What Are Mast Cell Mediators?

This post discusses mast cell mediators. When activated, mast cells produce many chemical mediators. Many mast cell mediators are crucial to our survival, so the goal is not to get rid of them but to keep your mast cells from being too activated and degranulating.

What is MCAS?

Mast Cell Activation Syndrome (MCAS) is a chronic condition that affects all organ systems. MCAS is serious and disabling and people with MCAS experience often significant and debilitating symptoms daily, including anaphylaxis, which can be fatal.

MCAS is often found in combination with other chronic conditions such as Ehlers-Danlos Syndrome (EDS) and Postural Orthostatic Tachycardia Syndrome (POTS).

Frequently healthcare providers do not know about MCAS, and the tests for MCAS are problematic because they are not uniformly reliable. MCAS can be difficult to manage. Treatments include blocking mast cell mediators with anti-histamines and mast cell stabilizers, as well as avoiding triggers.

Check out this post on how to manage MCAS.

Mast cell mediators

Mast cell mediators are the chemicals stored inside mast cells. Mediators play a lot of roles in your body, including defense and healing. 

Mast cells store some mediators in “pockets” of the mast cell, and when they release them it is called degranulation. Other mediators are made as needed in the body in response to stressors. MCAS occurs when degranulation occurs too much and too often.

When your body is exposed to a perceived threat, the overactive mast cells secrete massive amounts of chemical mediators from the cytoplasm of the cells. Mast cell mediators include histamine, leukotrienes, heparin, cytokines, phospholipases, tryptase, chymase, chemokines, growth factors, and cholinesterase. These mediators are released into the surrounding tissues, leading to swelling and inflammation, which helps healing to occur.

But the chronic release of chemical mediators triggers a negative immune response rather than a protective response. This can lead to chronic, multisystem inflammation.

Mast cell disease is managed by treating the symptoms caused by mast cell mediator release or by interfering with mediator release. – source

The bucket theory

The bucket theory offers a helpful analogy for understanding symptom reactions with MCAS.

Think of your body as an empty bucket that you want to keep from overflowing. Different foods and activities fill your histamine bucket at different speeds but they combine to form the total level of histamine in your body (how full your bucket is). A fuller bucket means you have more histamine symptoms. When you manage triggers, reduce exposure to known triggers, and take medications and supplements to reduce histamine, you can manage the level of your bucket.

Know your typical symptom progression

Knowing your symptom progression in a symptom flare is the key to developing your own rescue plan. In this post, I discuss how to determine your own symptom progression. Once you know what typically happens in your symptom progression you can design a rescue plan to address those symptoms.

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How mast cell mediators work

This post covers some of the most common mast cell mediators and the roles they play, but it’s estimated that there are over a thousand different types of mast cell mediators. 

If you have Mast Cell Activation Syndrome, it’s likely the receptors on your mast cells don’t properly control degranulation. Then the mast cells continue to degranulate and become hyper-reactive, starting a downward spiral of inflammation, which causes mast cells to over-respond, which causes elevated levels of inflammatory mast cell mediators, which can cause more inflammation in the tissues, which triggers more mast cells to get involved and over release inflammatory mediators.

Common mast cell mediators

Mast cells produce a multitude of mediators including tryptase, histamine, prostaglandin D2, leukotrienes C4, D4, and E4, heparin, and chromogranin A[i]. – source They are responsible for many of the acute signs and symptoms of mast cell-mediated allergic reactions. Some of the more common mast cell mediators are on this chart:

Tryptase

Tryptase is a mast cell mediator that is released when mast cells degranulate. It is responsible for allergic responses and immunity. Tryptase is also a marker that can show the amount of degranulation that has taken place in mast cells. Serum tryptase levels from blood tests that are over the normal count but under 20 ng/ml indicate the possibility of Mast cell activation. When over 20 ng/ml, it indicates the probability of systemic mastocytosis. However, testing for tryptase is not always accurate.

Keeping Tryptase from being released by mast cells helps to keep MCAS under control.

“Products that can do this include cromolyn (Nasalcrom, Gastrocrom, Intal), a drug that prevents the release of histamines and quercetin, a bioflavonoid obtained from buckwheat and citrus fruits. Quercetin stabilizes the membranes of mast cells. The recommended dose is 400 mg twice a day between meals.” – Source

Histamine

Histamine is the best-known mast cell mediator. It has numerous roles, including being involved in inflammation and acting as a neurotransmitter.

Histamine is a chemical made by the immune system that helps the body get rid of anything causing it stress. – source

I’ve covered histamine in these posts:

This post gives a list of generally tolerated lower histamine foods.

This post provides information on anti-histamine foods.

Proteoglycans

Proteoglycans are an important mast cell mediator that is responsible for:

• Lubricating fluid in the joints.
• Hydrating cartilage.
• Participating in cell and tissue development.
• Controlling blood coagulation.

Proteoglycans are a helpful part of inflammation. Heparin is synthesized by mast cells as a proteoglycan and is necessary for blood clotting.

Prostaglandin D2

Prostaglandins are responsible for blood vessel constriction or dilation. Prostaglandin is primarily found in the central nervous system and peripheral tissues. It has an inflammatory action.

Prostaglandin also helps with the regulation of sleep and the perception of pain. It is also a strong bronchoconstrictor and is considered ten times more potent than histamine. Those who suffer from asthma can have prostaglandin levels more than 150 times that of those who have never suffered an attack. Elevated levels of prostaglandin have also been found in those who suffer from chronic coughing.

In those with asthma, prostaglandin may cause airway inflammation and hyperreactivity and inhibit eosinophil cell death. Eosinophil cells play an important role when it comes to allergies. If their removal is inhibited, the result is an inflammatory illness such as asthma.

Mast cells, in many instances, are often paired with neurons and autonomic nerve fibers. Besides histamine, leukotrienes, and prostaglandin, they secrete up to 200 different chemicals, each with its own action and response to different environmental stimuli.

In the case of those with Mast Cell Activation Syndrome, the mast cells secrete these chemicals inappropriately. – source

Platelet activation factor (PAF)

Platelet activating factor is part of inflammation, anaphylaxis, platelet functioning, and immune defense. PAF is released by many different cells, including eosinophils, mast cells, neutrophils, monocytes, macrophages, and endothelial cells. 

PAF is most well known for its effects on the airway. It causes constriction of the airway and can affect the way oxygen is brought into the lungs. However, it also has many other effects on the body, many of which affect anaphylaxis and the severity thereof. – source

PAF is closely linked to asthma. One study found higher levels of PAF as well as an enzyme that inactivates PAF in the plasma of asthmatic adults both during attacks and when not. When exposed to allergens, PAF level in the blood rapidly increases. – source

Cytokines

Cytokines are responsible for increasing and reducing inflammation and cell signaling. – source

Interleukins are a group of cytokines made by white blood cells and other cells in the body.

Tumor necrosis factor alpha

Tumor necrosis factor alpha (TNF alpha) is an adipokine and a cytokine. TNF alpha is an inflammatory cytokine produced by macrophages/monocytes during acute inflammation and is responsible for a diverse range of signaling events within cells. The protein is also important for resistance to infection and cancers.

TNF, at the site of nerve injury, may activate mast cells which mediate symptoms such as headache and pain. TNF is the only cytokine stored in mast cells and can be rapidly released after mast cell stimulation.

Leukotrines

Leukotrienes are another compound released by mast cells and they are responsible for blood vessel constriction or dilation. There are two types of leukotrienes, and each has a unique presentation in the body.

The first type is involved in killing as many germs as possible. They are the most abundant immune cells found in the blood, and they are the immune system’s first line of defense.

The second type of leukotriene is acts on the airway tissue and bronchial smooth muscles. They are acutely active in cases of infection and asthma, for example, where they reduce airflow to the alveoli. – source

What can be done?

Mast cells are an important part of your immune system and necessary to heal from injury. MCAS occurs when mast cells are overactive and release too many chemical mediators. There are natural strategies to help people manage the symptoms of MCAS. The first step is to identify and remove any potential triggers of your symptoms. Then you will want to address any toxins, infections, pathogens, or other environmental triggers. Implementing a low histamine and/or low FODMAP diet may relieve symptoms. See this post on the MCAS diet. Additionally, supplementing with flavonoids and other nutrients that help to stabilize mast cells may be very beneficial for helping improve the immune response. See this post on supplements for MCAS.

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