SMPDL3B-Shedding Mechanistic Chain
Michael Daniels · GLA Framework · Version 2.3 · December 2025
A bounded, evidence-anchored sequence linking post-viral context to membrane-level SMPDL3B loss (shedding), endothelial instability, perfusion-driven metabolic strain, and PEM chronicity.
Research-facing • v2.3
(Post-viral innate priming → EV-glycome shift → ER–Golgi strain → stress-sensitized PI-PLC →
SMPDL3B shedding → membrane fragility → endothelial instability → perfusion failure → intermittent ischemia →
ATP/Ca²⁺ strain → delayed ROS → flare amplifiers → renal/volume feedback → hepatic load → autonomic lock-in →
PEM chronicity)
i How to read this page
Each step includes a Type label and a Boundary statement to prevent over-claiming.
This document does not assert universal causality across all ME/CFS phenotypes; it describes a
mechanistically plausible and testable chain for an SMPDL3B shedding pattern.
Direct evidence
Mechanistic inference
Systems synthesis
Diagram 1 – Layered Architecture (Shedding-focused: Initiation → Maintenance → Effector)
Top-level overview of the SMPDL3B shedding phenotype, showing how post-viral ER/Golgi stress and EV-glycome shifts (Initiation Layer) lower membrane cleavage thresholds, drive membrane fragility and organ-axis dysregulation (Maintenance Layer), and culminate in perfusion-driven PEM and Na⁺/K⁺-ATPase failure (Effector Layer).
This diagram provides a structural overview of the mechanistic chain below. The Initiation, Maintenance, and Effector layers correspond to the progression of steps that follow, helping orient where each mechanism sits in the overall system without duplicating step-level detail.
1 Post-viral innate priming with EV-glycome context shift
Following viral infection or other immune stressors, a subset of individuals develop a persistent alteration in innate immune tone characterized by sensitized pattern-recognition and stress-response pathways rather than complete immunologic resolution. Multiple ME/CFS and post-viral cohorts demonstrate immune abnormalities consistent with chronic innate priming, even in the absence of sustained high cytokine levels or active infection (Che et al., 2025; Blundell et al., 2015; Hardcastle et al., 2015; Roerink et al., 2017; VanElzakker et al., 2019).
Concurrently, extracellular vesicle (EV) biology shows durable alterations in post-viral conditions, including changes in EV abundance, cargo, and surface glycosylation that reflect cellular stress state rather than acute immune activation alone (Williams et al., 2018; Giloteaux et al., 2024; Glass et al., 2025).
Within this framework, post-viral illness establishes a contextual immune and cellular stress background that lowers tolerance to subsequent physiological load. This step does not posit ongoing infection or continuous inflammatory signaling; rather, it defines a primed state in which downstream stress-response pathways are more easily engaged.
Concurrently, extracellular vesicle (EV) biology shows durable alterations in post-viral conditions, including changes in EV abundance, cargo, and surface glycosylation that reflect cellular stress state rather than acute immune activation alone (Williams et al., 2018; Giloteaux et al., 2024; Glass et al., 2025).
Within this framework, post-viral illness establishes a contextual immune and cellular stress background that lowers tolerance to subsequent physiological load. This step does not posit ongoing infection or continuous inflammatory signaling; rather, it defines a primed state in which downstream stress-response pathways are more easily engaged.
Boundary: This step describes persistent innate sensitization and EV-context shift, not chronic cytokine storm, autoimmunity, or unresolved viral replication.
2 Increased EV burden with high-mannose surface glycosylation
Post-viral and chronic inflammatory states are associated with increased extracellular vesicle (EV) production alongside reproducible alterations in EV surface glycosylation. In particular, enrichment of high-mannose EV populations—including Galanthus nivalis agglutinin (GNA)–binding EVs—has been observed in Long COVID and related post-viral plasma datasets, indicating altered vesicle biogenesis and glycan processing rather than nonspecific inflammation (Pesqueira Sanchez et al., 2025).
EV glycosylation patterns are biologically meaningful and reflect intracellular processing context, influencing vesicle trafficking, cellular uptake, and downstream signaling behavior (Williams et al., 2018; Walker et al., 2020). Selective removal of mannose-enriched EV subsets alters predicted downstream pathway activity, supporting the interpretation that this EV population represents a functionally distinct stress-associated signal rather than a passive biomarker (Pesqueira Sanchez et al., 2025).
Within this framework, increased high-mannose EV burden is interpreted as a stable EV-glycome signature of unresolved cellular stress, providing a measurable link between post-viral immune context (Step 1) and intracellular processing strain (Step 3).
EV glycosylation patterns are biologically meaningful and reflect intracellular processing context, influencing vesicle trafficking, cellular uptake, and downstream signaling behavior (Williams et al., 2018; Walker et al., 2020). Selective removal of mannose-enriched EV subsets alters predicted downstream pathway activity, supporting the interpretation that this EV population represents a functionally distinct stress-associated signal rather than a passive biomarker (Pesqueira Sanchez et al., 2025).
Within this framework, increased high-mannose EV burden is interpreted as a stable EV-glycome signature of unresolved cellular stress, providing a measurable link between post-viral immune context (Step 1) and intracellular processing strain (Step 3).
Boundary: This step reflects altered EV biogenesis and glycan composition, not generalized vesicle release due to acute inflammation or tissue damage.
3 Persistent ER–Golgi secretory pathway strain
A persistent enrichment of high-mannose surface glycans is consistent with incomplete ER→Golgi N-glycan maturation and ongoing secretory-pathway strain, rather than a purely transient immune activation state. EV glycosylation reflects vesicle biogenesis context and intracellular processing dynamics, making EV-glycome patterns a plausible readout of altered secretory pathway function (Williams et al., 2018; Walker et al., 2020).
At the molecular level, high-mannose glycan persistence is a recognized indicator of disrupted glycoprotein quality control and impaired maturation through the ER–Golgi system, particularly under conditions of chronic cellular stress (Xu & Ng, 2015; PubMed 26465718). In this framework, the high-mannose EV signature provides a mechanistically grounded bridge between post-viral immune priming (Step 1), altered EV phenotype (Step 2), and downstream stress-permissive signaling states that increase susceptibility to membrane remodeling events.
At the molecular level, high-mannose glycan persistence is a recognized indicator of disrupted glycoprotein quality control and impaired maturation through the ER–Golgi system, particularly under conditions of chronic cellular stress (Xu & Ng, 2015; PubMed 26465718). In this framework, the high-mannose EV signature provides a mechanistically grounded bridge between post-viral immune priming (Step 1), altered EV phenotype (Step 2), and downstream stress-permissive signaling states that increase susceptibility to membrane remodeling events.
Boundary: This step does not claim acute unfolded protein response (UPR) spikes or prove ER stress in every patient; it defines a persistent processing-strain phenotype compatible with the observed EV-glycome pattern.
4 Stress-sensitized PKC / PI-PLC signaling lowers membrane-cleavage thresholds
Persistent ER–Golgi processing strain alters intracellular Ca²⁺ handling and lipid signaling context, creating a cellular environment in which membrane-proximal signaling enzymes operate with reduced activation thresholds rather than continuous activity. Chronic ER stress is known to perturb Ca²⁺ homeostasis, providing permissive conditions for PLC and PKC engagement without requiring sustained receptor stimulation (Sakaki et al., 2008).
Oxidative and inflammatory stress further act in concert with ER stress to prime PLC and PKC isoforms through redox-sensitive mechanisms, rendering these pathways more responsive to otherwise modest stimuli (Wang et al., 2001; Steinberg, 2015). In this sensitized state, transient physiological or immune inputs can elicit disproportionately large PLC/PKC responses compared with non-stressed cells.
Within the shedding framework, this stress-primed signaling environment provides a mechanistically plausible link between secretory-pathway strain (Step 3) and permissive activation of PI-PLC–dependent membrane cleavage events, without implying constant kinase firing or indiscriminate membrane disruption.
Oxidative and inflammatory stress further act in concert with ER stress to prime PLC and PKC isoforms through redox-sensitive mechanisms, rendering these pathways more responsive to otherwise modest stimuli (Wang et al., 2001; Steinberg, 2015). In this sensitized state, transient physiological or immune inputs can elicit disproportionately large PLC/PKC responses compared with non-stressed cells.
Within the shedding framework, this stress-primed signaling environment provides a mechanistically plausible link between secretory-pathway strain (Step 3) and permissive activation of PI-PLC–dependent membrane cleavage events, without implying constant kinase firing or indiscriminate membrane disruption.
Boundary: This step describes lowered activation thresholds and stress susceptibility, not constitutive PKC/PI-PLC activation or continuous Ca²⁺ release.
5 PI-PLC–mediated cleavage of membrane-anchored SMPDL3B
SMPDL3B is a membrane-associated protein whose surface availability can be reduced through phosphatidylinositol-specific phospholipase C (PI-PLC)–mediated cleavage. In ME/CFS, SMPDL3B has been identified as a mechanistically relevant biomarker, with evidence indicating that stress-linked signaling pathways can promote PI-PLC–dependent removal of SMPDL3B from the plasma membrane (Rostami-Afshari et al., 2025a).
Crucially, this mechanism produces functional SMPDL3B loss at the membrane without requiring transcriptional down-regulation, distinguishing the shedding phenotype from SMPDL3B deficiency. The enzyme itself may remain expressed intracellularly or detectable in circulation, while its membrane-localized regulatory function is diminished.
Crucially, this mechanism produces functional SMPDL3B loss at the membrane without requiring transcriptional down-regulation, distinguishing the shedding phenotype from SMPDL3B deficiency. The enzyme itself may remain expressed intracellularly or detectable in circulation, while its membrane-localized regulatory function is diminished.
Boundary: This step does not imply continuous or indiscriminate cleavage. Rather, it reflects a stress-permissive state in which PI-PLC–mediated SMPDL3B removal occurs more readily under physiological or inflammatory load.
6 Reduced surface SMPDL3B defines the shedding phenotype
Following PI-PLC–mediated cleavage, membrane-localized SMPDL3B is reduced, establishing the SMPDL3B shedding phenotype. In this state, functional SMPDL3B loss occurs at the plasma membrane despite preserved transcriptional capacity, distinguishing shedding from SMPDL3B deficiency (Rostami-Afshari et al., 2025a; Rostami-Afshari et al., 2025b).
Circulating or soluble SMPDL3B may remain detectable, reflecting redistribution rather than under-expression. The critical pathological feature is loss of SMPDL3B’s membrane-associated regulatory role, not absolute protein absence.
Circulating or soluble SMPDL3B may remain detectable, reflecting redistribution rather than under-expression. The critical pathological feature is loss of SMPDL3B’s membrane-associated regulatory role, not absolute protein absence.
Boundary: This step defines a stable phenotypic state, not an active process. Cleavage may occur episodically, but the resulting reduction in surface SMPDL3B persists sufficiently to alter membrane behavior and downstream signaling.
7 Membrane microdomain instability and loss of innate restraint
SMPDL3B normally functions as a membrane-associated regulator of lipid microdomain organization and innate immune receptor signaling. When surface SMPDL3B is reduced, membrane microdomains lose structural and functional stability, impairing the cell’s ability to buffer receptor clustering and signal initiation (Rostami-Afshari et al., 2025a).
Loss of SMPDL3B removes an important restraining influence on innate immune receptors—particularly pattern-recognition receptors whose signaling strength depends on membrane lipid organization. As a result, receptor activation thresholds are lowered, and signaling responses become exaggerated relative to stimulus intensity.
This state does not require stronger upstream inflammatory triggers. Instead, normal physiological or immunological inputs are more likely to provoke disproportionate signaling due to reduced membrane-level buffering capacity.
Loss of SMPDL3B removes an important restraining influence on innate immune receptors—particularly pattern-recognition receptors whose signaling strength depends on membrane lipid organization. As a result, receptor activation thresholds are lowered, and signaling responses become exaggerated relative to stimulus intensity.
This state does not require stronger upstream inflammatory triggers. Instead, normal physiological or immunological inputs are more likely to provoke disproportionate signaling due to reduced membrane-level buffering capacity.
Boundary: This step describes heightened reactivity, not autonomous immune activation. Innate signaling remains stimulus-dependent but is less effectively restrained by membrane microdomain architecture.
8 Endothelial fragility and nitric-oxide signaling instability
Loss of membrane-level buffering and microdomain stability extends to endothelial cells, where SMPDL3B-dependent membrane organization contributes to vascular signaling robustness. Reduced surface SMPDL3B is proposed to render endothelial membranes more structurally fragile, impairing coordinated nitric-oxide (NO) signaling and weakening adaptive control of vascular tone (Haffke et al., 2022; Flaskamp et al., 2022).
Rather than producing a fixed vasoconstrictive or vasodilatory state, this membrane fragility results in unstable and poorly buffered endothelial responses. NO signaling becomes less resilient to physiological stress, and endothelial permeability control degrades, increasing susceptibility to regional flow disturbances under otherwise modest load.
This pattern is consistent with endothelial dysfunction observed in ME/CFS and post-COVID cohorts and is best understood as a loss of regulatory stability, not primary vascular disease or structural occlusion (Vassiliou et al., 2023).
Rather than producing a fixed vasoconstrictive or vasodilatory state, this membrane fragility results in unstable and poorly buffered endothelial responses. NO signaling becomes less resilient to physiological stress, and endothelial permeability control degrades, increasing susceptibility to regional flow disturbances under otherwise modest load.
This pattern is consistent with endothelial dysfunction observed in ME/CFS and post-COVID cohorts and is best understood as a loss of regulatory stability, not primary vascular disease or structural occlusion (Vassiliou et al., 2023).
Boundary: This step reflects impaired endothelial signal buffering and responsiveness, not chronic vasospasm, atherosclerotic disease, or fixed endothelial injury.
9 Perfusion failure under everyday physiological load
Under common physiological stressors—orthostasis, exertion, heat exposure, or post-prandial blood-flow redistribution—regional perfusion becomes unreliable. This manifests most clearly as reduced cerebral blood flow during orthostatic stress, consistent with a distribution problem rather than a primary cardiac limitation (van Campen et al., 2020; Christopoulos et al., 2025).
In this framework, endothelial fragility and impaired vascular signal buffering reduce flow reserve and increase susceptibility to regional hypoperfusion across cerebral, muscular, renal, and splanchnic vascular beds. The resulting phenotype aligns with documented orthostatic intolerance and autonomic dysfunction patterns in ME/CFS cohorts (Jason et al., 2024; Issa et al., 2025).
In this framework, endothelial fragility and impaired vascular signal buffering reduce flow reserve and increase susceptibility to regional hypoperfusion across cerebral, muscular, renal, and splanchnic vascular beds. The resulting phenotype aligns with documented orthostatic intolerance and autonomic dysfunction patterns in ME/CFS cohorts (Jason et al., 2024; Issa et al., 2025).
Boundary: This step describes a perfusion distribution / regulation failure (loss of reserve and buffering), not deconditioning, primary heart failure, or fixed structural vascular obstruction (van Campen et al., 2020; Jason et al., 2024).
10 Intermittent ischemic metabolism
When regional oxygen delivery becomes unreliable, tissues intermittently shift toward ischemic and anaerobic metabolism. This produces a pattern where exertion can appear tolerable in the moment, yet metabolic strain accumulates and clearance kinetics worsen, contributing to delayed symptom escalation rather than immediate collapse (Hoel et al., 2021; Jones et al., 2010).
ME/CFS cohorts demonstrate distinct metabolic phenotypes consistent with impaired energetic flexibility, and muscle studies show abnormalities in pH handling and exertional physiology that align with episodic oxygen-delivery and metabolite-clearance constraints (Hoel et al., 2021; Jones et al., 2010; Rutherford et al., 2016). In the GLA framing, this represents perfusion-driven metabolic instability (M2 → M1 coupling), not a primary mitochondrial disease starting at rest.
ME/CFS cohorts demonstrate distinct metabolic phenotypes consistent with impaired energetic flexibility, and muscle studies show abnormalities in pH handling and exertional physiology that align with episodic oxygen-delivery and metabolite-clearance constraints (Hoel et al., 2021; Jones et al., 2010; Rutherford et al., 2016). In the GLA framing, this represents perfusion-driven metabolic instability (M2 → M1 coupling), not a primary mitochondrial disease starting at rest.
Boundary: Resting metabolism can appear relatively preserved; the core abnormality is load-dependent metabolic instability emerging when perfusion reserve is exceeded (Hoel et al., 2021).
11 ATP strain and calcium handling failure
As intermittent ischemic metabolism accumulates, ATP availability becomes constrained during and after exertion. Reduced ATP impairs ion handling and Ca²⁺ extrusion mechanisms, increasing intracellular Ca²⁺ burden and forcing mitochondria to operate under higher stress to maintain homeostasis (Syed et al., 2025; Rutherford et al., 2016).
This provides a mechanistic bridge between perfusion-driven metabolic instability and the characteristic delayed escalation of exertional symptoms described in ME/CFS exertion models: the system initially compensates, then fails as ATP-dependent buffering capacity is exceeded (Wirth & Scheibenbogen, 2021; Wirth & Steinacker, 2025).
This provides a mechanistic bridge between perfusion-driven metabolic instability and the characteristic delayed escalation of exertional symptoms described in ME/CFS exertion models: the system initially compensates, then fails as ATP-dependent buffering capacity is exceeded (Wirth & Scheibenbogen, 2021; Wirth & Steinacker, 2025).
Boundary: This step is load-dependent and may not be evident at rest; the core feature is reduced energetic reserve and impaired buffering under physiological stress (Wirth & Scheibenbogen, 2021).
12 Delayed mitochondrial ROS amplification (PEM timing)
Following exertional load, mitochondrial stress can produce delayed oxidative amplification hours later, aligning with the characteristic timing of post-exertional malaise (PEM). In ME/CFS, exertion-linked studies demonstrate delayed biochemical and physiological changes consistent with a second-phase escalation rather than immediate fatigue alone (Baraniuk, 2025; Wirth & Steinacker, 2025).
Within this chain, intermittent ischemic metabolism and ATP/Ca²⁺ buffering strain increase mitochondrial workload and vulnerability, making delayed ROS bursts more likely during recovery windows—when the system attempts to restore ion gradients and redox balance (Syed et al., 2025; Wirth & Scheibenbogen, 2021).
Within this chain, intermittent ischemic metabolism and ATP/Ca²⁺ buffering strain increase mitochondrial workload and vulnerability, making delayed ROS bursts more likely during recovery windows—when the system attempts to restore ion gradients and redox balance (Syed et al., 2025; Wirth & Scheibenbogen, 2021).
Boundary: ROS is treated here as a downstream amplifier that deepens crashes and prolongs recovery, not the baseline initiating defect (Wirth & Scheibenbogen, 2021).
13 Secondary lipid and kinase amplifiers during flares
During crashes, delayed oxidative stress can transiently amplify membrane-proximal signaling, including redox-sensitive kinase behavior and PLC/PKC responsiveness. This can transiently deepen the shedding phenotype during flare windows by increasing the likelihood of PI-PLC–mediated membrane cleavage events under stress, thereby worsening membrane fragility and innate reactivity during flare windows (Steinberg, 2015; Rostami-Afshari et al., 2025a).
In other words, ROS and stress signaling can create a self-reinforcing loop: membrane instability increases stress sensitivity, stress increases cleavage permissiveness, and cleavage further reduces membrane buffering. This loop helps explain why crashes can become disproportionately severe once a threshold is crossed and why recovery kinetics may be prolonged even after the trigger has passed (Wirth & Scheibenbogen, 2021; Wirth & Steinacker, 2025).
In other words, ROS and stress signaling can create a self-reinforcing loop: membrane instability increases stress sensitivity, stress increases cleavage permissiveness, and cleavage further reduces membrane buffering. This loop helps explain why crashes can become disproportionately severe once a threshold is crossed and why recovery kinetics may be prolonged even after the trigger has passed (Wirth & Scheibenbogen, 2021; Wirth & Steinacker, 2025).
Boundary: These lipid/kinase amplifiers modulate crash depth but do not define the baseline shedding phenotype; the primary phenotype distinction remains membrane loss of SMPDL3B via cleavage rather than transcriptional insufficiency (Rostami-Afshari et al., 2025a).
14 Renal perfusion instability and effective circulating volume dysregulation
In a perfusion-fragile physiological state, renal blood-flow regulation becomes vulnerable to autonomic and vascular instability. In ME/CFS, altered renal function has been documented in association with systemic symptoms, supporting the presence of functional renal involvement rather than primary renal disease (Miwa & Fujita, 2016).
Autonomic dysregulation—long recognized as a core feature of ME/CFS—can impair renal perfusion control and sodium–fluid handling, reducing effective circulating volume and preload (Freeman & Komaroff, 1997). This volume dysregulation lowers orthostatic tolerance and further constrains perfusion reserve, particularly under upright posture, exertion, or heat stress.
Within the shedding framework, renal perfusion instability acts as a reinforcing amplifier rather than a root cause. Reduced effective volume worsens global and regional hypoperfusion, which in turn increases ischemic metabolic strain and susceptibility to post-exertional deterioration. This physiology is consistent with exertion models in which impaired circulatory support contributes to downstream metabolic and muscular failure rather than primary mitochondrial disease (Wirth & Scheibenbogen, 2021).
Autonomic dysregulation—long recognized as a core feature of ME/CFS—can impair renal perfusion control and sodium–fluid handling, reducing effective circulating volume and preload (Freeman & Komaroff, 1997). This volume dysregulation lowers orthostatic tolerance and further constrains perfusion reserve, particularly under upright posture, exertion, or heat stress.
Within the shedding framework, renal perfusion instability acts as a reinforcing amplifier rather than a root cause. Reduced effective volume worsens global and regional hypoperfusion, which in turn increases ischemic metabolic strain and susceptibility to post-exertional deterioration. This physiology is consistent with exertion models in which impaired circulatory support contributes to downstream metabolic and muscular failure rather than primary mitochondrial disease (Wirth & Scheibenbogen, 2021).
Boundary: This step does not imply intrinsic kidney pathology. It describes a functional renal–autonomic–volume feedback loop arising downstream of endothelial and autonomic instability, amplifying orthostatic intolerance and lowering the threshold for crash initiation.
15 Hepatic metabolic load and FGF21 elevation
Sustained systemic stress and impaired recovery capacity increase hepatic metabolic load, reflected in altered endocrine-metabolic signaling. In ME/CFS and related symptom-overlap conditions, circulating FGF21 has been reported as elevated and associated with symptom patterns and cognitive profiles, supporting its role as a load and metabolic-flexibility marker rather than a purely adaptive fasting response (Azimi et al., 2025).
Broader metabolomic work in ME/CFS identifies distinct metabolic phenotypes consistent with impaired energetic flexibility and reduced capacity to restore homeostasis after stress (Hoel et al., 2021). In the shedding framework, hepatic load signals (including FGF21) contribute to slow recovery kinetics: when metabolic buffering is constrained, post-exertional perturbations persist longer and require more time to resolve.
Broader metabolomic work in ME/CFS identifies distinct metabolic phenotypes consistent with impaired energetic flexibility and reduced capacity to restore homeostasis after stress (Hoel et al., 2021). In the shedding framework, hepatic load signals (including FGF21) contribute to slow recovery kinetics: when metabolic buffering is constrained, post-exertional perturbations persist longer and require more time to resolve.
Boundary: This step frames FGF21 as a downstream marker and amplifier of metabolic load, not a single initiating cause of ME/CFS or the SMPDL3B shedding phenotype (Azimi et al., 2025; Hoel et al., 2021).
16 Autonomic sympathetic bias locks the pattern
Persistent autonomic dysregulation—characterized by sympathetic dominance and impaired baroreflex control—further destabilizes vascular regulation and perfusion reserve in ME/CFS. Autonomic abnormalities have been consistently documented across cohorts and are strongly associated with orthostatic intolerance, exertional symptoms, and delayed recovery (Freeman & Komaroff, 1997; Issa et al., 2025; Jason et al., 2024).
Within this framework, sympathetic bias does not initiate the disease process but locks in and stabilizes the low-tolerance state created by upstream membrane, endothelial, and metabolic instability. Reduced parasympathetic buffering and impaired reflex control limit adaptive cardiovascular responses, lowering the threshold at which everyday physiological stressors precipitate hypoperfusion and post-exertional deterioration.
This autonomic lock-in explains both chronicity and relapse susceptibility: even after partial recovery, the system remains prone to rapid destabilization when challenged, perpetuating cycles of crash and incomplete resolution.
Within this framework, sympathetic bias does not initiate the disease process but locks in and stabilizes the low-tolerance state created by upstream membrane, endothelial, and metabolic instability. Reduced parasympathetic buffering and impaired reflex control limit adaptive cardiovascular responses, lowering the threshold at which everyday physiological stressors precipitate hypoperfusion and post-exertional deterioration.
This autonomic lock-in explains both chronicity and relapse susceptibility: even after partial recovery, the system remains prone to rapid destabilization when challenged, perpetuating cycles of crash and incomplete resolution.
Boundary: Autonomic dysfunction is framed here as a downstream stabilizer and amplifier, not a primary etiologic driver of the SMPDL3B shedding phenotype (Freeman & Komaroff, 1997; Issa et al., 2025).
Diagrams
Diagram 2 – Feedback Loop Map
Circular representation of the major self-reinforcing loops: Innate, Endothelial, Volume–Autonomic, EV-Glycome, and Na⁺/K⁺ pump loops.
Diagram 3 – Linear Mechanistic Chain
A simplified left-to-right view of the mechanistic chain from viral trigger and EV glycosylation, through SMPDL3B loss and endothelial dysfunction, to ischemia, Ca²⁺/ROS, autonomic/volume effects, and Na⁺/K⁺-ATPase failure.
References
Links are provided as DOI / PubMed / PMC when available. This list includes only the references already cited in this page.
EV-glycome / high-mannose EVs
Increased mannosylation of extracellular vesicles in Long COVID plasma
Pesqueira-Sanchez, M.A.P., et al. (2025). (preprint)
ER–Golgi glycosylation quality control
Glycosylation-directed quality control of protein folding
Xu, C., & Ng, D.T.W. (2015). Nat Rev Mol Cell Biol
ER stress ↔ Ca²⁺ / PKC permissive context
Protein kinase Cθ is required for autophagy in response to ER stress
Sakaki, K., et al. (2008). J Biol Chem
Oxidative stress → PLCγ1 priming
Oxidative stress-induced phospholipase C-γ1 activation enhances cell survival
Wang, X.T., et al. (2001). J Biol Chem
Redox regulation of PKC
Mechanisms for redox-regulation of protein kinase C
Steinberg, S.F. (2015). Front Pharmacol
SMPDL3B biology (shedding phenotype anchor)
SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis
Rostami-Afshari, B., et al. (2025). J Transl Med
The Lipid-Modifying Enzyme SMPDL3B Negatively Regulates Innate Immunity
Heinz, L.X., et al. (2015). Cell Reports
Endothelial dysfunction / instability
Endothelial dysfunction and altered endothelial biomarkers in post-COVID-19 syndrome and ME/CFS
Haffke, M., et al. (2022). J Transl Med
Perfusion failure (orthostatic cerebral blood flow)
Cerebral blood flow is reduced in ME/CFS during head-up tilt testing
van Campen, C.L.M.C., et al. (2020).
Metabolic phenotype map
A map of metabolic phenotypes in patients with ME/CFS
Hoel, F., et al. (2021). JCI Insight
Exertion model scaffolding
Pathophysiology of skeletal muscle disturbances in ME/CFS
Wirth, K.J., & Scheibenbogen, C. (2021). J Transl Med
PEM timing / delayed second-phase biology
Metabolic stress, redox imbalance, and PEM amplification
Oxidative stress is a shared characteristic of ME/CFS and Long COVID
Shankar, V., et al. (2025). PNAS
FGF21 load marker
Circulating fibroblast growth factor 21 in ME/CFS and fibromyalgia
Azimi, G., et al. (2025). Scientific Reports
Autonomic / volume regulation
Does the chronic fatigue syndrome involve the autonomic nervous system?
Freeman, R., & Komaroff, A.L. (1997). Am J Med
Framework documents
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Daniels, M. (2025).
GLA Disease Concept v2.1 (foundational framework)
Extended update: GLA v2.3 — EV-glycome, ER stress & BA–GLA refinements