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)

IgE-independent anaphylaxis; or, I haven’t been this excited on a Tuesday night in a long time

Mast cell patients are intimately familiar with the phenomenon of testing positive for allergies to things you know aren’t problems and negative for things that almost killed you.  If you ask any health care provider what the allergy antibody is, they will say it is IgE.  And for the most part, that is true.  But mast cell patients suffer reactions that do not demonstrate an IgE pathway to their allergies and anaphylaxis, and it is reason most of us suffer for years before being diagnosed correctly.

The idea that anaphylaxis is a function directly executed by IgE is a deeply ingrained part of western medicine.  In this model, IgE specific for an allergen binds to the allergen, and binds to the IgE receptor on mast cells and basophils, resulting in massive degranulation.

This is the classic model of anaphylaxis, with some creative license:

  1. You come into contact with something. Let’s say it’s Peanut, an anthropomorphic peanut.
  2. Immune cells called B cells think they once saw Peanut in a dark alley behind a bar. Peanut could have been waiting for a ride like any responsible peanut who has been drinking, but dark alley = shady = Peanut is trouble.
  3. The B cells make “Wanted!” posters with a picture of the peanut on it. Many, many posters.
  4. The B cells make lots of IgE to make sure every cell in the body sees the Wanted! posters. There will be nowhere for peanuts to hide. (I swear that as I was typing, I just heard the theme to the Good, the Bad and the Ugly.  I SWEAR.)
  5. Everyone knows that Peanut is a bad guy. They have seen the poster many times.  They do not need to see it again.  Do not show the poster again.  WE KNOW PEANUT IS BAD, IGE.  GO HOME, IGE, YOU’RE DRUNK.
  6. You guys know what happens next.  Peanut shows up.
  7. Someone remembers that IgE has been coming around the bar with the poster of Peanut. Peanut = bad guy.
  8. Everyone is hoping that if they tell IgE where Peanut is that IgE will leave them alone. No one really likes IgE but he is making such a big deal about Peanut and maybe Peanut is bad.  A little bad.  No one really knows but they know they do NOT want to deal with IgE if Peanut gets away.
  9. IgE and Peanut have a Western style gun duel at high noon. IgE captures Peanut by binding to him.
  10. While IgE is bound to Peanut, he also binds to a mast cell, which is like home base. IgE knows that Peanut is trouble and he is part of a Peanut gang and they are all bad, too.
  11. Mast cells deploy the tanks, duckboats, submarines, helicopters and fighter planes in the early allergy response to fight the Peanut gang. This causes massive inflammation with effects throughout the whole body.  Mediators released in the early response include histamine and tryptase.
  12. Mast cells start building more defenses and release them a little at a time later on in the late allergy response. Mediators released in the late response include prostaglandins and leukotrienes.

But we all know that it doesn’t always happen like this, because mast cell patients often have normal tryptase and IgE despite having a massive anaphylactic event, or even normal histamine or prostaglandins.

Last month, a comprehensive paper described alternative anaphylaxis pathways in mice that may be analogous to what is happening to mast cell patients having anaphylaxis that is not mediated by IgE.  That is to say, this pathway needs more research to know for sure if it is what is happening to us, but I have been watching the literature on this closely for a while and I100% think this is real.

There have now been multiple reports of the ability to induce anaphylaxis in mice while interfering with the IgE allergy pathway (either by not making IgE or the IgE receptor, or by treating the mice with anti-IgE, which blocks the IgE from binding to the receptor). Scientists found that by anaphylaxis could be mediated by IgG if the trigger was given intravenously. In particular, they were able to identify the murine IgG2b as the antibody subclass responsible.  In mice, IgG2b can cause anaphylaxis when IgE is not able to participate, at all.

The most important mediator in IgE anaphylaxis is histamine.  But the most important mediator in IgG anaphylaxis is platelet activating factor (PAF).  PAF levels have been linked with severity of anaphylaxis previously (I wrote a post about this around this time last year).  This could explain why many patients have normal tryptase, n-methylhistamine or histamine levels despite a very short amount of time elapsed from anaphylaxis. This is not a histamine show.  And maybe the reason so many mast cell patients cannot get complete relief despite taking huge doses of antihistamines is because histamine isn’t the PRIMARY issue.  (Author’s note: Please do not stop taking your antihistamines.  I love my antihistamines.  Just saying I think maybe there is something happening above histamine in these reactions.)

It’s also not just a mast cell show.  IgG can activate basophils, monocytes and macrophages, and neutrophils to release PAF.  Human neutrophils can mediate IgG dependent anaphylaxis when infused into mice.  So now we have a mechanism for anaphylaxis that is not IgE independent – it can also be mast cell independent.  Mind blowing. (Worth mentioning here that the phenomenon of mast cell independent anaphylaxis is not new or specific to IgG anaphylaxis – groups have found instances of mast cell independent anaphylaxis for almost thirty years.)

PAF levels are much higher in anaphylaxis patients than in control patients, and the enzyme that degrades PAF, called PAF acetylhydrolase, is much lower. It is important to note that binding at the IgE receptor can also produce PAF, but that also causes degranulation and release of histamine and tryptase, which seems to be absent in some patients.

To induce IgG mediated anaphylaxis, you need more allergen than for IgE anaphylaxis.  A lot more. 100-1000x more.  So in mice that have both IgE and IgG for peanut (not really peanut), doesn’t it seem like the IgE would react first to the peanut, and you would have IgE anaphylaxis?  But that’s not what happens.  What happens is that the IgG scoops up the peanut faster than the IgE can.  The IgG can block IgE anaphylaxis.  (WHAT UP MAST CELL PATIENTS DOING WAY BETTER ON IVIG?!?!)

IgG anaphylaxis in mice has been exclusively isolated to triggers administered intravenously.  The reason this fact matters is because of the frequency with which people (who don’t always have mast cell disease) have anaphylaxis to intravenous antibody treats, like IVIG, monoclonal antibodies for treating various diseases, or transfusions (which contain IgG antibodies). Treatments of this kind provide a huge influx of allergen. This pathway favors IgG anaphylaxis over IgE anaphylaxis because of how the IgG will scoop the allergen up (see previous paragraph).

As a final aside, there is also the curious fact that a group of patients with CVID (common variable immunodeficiency, a primary immunodeficiency disease) have a mutation that makes one of the IgG receptors found on cells like mast cells WAY more active.  The CVID patients with this mutation also have antibodies to IgA and experience anaphylaxis after IVIG.

I know I have gone on and on but this is the most exciting thing to happen to tryptase and histamine normal anaphylaxis patients in the last decade, at least.  There is SO much work that needs to be done.  Mouse and human mast cells are different.  Mouse and human IgG antibodies are different.  They could not induce food allergy in mice with an IgG dependent mechanism.  We need to pursue research on the role of PAF specifically in anaphylaxis patients with normal tryptase and histamine.

But now, when you tell your doctor that anaphylaxis is not always IgE dependent, you can give them a reference to a solid paper that fairly describes the findings, the caveats and the strengths of the current research on IgE independent anaphylaxis.  And it’s not just speculation. PEOPLE OUTSIDE OF MAST CELL DISEASE RESEARCH GROUPS ACKNOWLEDGE THAT THIS IS REAL.  IGE INDEPENDENT ANAPHYLAXIS IS REAL.

Boom.

Someone hold my Epipens while I make my dog dance with me.

Reference:

Finkelman FD, Khodoun MV, Strait R. Human IgE-independent systemic anaphylaxis. J Allergy Clin Immunol 2016.