck and receives sponsored research support from GSK. Pamela Aderhold is a current employee of Werewolf Therapeutics. Cameron McAlpine is a paid consultant of Granite Bio. Clifford Woolf is a founder of Nocion Therapeutics, QurAlis and BlackBox Bio, and is on the scientific advisory board of Lundbeck Pharma, Axonis and Tafalgie Therapeutics. Alexandra-Chloe Villani has a financial interest in 10X Genomics, a company that designs and manufactures gene sequencing technology for use in research, and such technology is being used in this research.