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Mast Cell Activation Syndrome: Don’t Shoot the Messenger

Mast cells are frontline immune cells that are found in rich quantities in any of the body’s surfaces that are exposed to the environment, explaining why they can have such a key part in inflammatory processes of the airways, the intestinal wall and skin. Since being discovered by Paul Ehrlich in 1878, focus has largely been on their role in allergies and this mast cell-allergy fixation still clouds our thinking to this very day.

Research over the last few decades has allowed an overdue understanding of what mast cells actually do in health and disease, and paints a picture of the role of mast cells as the ‘first responders’ of the innate immune system, the cells that serve the team by releasing a range of chemical mediators that actually change the local conditions. It is this ‘effector’ role that identifies mast cells from other cell lines involved in the immune response; whereas other immune cells involved in this early response contribute primarily by ‘raising the alarm’ all secrete cytokines that recruit other cells into the fight, it is the mast cells that pump out chemicals like histamine, tryptase, serotonin, prostaglandins, heparin and many others. These chemicals can induce swelling, heat, pain and allow for resolution of injuries and infections (through increased influx of other immune cells and nutrients). Just for good measure, mast cells also produce more inflammatory cytokines (to recruit more immune cells) and repair factors like (like NGF and VEGF) to aid subsequent repair of damaged tissue.

What Activates Mast Cells

There are a wide variety of circumstances that can call for this ‘effector’ function performed by mast cells and, accordingly, mast cells have receptors for a myriad of compounds that are expressed in cases of tissue damage or infection. Examples of what activates mast cells:

  • TLRs (Toll Like Receptors) activated by bacteria, yeast, parasites and viruses. Because of the way TLRs work by recognizing molecular patterns, this means that they can also recognise fragments of dead bacteria that have made their way into the bloodstream (something I have written about here) and mould toxins.
  • Cytokines. These are immune system messenger chemicals that allow various parts of the immune system to coordinate a coherent response. Various sub-types of immune cells release cytokines that can activated mast cells, with macrophages playing a major role (an over-simplification of their close relationship is that macrophages act as a ‘lookout’ for problems and mast cells start the actual process of dealing with it). IL-1, IL-6 and IL-33 are known to be particularly important in activating mast cells.
  • Complement (C3a and C5a are the key chemicals here that activate mast cells). These complement proteins get their name from the fact that they mainly assist existing immune processes rather than acting in a stand-alone capacity. The proteins can be formed from three pathways: the classical pathway, triggered by immune complexes (which occur when a foreign protein enters the blood stream or in food intolerances); the alternative pathway, which normally relates to endotoxins; and the lectin pathway, which responds to endogenous or dietary lectins. Note: Dietary lectins can also bind with parts of the IgE receptor to go someway towards mimicking an allergic response.
  • Antibodies. Mast cells have receptors for activated (cross-linked) antibodies, such as IgE (which is the antibody that drives allergies and anaphylactic reactions) and IgG (the latter of which has a more complex relationship with mast cells, due to varying receptor affinity and nuanced responses).
  • CRH (Corticotropin Releasing Hormone, released by the hypothalamus in response to stress) can directly activate mast cells.

The above factors all activate mast cells in different ways, with different induces resulting in different outputs from the mast cells; depending on the type of stimulus (and therefore, the specific receptors that has been activated), the mast cell may alter the amount of each chemical mediator it releases. It’s also worth noting that, despite what was previously assumed as a result of allergy research, mast cells do not always degranulate; there are various circumstances where they secrete their chemicals without degranulation (for example, when exposed to when exposed to endotoxins). In short, mast cells are always tasked with modifying the environment to aid the immune response to a threat but do so in a number of ways and, in most cases, work as part of a team to do so.

 

Allergy Paradigms: Unhelpful in Non-Allergic Disease

When we examine the factors that activate mast cells and the wide variety of chemicals that they produce, it becomes clear that the paradigm of allergy à mast cell à histamine is woefully inadequate. Mast cells do most of their work as part of a network of immune cells, with their direct (‘independent’) activation something that occurs only in unusual circumstances (such as allergic responses). The fact that is was the most obvious mast cell pathology and the only one that is deemed life-threatening, we begin to see why mast cells were written off for decades as ‘just’ mediators of allergic response.

And, while knowledge in the sphere of mast cells has come on leaps and bounds in recent decades, this idea of mast cells acting independently appears to have left a problematic legacy when it comes to treatment provided in Mast Cell Activation Syndrome. It’s not that practitioners think that this is an allergy – far from it, as the absence of allergic reactions is recognized as one of the hallmarks of this issue – but that therapeutic strategies often start and end with the mast cell itself, rather than giving due consideration to the pathway that leads to their activation.

Consequently, treatment tends to revolve around stabilizing the mast cell (with medications like ketitofen or natural equivalents like quercetin or Vitamin C) or through mediating the activity of the chemicals released (either blocking them with anti-histamines, improving their clearance with methylation support or compensating with low-histamine diets). It’s important to say that these interventions can be highly effective for some individuals but remain hugely disappointing for many. After all, if the mast cell is already entirely ‘stable’ but is being pummelled by an enduring flood of pro-activation factors, then can we really expect the addition of a mast cell stabilizer to make a difference?

Mast Cell as Messenger

I have it easier to think of the mast cell as a representative of the innate response, and therefore a ‘messenger’ of what may be going on beneath the surface. Thinking of the mast cell in this way allow for more flexible thinking in tracking its supposed misbehaviour back to a source. In many cases, the mast call is not at all dysfunctional and simply acting on the information it receives; consequently, we may achieve much better outcomes by retrospectively considering what messages it is receiving and why.

Let’s take a second look at that diagram above, but now consider potential sources of dysregulation. It turns out that we have therapeutic options at almost every step of the way. Take these for starters:

  • Stress. A huge topic that we won’t attempt to unpack here, but options include lifestyle changes, blood sugar level regulation, sleep hygiene, neurotransmitter support (eg. theanine, serotonin, glycine, etc), HPA axis support (adaptogenic herbs, licorice) as well as steps to rewire the central nervous system (such as psychotherapy and neurofeedback).
  • Vagus nerve activity. Stress plays a huge role in the activation of the vagus nerve, but so too does choline status and inflammatory reactions in the intestines. Additional options are numerous and include cold water immersion, gargling techniques laughter yoga.
  • While vagus nerve activity stands out as the most powerful mediator of macrophage activity, there exists a bounty of nutrients that encourage anti-inflammatory activity in the macrophages. These include folate, vitamin A, vitamin D, butyrate and lactic acid.
  • There are many more potential inflammatory mediators in the diet but I have included oxalates as an example as they are so easily measured (for example, the Organic Acids test includes three oxalate markers) and so easily removed from the diet. A 2017 audit indicated that a whopping 96% of my chronic fatigue clientele have oxalate issues.
  • Chronic infections (bacteria, viruses, fungi and parasites). Another huge topic that we will only briefly skim here, but chronic infection can have a devastating impact across a wide range of body systems. Undertaking some basic preparation steps to support immune activity (think activation of the stress response, sufficient temperatures, good sleep and nutrient status) and then embarking upon an effective anti-microbial protocol (with appropriate anti-microbial foods and herbs, together with probiotics) is a reliable way to improve wellbeing in most people I work with.
  • Endotoxemia. I have previously explored (here) the connection between over-activation of the adrenal response and the increased amounts of endotoxins produced in chronic gut infections, so this represents yet another example of cross-over between multiple imbalances. However, steps to support gut lining (Vitamin A, glutamine, Aloe, Gamma-oryzanol, etc) and steps to bind endotoxins (charcoal, immunoglobulin formulas) are worthy of consideration; they miss the mark in some but work well in others.
  • Food intolerance and allergies. While most individuals I work with already know if they have a ‘type A’ allergic reaction (classical allergy), there are a number that will experience ‘type B’ responses (delayed hypersensitivity, often referred to as food intolerances). Despite the ongoing disagreement in the literature over the utility of IgG blood testing, I have found this helpful when used alongside dietary elimination/challenge.
  • Lectins. There are not yet any tests that can be done to indicate lectin issues and, given that they are found in so many foods, temporary elimination is a big challenge for many. However, this has proved important for around 30% of the chronic fatigue individuals I have worked with so should not be overlooked.
  • Mould exposure. If there is any hint of mould exposure, then this would always be my priority in mast cell disorders. I do not expect any progress until we have eliminated mould from the environment and then made use of binders to remove any residual mycotoxins.

 

Summary

Mast Cell Activation Syndrome is a complex disorder that has much more to it than the stability/activity of the mast cell itself. Working backwards to assess the inputs that the mast cell receives continues to pay off for many individuals I work with. This is not to say that therapies that focus on the mast cell itself do not work (indeed, I do record plenty of positive results from this, especially when it comes to porphyrin issues) and the same applies for downstream approaches (histamine control, impact on microglia in brain fog and anxiety). However, this stands out as the one area that is rarely discussed and yet so often proves vital to turning a corner in this most unpleasant and challenging condition.

 

Leave a comment

  1. Interesting, I like your take and your method of thinking of the immune system sort of like an orchestra, rather than just one player (referring to mast cells). I have multiple chronic autoimmune diseases, and obviously my immune system is dysregulated. Ive tried many therapies, but am mostly on my own as I cannot afford to pay for alternative docs. With regard to your suggestion about stress, this has had a huge impact on my life and I’ve tried many different things to try and deal with it….including L-Theanine….I had a paradoxical response to theanine and in fact became very anxious and was awake all night when I took it. What do paradoxical reactions suggest?

    1. Yes, humans can be complex and boiling it down to single components rarely works well… As for paradoxical reactions, this is a complex subject that ties together energy availability, inflammatory activity and the stress response, and its a subject that I won’t be able to do justice to here. However, from what you’ve said, it’s very likely that Theanine has a sufficient effect to move you from an ’emergency’ state to a ‘post-emergency’ state…. The issues here often relate to an increase in sensory signals (lower adrenaline = increase signalling). You can clarify this further by measuring your HRV values (using the Camera HRV app or the wearable devices), and seeing if Theanine takes your rMSSD values from below below 35ish to above this figure (this would be a classic pattern)… If this all ties in, then most people will find that they can undertake this transition into a more relaxed state through improved energy signalling (mitochondrial support, as indicated by an Organic Acids test, or improved oxygen delivery, which can relate to postural/chiropractic work with Ginkgo sometimes helping, or insulin sensitivity), inflammatory control (the most obvious first steps is to consider/trial removals of the triggers I discuss here) or help with sensory processing (TRE/Tension Release Exercises can be very helpful in many, while Somatic Experiencing (and similar approaches) can be the key in others). We should not forget adrenal activity (which can be measured on an Adrenal Stress Profile). Typically, it’s a combination of all of the above, with the contributions varying from one person to the next.

  2. I have chronic urticaria and tachycardia induced by stress, pressure, high histamine foods, exercise, temperature changes, and some unknown triggers. This happened a few months post- sepsis after a salmonella infection from goose feces.

    I am getting desperate to find relief. I have severe insomnia, getting maybe 4 hours of sleep.

    A low HI diet has helped somewhat. I struggle with Quercitin and vitamin c. I am struggling taking supplements and media actions.

    I think Zyrtec is causing more GI distress, and maybe even leaky gut and skin burning, but can help me get an extra hour or two of sleep.

    DAO may be causing issues. I am trying butyrate, but suspect it is also causing heat and redness in my legs and feet.

    I have MTHFR 667t++ and past SIBO.

    Can Low Dose Neldextrone help? Or vit c IV?

    1. Hi Jennifer. There is clearly a lot going on here and, in such situations, its unlikely that any of these questions have a ‘yes/no’ answer. This is because, if they are going to have an impact in the body, there is a number of systems that they will likely impact on (and thus, there may be aspects to this that are positive and aspects that are challenging). For this reason, when we see these type of scenarios – multiple factors playing a role, with unexplained patterns – the priority is always in identifying (and resolving) the ‘obvious’ obstacles. Especially those that tie in to the mast cell activation (as per this article). Not only does this help with a certain number of patterns, it also clears the noise so that you can see what patterns remain (and thus, what interventions are called for in YOUR case). An Organic Acids test is always a good start, although the supplement reactions you describe flag up a potential benefit of testing porphyrins and the reactions to stress speak to a role for the Adrenal Stress Profile and HRV tracking.

    2. Marek you missed the most important part.
      IG-E meditated or Non IG-E mediated
      MC activation.

      This is crucial.

      People with severe Mcas can be controlled very well these days with Omalizumab (Xolair)

      if you happen to know more about the real bad cases of MCAD patients, there seem to be mutations and epi genetics changes on a cellular level on the inappropriately active or over active mast cells.
      To reverse that… that’s a big one.
      Until we can’t fix this people will have to be on medication.

      1. There’s a number of statements here that will be difficult to address in a short comment as they are dogmatic and not borne out by the evidence. Also I’m not sure what you mean about missing IgE-mediated versus non-IgE-mediated activation (as, by definition, all reactions fall into one of these two categories, and I’ve outlined the role of IgE and antibodies in the second paragraph)…

  3. Do you have experience or opinions on The DNRS (Dynamic Neural Retraining System for limbic system) Program, The Gupta Program (amdygala training) or LENS neurofeedback for treating MCAS symptoms, including urticaria?

    What do you specifically recommend for limbic system and stress?

    1. These programs are well put together and I know of several individuals who have benefitted. However, I don’t expect high rates of success in these programs when individuals are also subject to mitochondrial/energy/fatigue issues (making self-regulation hard or impossible) or when there is a lack of sensory sensitivity (which has a strong relationship with physical tension, something that is hugely underdiscussed in this area). In such scenarios, I’d expect approaches like TRE (Tension Release Exercises) to be a good start. although I see the highest likelihood of improvements with one-to-one approaches like Somatic Experiencing, Reichian therapy or transformational breathwork. However, in all cases, results are heavily influenced by the physiological platforms (energy metabolism, neurotransmitter balance, adrenal/cortisol signalling) and no one size fits all.

  4. I’m suffering from aquagenic urticaria where some parts of my body is allergic to water. I develop hives after my body comes into contact with water. I believe this has something to deal with mast cells.What is ur view in this

    1. I myself have not worked with anyone with aquagenic urticaria but, based the mechanisms, I too would be looking to the mast cells (and therefore in any stabilizer factors are in short supply, or destabilizing factors in excess).

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