by Garrett Dunlap
figures by Xiaomeng Han

What do a homemade sweater, a new laundry detergent, and a mosquito all have in common? All of these things have the potential to cause the uncomfortable, and sometimes maddening, sensation of itch. In fact, itching can be the result of many different things, including allergies, insect bites, illness, medication, and dry skin. But what exactly is an itch, and how does our body sense and react to it?

Though itch can be unpleasant, it often serves as a helpful sign of an irritant that warrants removal from the skin. In this way, itching acts much like a cough or sneeze, aiming to rid the body of something bothersome. While most times these triggers are only temporarily bothersome, itch can be unrelenting and potentially debilitating for some, and unfortunately no therapies exist to successfully treat chronic itch. Recently, however, new research has begun to uncover how an itch arises, and has found that communication between the immune system and the nervous system plays an unexpected role in this sensation. 

Unlocking Itch

As a barrier between our inner organs and the outside world, the skin is constantly assaulted by bacteria, viruses, chemicals and other irritants. Possibly to aid our body in getting rid of these nuisances before they can cause damage, our skin is home to a unique set of neurons known as pruriceptors that detect these stimuli. 

These pruriceptors are similar in many ways to other neurons spread throughout our body that sense pain, smell, and our other senses. Many of these sensory receptor neurons rely on G protein-coupled receptors, or GPCRs, which are proteins that sit on the neuron’s surface and act as locks searching for their specific key. Once the right key, or in this case a chemical signal released by our cells after encountering an irritant, connects with the GPCR lock, a communication network is unlocked that travels through neurons to  the brain, sending alert of the stimulus, whether it be a noxious odor or a scratchy sweater (Figure 1).

In the case of pruriceptors, the GPCRs responsible for sensation and reaction to itch have not been well-understood, as a result limiting the development of treatments to block the sensation. Recently, studies have formulated a better picture of what it takes to unlock these pruriceptor GPCRs, even developing an actual sub-microscopic picture of what the lock actually looks like. 

The Immune System: Keepers of the Keys

While research has advanced our understanding of what it takes to activate these neurons and initiate the sensation of itch, scientists still had an unclear image of which cells act as “key-makers” for these GPCRs. After many years of searching, scientists zeroed in on our immune system as a key player in activating our itch receptors, as various immune cells are located in our skin and protect its integrity. Three types of immune cells were found to be likely culprits in catalyzing a response from pruriceptors: mast cells, basophils, and T cells (Figure 2).

Mast cells are present in many tissues of the body, where they work to aid in inflammation. Inflammation is the redness and swelling that can occur in the body in response to something trying to do it harm. These mast cells carry payloads of chemicals called histamines, which they release upon running into allergy causing agents called allergens. These histamines, along with a few other chemicals released from mast cells, go out into the surroundings and inform other immune cells to come check out a potentially dangerous situation. But in addition to this, these histamine chemicals were also found to be a key for unlocking our itch receptors. 

Basophils are similar in many ways to mast cells. They work to identify and respond to allergens, and they even release histamines in response to an allergic stimulus. Thus, it was perhaps no surprise that scientists also found a connection between these basophils and our pruriceptors. Together, mast cells and basophils, along with their histamine cargo, have begun to be a very intriguing target for future therapies. While antihistamines are already readily available for the treatment of seasonal allergies, they don’t appear to affect the presence of itch. Instead, scientists are currently pursuing clinical trials on new antihistamines that work on itch-specific histamine chemicals.

New research has further connected an entirely different type of immune cell to the itch response. A cell known as a T-helper (Th) cell has been found to potentially hold the keys that our pruriceptors rely on to become activated. Normally, these Th cells provide help to other immune cells, communicating to them through a collection of chemical messages called cytokines. Interestingly, these very cytokines that are most often used to recruit and activate other types of immune cells may be able to directly unlock our itch receptors. In effect, these Th cells can potentially bypass the need to recruit other cells, including basophils and mast cells, when they identify danger and directly alert our nervous system.

Looking to the Future

While new antihistamines have emerged as leading candidates in the treatment of itch, these recent advances have paved the way for other therapeutic avenues. Advances in our understanding of T cells have helped start clinical trials for therapies that prevent these cells’ cytokines from finding their GPCR locks. Additionally, other therapies are now being developed that function to keep our skin’s immune cells from being activated and releasing their keys in the first place.

Altogether, recent connections between the immune system, nervous system, and our skin have deepened our understanding of what it takes to form the sensation of an itch. Though scientists are still continuing to work to better understand the “locks” and “keys” that lead to itching, the identification of the immune system’s role has already suggested the potential of multiple new therapies to help those with chronic itch.

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Garrett Dunlap is a graduate student in the Biological and Biomedical Sciences Ph.D. program at Harvard Medical School. He can be found on Twitter at @dunlap_g.

Xiaomeng Han is a graduate student in the Harvard Ph.D. Program in Neuroscience. She uses correlated light and electron microscopy to study neuronal connectivity.

For more information:

• SITN has  previously covered the science of allergies, which is one of the many causes of itch.
• Learn more about the many immune cells of the skin here.