The Disease Triad: POTS, Ehlers Danlos Syndrome, & MCAS

Updated: Sep 1, 2021

This is something quite difficult to understand, and so that's exactly what I've tried to do. For those of you who want to know precisely the physiology of these diseases, this article is definitely for you.

Let's talk about the disease triad:

POTS, Ehlers Danlos Syndrome, & Mast Cell Activation Disorder.

I have been so busy making up charts with the diseases and all possible interchangeable symptoms to try to narrow down the disease with the most shared symptoms in attempts to reach the one true disease origin. What I've discovered was something that everyone has been boasting for years; "The source of all disease is inflammation!" But what kind, and from where? Here are my postulations.

What is the source of dis-ease?

NFLAMMATION! But exactly what inflammatory cell? I asked myself this for years. Mine-and many others' CRP comes back at normal levels. The source of inflammation is likely TNF-a (tumor necrosis factor-an inflammatory cytokine cell) and IL-6. (Cytokines also play a role in autoimmune diseases, insulin resistance, psoriasis, rheumatoid arthritis ankylosing spondylitis, tuberculosis, autosomal dominant polycystic kidney disease, and cancer.) Some ppl are predisposed to making more because of a genetic mutation. It seems to be a common thread among these diseases and why many present with all 3. Both TNF and IL-6 are related to preload failure in POTS and CFS. TNF-a is also the only cytokine in a mast cell, which can be released (degranulated) to look like MCAS (but isn't always macs). POTS, when NOT caused by trauma, meds, viruses, etc, can simply be “Inflammatory POTS,” as inflammation is represented in the cardiopulmonary system as POTS. TNF also induces matrix metalloproteinases & pain. TNX is a glycoprotein that regulates collagen, and is a topic of interest in the connective tissue disorder of Ehlers danlos syndrome. TNX is found in our extracellular matrix (ECM-the non-cellular component of tissues and organs, examples being fibrous elements like collagen & adhesion cells). The ECM is responsible for things like cellular support and structure, as well as communication between cells. Since TNX is expressed widely in loose connective tissue, its deficiency contributes to ehlers danlos, creating weak connective tissue structures.

(For those interested, there are 4 types of tenascin: tenascin-X, C, R, & W).

So what's the connection between MCAS & POTS?

In a nutshell, TNX is found in many inflammatory conditions such as MCAS & POTS (not to mention in fibrosis, dercums disease, & cancer).

Mast cells regulate adhesion cells & TNX, which we now know are found in connective tissue. When adhesion cells are signaled to adhere more strongly to other cells in the extracellular matrix such as glycoproteins and several types of collagen, they allow for more aggressive communication.

Mast cells are particularly found near nerves in the periphery (arms & legs), which is problematic for EDS joints.

Adhesion cells do several things, one of which is develop and maintain tissues. Mast cells then break down (degranulate) to expel the inflammatory TNF-a cytokine within that region and

Mast cells also stick in lipedema fat and perpetuate inflammatory flares.

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Aoki H., Matsumoto K. (2020). The roles of tenascins in cardiovascular, inflammatory, and

heritable connective tissue diseases . Frontiers in Immunology, 11, 1-10. doi:


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