A small thread about mast cells and autonomic nerves ⬇️

1. Anatomical Link
2. Functional interaction
3. Link to Small Fiber Neuropathy
4. Link to Dysautonomia

1. The Anatomical Link (Proximity)

Mast cells are strategically located at the interfaces between the body and the environment (skin, gut, lungs) and are almost always found in close physical proximity to autonomic and sensory nerve fibers. 

1.1 Synapse-like structures: In some tissues, mast cells and nerve endings are only 20 nanometers apart (allowing for extremely fast and localized signaling)

1.2 Widespread presence: This association has been confirmed in the gastrointestinal tract, the bladder, the heart and the dura mater (the lining of the brain). 2. The Functional Link (Communication)

The interaction works like a feedback loop where the nervous system "talks" to the immune system and vice versa

From Nerve to Mast Cell
Autonomic nerves can directly trigger mast cells through the release of neurotransmitters and neuropeptides, such as Substance P, Acetylcholine, or Norepinephrine.
When these nerves fire, the chemicals they release bind to receptors on the surface of nearby mast cells. This can cause the mast cell to "degranulate" (burst open), releasing its inflammatory contents even if no traditional allergen is present.

From Mast Cell to Nerve
Conversely, when a mast cell is activated, it releases a potent cocktail of mediators like histamine, tryptase and prostaglandins. These substances act directly on autonomic nerve endings. They can sensitize the nerves, making them hyper-reactive to stimuli, or they can physically alter the way the nerve sends signals. For example, histamine can cause nerves to send "pain" or "itch" signals to the brain more frequently, or it can interfere with the autonomic signals that tell blood vessels to constrict.

BH2, BH4 and ACE2 levels have been found in people with ME during PEM ! Discovered by (@JackHadfield14 | @NBoydGibbins )

I have asked ChatGPT 5 Pro, Gemini 2.5 Pro, Perplexity Pro and Claude Sonnet 4,5

See below ⬇️ ChatGPT 5 Pro

Short answer: post-exertional malaise looks like a perfect storm of oxidative/inflammatory stress plus autonomic/vascular dysregulation. That combination can deplete biopterins (BH4 and BH2) and downshift ACE2, creating a feed-forward loop that worsens perfusion and symptoms.

Here are the most likely, mutually reinforcing mechanisms:

1) Oxidative/nitrosative stress oxidizes BH4 and collapses the total biopterin pool
- During PEM, reactive oxygen/nitrogen species (ROS/RNS) rise. Peroxynitrite very rapidly oxidizes BH4, driving “NOS uncoupling” so nitric oxide synthase makes superoxide instead of NO. This further amplifies oxidative stress. Ascorbate can partially recycle a BH3• radical back to BH4 but doesn’t fully protect against loss.
- Evidence: peroxynitrite oxidizes BH4 and uncouples eNOS; BH4 supplementation re‑couples eNOS in cells [PubMed](pubmed.ncbi.nlm.nih.gov/12692136/).
- Net effect: BH4 falls; if oxidation proceeds and recycling is limited, BH2 and even fully oxidized biopterin can be cleared, so both BH4 and BH2 measured in plasma can drop (a shrinkage of the total pterin pool rather than a simple BH4→BH2 shift).

2) Redox/energy constraints limit BH4 recycling
- Recycling BH2 back to BH4 requires dihydrofolate reductase (DHFR) and NADPH; quinonoid BH2 is recycled via QDPR (NADH). If NADPH availability is constrained (e.g., impaired pentose phosphate pathway flux during/after exertion), recycling stalls, so BH4 stays low and total pterins can decline.
- PPP is the primary cellular source of NADPH needed for antioxidant systems and redox repair [Journal of Biology](jbiol.biomedcentral.com/articles/10.11…).

3) High iNOS demand during innate immune activation
- Exercise-like triggers can transiently upregulate iNOS in immune/endothelial cells. NOS enzymes require BH4; high demand in a low‑BH4/redox‑stressed environment promotes uncoupling and further BH4 loss (with less NO and more superoxide) [BH4–NOS review](pmc.ncbi.nlm.nih.gov/articles/PMC84…).

4) Endothelial dysfunction links BH4 depletion to ACE2/RAAS
- Low BH4 uncouples eNOS, reducing NO bioavailability and worsening microvascular control. Reduced NO favors angiotensin II signaling and NADPH oxidase activity, which increase ROS—further stressing BH4.
- ACE2 converts Ang II to Ang-(1–7), which counters vasoconstriction, oxidative stress and inflammation. When ACE2 is reduced, the protective Ang-(1–7)/Mas axis wanes and Ang II effects dominate, increasing oxidative stress and inflammation [Clinical Science](portlandpress.com/clinsci/articl…).

5) How ACE2 itself can fall during PEM-like stress
- Inflammatory and Ang II–AT1R signaling activate ADAM17, the sheddase that cleaves membrane ACE2, lowering its cell-surface levels and often shifting it into a soluble form; oxidative stress can also promote this process [Frontiers review](frontiersin.org/articles/10.33…), [PMC](pmc.ncbi.nlm.nih.gov/articles/PMC74…).
- Experimental systems show ADAM17-mediated ACE2 shedding in kidney and other epithelia, increased by stressors (e.g., high glucose, Ang II) and blocked by ADAM17 inhibitors [PLOS One](journals.plos.org/plosone/articl…).
- AT1R signaling can also drive ACE2 internalization; both shedding and internalization reduce functional membrane ACE2 [Nature Communications review](digitalscholar.lsuhsc.edu/cgi/viewconten…).

6) Vicious cycle that ties it together
- Exertion → innate immune surge and ROS/RNS → BH4 oxidation and NOS uncoupling → less NO, more superoxide → RAAS tilt toward Ang II → ADAM17 activation and ACE2 loss → even less Ang-(1–7) protection, more oxidative stress/inflammation → deeper BH4 depletion and microvascular dysregulation.