‘Mast Cell Diseases & Systemic Mastocytosis: The Basic Science’
In this episode of the “Allergy, Asthma & Immunology Innovations” podcast series, we focus on mast cell diseases and systemic mastocytosis. This is the first of a 6-part podcast series on mast cell diseases. The podcasts are sponsored by Blueprint Medicines.
The podcast is a collaboration between Allergy & Asthma Network and The Itch Podcast. It is hosted by The Itch Podcast’s Kortney Kwong Hing and allergist/immunologist Payel Gupta, MD.
In this episode, Kortney and Dr. Gupta discuss the science behind mast cell diseases, including systemic mastocytosis, mast cell activation disease, and others. They explain what mast cells are, how they function, and how they play a role in these diseases.
You can listen to or download the podcast on ItchPodcast.com anytime, anywhere. The podcast can also be downloaded at:
Timestamp overview
- 1:05 – What is a mast cell?
- 2:15 – What is histamine?
- 3:15 – A look at what triggers a mast cell and how mast cells work
- 7:05 – Are mast cells found in our blood?
- 8:20 – What is mast cell disease?
- 9:28 – Three forms of mast cell disease
- 11:34 – Seven types of mastocytosis
- 16:10 – Don’t get scared when you Google mastocytosis
- 17:15 – The role of allergists in mastocytosis
- 19:08 – What causes mast cell diseases?
Full Transcript
Kortney Kwong Hing: You’re listening to The Itch, a podcast exploring all things allergy, asthma and immunology. I’m your co-host Kortney, a real-life allergy, asthma and eczema girl.
Payel Gupta, MD: And I’m your second host, Dr. Payel Gupta, a board-certified allergy, asthma and immunology doctor. Kortney and I hope to balance each other out so that we get you all the information that you want and need about allergies, asthma and immunology.
Kortney: We are embarking on a new series today in our special collaboration podcast with Allergy & Asthma Network. If you haven’t heard about this podcast series yet, it’s called the Allergy, Asthma, and Immunology Innovations podcast. Today is the first of a six-part series about systemic mastocytosis. We want to thank Blueprint Medical for their sponsorship of this series.
Dr. G, this is a completely new subject matter for me, and I’m really excited to jump in and learn along with everyone. Why don’t we just get to it? Let’s start with this: what is a mast cell?
Dr. Gupta: Yes, this is an exciting topic, and I’m really excited to have a full series on it and really explain the condition, and talk to some patients, talk to some doctors that treat it more often, and are also doing some research. I think we have a really nice series planned.
What is a mast cell? We have actually talked about mast cells in the past, Kortney. A mast cell is a part of our immune system and it is a white blood cell. So everyone has mast cells in their body, and they actually play many roles in keeping us healthy. They protect us from foreign invaders like germs and parasites, and they also participate in the inflammatory response, which is an important part of how we protect our body.
So mast cells are also called the allergy cell because they are also responsible for immediate allergic reactions. Mass cells cause symptoms of allergies by releasing products called mediators. And mediators are basically chemicals that are stored inside of them. Histamine is one of those mediators. And histamine is one of those mediators, and we definitely know what histamine is. We’ve talked about it a lot on our podcast. It causes hives. It causes a lot of the symptoms that we associate with allergies. And again, everyone has mast cells, and although they are helpful in the immune system, they can also cause problems and lead to allergic reactions and anaphylaxis.
Kortney: Yes, I think that if you listen to our episodes about urticaria or about anaphylaxis, or some of our really early on episodes about food allergies and the science behind food allergies, you know what mast cells are.
Just so I can clarify again, so I’m on the same page with everyone, mast cells really have a specific function, and that’s to protect us from parasites and germs, and sometimes something happens, and that’s an allergic reaction, and that’s the mast cell reacting to something that’s not like a germ, but maybe a food. Can you just elaborate a little bit more about this, Dr. G?
Dr. Gupta: Yes, exactly. So first, you need to understand that our body uses receptors on cells to communicate with the cell and to tell it when it should become activated. And so with that in mind, mast cells have lots of different receptors on them, and the mast cell is waiting to get triggered by the activation of these receptors.
During an allergic reaction, our body essentially communicates with the mast cell because of IgE antibodies that bind to IgE receptors that are present on the mast cell. These IgE antibodies see the allergen that the IgE antibody is specific for. And then once that allergen protein binds to the IgE and the IgE receptor complex, that binding causes the mast cell to be activated. And then the mast cell degranulates, or releases all the chemicals it stores inside of it, that causes the reaction.
Kortney: In terms of food allergy, because that’s basically what I know the best, I know that histamine is a part of our allergic reaction. So when you say degranulate and there’s a release of chemicals, is histamine then one of those chemicals that the mast cell releases?
Dr. Gupta: Yes. So degranulating means that the mast cell opens and releases a bunch of chemicals, and one of those chemicals is histamine. But there are so many chemicals that get released, and many of those chemicals then communicate with other cells. That results in basically a downward cascade of inflammation, which the body tries to rid itself of infection and harm. One analogy that I’ve seen that’s used is super helpful, and that’s of a pinata. So think of the pinata as the mast cell, and then the allergen and IgE combo as the stick and the person holding the stick that hits the pinata and causes the release of all the candy. But in this case, it’s all the chemicals, and chemicals then go on to cause chaos, like candy can cause chaos in the brains of little kids.
Kortney: That’s a great analogy. That’s really hilarious to think of a swarm of children running like crazy to all of these candies. And that’s indeed chaotic, and that’s indeed a reaction. So can you explain to us then if anything else can cause this chain of events other than just an allergen? Is there anything else that can be a stick, say, in your analogy?
Dr. Gupta: Yes. Medications, infections, and venom, like from bees and other stinging insects – those can also be triggers. And what is important to note is that these responses are carried up by normal mast cells that are not desirable. This is known as secondary activation because it is caused by external stimuli.
Kortney: Okay, so I think that we understand how a mast cell works. Just to be clear, a germ would be more of a desirable thing to degranulate the mast cell, but an allergen isn’t desirable, and you called it secondary activation. Now, you mentioned that mast cells are white blood cells, which to me, I hear ‘mast cell, white blood cell,’ I think, ‘Okay, then they must be found in our blood.’ Is that right? Are mast cells found in our blood, or are they in other places in our body that I just don’t know about?
Dr. Gupta: That’s a great question. So actually mature mast cells, which means that mast cells that would actually work and do something and can get activated, are actually not circulating in the blood. They’re actually found in what we call connective tissues. So connective tissue is that tough, often fibrous tissue that basically binds the body structures together. And it provides support and elasticity to lots of different parts of our body, and it’s present in almost every organ. It forms a large part of the skin, tendons, joints, ligaments, blood vessels, and muscles. And so we need white blood cells all over the body so that our body is able to protect itself. And this is just another example of how cells can be found in connective tissues. And one of those cells is the mature mast cell.
Kortney: Okay, that’s super interesting. So pretty much mast cells are found everywhere in the body, because this connective tissue is everywhere. So now, our podcast is about mast cells and what happens when mast cells aren’t doing everything that they’re supposed to be doing correctly. Dr. G, what is mast cell disease?
Dr. Gupta: Mast cell disease is a general term used for diseases that affect the mast cell. So these diseases can be caused by an abnormal amount of and/or overly active mast cells. For any cell in our body, we want them there, but only in certain amounts and functioning properly. If we have too many that are present or if they’re being overly active and not responding the way that we want them to, that will all cause problems in the way that we normally want these cells to function.
Kortney: What happens if there aren’t enough or mast cells aren’t functioning properly?
Dr. Gupta: With mast cells, we’re actually not – there aren’t any conditions that there aren’t enough or not functioning properly that we know about at this point. What we’re really dealing with is too much activation and too many of them being present in certain disorders.
Kortney: What are we talking about when we talk about mast cell disease? Which conditions or which diseases?
Dr. Gupta: There are three forms of mast cell disease. Mastocytosis, mast cell activation syndrome, and then something called hereditary alpha tryptasemia. I’m going to break each of these down, and then we’ll repeat everything for everyone because it’s going to be a lot of information.
But basically, mastocytosis means that there’s extra mast cells that are being produced by the body, and then there is essential infiltration of the skin or other tissues and organs with mast cells that shouldn’t be there. So all of the connective tissue where these are normally present, there’s just too many. There’s more than there should be. And that means that when they get activated, there are more of them to actually get activated, which means that more chemicals are being released and then more of everything else that happens after is happening. So more inflammation, more histamine, all of that stuff, all of those downward effects. There’s just a ton of kids that are coming into the picture that shouldn’t be, essentially.
And then mast cell activation syndrome is where there’s an increased and inappropriate activation of mast cells. So the number is the same. But when they get activated, they’re just activating for no reason most of the time, and they’re not working normally.
And so you’re getting the release of this chemical without having that stick and child that initially hits the pinata actually doing that. The mast cell is just by itself deciding to break open. So the pinata is just deciding to break open on its own and then releasing all of those chemicals.
In hereditary alpha tryptasemia, there is a genetic mutation that leads to an overproduction of alpha-tryptase, which is a protein that’s released by mast cells. So when mast cells degranulate, like we discussed earlier with histamine, they release tryptase also. When the mast cell gets activated, then the tryptase is in abundance. All these chemicals that are released, there’s a fine balance to which ones are released when the mast cells degranulate. And in this case, there’s just too much of one of these chemicals, and that can cause problems, too.
Kortney: That was a lot of information, like you said it would be. I think using your pinata analogy has been really helpful. Do you think, or I’m not going to give you the option, I’m going to summarize everything. Let’s see if I can remember. And then if I can remember, I would assume that the audience also can remember what everything is.
We started with mastocytosis, and that’s basically when there is an excess of mast cells in the connective tissue. What that means is that if there are too many mast cells, when they get activated, that means you’re just going to have way more chemicals than you would normally have released, and so the reaction is just so much bigger. Then we have mast cell activation syndrome, and that’s when the mast cells degranulate but without a trigger. So like you mentioned, the pinata just explodes open while it’s hanging off of the tree or something, and you don’t exactly know why it did that.
The third one you mentioned was hereditary alpha-tryptasemia, and that’s caused by a mutation, which leads to the overproduction of the protein alpha-tryptase, and that protein is found inside the mast cells.
So If I were to use the pinata analogy, it’s like you hit the pinata, it opens, all of the candies come out, and you realize that there are way too many of one particular candy, and it is not equally spread out the way you normally want it to be. Is that right, Dr. G? Did I remember all three?
Dr. Gupta: Yes, Kortney, that’s exactly right. I think you summarized it really well, and I think it’s always good to hear it again, basically said again, over and over. And that’s what we’re going to do in this series. We’re going to keep talking about these concepts over and over again so that it all really makes sense at the end of the day. Those are the three large buckets of mastocytosis. And then, specifically for mastocytosis, there is a varying degree of severity, and because of that varying degree of severity, they actually act like totally different disease states.
And so in 2008, the World Health Organization actually classified mastocytosis into seven different categories because of all the differences that we were finding. There’s cutaneous mastocytosis, there’s indolent systemic mastocytosis, there’s smoldering systemic mastocytosis, there’s systemic mastocytosis, mastocytosis with non-associated hematologic non-mast cell disease. There’s aggressive systemic mastocytosis. There’s mast cell leukemia. There’s mast cell sarcoma. And then there’s extracutaneous mastocytoma. So that’s a lot of different terms, and we’re not going to go into all of them. It’s basically to remember that there’s lots of different types of mastocytoma mastocytosis.
If you Google the term mastocytosis, it might make you scared because if you’ve just been newly diagnosed with it, and you’re not completely aware of which form you have, then you could start going into a rabbit hole and looking at the more severe types of disease and then getting really worried.
So it’s just really important to know that there are a lot of different types. Some of them are more severe and some of them are less severe. Another way to categorize them is that there’s cutaneous mastocytosis, and this is the most common type of mastocytosis. And cutaneous means that it’s really limited to the skin, whereas in systemic mastocytosis, the internal organs are involved.
Then systemic mastocytosis is the type of mastocytosis that affects the bone marrow and other organs, like the liver, spleen, lymph nodes, and it can cause more serious symptoms than cutaneous mastocytosis.
Then mastocytosis with an associated hematologic disorder – this type of mastocytosis is associated with other hematologic disorders like leukemia and lymphoma. Again, it’s just important to remember that there’s lots of different categories. If you’re searching online, if you’re doing a search after you get done with your doctor’s appointment, we just don’t want you to be worried.
Kortney: Oh, my gosh. Okay. I don’t know if everyone saw my face, but that’s a lot. I’m very pleased that you said two things. First is that we’re not going to cover everything because I have a feeling that not everything is in the wheelhouse of an allergist. But I’ll get to you on that in a second. The second thing is that Googling certain things can really freak you out if you aren’t guided by a professional and you just get into, like you said, this dark hole.
I heard leukemia, and all of a sudden, my little antenna went up like, ‘Oh, my gosh, cancer.’ So thank you so much for reminding everyone that you’ve got your diagnosis, but get more information from your doctor before you start freaking out completely.
The first thing I said was there were a lot of those, and I have a suspicion that not all of them are seen by allergists. So, can we talk a little bit about which ones we’re going to be covering over the next five episodes?
Dr. Gupta: I want us to start off by saying that when extra cells are being produced by the body, that is essentially what happens with any cancer. With more severe forms of mastocytosis, these conditions are treated and named to reflect more of that, this is a cancer, and this is really an abnormal infiltration of cells that are causing a lot of harm.
I don’t think that we need to go into these different diseases because, again, they are complicated, even for physicians to discuss. These are very complicated disorders. Still, the most important thing to note is that there are various forms, and the severity will dictate the type of symptoms you have and the type of treatment that’s given. Allergists mostly see the cutaneous and the indolent systemic mastocytosis, and the more severe forms are treated by hematologist oncologist because, again, they act more like cancers.
Kortney: Great. That makes sense because if we remember, mastocytosis is an overproduction of mast cells. Thank you for that small explanation about cancer. I think it clarified everything very much for me. I want to get into the nitty-gritty of everything. I want to know about symptoms. I want to know about treatments. I’m getting ahead of myself here. I know that we have already covered a ton of information, which has been really good base information. Again, we’ve got five more episodes to go there, so I won’t, I promise. Instead, I will say, let’s start to wrap up this episode.
Before we go, let’s leave the listeners with something. Do we know what causes mast cell disease?
Dr. Gupta: For more than 90% of patients with systemic mastocytosis, they have a mutation in something called the kit receptor. The kit gene is actually a gene that provides instructions for producing a protein called kit or C-kit, which is a receptor found on the surface of mast cells. That’s how mast cells are associated with this kit. This receptor that’s found on the surface of mast cells plays a crucial role in the regulation of mast cell growth and function.
In mastocytosis, a genetic mutation affecting the kit gene causes that kit receptor to become overactive. The overactivity of the receptor signals the mast cells to grow and divide uncontrollably, which results in an increased number of mast cells. Again, those mast cells can be all over the body. The mutated kit, or K-I-T – I just wanted to spell it out in case anyone wanted to look it up – the mutated kit receptor is often found in a large proportion of mast cells in individuals with mastocytosis.
Kortney: Okay, so that was a lot of information, and I took some notes. Let me see if I can simplify this. First, I think we need to recall some basic science. The basic science is that the role of a gene is to make a protein. Once we understand that, we can talk about the kit protein, which is the one that’s impacted. The kit protein is a receptor found on the mast cell. This receptor is responsible for the growth and development of mast cells.
When there’s a mutation on the kit gene, there’s then a mutation that’s impacting the receptor, and the receptor is becoming overactive. And when you have an overactive receptor that is responsible for the production and growth of mast cells, you then have an overproduction of mast cells.
Dr. Gupta: Perfect. Yep, that’s exactly right. It’s not the kit gene. We actually don’t know what causes it. So that’s exactly how everything works. And that was a great summary because it is very complicated, some of this stuff. I’m really glad that you summarized it. And as usual, you figured it out perfectly. And so hopefully that extra summary really helps everyone that’s listening.
We have for mastocytosis, and then for mast cell activation syndrome, it’s not the kit gene, and we actually don’t know what causes disorder or activation syndrome. For hereditary alpha-tryptasemia, it is a mutation in a different gene, and that gene is called TPSAB1, which codes for alpha-tryptase. And that leads to an increased amount of alpha-tryptase in mast cells.
So now that you’ve explained genes and how those work, so now we get it, that this other disorder has a different gene that mutated, and that causes the increase in the mast cells for that particular chemical alpha-tryptase.
Kortney: Okay, thank you, Dr. G. Yeah, at first here, it sounds like it makes sense. Then when you try to say it out loud, it makes zero sense because you’re like, ‘Oh, okay. It sounded really good. But actually, now that I’m trying to put it into my own words, I have no idea what’s going on.’ So thank you for letting me take a second there and figure it out.
Just to summarize what we talked about today, there were three big mast cell diseases we talked about. We talked about mastocytosis, which we then learned has a lot of different things going on there. And there were seven different types that you discussed. We talked about mast cell activation syndrome, and we talked about hereditary alpha-tryptase. We discussed the causes for these different diseases.
That was a lot of science for you guys, again, it’s really important to know the science so that when we start talking a little bit more in-depth, you have a foundation. That was a lot for me. I’m going to say we should probably stop there. I don’t know how you feel, Dr. G, but we are definitely going to be covering symptoms, or you’re definitely going to be covering treatments, diagnosis, and what it’s like to live with mast cell disease.
Dr. Gupta: All of that is coming up in the next five episodes, so stay tuned.
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