The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 60

74. Is mast cell activation the cause of many other diseases?

No, but it is involved in many other diseases.

I write a lot about mast cells and the way they are involved in various other conditions. Mast cells live throughout the body in many tissues. Because they are in so many tissues, their role in many diseases is well researched.

Mast cell activation is not the same as mast cell activation syndrome. I have written about this here. Basically, there are tons of things in the body that cause mast cell activation. These are conditions where we want or need mast cells to become activated because then the mast cells help keep our body working the way it is supposed to. For example, during a woman’s menstrual cycle, if mast cells could not become activated the way they normally do, a woman’s period could become very irregular. This in turn could affect the amounts and types of hormones in a person’s body, causing symptoms and problems.

Situations where mast cells normally become activated include labor and delivery, during any type of infection, during situations where the GI tract is inflamed, when your body is growing new blood vessels, any time your body is healing, and when you have cancer or a tumor. In these situations, the mast cells activate to send signals to other cells in the body to help regulate what is happening. Mast cell activation is not always bad. It is, in fact, a normal and necessary process that happens in the body of everyone every day. Mast cell activation is necessary to stay alive.

Now let’s look at the role of mast cells in diseases that are not mast cell diseases.

When I was little, I was a Girl Scout for three weeks before I got kicked out. (This is true and not related to mast cell activation.) There was a game that we used to play called “Telephone.” During this game, everyone would sit in a big circle. One person would think up a short sentence and whisper it into the ear of the person next to her, who would in turn whisper into the ear of the person next to them, and so on. Often, people misheard the sentence and so it was completely wrong by the time it got back to the person who started it.

Diseases in the human body are like a very complex game of Telephone. In every disease, many cells that did not cause the disease can cause symptoms even though they are not the cause. The way to know if a disease is a true mast cell disease is to know which cell first messed up the sentence in the game of Telephone.

Here’s what this sounds like in people:

Lisa says to Pari: Puff the magic dragon

Pari says to Dana: Puff the magic dragon

Dana says to Celeste: Puff’s magic is dragging

Celeste says to Lisa: Puff’s magic is dragging

So in this situation, Dana changed the sentence. Because she changed it, Celeste also had the sentence wrong. So Dana caused the problem. Celeste did not. (In real life, Dana is lovely and not a problem.)

When your body has a disease, the symptoms and damage are caused by cells giving or receiving messages incorrectly. Instead of using words to talk to each other, cells use molecules. Even though they use molecules to talk to each other, it is very much like a language. If the message is “said” wrong in this cell language, then all the cells after the mistake are doing things that are unhelpful or dangerous. However, they are NOT the cause of the disease because they are not the one that changed the message.

Now let’s look at this with cells in the human body during a disease. I’m going to use a very simplified explanation of rheumatoid arthritis as an example.

T cell says to B cell: I think our body is dangerous to us!

B cell says to T cell: Oh, snap! Let’s get the word out!

B cell needs to tell the body about this danger. It makes a message that says, “Danger right here! Danger!”

B cell says to mast cell: WE ARE IN GRAVE DANGER! ATTACK! ATTACK!

Mast cell to other cells: KILL THIS INVADER KILL IT TO DEATH

Except there is no invader. It is just your regular joints being regular and not dangerous.

Other cells: *trying to kill your joints*

Joints: Uh, guys, I’m actually supposed to be here –

Mast cell: I CAN’T HEAR YOU OVER THIS SCREAMING B CELL

Let’s recap.

T cell gives the B cell bad information. This causes B cell to alert other cells of “danger.” But this wasn’t the B cell’s fault. It was the fault of the T cell which gave the B cell bad information. And that means that everything that comes after the T cell giving the B cell the bad information makes the problem worse but is not really the cause of the problem.

I used rheumatoid arthritis as an example because a lot of treatment of rheumatoid arthritis revolves around blocking those danger signals from mast cells. But is the mast cell the cause of the rheumatoid arthritis? No, it is not. It is not the cause because mast cells have to respond to commands from B cells in order to help protect us against infection and do other helpful things. The mast cell did not decide the joints were dangerous. The B cell told the mast cell this so the mast cell is working with bad information that it doesn’t realize is bad.

If the mast cell isn’t the cause of the rheumatoid arthritis, why do we bother blocking mast cell signals instead of telling the T cell and B cell to be quiet? Because quieting the mast cell signal will help with symptoms and we know how to quiet the mast cell signal and we don’t always know how to quiet the other signals. Stopping the mast cell signal can make symptoms much better but it does NOT cure rheumatoid arthritis. Why? Because mast cells do not cause rheumatoid arthritis.

So mast cells are involved in many diseases without causing most of them. The way you can tell they are not the cause is that they did not start the wrong “message” that caused the symptoms and damage.

Now, I would like to address the fact that there are some diseases that have some research to suggest that they may genuinely be a form of mast cell activation disease. Fibromyalgia is one of these diseases. However, at this time, there is not enough evidence for it to be classified as a mast cell disease.

I tried to be as clear as possible about a very complicated topic. If I didn’t do it well, tell me and I’ll have another go at it.

(Author’s note: This is a SUPER simplified version of rheumatoid arthritis. RA is an autoimmune disease and it is still not clear exactly how the T cells and B cells start sending the wrong messages in an autoimmune disease. I just simplified it here to make it easier to see my point.)

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 32

39. How are mast cell disease, Ehlers Danlos Syndrome and POTS connected? (Continued)

I’m answering this question in two parts because there is a lot of information to relay and it’s important that it is done clearly. This is the second part.

Mast cells are found throughout the body. There is no record of a person living without mast cells. They perform many essential functions. This is the reason why killing off all of a person’s mast cells is not a viable treatment for mast cell disease. While mast cells cause so many symptoms and problems for patients with mast cell disease, life is unsustainable without mast cells.

Let’s specifically consider just a few of the mast cell’s essential functions here and how they relate to POTS and EDS.

Mast cells help the body to regulate blood pressure and heart rate. Many of the mast cell’s chemicals do this so it happens in many different ways all stemming from mast cells. This means that when mast cells are not behaving appropriately, there are many ways in which this dysfunction can lead to not regulating blood pressure and heart rate correctly.

  • Histamine can affect blood pressure and heart rate differently depending upon how it acts on the body. If it uses the H1 receptors, it can cause low blood pressure. If it uses the H2 receptors, it elevates blood pressure. If it uses the H3 receptor, it can cause low blood pressure. When it does this at the H3 receptor, it’s because it tells the body not to release norepinephrine. Not releasing as much norepinephrine lowers heart rate and making the heart beat more weakly.
  • Prostaglandin D2 lowers blood pressure and causes fast heart beat. However, the molecule made by breaking down PGD2, called 9a,11b-PGF2 increases blood pressure.
  • Vasoactive intestinal peptide lowers blood pressure.
  • Heparin, chymase and tryptase can decrease blood pressure. They do this by helping to make a molecule called bradykinin. When this happens, a lot of fluid falls out of the blood stream and gets stuck in the tissues, causing swelling.
  • Thromboxane A2 increases blood pressure.
  • Many mast cell molecules affect the amount of angiotensin II. This molecule strongly drives the body toward high blood pressure. Some mast cell molecules that affect blood pressure this way include chymase and renin.

Another very essential function of mast cells is to make connective tissue. Mast cells help the body to shape itself correctly and to make tissue to heal wounds. When mast cells are not behaving appropriately, their dysfunction can interfere with making connective tissue and wound healing. It can cause wounds to heal very slowly or for there to be too much scar tissue. It can also cause the connective tissue to be too weak or too strong.

The interaction between POTS and mast cell disease

In POTS, the body is already predisposed toward not regulating blood pressure and heart rate correctly. When a person with POTS stands up, their body quickly causes the heart to beat very fast. When your body does this, it takes steps that cause mast cells to become activated. In turn, the mast cells release chemicals to try and regulate the heart rate. However, if you have mast cell disease, the mast cell may release the wrong chemicals, or too many chemicals, failing to regulate the heart rate. This in turn results in a situation where the body becomes very stressed. Stress activates mast cells, which results in more release of chemicals. Patients can very easily become trapped in a cycle where POTS and mast cell disease irritate each other.

POTS can be exacerbated by the use of medications that affect blood vessels. Medications that are vasodilators (that make the blood vessels bigger) are taken by many people, including mast cell patients. In some people, using medications that blocks the action of histamine or prostaglandins can help to improve symptoms of both POTS and mast cell disease. Conversely, some of the medications used to manage POTS, like beta blockers, can trigger mast cell reactions and raise the risk of anaphylaxis. However, some POTS treatments can also help alleviate mast cell symptoms, specifically the use of IV fluids.

A paper published in 2005 found that hyperadrenergic POTS was sometimes found in patients with mast cell activation disorders.

The interaction between EDS and POTS

POTS is a form of dysautonomia. Dysautonomia means dysfunction of the autonomic nervous system. This is the part of your nervous system that helps to control automatic functions like heart rate, blood pressure and digestion.

In EDS patients, the body does not make collagen correctly. Collagen is the most common connective tissue protein in the body. This can cause vascular laxity. Blood vessels change size depending upon how much blood they need to move through them. If they get larger, it is called vasodilation. When they get smaller, it is called vasoconstriction. When a person has vascular laxity, their vessels can get larger than they should and they can stay that way longer.

POTS is the most common form of orthostatic intolerance in HEDS. Orthostatic intolerance is when a patient has symptoms specifically as the result of standing up. All EDS patients have more autonomic symptoms than healthy people. Among patients with EDS, autonomic symptoms are more common and more severe in HEDS. 94% of HEDS patients have orthostatic symptoms, including lightheadedness, dizziness, palpitations, nausea, blurred vision, and anxiety. Dysautonomia is much worse in HEDS compared to CEDS and VEDS patients.

Patients with HEDS were found overall to have overactive sympathetic nervous systems. However, when their body needed to activate in response to regulate heart rate and blood pressure in response to changing position, their responses were not strong enough.

In EDS patients, the connective tissue does not support blood vessels enough. This makes the harder for the blood vessels to get the blood back to the right places when you stand up, exacerbating POTS.

The interaction between EDS and mast cell disease

Mast cells are involved in making and repairing connective tissue, which involves collagen. For this reason, there are many mast cells living in connective tissues. Mast cells are stimulated when the body is making or trying to make collagen. Because EDS causes the body to make collagen incorrectly, mast cells can become activated to try and make collagen and other connective tissue correctly. When mast cells in one place are activated a lot over a long time, they can activate other mast cells elsewhere, resulting in systemic symptoms.

The interactions among mast cell disease, POTS and EDS

It is undeniable that there is an association among mast cell disease, EDS and POTS. However, there is not much data published on this topic. There was a poster presented in 2015 that found some combination of EDS, POTS and MCAS in a group of 15 patients. This is a very small population and we need larger studies to understand incidence. There is ongoing work to tie this group of conditions to specific genetic markers. However, this also requires further investigation and more patients. In the absence of hard data, we are forced to use some early data and understanding of similar conditions to try and figure out exactly what happens. As more data comes out, this understanding may change.

This is very much a chicken and egg situation where it’s not clear exactly what begets what. EDS is a genetic disorder and considered primary. However, that does not necessarily mean POTS or mast cell disease is secondary in this scenario.

Regardless of which is the initiating condition, the relationship seems to be something like the following:

1. A patient has EDS. They make defective connective tissue. These defective tissues do not support the bodily organs and vessels properly.

2. A patient stands up. Blood quickly moves from the torso into the legs.

3. The blood vessels in the legs try become more narrow and more able to keep fluid in the bloodstream. However, in an EDS patient, the blood vessels are stretched out and not held in the right place because the connective tissue is too weak.

4. The blood vessels in the legs are not able to pump blood back to the heart quickly enough. The body interprets this as having low blood pressure.

5. The nervous system sends signals to increase heart rate to compensate for the “low” blood pressure.

6. The signals sent to increase heart rate activate mast cells.

7. Mast cells activate release mediators to try and regulate blood pressure and heart rate.

8. Mast cell mediators activate other mast cells, eventually affecting other parts of the body.

9. The molecules released by mast cells make blood vessels bigger and more leaky.

10. As fluid leaves the bloodstream and gets stuck in places where it can’t work (third spacing), blood pressure decreases and heart rate increases. This exacerbates POTS symptoms. The cycle repeats.

For more detailed reading, please visit these posts:

Cardiovascular manifestations of mast cell disease: Part 1 of 5

Cardiovascular manifestations of mast cell disease: Part 2 of 5

Cardiovascular manifestations of mast cell disease: Part 3 of 5

Cardiovascular manifestations of mast cell disease: Part 4 of 5

Cardiovascular manifestations of mast cell disease: Part 5 of 5

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part 1)

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part 2)

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part 3)

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part 4)

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part 5)

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 1

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 2

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 3

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 4

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 5

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 6

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 7

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Disease, Part 23

I answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

  1. Is mast cell activation the same as mast cell activation syndrome?
  • No.
  • This is the single most important clarification I make as an educator. It is crucial to understand that they aren’t the same thing, especially if you research mast cell activation syndrome online.
  • Mast cell activation is a normal and healthy process. Mast cell activation mostly means that they are ready to release chemicals in response to signals from inside the mast cell or from other cells. It is one of the major ways mast cells carry out their normal functions, like fighting infections, healing the body post trauma, and regulating the menstrual cycle.
  • Many things activate mast cells to tell mast cells to act in their normal functions. Bacteria, viruses, fungi, cancer cells, diarrhea, pain, surgery, physical or emotional stress, and many other things all activate mast cells normally. It is not surprising that these things activate mast cells because they should activate them.
  • Sometimes mast cells overreact to signals to activate, like in allergies and anaphylaxis.
  • The reason mast cell activation is a problem in mast cell disease is because mast cells respond way too strongly to activation signals. They release too many chemicals too often.
  • The other reason mast cell activation is also a problem in mast cell disease is because they become too easily activated.
  • Think of mast cells like houses. Like any house, they have doors. In healthy people, you need a lot of people knocking on the doors and windows at the same time to get the mast cell to open the doors and release chemicals. In mast cell patients, one person can knock a few times and all the doors open and release chemicals at once.

For more information, please visit this post:

The Provider Primer Series: Introduction to Mast Cells

The MastAttack 107: The Layperson’s Guide to Mast Cell Diseases, Part 17

I answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

25. How do I know what I will react to?
There is no way to definitively know what things will make you react. It is difficult to predict. There are some general guidelines many of us use to figure out what may be a problem but the only way to really know is to try something.
• Please note that because mast cell reactions are not known to be triggered by the same mechanisms as traditional allergies, you cannot exclude an entire class of drugs because you react to one in the way that you do for traditional allergies. This is particularly worth noting for opiates: reaction to morphine, for example, does not exclude fentanyl or hydromorphone.
• Mast cell reactions are not inherently triggered by IgE the way that “true” allergies are. This means that blood tests for IgE allergies will not identify triggers accurately for most mast cell patients. (Although some mast cell patients do have some IgE allergies.)
• Additionally, skin testing is wildly inaccurate in mast cell patients because of how reactive our skin is.
Stopping antihistamines is dangerous for mast cell patients.
Allergy testing is not accurate for mast cell patients.
• There are several ways that various things can cause mast cell reactions. Generally, they do it in one of the following ways: they cause mast cells to empty the chemicals in their pockets into the body (degranulation); they cause mast cells to release chemicals in another way; they already contain significant amounts of histamine; or the interfere with the mechanisms for controlling mast cell activation.
There are a number of medications that can cause mast cell degranulation or histamine release. Please note that not all of these medications are problematic for every patient. Only a provider managing your case can determine if these are safe for you or not. The major medications that may cause degranulation or histamine are listed below. This list is not exhaustive.

-Alcohol: Widely used to sterilize body area, surfaces, or tools; also used when preparing many medications that are not soluble in water
-Amphoterecin: Antifungal
-Aspirin: NSAID, for pain, inflammation, to block prostaglandins, to prevent clot formation
-Atracurium, mivacurium, rocuronium: Muscle relaxant
-Caine anesthetics (esters): Anesthetics, to numb
-Codeine, morphine, meperidine: Opiates, for pain or cough
-Colistin: Antibiotic
-Dextran: Volume expander, used in surgical or emergency situations to improve blood pressure
-Dextromethorphan: Cough suppressant
-Miconazole: Antifungal
-Nefopam: For pain
-NSAIDs (non steroidal anti-inflammatory drugs): For pain, inflammation, blocking production of prostaglandin
-Polymyxin B: Antibiotic
-Radioopaque contrast: To visualize structures in medical scanning procedures
-Reserpine: High blood pressure medication and antipsychotic
-Succinylcholine: Paralytic used for surgical procedures
-Thiopental: Anesthesia induction for surgical procedures
-Vancomycin (especially IV): Antibiotic

• There are a number of medications that are known to interfere with the mechanisms for controlling mast cell activation. Adrenaline is naturally made by the body to help control mast cell activation and other activities. When you interfere with the ability of adrenaline to act, it can potentially trigger mast cell activation. Drug classes that do this include beta blockers and alpha adrenergic blockers. This is particularly an issue if there is a history of anaphylaxis because these medications can interfere with Epipens.
Many foods either contain histamine or can trigger mast cell release of histamine. As with medication, you cannot exclude an entire family of foods because you react to one in the way that you do for traditional allergies.
• There are many lists of foods to avoid. They often conflict with each other. There is not yet a definitive list available. Despite this, there are some general rules of thumb that are agreed upon on what to avoid.
• Products that are fermented, contain alcohol, are overly ripe or leftover from previous days (especially meats), or contain dyes or preservatives are generally excluded.
• Beyond this, recommendations vary a lot more. Many diets recommend excluding yeast, citrus fruits, and nightshade vegetables.
Many activities inherently activate mast cells. Being too hot, standing or sitting in direct sunlight, exercise, sexual activities, menstruation, infection, and any type of physical trauma, even minor, can trigger mast cell activation as part of normal mast cell function.
Premedication is recommended for any medical procedure, even minor, as they can trigger mast cell activation.
• Patients may find that premedication prior to other activating activities is helpful for suppressing reactions.
Ultimately, the only way to know what is activating is through trial and error. Patients should consult their care team about what to trial, when, and how to make it as safe as possible.

For more detailed reading, please visit these posts:

Food allergy series: Mast cell reactions and the low histamine diet

The Provider Primer Series: Introduction to Mast Cells

The Provider Primer Series: Medications that impact degranulation and anaphylaxis

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 11

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

19. How do other conditions affect mast cell disease?
Mast cell activity can affect literally every system in the body.
• Mast cells are found throughout the body and live in many tissues and organs in significant numbers.
• There are essentially three types of damaging mast cell activity:
Normal mast cells are getting bad signals from other cells and they do bad things. This is not mast cell disease because these mast cells are not broken. They are getting signals from other broken cells.
Abnormal mast cells do bad things and tell other nearby cells to do bad things. This is mast cell disease, specifically mast cell activation syndrome and sometimes monoclonal mast cell activation syndrome.
You make way too many mast cells, they are abnormal, they do bad things, and they tell other nearby cells to do bad things. This is mast cell disease, specifically all forms of mastocytosis (systemic, cutaneous, and mast cell leukemia), sometimes monoclonal mast cell activation syndrome and mast cell tumors (mastocytoma and mast cell sarcoma).
• Generally speaking, if you have mast cell disease, any other condition you have will irritate your mast cell disease. This can also work the other way around and mast cell disease can irritate your other conditions.
• Many conditions naturally trigger higher level mast cell activation.
• Any disease that causes your body to make a lot of cells very quickly is likely to trigger to mast cell activation. Cancers are mast cell activating. Non cancerous diseases where you make too many blood cells at once, like polycythemia vera or essential thrombocythemia, are are mast cell activating.
• Mast cells are usually found very close to tumors. Sometimes, they are found inside tumors. Mast cells are important for tumors to survive because they can make blood vessels to bring tumors the blood they need.
Diseases affecting the immune system are triggering to mast cells. In fact, many patients have mast cell activation syndrome caused by the immune disease irritating their mast cells so much. Many mast cell patients have autoimmune diseases like lupus or rheumatoid arthritis. Many patients also have deficiencies in their immune system. Because mast cells are immune cells, they are very responsive to signals from other immune cells. Mast cells think those cells need help from them to fight an infection or disease so they respond strongly to “help”.
Diseases that cause inflammation also trigger mast cells. This can happen whether the inflammation is local or not. Systemic inflammation is more irritating to mast cells since that kind of inflammation can find more mast cells throughout the body. Local inflammation can irritate mast cells nearby. It can also call mast cells from other parts of the body to that location.
• Mast cells are actively involved in fighting infections from viruses, bacteria, fungi, and parasites. This is the reason many mast cell patients find they are more reactive when they have even a minor illness, like a cold.
Any type of physical stress can activate mast cells. This can be something as simple as exercise or something more traumatic such as a car accident, a surgery, or childbirth. Even things that should be easy to recover from can activate mast cells, like a small cut, dehydration, or getting overheated. This also includes stress caused by another disease.
Emotional stress can activate mast cells, even if the big emotion is joy.
For more detailed reading, please visit this page:

Symptoms and effects of mast cell disease

 

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 3

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

6. What symptoms does mast cell disease cause?

  • Mast cell disease can cause just about any symptom. Seriously.
  • Mast cell disease can cause symptoms in every system of the body. This is because mast cells are found in tissues throughout the body. They are intimately involved in lots of normal functions of the human body. When mast cells are not working correctly, lots of normal functions are not carried out correctly. When this happens, it causes symptoms. In short, mast cells can cause symptoms anywhere in the body because they were there already to help your body work right.
  • Skin symptoms can include flushing, rashes, hives (urticaria), itching, blistering, and swelling under the skin (angioedema).
  • GI symptoms include nausea, vomiting, diarrhea, constipation, problems with the GI not moving correctly in general (GI dysmotility), swelling of the GI tract, chest and abdominal pain, belching, bloating, discolored stool, excessive salivation, dry mouth, and trouble swallowing.
  • Cardiovascular symptoms include high or low blood pressure, fast or slow heart rate, irregular heartbeat, and poor circulation.
  • Neuropsychiatric symptoms include brain fog, difficulty concentrating, difficulty sleeping at night, excessive tiredness during the day, grogginess, anxiety, depression, tremors, numbness, weakness, burning and tingling (pins and needles), hearing loss, and auditory processing (difficulty understanding what was said to you).
  • Genitourinary symptoms include bladder pain, painful urination, painful intercourse/sexual activities, painful or irregular menstrual cycle (periods), and excessive or inadequate urination (too much or too little urine produced).
  • Respiratory symptoms include cough, excessive phlegm, wheezing, runny nose, sinus congestion, sneezing, and swelling of the airway.
  • General symptoms include fatigue, lack of stamina, difficulty exercising, itchy or watery eyes, and bruising easily.
  • There are some additional symptoms that I have observed in a large number of people that are not classically considered mast cell symptoms, but I now firmly believe them to be. One is fever. I think discoloration of the skin may be mast cell related for some people. Another is dystonia, involuntary muscle contraction, which can mimic appearance of a seizure. There are also different seizure-type episodes that may occur due to the nervous system being overactive. I am reluctant to call them pseudoseizures because that term specifically means they are caused as a result of mental illness. I have no evidence that these seizure-type episodes in mast cell patients occur due to mental illness. I personally refer to them as “mast cell derived seizures.” (For people who are wondering, I have been heavily researching this phenomenon and have some theories about why this happens. It’s not fleshed out enough yet to post but it’s on my think list.)
  • Having mast cell disease can make you more likely to have other conditions that cause symptoms.
  • I’m sure there are other symptoms I have forgotten to mention.

7. Why are skin and GI symptoms so common?

  • The skin has a lot of mast cells relative to other tissues. Your skin also comes into contact with lots of things in the environment. Think about the things your skin touches on a daily basis! It makes sense that it would get the exposure so skin symptoms can be common. Additionally, some of the chemicals mast cells release can cause fluid to become trapped in the skin. For these reasons, symptoms affecting the skin are pretty common.
  • The GI tract also has a lot of mast cells relative to other tissues. Your GI tract also comes in contact with lots of things in the environment. Let’s think about this for a minute. Your GI tract is essentially one long tube through your body. You put things from the environment in your GI tract at the top and they come back out the bottom of the tract. In a way, your GI tract is kind of like the outside of the inside of your body.
  • This is the analogy I learned in anatomy and physiology class to visualizing the GI tract as the outside of the inside of the body. Think of the body as a donut. (A low histamine, fully allergy friendly, requires no GI motility, wonderful donut.) Now think of the GI tract as the donut hole. You can put your finger through the hole in the middle of the donut. Only that center part of the donut will touch your finger. This is kind of like putting food throughout the GI tract. That food only touches a very small part of the body as it passes through.
  • Since what we put into our mouths (or other GI openings) is from the outside, your body has many mast cells in the GI tract to protect the body. Some of the chemicals mast cells release can cause fluid to become trapped in the layers of GI tissue. Some of the medications we take for mast cell disease can affect the GI tract. Some of them change how much acid we make in our stomachs. Some of them slow down the GI tract. A few of them speed it up or make the GI tract more fragile. For these reasons, symptoms affecting the GI tract are very common.

For more detailed reading, please visit these posts:

The Provider Primer Series: Management of mast cell mediator symptoms and release

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The Provider Primer Series: Cutaneous Mastocytosis/ Mastocytosis in the Skin

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 1

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

  1. What are mast cells?
    • Mast cells are white blood cells that live in tissues. It is a little misleading that mast cells are white blood cells because they don’t live in the blood. Mast cells are born in the bone marrow, the squishy tissue inside bones where blood cells are made. From the bone marrow, they are sent to the blood stream. Mast cells use the bloodstream to carry them to their final destination so they do not stay in the blood for very long. Mast cells move out of the blood stream and into tissues throughout the body. Mast cells live for months or years, a long time for cells to live in the human body.
    • Mast cells do many things in the body. They are largely responsible for allergic reactions and anaphylaxis. They have many other jobs, like healing wounds, regulating reproductive activities (menstruation, pregnancy), and fighting infections from viruses, bacteria, fungi, and even intestinal parasites like worms. The original function of mast cells thousands of years ago was probably to fight off intestinal parasites. Mast cells are found in many tissues and are essential for correct functioning of the body.
    • Mast cells have many pouches inside of them called granules. These granules hold chemicals made by the mast cells. These chemicals help the mast cells to do their various jobs. They also help mast cells to communicate with other cells nearby or in other parts of the body. These chemicals can be released into the bloodstream to signal for other immune cells to come to the mast cell that released them.
  2. What is mast cell disease?
    • Mast cell diseases are rare diseases in which your body makes too many mast cells and/or mast cells do not function correctly. In the US, diseases that affect fewer than 200,000 people are called rare diseases.
    • Mast cell diseases are broadly classified into two groups: clonal and non-clonal (also called proliferative and non-proliferative).
    • When the body makes too many copies of a broken cell, those cells are called ‘clonal’ cells. In clonal forms of mast cell disease, the bone marrow makes too many mast cells. Those mast cells also don’t work correctly. They use too much energy on the wrong things. Because these mast cells are often busy making truble, they don’t have as much energy to do their normal necessary functions.
    • Clonal mast cell diseases include all forms of systemic mastocytosis (indolent, smoldering, aggressive, and mast cell leukemia); all forms of cutaneous mastocytosis (urticaria pigmentosa, of which telangiectasia macularis eruptiva perstans is a subtype, diffuse cutaneous mastocytosis); mastocytoma (usually found on the skin but also found elsewhere); mast cell sarcoma; and monoclonal mast cell activation syndrome. Importantly, in clonal mast cell diseases, the problem is not just that too many mast cells are made – those mast cells must also be dysfunctional for the disease to be clonal.
    • In non-clonal mast cell disease, the number of mast cells may be normal, but the cells are broken. Importantly, people with non-clonal mast cell disease may make more mast cells than normal, but not enough to be considered a clonal disease. In these diseases, even if the bone marrow makes the normal amount of mast cells, they still do not work correctly. They use too much energy on the wrong things. Because these mast cells are often working to inflame the body when it is not needed, they don’t have as much energy to do their normal necessary functions.
    • Non-clonal mast cell diseases include all other forms of mast cell disease: mast cell activation syndrome (secondary and idiopathic); familial hypertryptasemia; and mastocytic enterocolitis, which is recognized by some groups as its own disease, and by other groups as part of different mast cell diseases.
    • In these diseases, mast cells do not function properly. In all mast cell diseases, mast cells can get irritated easily. They respond to things in the environment and inside the body that they think are dangerous, even when those things are normal and safe for most people. This response is called mast cell activation.
    • Mast cell activation causes many symptoms. Many of these symptoms are “allergic” in nature. Some are not directly recognizable as “allergic”. Symptoms can affect every bodily system or may be localized to only one or two. It differs from person to person and can change over time within a person. You cannot know which mast cell disease a person has based upon their symptoms.

For more detailed reading, please visit these posts:

The Provider Primer Series: Introduction to Mast Cells

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The Provider Primer Series: Cutaneous Mastocytosis/ Mastocytosis in the Skin

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

The Provider Primers Series: Introduction to Mast Cells

Mast cells : Introduction

  • Mast cells are bone marrow derived. They migrate to tissues before maturity and remain tissue bound.[i]
  • Mast cell development in tissues is regulated by a number of molecules, most significantly stem cell factor (SCF) which binds at the CKIT (CD117) receptor. A number of other molecules, including IL-3, IL-4 and IL-10, also participate in this process.[ii]
  • Mast cells are long lived, with some living for years in tissue.[ii]
  • Mast cells are versatile actors. Their functions and granule contents are tailored to the needs of the local microenvironment.[iii]
  • Mast cells perform a number of critical roles, including immune defense against microbes and larger parasites; clotting; wound repair; tissue remodeling; angiogenesis; regulation of reproductive cycle; digestion and GI motility; pain response; participation in stress response via interaction with HPA axis; inflammatory response; and regulation of sleep and some aspects of cognition.[iv]
  • Mast cells produce a multitude of mediators which are stored in granules or produced de novo. Stored mediators of consequence include histamine; tryptase; heparin; bradykinin; serotonin; and substance P. De novo mediators include prostaglandin D2; leukotrienes C4, D4, and E4; platelet activating factor; tumor necrosis factor; interferons; and a number of interleukins, including IL-1a, IL-1b and IL-6, among many others. [iii]

Mast cell involvement in disease

  • Mast cells are involved in the pathology of many conditions, including asthma[iv]; autoimmune diseases[iv]; GI dysmotility, including post-operative ileus[v]; cardiovascular events[iv], such as myocardial infarction, rupture of atherosclerotic plaques or aneurysms, and coronary syndromes, including Kounis syndrome[vi]; cardiovascular disease; malignant and neoplastic [iv]; chronic kidney disease[iv]; cutaneous conditions[iv], including many forms of urticaria; depression and anxiety; and chronic pain[vii].
  • Mast cells are effectors in all mast cell diseases.
  • Most famously, mast cells are involved in allergy and anaphylaxis.[viii]

Mechanisms of mast cell activation

  • Mast cells are primarily activated via IgE crosslinking at the FcεRI receptor. This is the mechanism for the classic allergy model in which specific IgE binds the target allergen and crosslinks at the FcεRI receptor on the surface of mast cells and basophils. In this traditional model, crosslinking causes immediate degranulation of stored mediators and late phase release of mediators produced de novo upon activation[viii].
  • There are several other mechanisms for direct mast cell activation that are independent of IgE.
  • A number of inflammatory molecules can directly activate mast cells by binding surface receptors including corticotropin releasing hormone; substance P; histamine; cysteinyl leukotrienes; adenosine; stem cell factor; IL-3; IL-4; IL-9; and IL-33, among others[ix].
  • Substances associated with immune defense and infection can directly activate mast cells. Products derived from pathogens can activate via toll like receptors (TLR2 and TLR4), Dectin-1 or CD48. Host production of β-defensins and complement C3a and C5a can also provoke mast cell activation[ix].
  • IgG can bind at FcγR receptors on mast cell surfaces. Immunoglobulin free light chains have triggered degranulation in murine models but this has not yet been demonstrated in humans[ix].

Definition of anaphylaxis

  • The definition of anaphylaxis continues to be disputed. The 2006 NIAID/FAAN criteria detailed below have been validated and are widely used.[x]
  • Anaphylaxis is likely when any one of the following three criteria is met:
  • Criterion 1: Acute onset of illness with skin and mucosal issue involvement (hives, itching, flushing, swelling of lips/tongue/uvula) with at least one of the following: compromised airway (difficulty breathing, wheezing, low blood oxygenation); or reduced blood pressure or symptoms thereof (fainting, incontinence.)
  • Criterion 2: Two or more of the following occurring after exposure to a likely allergen: skin or mucosal tissue involvement (hives, itching, flushing, swollen lips/tongue/uvula), compromised airway (difficulty breathing, wheezing, low blood oxygenation); reduced blood pressure or symptoms thereof (fainting, incontinence); or persistent GI symptoms (cramping, abdominal pain, vomiting).
  • Criterion 3: Reduced blood pressure after exposure to known allergen.  For adults, this is <90 mm Hg systolic, or at least 30% decrease from baseline.  For children under 1 year of age, this is <70 mm Hg systolic; ages 11-17, <90 mm Hg systolic.  For children 1-10 years of age, this is <(70 mm Hg + (2x age)).  So for a child who is 8 years old, this would be <(70 + (2 x 8)) = <86 mm Hg.

References:

[i] Dahlin JS, Hallgren J. (2015). Mast cell progenitors: origin, development and migration to tissues. Molecular Immunology 63, 9-17.

[ii] Amin K. (2012). The role of mast cells in allergic inflammation. Respiratory Medicine, 106, 9-14.

[iii] Theoharides TC, et al. (2012). Mast cells and inflammation. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1822(1), 21-33.

[iv] Rao KN, Brown MA. (2008). Mast cells: multifaceted immune cells with diverse roles in health and disease. Ann NY Acad Sci, 1143, 83-104.

[v] De Winter, BY. (2012). Intestinal mast cells in gut inflammation and motility disturbances. Biochimica et Biophysica Acta, 1822, 66-73.

[vi] Kounis NG. (2016). Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med, 54(10), 1545-1559.

[vii] Chatterjea D, Martinov T. (2015). Mast cells: versatile gatekeepers of pain. Mol Immunol, 63(1), 38-44.

[viii] Galli SJ, Tsai M. (2013). IgE and mast cells in allergic disease. Nat Med, 18(5), 693-704.

[ix] Yu Y, et al. (2016). Non-IgE mediated mast cell activation. European Journal of Pharmacology 778, 33-43.

[x] Sampson HA, et al. (2006). Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol, 117(2), 391-397.

Take home points: July 2015

Mast cell interactions with B and T cells
• Mast cells communicate with other cells by:
o Releasing chemicals to tell another cell to do something
o Other cells releasing chemicals to tell mast cells to do something
o Moving right up against other cells, which allows the cells to “talk”
• B cells are white blood cells that make antibodies and protect against infections.
o Mast cells can tell B cells to make IgE, an allergy antibody.
o When mast cells touch B cells, the mast cells can release IL-6 which tells B cells to live longer.
o Mast cells can tell B cells to make IgA, an antibody.
• T cells are white blood cells that have many functions.
o T cells and mast cells are found close together in many inflammatory conditions, like ulcerative colitis.
o Activated T cells can activate mast cells.
o Mast cells can tell T cells to proliferate and produce inflammatory molecules.
o A kind of T cell called Treg (T reg, like in regulatory) cells can make mast cells harder to activate and interfere with degranulation.

Mast cells in kidney disease
• Kidney disease is often not identified until 60-70% of functional kidney cells have been damaged beyond repair.
• Mast cells are rare in healthy kidneys.
o Damaged kidneys can have up to 60x the normal amount of mast cells.
o Mast cell count is not related to disease severity.
• Atopic disease, like atopic dermatitis and allergic asthma, is linked to idiopathic nephrotic disease, kidney disease of unknown origin.
o The nephrotic disease and atopic disease could be manifestations of the same overarching condition.
o In patients with both, IgE levels are high.
• Tryptase is elevated in some patients with kidney damage.
• Mast cells are responsible for bringing other inflammatory cells to the damaged kidney.
• Mast cells can cause fibrosis in kidneys.
• In some roles, mast cells can protect kidneys from damage.

Regulation of mast cells by IgE and stem cell factor (SCF)
• Mast cells are mostly regulated in two ways
• IgE binds to the IgE receptor (FceRI) on mast cells and activates them
o Activation by IgE results in degranulation and secretion of mediators
o IgE induces mediator release by affecting the amount of calcium inside mast cells
• Stem cell factor (SCF) binds to the CKIT receptor on mast cells and tells them to stay alive
o SCF also increases degranulation and production of cytokines
o SCF helps mast cells to adhere to other cells

Mast cells in vascular disease: Part 3
• Mast cells are involved in the formation and growth of aneurysms
• Activated mast cell populations are increased in vessels that rupture
• Chymase, a mast cell mediator, can degrade vessels and increase risk of rupture
• Leukotrienes contribute to aneurysm formation

Patient questions: Is mast cell disease autoimmune?

Autoimmune disease is when your body has an abnormal immune response to something that is a normal part of the body. There are more than eighty currently identified autoimmune diseases and they affect a significant population worldwide. At least 2% of women are estimated to have at least one autoimmune condition. Multiple sclerosis, rheumatoid arthritis and lupus are examples of autoimmune disease. Autoimmune diseases can affect small areas or multiple organs or targets throughout the body.

There are a number of possible causes of autoimmune disease. Some well supported theories include:
1. Molecular mimicry. This occurs when the body is exposed to an external danger and direct antibodies and immune defense against this danger. However, once the danger has been resolved, the antibodies and immune defense are directed toward damaging some normal part of the body that by happenstance looks like the dangerous thing. A classic example of this is development of rheumatic fever, PANDAS and other complications after a Streptococcus infection. The body makes antibodies to fight Strep, the Strep is killed and infection resolved, but the antibodies then attack things in the body that look like strep to the antibodies.
2. Genetic predisposition. Mutations and improper expression of genes that mediate tolerance, like HLA genes, can result in autoimmune disease. In these patients, these anomalies cause the body to fail to recognize itself as “safe”.
3. Cryptic determinants. This refers to the situation in which a hidden part of a normal structure in the body is not usually “seen” by the rest of the body. When that hidden part is exposed to the rest of the body, the immune system does not recognize it and attacks it, thinking it is dangerous. I imagine this as a waterway in a year of drought. A river has many small black rocks on the bottom. When the water is high, like most years, you cannot see these rocks. In a year of drought, the water level drops and you can the black rocks on the bottom. They were always a natural part of the riverbed, and they were always there, you just couldn’t see them. This can happen inside the body too. Sometimes your immune system sees things that were always there but not seen by it before.

The key feature unifying autoimmune diseases is that the immune system directly targets a part of the body that is normal and healthy. In lupus, the body makes antibodies that target the DNA inside our cells, which is not just normal but critically important to survival. It doesn’t target defective DNA, it targets regular old, keeps us alive, DNA.

Mast cell diseases are not autoimmune diseases. Mast cell diseases are not directly their attacks to a normal, healthy part of the body. In mast cell disease, mast cells are dysregulated and behave inappropriately. While this can damage parts of the body, this damage occurs due to the general inflammatory environment rather than because mast cells specifically targeted those parts of the body. Aberrant mast cells aren’t saying, “Quick, there’s an intruder in the liver! Let’s go get them!” when it’s just your regular liver hanging out. They are just so activated that mediator release could damage some cells in the liver, and in other places at the same time. The mast cell activation does not specifically target the liver in this scenario.

A confusing aspect of mast cell disease is that MCAS can occur secondary to autoimmune disease and many MCAS patients have autoimmune disease. In this patient population, the MCAS is probably induced by the inflammation caused by the autoimmune disease. Even still, while the primary autoimmune disease targets specific parts of the body, MCAS does not target specific parts of the body to attempt to destroy them.