Mast Cells: When Your Body Reacts to Everything

Does this sound like you?

No one has all of these, and none of them alone means mast cell activation. The pattern that suggests it is symptoms in several unrelated systems at once, that come and go, and that don't line up with any single diagnosis.

What a mast cell is

A tissue-resident immune cell, born in the bone marrow, that moves into a tissue and lives there for months to years — packed with pre-loaded granules ready to fire.

Where they live

Everywhere the body meets the world, and everywhere blood meets tissue. Their location explains why a flare can feel like it is "everywhere at once."

What one activated mast cell releases

Three waves, dozens of the most important signals shown here. Color shows the wave: pre-formed granule contents fire first, lipid messengers within minutes, cytokines and growth factors over hours.

What pushes the button

A mast cell carries many different "docking stations" on its surface. IgE allergy is only one of them. People with mast cell activation can react through true allergies and non-allergic triggers together, or through non-allergic triggers alone: plenty of people with strong mast cell reactivity have no allergies at all.

Classic allergy vs. mast cell activation

Allergy is one key in one lock. Mast cell activation is a cell with every door propped open and the threshold set too low. Normal allergy tests alongside dramatic reactions is a common picture, not a contradiction. The two aren't mutually exclusive either: someone can have genuine IgE allergies and broader mast cell reactivity at the same time, and each adds to the other's load. The description people most often give is that their body suddenly became reactive to everything, and stopped being predictable.

Why they stay primed

Mast cells are shaped by their surroundings. Inflammatory conditions can change their numbers and behavior, and some immune signals increase receptor expression and amplify later responses. These are the loops that can keep the alarm armed — not every flare leaves the system permanently worse.

How immune and nerve signals amplify one another

Mast cells are wired into the threat circuitry. The amygdala reads danger, the hypothalamus starts the stress-hormone cascade, and adrenaline and noradrenaline flood the body. CRH made locally in tissue can act on mast cells directly. The mast cell's own mediators then feed back to the brain and confirm the threat.

Top-down and bottom-up

The loop above runs from the brain outward. It also runs the other way, and that direction explains more of how people actually feel.

Why a flare can feel the way it does

These pathways help explain why immune and nervous-system symptoms interact. They are possible mechanisms, not a way to read the cause of a symptom from the symptom alone.

The sleep circuit runs both ways. Orexin neurons excite the histamine neurons of the tuberomammillary nucleus, and histamine at the H1 receptor is what keeps the cortex awake — orexin's arousal effect disappears in animals without the H1 receptor. The histamine neurons project back and densely innervate the orexin neurons, so the two drive each other. Histamine made in the body does not cross a healthy blood–brain barrier easily, but it still reaches this circuit: through sensory nerve signaling, cytokines and autonomic arousal, through a barrier that inflammation has loosened, and through mast cells that live in the brain and meninges. That is why lowering histamine in the body, not only in the brain, can improve sleep.

Mast cells and blood vessels

Mast cells sit on the outside of small blood vessels throughout the body. When they fire, the vessel leaks, widens, then the body slams on the brakes with adrenaline and angiotensin. In some people that push–pull can contribute to orthostatic intolerance and POTS-type symptoms — flushing, then cold hands, in the same hour.

The vessel lining: the long game

Every vessel is lined with a sugar-protein "fur" called the glycocalyx. It helps the lining cells sense blood flow and produce nitric oxide, and keeps cells and LDL from sticking. Mast cell enzymes strip it — heparanase cuts the heparan sulfate chains that form its backbone, while tryptase, chymase, cathepsin G and MMP-9 break down the rest. Over years, sustained inflammation of the lining is a recognized vascular risk path.

That sequence describes the large arteries, and it plays out over years. The same damaged lining has a second, faster consequence in the smallest vessels — and that one is usually what people are actually feeling.

When flow slows down

Capillaries are barely wider than a single red cell, so they feel a stripped lining and thickened blood long before a large artery does. Thick, sluggish blood there is not the same as a clot in a leg. It is a quieter problem: tissue gets less oxygen than it needs. Most microclots aren't blocking anything — they are slowing delivery.

Mast cells, hypermobility and dysautonomia

Three things travel together often enough that many people are eventually told they have all three: mast cell reactivity, dysautonomia such as POTS, and hypermobile joints. Not everyone with one has the others, and one did not simply cause the rest, but they are connected.

Connective tissue is the common ground. Mast cells live in it, and their enzymes (tryptase, chymase and MMP-9) remodel it. Where tissue is lax, veins stretch and blood pools on standing. Lax tissue also means more everyday strain, pain and micro-injury, and injured tissue releases the alarm signals that activate mast cells.

So the loop can run in any direction: mediators loosen tissue, loose tissue strains and signals, strain and low vagal tone activate mediators. It also means work on any one of the three tends to ease the others, which is the useful part.

What the research shows

The overlap is well documented (Kohno et al., 2021). In people with POTS and flushing, those with measurable mast cell activation had a distinct hyperadrenergic pattern: a sharp rise in heart rate on standing, and blood pressure that went up rather than staying flat (Shibao et al., 2005). Mast cell disorders are common in the Ehlers-Danlos syndromes (Seneviratne et al., 2017), and the hematologist Dr. Lawrence Afrin has proposed that some cases of hypermobile EDS may be rooted in mast cell activation itself (Afrin, 2021).

Two 2025 studies are changing how hypermobile EDS is viewed. The first compared blood proteins in 29 women with hypermobile EDS and 29 matched controls and found 35 that differed. Most were not structural: 80% belonged to immune, clotting or inflammatory pathways, and 43% to the complement system, the part of the immune system that tags and clears threats. Several complement proteins (C1q, C3, C8 and C9) were consistently low, and the cytokine pattern pointed to a dysregulated inflammatory response. The authors concluded that hypermobile EDS involves systemic immune dysregulation, not only a connective tissue problem (Griggs et al., 2025).

Why complement was low is not yet known. One possibility is consumption: in lupus, complement levels fall because ongoing immune activation uses them up, and an inherited lack of C1q is one of the strongest known risk factors for lupus. Whether something similar happens in hypermobile EDS has not been tested.

The second study looked at genes. In 200 people with hypermobile EDS, it found variants across the kallikrein genes, a family of enzymes that cut proteins, including a recurring KLK15 variant in several families. In mice, that variant altered tendons and heart valves and disturbed immune signaling. It is one of the most promising leads toward a gene for hypermobile EDS, though not yet confirmed (Gensemer et al., 2025). Together the two studies point the same way: hypermobile EDS involves immune signaling and protein-cutting enzymes, not only collagen.

Clinicians who see these patients don’t fully agree on how much mast cells drive the other two. Some, including cardiologist Dr. Andrew Maxwell, argue that mast cell enzymes can break down connective tissue enough to create hypermobility. Others, including mast cell specialist Dr. Tania Dempsey and pain specialist Dr. Linda Bluestein, see mast cell activation mainly worsening hypermobility, which can ease back toward a person’s baseline once it is controlled. Dr. Dempsey also sees POTS as a common consequence of mast cell activation. Pediatric cardiologist Dr. Jeffrey Boris is skeptical, because most of his patients were hypermobile before they became ill. What they agree on is that the three travel together and need to be looked at together.

What I see in practice

In my practice, I see acquired hypermobility regularly. Clients with no history of hypermobility develop it during a triggering event: mold exposure, a virus or other illness, or an infection. I see it the way I see most chronic illness: genetics can set the stage, but the environment pulls the trigger.

Two people can go through the same mold exposure or the same virus and come out with very different problems: joint laxity and POTS in one, gut or skin reactivity in another, brain fog or mood changes in a third. Which form the inflammation takes depends on each person’s history and total body burden: earlier infections, mold and toxin load, gut health, hormones, stress, past injuries and genetics. Reactive arthritis shows how the genetic piece can matter: after the same gut or urinary infection, people who carry the gene variant HLA-B27 are more likely to develop joint inflammation, and to have a more severe or lasting course (Colmegna et al., 2004). For hypermobility, I believe some people carry a predisposition to this inflammatory response and to the protease activation that loosens connective tissue. That last part is my clinical view, not an established finding.

A bigger problem since COVID

In a US database of more than 65 million adults, the rate of new POTS diagnoses rose sharply after March 2020, from about 1.4 to about 20 per million person-years, though some of that rise may reflect greater awareness and testing (Dulal et al., 2025). In a Cedars-Sinai cohort of nearly 285,000 people, the odds of a new POTS diagnosis were higher in the 90 days after COVID infection than in the 90 days before it (Kwan et al., 2022). In people with long COVID, mast cell activation symptoms were found to match those of people with diagnosed MCAS, even though their symptoms before COVID had looked the same as healthy controls (Weinstock et al., 2021). Hypermobility has not been tracked in the same way. Still, many functional practitioners who work in this area, myself included, now see far more mast cell activation, POTS and other dysautonomia, and hypermobility in their client populations than they did before the pandemic.

One explanation I find convincing, though it has not been tested directly, is that mast cells are a link in this chain. In the lab, the spike protein makes human mast cells release tryptase and chymase, the same protein-cutting enzymes that remodel connective tissue (Tsilioni & Theoharides, 2023). A small study found raised mast cell enzymes in the blood of people with long COVID (Wechsler et al., 2022). And in a UK study of about 3,000 people, those with hypermobile joints were about 30% more likely not to have recovered from COVID (Eccles et al., 2024). Put together, this suggests that in susceptible people the virus can tip mast cells into ongoing reactivity, and that reactivity may then drive both the autonomic symptoms and, in some, new or worsening joint laxity. That last step is what I see in practice.

One cell, many systems

Because mast cells are everywhere, chronic activation shows up as a pattern across systems rather than one disease. Mast cells do not operate in isolation: this map shows possible connections; it does not mean every pathway is active in you.

How I approach this

You cannot out-supplement a trigger that is still there. Stabilize symptoms while lowering the load, calming the wiring and repairing barriers — the levers run together.