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.

Patient questions: Why isn’t tryptase used to track SM progression in patients with SM-AHNMD?

Tryptase can be a useful tool for measuring progression of systemic mastocytosis. However, it is not used in patients with systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD). Patients with SM-AHNMD have systemic mastocytosis and also have another blood disorder that causes excessive proliferation of cells that aren’t mast cells. It is essentially having individual diseases that affect the bone marrow.

The reason tryptase is not tracked in patients with SM-AHNMD is because other proliferative diseases of bone marrow can increase production of mast cells. (Actually, proliferative diseases in most organs can cause increased production of mast cells). This is called mast cell hyperplasia, overproduction of mast cells. It is NOT the same as SM. A patient with no mast cell disease of any kind who has a blood disorder like chronic myelogenous leukemia or essential thrombocythemia could experience an increase in mast cells. It is not uncommon for people with conditions like this to experience allergic symptoms due to mast cell activation.

This can occur for a few reasons. The blood disorder might increase the amount of cells that could become mast cells. The blood disorder could cause increased release and production of molecules that encourage mast cell development. Mast cells are also part of the immune response and heavily involved in tumor biology. Proliferation of another cell type can be interpreted by the body as tumor formation so more mast cells can be made to address the “tumor”, whether or not it actually is a tumor..

A patient with SM-AHNMD may have a baseline tryptase before developing the second blood disorder of 30 ng/mL. (Just making up a number here). After diagnosis with the second blood disorder, a tryptase test could reveal an increase to 35 ng/mL. However, if this were the case, we wouldn’t know if the additional tryptase is coming from mast cells made by SM ramping up or as a side effect of the other blood disorder. Because we can’t tell, it isn’t used as an indicator of increased mast cell production as a direct cause of SM.

For patients with SM-AHNMD, other markers are used to track disease progression of SM. That includes checking for things like inappropriate blood cell counts and organ swelling and dysfunction (B and C findings).

Patient questions: Everything you wanted to know about tryptase

I get a lot of questions about tryptase.

Tryptase is one of the most well characterized mast cell mediators and the first to be unique to mast cells. Serum tryptase is the most well known test for systemic mastocytosis and anaphylaxis. But mast cell patients sometimes test negative, complicating their lives and care.

There are a lot of reasons why mast cell patients test negative for tryptase. One reason is that a lot of the understanding of anaphylaxis hinged upon the ability of mediators to get quickly to the bloodstream to quickly spread to various organ systems. While this does happen, not all mediators move at the same speed. Tryptase is released from granules as large complexes with other mediators, like heparin. It takes time for it to dissociate enough to be active.

Tryptase also does a lot of things and breaks down lots of things. If there are things for it to break down in the immediate environment, it will still break them down whether or not you are having anaphylaxis. Eventually, the tryptase that wasn’t used up breaking things down gets to the bloodstream. This is why the ideal time to test for tryptase in blood is about 90-120 minutes after an allergic event/severe reaction/anaphylaxis. Following severe reaction/anaphylaxis, it can take about two weeks for tryptase to return to baseline.

The reason that most patients with systemic mastocytosis have high tryptase levels is because they have more mast cells and many mast cells secrete tryptase at rest. This means that even if they aren’t activated, they will still release tryptase regularly. The reason why baseline tryptase level is such an important marker for SM is because it distinguishes mastocytosis from anaphylaxis.

However, we have learned a lot about tryptase in the last several years, and it doesn’t seem like all mast cells secrete tryptase all the time. Mast cells are heavily influenced by their environment and the cells around them. Some mast cells make more tryptase than others and some release tryptase regularly and some don’t.

About 80-90% of SM patients have a baseline tryptase over 20 ng/ml. This means they tested over 20 ng/ml on two separate occasions when they had not recently had a severe event. But not all SM patients have elevated tryptase, but that doesn’t mean they don’t have more mast cells than usual. It is possible that their mast cells are concentrated in places in the body where tryptase will be used up before it gets to the bloodstream or that it will take too long to get there for the test to catch it. There is some evidence that tryptase testing is less reliable in overweight and obese women, and I’m sure that’s true. Some mast cells live in adipose tissue and that tissue is harder for large molecules to move through, like tryptase.

Our understanding of MCAS is that there is aberrant mast cell behavior without an abnormal number of mast cells. These patients generally have repeat negative biopsies and so the assumption is that they definitely don’t have SM. But tryptase is a crummy test and I think as a community we can’t really know if they have too many mast cells until we have more robust tests. I’m not saying MCAS patients have too many mast cells, but I’m saying I don’t really trust tryptase for detection of reaction/anaphylaxis in MCAS patients or, to be frank, in anyone.

So why do we still use tryptase if it’s a crummy test? It’s not a crummy test for everything. In particular, it is a very good indicator of disease progression (ISM to SSM to ASM) in patients who have a lot of mast cells. A steadily increasing tryptase level means that there is increased proliferation and can indicate moving to a state where organ damage is more likely. So it is helpful for those people. It’s not helpful for everyone else.

Tryptase testing is not affected in a meaningful way by any medications that I can think of. Mast cell stabilizers can decrease degranulation, but tryptase can also be released in other ways, and there has not been any demonstration that mast cell stabilizers are effective enough to affect this test. Antihistamines/other meds/steroids don’t affect tryptase level.

There was a consensus paper that came out several years ago in which it was posited that an increase in tryptase level of 2 ng/ml + 2% from baseline was indicative of mast cell activation and could be used in the diagnosis of MCAS. This is not widely agreed to in the US and the data supporting this has never been published so I personally understand the reluctance of providers to acknowledge this as a marker of mast cell activation.

The other big reason why mast cell patients may test normal for tryptase is that their reactions/anaphylaxis are not mediated by a pathway that triggers tryptase release like IgE does.  IgG activation and other pathways do not always demonstrate tryptase release.

I think I got everything. If you have more questions about tryptase, let me know.