A new review published in Experimental Dermatology explained that there is a lot more than histamineHistamine A chemical released by mast cells when they are activated. Histamine causes many of the allergy-type symptoms in mastocytosis, including flushing, itching and hives. behind the persistent itch and pain that often come with chronic skin disorders such as urticaria pigmentosaUrticaria pigmentosa A skin condition marked by itchy, red-to-brown spots, especially on the neck, limbs and torso. It is caused by surplus mast cells and occurs in up to 85% of patients with SM., a condition seen in many patients with systemic mastocytosis (SM). Much of it comes from direct signaling between mast cells and sensory neurons, the authors wrote.
Two very different triggers can activate a mast cellMast cell A type of white blood cell produced in the bone marrow. They help defend against infections and play a key role in allergic reactions. In SM, mast cells become overactive and build up throughout the body.. An allergy-driven one likely familiar to many patients with SM runs through IgE-mediated activation and mediator release; histamine dominates this pathway, but it is released alongside a range of other mediators. Histamine lands on receptors on nearby sensory neurons and sets off itch or pain that antihistaminesAntihistamines Medications that block the effects of histamine, the chemical found in mast cells that is responsible for many of the symptoms of SM, as well as many allergic reactions. are built to block.
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The other trigger runs through a receptor called MRGPRX2 that responds to neuron signals with no allergic trigger at all, releasing tryptaseTryptase A protein enzyme that is primarily produced by mast cells and stored in small pockets within the cells, known as granules. High levels of tryptase are a key indicator of SM. and many other mediators. In chronic disease, this becomes a feedback loop: Neurons release molecules such as substance P that activate the MRGPRX2 receptor, and the mast cell then releases its mediators, which in turn make the neurons more reactive.
The review discusses this signaling in urticaria pigmentosa, the most common form of cutaneous mastocytosis. The condition usually appears as tan-to-brown spots and bumps that welt when rubbed, as the excess mast cells in the skin release their contents. In children, urticaria pigmentosa rarely extends beyond the skin. In adults, up to half of cases occur alongside systemic mastocytosisMastocytosis Rare disease caused by the buildup of mast cells. Cutaneous mastocytosis primarily affects the skin and is more common in children, while systemic mastocytosis affects internal organs and is more common in adults..
Read more about this condition: “What is urticaria pigmentosa?“
Because the itch in urticaria pigmentosa travels along both the histamine route and the MRGPRX2 route, antihistamines only address part of it — which is why they often fail to fully control the itch in these patients.
A clearer picture of these pathways is guiding the development of more targeted therapies. Mast cells rely on a receptor called KIT as a survival switch: When the signaling molecule stem cell factor binds KIT, the cell is told to grow and stay alive. The antibody barzolvolimab exploits that dependence, blocking KIT so mast cells lose the signal and die off — an approach that has shown positive trial results in chronic hives.
Mastocytosis also runs on KIT, but in a different way: Most cases are driven by a mutation, KIT D816V, that leaves KIT switched on by itself, with no stem cell factor needed. Blocking the incoming signal does little when the receptor is already stuck on, so mastocytosis is instead treated with small-molecule KIT inhibitors such as avapritinib, drugs that switch off the mutated receptor directly.
Looking ahead, the authors point to MRGPRX2-blocking drugs in early development and to a newer discovery: Neuron circuits that can calm mast cells rather than fire them up. Turning those calming circuits into treatments, they wrote, may “reveal novel approaches for restoring neuroimmune homeostasis” — the balance that breaks down when mast cells and neurons keep driving one another.
Learn about urticaria pigmentosa and SM: “Can mastocytosis spots be removed?”
