How mast cells learn

Many people with hereditary connective tissue disorders like Ehlers-Danlos syndromes (EDS)/hypermobility spectrum disorders (HSD) have immune problems. These immune problems often come in the guise of “mast cell activation syndrome” or “MCAS,” so named because a type of immune cell known as the mast cell isn’t functioning properly in these conditions. Instead, mast cells in MCAS are overly aggressive and react to what are normally relatively benign environmental or bodily stimuli.

People with MCAS can be triggered by things like environmental allergens, food, perfumes, cleaning agents, UV light, physical pressure on the skin (e.g., dermatographism), alcohol, antibiotics, and even general anesthesia. Most often, when tested via the blood, doctors will find these reactions are not true allergies even though they can be triggered by allergens, can lead to mast cell degranulation, and are often alleviated by antihistamines. But because they are not typically mediated by an IgE antibody, they are not considered a “true allergy” even though all the symptoms may be the same or similar.

Mast cells are vital first responders of the most ancient branch of the immune system known as the “innate immune system.” While its younger counterpart, the adaptive immune system, is capable of producing antibodies that help recognize and fend off the recurrence of past infections, it was once believed that the innate immune system was incapable of learning from pathogens in a similar manner.

The immune system identifying a familiar pathogen. Image borrowed from https://www.thepartnershipineducation.com/resources/immune-system

While mast cells, for instance, don’t produce antibodies by which to achieve immune memory, recent research has shown that run-ins with infectious agents or even non-infectious stimuli (e.g., physical trauma) can prime mast cells for further exposures, at least for a little while. This is is known as “trained innate immunity” and is mostly achieved by epigenetic changes governing DNA expression, which can alter how a mast cell behaves and can be passed on to future generations of cells [1]. Therefore, these kinds of exposures can potentially alter the aggressiveness of mast cells over many generations, particularly if they continue to be primed.

What does trained immunity have to do with MCAS? Well, understanding whether MCAS is an exaggerated form of trained innate immunity may help us better design targeted treatments in future. For now, MCAS sufferers are typically stuck with the usual slew of bandaid approaches that try to keep mast cells from stimulating themselves more and creating a snowball effect (typical drugs include antihistamines, mast cell stabilizers, leukotriene antagonists, etc.). But if we can better target the roots of this trained immunity, we may have a better chance at returning these aggressive little mast cells back to a more tolerant state. For instance, scientists have previously found that inhibiting cyclic adenosine monophosphate (cAMP) helps build innate tolerance in cells of the innate immune system (i.e., suppresses trained immunity), suggesting such drugs could be useful for at least short term therapy [2].

The cyclic AMP cycle.

Another important question is why are people– especially women– with EDS/HSD so prone to MCAS? Truthfully, I don’t know. But given the important roles that connective tissue plays in regulating the immune system, I suspect that impairments in connective tissue are directly influencing how the immune system functions. Connective tissue, for instance, is an important storehouse for many immune-related molecules and if it’s not functioning properly, it’s possible that storage of these molecules is affected somehow [3]. Another possibility is that the rapid degradation of collagen in these conditions may also send out constant tissue damage signals to immune cells, placing them on perpetually higher and higher alert [4].

Another possibility is that the immune system plays a causal role in the development of conditions like hEDS/HSD in the first place, particularly involving features like pain and physical disability. Our own previous work suggests that the maternal immune system is an important determinant in whether the child will ultimately develop EDS/HSD. What’s more, other research indicates that there may be an excessive pathological turnover of fibroblasts (cells that produce connective tissue) in hEDS. This is something quite different from the behavior of fibroblasts seen in cEDS and vEDS in which collagen is not made properly in the first place. This suggests the immune system could be playing a driving role in hEDS/HSD.

Fibroblasts stained with immunofluorescence. Image borrowed from https://www.creative-bioarray.com/filter/fibroblast-cell-and-media-12.html

Regardless of what causes MCAS in EDS/HSD, it seems to be a progressive condition that many times doesn’t get truly severe until adulthood or following some major trigger (e.g., illness, physical injury, even pregnancy), which suggests it’s a learned process. Trained immunity involving mast cells could be a key factor in that progressively worsening process. But hopefully the more we come to understand the biology underlying these conditions, the sooner we can offer better treatments that can stave off disease progression or even stop it altogether. As both a patient and a scientist, I know that’s what I’m hoping.

2 responses to “How mast cells learn

  1. Because mercury toxicity (along with genetic susceptibility to such) is the root cause of both?  Mercury binds sulfhydryl, which is the most important and ubiquitous functional group in the body; and mercury exposure at toxic levels is incurred routinely through dietary fish, dental amalgams, and certain vaccines.

    • As with most complex conditions, I don’t imagine there is a single cause but probably many and is a complex interplay of heredity and environment. General rule of thumb: the more common a condition, the more complex its roots.

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