Sensitization in POTS, Long COVID, and ME/CFS: A Guide for Patients

Authors: Dr Graham Exelby, Ms Michelle Hille, certified Vodder Therapist.  September 2025

Executive Summary

Sensitization explains why patients with POTS, Long COVID, and ME/CFS experience overwhelming fatigue, pain, and sensory overload from minor triggers. It develops in three stages: acute immune activation, post-viral maladaptation, and chronic high-alert signalling. At its core, sensitization is driven by pericyte–astrocyte dysfunction, mast cell–glial cross-talk, and a set of molecular “switches” (TLR4, NF-κB, RAGE, CCL2, STAT3, NLRP3) that keep the nervous system inflamed and reactive. Genetics can add further vulnerability, especially in pathways handling oxidative stress and immune regulation. Understanding these mechanisms validates that symptoms are biological, not psychological, and helps explain why even small stresses can cause major relapses.

Introduction

Sensitization is a process where the nervous system becomes abnormally responsive to normal stimuli. It explains why people with conditions such as POTS (Postural Orthostatic Tachycardia Syndrome), Long COVID, and ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) often feel heightened pain, extreme fatigue, or overwhelming sensitivity to light, sound, and touch. What begins as an appropriate immune or nervous system response becomes a self-perpetuating cycle, even after the initial trigger has passed.

This concept helps explain why many patients feel that their symptoms are “out of proportion” to everyday activities. It is not a matter of imagination—the nervous and immune systems are genuinely behaving as if the body is under constant threat.

The Three-Phase Pathway of Long COVID and Sensitization

Research into Long COVID and the 3 phases described below opened the door to understanding what is happening in the sensitized patients with POTS, Fibromyalgia and ME/CFS.

Phase 1 – Acute Infection and Immune Activation

When the body first encounters SARS-CoV-2, the immune system activates powerfully. Signals from viral fragments stimulate immune receptors, causing inflammation, blood vessel stress, and small clots. Cells that normally regulate brain blood flow—pericytes and astrocytes—are placed under strain. This is the “priming stage,” where the body begins laying the groundwork for long-term sensitization.

Figure 1: The Neurovascular Unit showing the Pericytes lining blood vessels and the close relationship with the Astrocytes

Source: Sato, Y.; Falcone-Juengert, J.; Tominaga, T.; Su, H.; Liu, J. Remodeling of the Neurovascular Unit Following Cerebral Ischemia and Hemorrhage. Cells 2022, 11, 2823. https://doi.org/10.3390/cells11182823

Phase 2 – Post-Viral Maladaptation

In some individuals, after the acute infection passes, the body fails to fully reset. Viral remnants or reactivation of other viruses (like Epstein–Barr virus) continue to stimulate the immune system. Mitochondria, the cell’s energy factories, become less efficient. Pericytes and astrocytes lose coordination, the blood–brain barrier becomes leakier, and waste clearance from the brain slows. Clinically, this is when fatigue, head pressure, and sensitivity to noise and light begin to emerge.

Phase 3 – Chronic Sensitization

Over time, a “chronic high alert” state develops. Glial cells in the brain remain on high alert, releasing inflammatory molecules. Pericytes detach, astrocytes misfire, and brain blood flow becomes unstable. The brain becomes more sensitive to normal signals, amplifying pain, fatigue, and sensory overload. At this stage, the nervous system itself is driving symptoms, even without ongoing infection.

The Pericyte–Astrocyte Axis

Pericytes and astrocytes are two key cell types at the interface between blood vessels and the brain:

• Pericytes line capillaries and help regulate blood–brain barrier function and blood flow. When they are injured, blood vessels leak, and inflammatory cells can enter sensitive brain regions.

• Astrocytes support neurons, regulate water balance, and remove excess glutamate, a brain chemical involved in stimulation. When astrocytes malfunction, glutamate builds up, creating a state of over-excitation.

When pericytes and astrocytes stop working together, the brain’s environment shifts from stable to unstable. This contributes to head pressure, tinnitus, dizziness, and cognitive fog in patients with Long COVID, POTS, and ME/CFS.

Astrocyte–Microglia–Mast Cell Cross-Talk as the Sensitization Core

A crucial, often under-recognized driver of sensitization is the interaction between astrocytes, microglia, and mast cells. These three cell types form a tightly linked network that coordinates immune and nervous system responses within the brain.

Mast cells act as initiators, releasing histamine, tryptase, and cytokines that destabilize the blood–brain barrier and activate surrounding cells. Astrocytes, normally protective, become reactive when exposed to mast cell mediators. Instead of buffering glutamate and maintaining water balance, they release inflammatory molecules, lose their water-channel polarity (AQP4, orientation of water channels that regulate brain fluid clearance), and amplify excitatory signalling. Microglia, the brain’s innate immune cells, once 'primed' by mast cell and astrocytic input, remain hypersensitive, producing large inflammatory responses even to minor triggers. This primed state lowers the threshold for pain and sensory perception.

Together this creates a self-perpetuating cycle. Mast cells set off astrocytic reactivity, astrocytes fuel excitotoxicity, and microglia sustain a chronic inflammatory memory. This explains why patients experience disproportionate responses to light, sound, exertion, or stress, and why relapses occur so readily.In essence, this triad lies at the very centre of sensitization, linking vascular strain, metabolic dysfunction, and immune signalling into one entrenched process.

• Mast cells act as initiators and acute amplifiers (via histamine, tryptase, VEGF), releasing histamine, tryptase, and cytokines that destabilize the blood–brain barrier and activate surrounding cells. They respond rapidly to infection, trauma, allergens, and stress signals, but in sensitization their activity remains exaggerated.  They are often the first responders, releasing histamine, tryptase, and cytokines that destabilize pericytes and astrocytes.

• Astrocytes act as metabolic and excitatory amplifiers (via glutamate, IL-6, AQP4 polarity loss). Normally protective, become reactive when exposed to mast cell mediators. Instead of buffering glutamate and maintaining water balance, they release IL-6 and other inflammatory molecules, lose AQP4 polarity which affects functioning of the glymphatic system (brain’s sewer), and amplify excitatory signalling

• Microglia provide the chronic memory of insult (via priming and inflammatory signalling).  They represent the brain’s innate immune cells. Once “primed” by mast cell and astrocytic input, they remain hypersensitive, producing large inflammatory responses (IL-1β, IL-6, TNF) even to minor triggers. This primed state effectively lowers the threshold for sensory and pain perception.  They provide the chronic memory of insult (via priming, NF-κB/STAT3 activation, IL-1β release).

Instead of calming once the threat has passed, the network continues to amplify incoming signals, lowering the threshold for pain, sensory overload, and fatigue from a self-perpetuating feedforward loop. Mast cells set off astrocytic reactivity, astrocytes fuel excitotoxicity, and microglia sustain a chronic inflammatory memory. Together they explain why patients with POTS, Long COVID, and ME/CFS experience disproportionate responses to light, sound, exertion, or stress, and why relapses occur so readily. This triad sits at the very centre of sensitization, integrating vascular strain, metabolic dysfunction, and immune signalling into a single, entrenched process.

Figure 2: Cross Talk between Microglia, Astrocytes and Mast Cells.

Source: Carthy, Elliott & Ellender, Tommas. (2021). Histamine, Neuroinflammation and Neurodevelopment: A Review. Frontiers in Neuroscience. 15. 10.3389/fnins.2021.680214

Immunometabolic changes in Sensitization

Sensitization in POTS, Long COVID, and ME/CFS is driven by a set of intertwined immune and metabolic pathways. These pathways keep the nervous system in a “primed” state, making the body overreact to even minor stressors.    Behind the cellular changes in sensitization are a series of “molecular switches” that keep the system in an overactive state:

• TLR4 (Toll-like receptor 4) detects viral fragments and danger signals from stressed tissues. Once switched on, it alerts the immune system even when no infection remains. When activated, it triggers NF-κB, a key inflammatory program.

• NF-κB is a master control pathway turned on by TLR4. NF-κB then stimulates the release of cytokines and primes glial cells, ensuring that even small triggers set off a large inflammatory cascade. It acts as an amplifier, increasing the release of inflammatory signals that prime the brain’s support cells.   Dysregulation of NFkB  signalling has been implicated in various health conditions, including autoimmune disorders, inflammatory diseases, cancer, and neurodegenerative diseases.

Figure 3. Downstream Signalling Pathways of TLRs

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Source: Mantovani S, Oliviero B, Varchetta S, Renieri A, Mondelli MU. TLRs: Innate Immune Sentries against SARS-CoV-2 Infection. Int J Mol Sci. 2023

• RAGE (Receptor for Advanced Glycation Endproducts), a central amplifier, stays chronically active in response to viral proteins, oxidative stress, and tissue damage.

  • This worsens pericyte contraction, astrocyte dysfunction, altering neurotransmitter release, glymphatic dysfunction and waste build-up in the brain. These changes can significantly impact brain homeostasis and play a role in both physiological and pathological processes. 

  • Activated astrocytes show morphological changes and altered function.  Excessive or prolonged RAGE signalling of astrocytes can lead to apoptosis and cell death.   RAGE activation can modulate astrocyte-neuron communication and triggers the release of glutamate from astrocytes which can impact synaptic signalling and potentially contribute to excitotoxicity in sensitization.  It stimulates production of reactive oxygen species which can lead to cellular damage and dysfunction.

  • Excessive glutamate release driven by RAGE signalling in astrocytes can over-activate NMDA receptors in neurons, leading to excitotoxic damage and contributing to chronic pain sensitization and neurodegenerative processes. 

• CCL2 (monocyte chemoattractant protein-1),  is a signalling molecule that draws immune cells across the blood–brain barrier, keeping inflammation active inside the brain. Once NF-κB and RAGE are activated, they increase the production of CCL2, a signalling molecule that pulls inflammatory cells across the blood–brain barrier. 

  • CCL2 plays a central role in the development and persistence of central sensitization by mediating neuroinflammation, glial cell activation, and neurotransmitter dysregulation.  Persistent activation of the TLR4/NF-κB/CCL2 signalling axis underpins chronic neuroinflammation, glial activation, and sensory neuron sensitization. 

  • CCL2 has been identified as a mediator that can be released by activated mast cells, and elevated levels of CCL2 have been found in the serum of patients with MCAS and POTS.  Mast cell degranulation releases histamine and other mediators, exacerbating vasodilation and vascular permeability, tachycardia and orthostatic symptoms.

  • Elevated levels of CCL2 have been implicated in various inflammatory conditions, including those affecting the nervous system with greater deficits in cognitive function, aberrant behaviour and Impaired development.  Dysregulation of CCL2 expression has been implicated in the pathogenesis of various health conditions, including rheumatoid arthritis, IBS, fibromyalgia, chronic fatigue, chronic pain syndromes, POTS, connective tissue disease, ADHD, autism.   Its dysregulation in various autoimmune and chronic conditions suggest that it may play a role in MCAS, breast cancer, POTS and  pelvic congestion.

  • By binding to CCR2 receptors on sensory neurons in the dorsal root ganglia (DRG), CCL2 amplifies nociceptive signalling and autonomic dysfunction, underpinning symptoms like tachycardia, fatigue, and widespread pain in POTS and Long COVID.

  • CCL2–NF-κB synergy ensures continuous recruitment of monocytes and sustained cytokine release across the blood–brain barrier.

• STAT3 locks glial and immune cells into a persistent inflammatory state, preventing recovery. At the same time, STAT3 reinforces the inflammatory state inside astrocytes and microglia, preventing them from returning to a resting, protective role. This creates a self-perpetuating cycle of immune activation.  This has broad consequences:

  • Fibrosis: STAT3 drives fibroblast proliferation and collagen deposition. Combined with mast cell–VEGF signalling, this promotes tissue scarring in vascular, cardiac, and connective tissues.

  • Autoimmunity: Persistent STAT3 signalling alters T-cell differentiation, favouring Th17 responses and suppressing regulatory T-cell activity. This lowers tolerance and raises autoimmune risk.

  • Cancer: STAT3 is a well-recognized oncogenic driver; chronic activation through NF-κB/CCL2 loops creates an environment of unchecked growth signals, impaired apoptosis, and angiogenesis.

  • Metabolic disease: Mitochondrial stress and STAT3 dysregulation impair insulin sensitivity and lipid handling, linking sensitization biology to diabetes-like metabolic phenotypes.

  • Vascular and autonomic dysfunction: Endothelial inflammation plus pericyte dropout destabilize vascular tone, while astrocyte–microglia signalling in the brainstem disrupts autonomic nuclei. Clinically, this underlies POTS, orthostatic intolerance, and dysautonomia.

• NLRP3 inflammasome is an “alarm complex” that, once triggered by oxidative stress and low energy states, can further amplify pain and fatigue, and plays a pivotal role in development of sensitization.  

  • When mitochondrial stress and oxidative damage persist, they activate the NLRP3 inflammasome inside glial and immune cells. This leads to bursts of cytokines IL-1β and IL-18, two powerful inflammatory molecules that further destabilize blood vessels, amplify pain signalling, and cement chronic sensitization.

  • Upon activation, microglia release IL-1β, a cytokine known to increase neuronal excitability by potentiating NMDA receptor function and suppressing GABAergic inhibitory pathways. This creates a hyperexcitable neuronal state, which underpins central sensitization observed in chronic pain syndromes, including fibromyalgia, long COVID, and other neuroinflammatory conditions.

  • The persistent release of IL-1β and IL-18 exacerbates neuroinflammation, disrupting pain regulation mechanisms in the CNS and lowering pain thresholds. 

Together, these pathways act as the engine room of sensitization. They explain why the brain and body fail to reset after infection or stress, why symptoms persist, and why even small triggers can cause severe relapses.   The net result is:

• Excitatory–Inhibitory Imbalance- As mitochondria fail, the balance between calming (GABA/aspartate) and excitatory (glutamate) neurotransmitters is lost. Low GABA and aspartate, combined with high glutamate, overwhelm astrocytes and fuel excitotoxicity. This explains why patients are so vulnerable to sensory overload and post-exertional crashes.

• Mast Cell–Glial Crosstalk- Mast cells release histamine, tryptase, and VEGF, which destabilize pericytes and astrocytes. This cross-talk amplifies neuroinflammation and can also promote fibrosis in surrounding tissues.

• Hypoxia–Metabolic Link- Orthostatic stress and reduced blood flow to the brain stabilize HIF-1α, a hypoxia sensor. This inhibits PDH (pyruvate dehydrogenase), forcing cells into inefficient energy use and locking in a cycle of fatigue, brain fog, and metabolic collapse.

Additional Modifiers of Sensitisation

While the central pathways of mast cell–glial cross-talk and immunometabolic signalling form the core of sensitisation, several other factors can further amplify symptoms and explain why different patients experience such wide variation.

1.     Peripheral Nerve InvolvementBeyond central mechanisms, peripheral nerves play a big role. Small fibre neuropathy, affecting both autonomic and sensory fibres, can amplify pain and dysautonomia. In people with hypermobility, joint instability and abnormal proprioceptive input further feed exaggerated CNS responses.

2.     Lymphatic and Glymphatic Dysfunction with Mechanical StrainSensitisation is worsened when the body cannot clear waste effectively. Lymphatic congestion in the chest, abdomen, or neck — sometimes linked to connective tissue strain or vertebral rotation in particular at T8 level — can add mechanical stress that reinforces sensitisation loops.

3.     Brainstem Nuclei VulnerabilitySpecific brainstem regions that regulate heart rate, blood pressure, and arousal — such as the nucleus tractus solitarius (NTS), vagal nuclei, and locus coeruleus — are especially vulnerable to hypoxia and inflammatory signalling. Dysfunction here explains why patients develop tachycardia, exaggerated startle responses, or overwhelming sensory input.

4.     Extracellular Matrix (ECM) and Connective TissueThe ECM does more than provide structure; it stores cytokines, growth factors, and DAMPs. In hypermobility or connective tissue disorders, disorganised ECM seems to amplify mast cell activation and sustain NF-κB/STAT3 signalling.

5.     Oxidative Stress and Redox Signalling

Persistent ROS and redox imbalance feed RAGE, NF-κB, and NLRP3 pathways, keeping both central and peripheral sensitisation active. Environmental and dietary oxidative stressors likely make this worse.

6.     Hormonal and Metabolic Modulators 

Hormonal shifts — menopause, postpartum, puberty, and andropause — change vascular tone, pericyte function, and mitochondrial efficiency. Metabolic challenges, like insulin resistance, also seem to feed these sensitisation pathways.

7.     Latent Viral Reactivation

Viruses such as HSV, EBV, VZV, and HHV-6/7 can reactivate intermittently, stimulating TLR4, RAGE, and NF-κB signalling. This keeps mast cells and glia primed, sustains excitotoxicity, and contributes to relapses of fatigue, pain, and dysautonomia.

8.     ATP / Energy Metabolism 

Mitochondrial dysfunction reduces ATP production, creating a low-energy state in neurons, glia, and peripheral nerves. Low ATP impairs ion channel function and glutamate clearance by astrocytes, fuelling excitotoxicity and hyperexcitability. Energy deficits also amplify TLR4/NF-κB and NLRP3 signalling via DAMP release. Peripheral tissues experience ATP shortfalls, which contributes to post-exertional malaise, fatigue, and poor recovery. Low ATP further interacts with hypoxia and HIF-1α pathways, reinforcing vascular dysregulation and CNS hypoperfusion.

9.     Trigger Diversity

Beyond infection, trauma, mould, and stress, other exposures such as environmental toxins, chemical or mycotoxin exposure, surgery, mechanical strain, and even chronic dehydration appear to contribute.

10.  Symptom Fluctuation 

These mechanisms help explain why symptoms can fluctuate dramatically — small changes in posture, minor infections, metabolic shifts, or sensory input can trigger severe relapses, including post-exertional malaise.

Taken together, these factors reinforce that sensitisation is a multi-system process: central glia, peripheral nerves, vascular tone, lymphatic flow, ECM structure, oxidative stress, hormonal/metabolic status, latent viruses, and ATP/energy deficits all intersect to create a nervous system locked into chronic over-reactivity.

Five Interconnected Domains

1. Immune–Glial Priming- Glial cells remain “primed,” responding excessively to even minor triggers, which explains why small stresses cause major symptom flares.

2. Mitochondrial and Redox Dysfunction- Energy metabolism is impaired, creating a low-energy, high-oxidative stress state. Clinically: fatigue, brain fog, and post-exertional malaise.

3. Vascular–Glymphatic Dysfunction- Poor blood flow and blocked waste clearance lead to accumulation of inflammatory byproducts. Clinically: upright head pressure, pulsatile tinnitus, sensory overload.

4. Autonomic–Limbic Amplification- The “fight-or-flight” system remains overactive while calming vagal signals are suppressed. Clinically: anxiety, poor sleep, and exaggerated startle responses.

5. Chronic Sensitization-These loops reinforce each other, embedding the nervous system in a long-term sensitized state. The result is ongoing pain, fatigue, and hypersensitivity.

DNA Mutations and Phenotypic Risk in Sensitization (for those interested in genetics)

Our recent analyses of patient DNA show that certain mutations increase the risk of dysfunctional immune–metabolic signalling. These do not act alone but add vulnerability, especially when combined with infections, trauma, or other stressors.  Common ones we have found include:

1. TLR4 mutations – exaggerated danger signallingVariants in TLR4 can heighten responses to viral fragments or stress signals -Damaged Associated Molecular Patterns (DAMPs). Patients with these mutations may experience stronger activation of NF-κB and cytokine release, leaving the nervous system in a “primed” state for longer.

2. Oxidative stress mutations – redox imbalanceMutations in genes controlling antioxidant defences (e.g., MnSOD, GST, NADPH oxidase regulation) reduce the body’s ability to neutralize reactive oxygen species (ROS). Excess ROS drives mitochondrial dysfunction and feeds into NLRP3 inflammasome activation, amplifying fatigue, brain fog, and PEM.

3. NLRP3 mutations – heightened inflammasome reactivityVariants in the NLRP3 pathway make the “alarm complex” more easily triggered. Once activated, it produces IL-1β and IL-18, powerful inflammatory cytokines that destabilize vascular and glial function. Clinically, this links to pain sensitivity, neuroinflammation, and relapse after exertion.

4. CCL2 mutations – persistent immune recruitmentCCL2 variants increase the signalling that draws inflammatory cells across the blood–brain barrier. This sustains microglial and astrocytic activation and prevents recovery. Patients often show phenotypes of prolonged fatigue, dysautonomia, and higher risk of chronic sensitization after infection.

Phenotypic IntegrationPatients carrying combinations of these mutations may present with overlapping but distinct phenotypes:

• TLR4/CCL2 dominant – stronger immune–glial priming, more autonomic instability, higher relapse risk.

• NLRP3/oxidative stress dominant – greater PEM, pain amplification, and fibromyalgia-like presentations.

• Mixed clusters – broader multisystem involvement, often with head pressure, cognitive fog, and vascular features.

This ties the genetic risk back to why some patients fail to “reset” after COVID or other activators, and why sensitization becomes chronic.   When mutations in TLR4, oxidative stress pathways, NLRP3, and CCL2 coexist, they converge on a common signalling hub: persistent NF-κB and STAT3 activation.

In summary: DNA mutations in these pathways do not just predispose to sensitization—they amplify a STAT3-centred feedforward loop. The result is a shared vulnerability to fibrosis, autoimmunity, malignancy, metabolic collapse, and vascular–autonomic instability, depending on which clusters of mutations and environmental triggers are present.

Activators of Central Sensitization

Table 1. Common Triggers that may Activate Sensitization 

• Viral infections (e.g., COVID-19)

• Trauma (upper cervical spine, coccyx, thoracic outlet injury)

• Mould

• Parasitic infections (e.g., Blastocystis hominis, H. pylori)

• Sustained stress and PTSD

• Pregnancy

• Surgical procedures

• Prolonged mechanical strain (e.g., backpack/camera use)

• Environmental exposures (mould, chemicals)

1.     Long COVID

COVID-19 has emerged as the primary modern activator of POTS. SARS-CoV-2 initiates a potent TLR4/RAGE-driven cascade, sustaining NF-κB and IL-6/STAT3 signalling. This cascade impairs pericyte integrity by promoting endothelial leak, microvascular clot persistence, and loss of blood–brain barrier stability. Simultaneously, astrocytes exposed to cytokine excess and excitatory amino acid imbalance (low GABA/aspartate, elevated glutamate) undergo impaired AQP4 polarization and disrupted glymphatic clearance.

Together, these changes drive brainstem hypoxia, neuroimmune sensitization, and the clinical hallmarks of post-COVID dysautonomia. The centrality of pericyte–astrocyte dysfunction in COVID-associated POTS underscores its role as both a primary driver of pathology and a template for understanding other activators.

2.     Post-viral (non-COVID) / Post-vaccination

Viral RNA and vaccine adjuvants trigger TLR4 and RAGE signalling, amplifying IL-6, TNF, and CCL2 pathways. Pericytes lose their protective coverage of endothelial cells, destabilizing the BBB and allowing immune cell infiltration. Astrocytes, overwhelmed by cytokines and excess glutamate, lose AQP4 polarity, impairing glymphatic clearance. This culminates in excitotoxicity, neuroimmune sensitization, and the classic POTS triad of fatigue, orthostatic intolerance, and cognitive dysfunction.

3.     Physical trauma / orthopaedic strain

Trauma (including concussion, cervical/orthopaedic strain, and thoracic outlet–type venous obstruction) can activate a cascade that converges on pericyte–astrocyte dysfunction. Mechanical venous congestion and microvascular shear release damage-associated molecular patterns (DAMPs) such as HMGB1, priming mast cells and microglia, amplifying TLR/RAGE–NF-κB–IL-6/STAT3 signalling, and impairing glymphatic flow. The result is a feed-forward loop of BBB instability, excitotoxicity, and brainstem hypoxia that phenocopies other POTS activators.

Trauma-induced venous outflow obstruction releases DAMPs and stabilizes HIF-1α. Pericytes contract in response to hypoxia, leading to impaired capillary regulation and BBB instability. Astrocytic clearance of metabolic waste fails as venous congestion blocks glymphatic flow, resulting in toxin accumulation. Patients present with upright head pressure, fascial stiffness, and amplified sensitization patterns.  

4.     Pregnancy / postpartum

Hormonal fluctuations, especially estrogen withdrawal, reduce pericyte survival and weaken vascular tone. IVC compression increases venous pressure, and postpartum immune rebound activates NF-κB/STAT3 signalling in astrocytes. These changes impair glutamate buffering and increase neuroinflammation, manifesting clinically as postpartum dysautonomia, fatigue, and orthostatic intolerance.

5.     Severe stress / PTSD

Chronic HPA axis activation and excess cortisol prime TLR4 responsiveness, while noradrenaline overload disrupts pericyte calcium homeostasis, causing BBB leak. Astrocytes, deprived of GABA and ethanolamine, lose the ability to buffer glutamate effectively, leading to excitotoxicity. Clinically, this manifests as central sensitization, heightened anxiety, and worsened orthostatic tolerance.

6.     Mould / chemical exposure

Mycotoxins and aldehydes activate TLR4/RAGE and inhibit mitochondrial enzymes in pericytes, destabilizing vascular integrity. Astrocytic glutamate transporters and AQP4 polarity are impaired, blocking glymphatic clearance. This leads to glymphatic stagnation, cognitive dysfunction, and hypersensitivity to chemical triggers.

7.     Chronic gut infections (Blastocystis, H. pylori)

Persistent antigen exposure induces IL-6 and CCL2 signalling, disrupting pericyte–endothelial tight junctions. Astrocytes, facing chronic ROS and glutamate exposure, become metabolically exhausted, losing protective capacity. This results in systemic fatigue, immune priming, and chronic dysautonomia.

8.     Lyme and post-infectious syndromes

Borrelia and other pathogens strongly activate TLR2/4 pathways, sustaining IL-6 elevation and autoimmunity. Pericytes become dysfunctional under constant inflammatory stress, while astrocytes accumulate extracellular glutamate, leading to excitotoxicity. This underpins chronic neuroinflammation, post-exertional malaise, and long-term autonomic instability.

Clinical Manifestations

Sensitization explains many of the hallmark symptoms across POTS, Long COVID, and ME/CFS:

• Heightened sensitivity to light, sound, and touch

• Head pressure and pulsatile tinnitus

• Fatigue and post-exertional malaise (PEM)

• Cognitive dysfunction (“brain fog”)

• Pain amplification and fibromyalgia-like symptoms

• Emotional lability, poor sleep, and anxiety

• Worsening of symptoms with posture change or exertion

Conclusion

Sensitization is a state where the nervous, immune, and vascular systems become locked into chronic over-reactivity. Mast cells, astrocytes, and microglia form the central amplifier, reinforced by pericyte dysfunction, mitochondrial stress, and persistent molecular signalling through TLR4, NF-κB, RAGE, CCL2, STAT3, and NLRP3. These changes explain why fatigue, pain, and hypersensitivity persist long after the original trigger. Genetic variants in these pathways increase vulnerability and shape individual patient phenotypes. Recognising sensitization as a biological mechanism validates patient experiences, reframes these conditions beyond psychology, and provides a framework for research and future therapies.