How to Read This Architecture
This document explains why the system fails to reset, not where the illness begins. It specifies the closed feedback interactions that sustain instability, produce oscillation, and drive relapse in the SMPDL3B-shedding phenotype.
The shedding phenotype is best understood as an oscillatory system:
- primed at baseline
- destabilized during stress
- most vulnerable during recovery
- partially restored between episodes, but never fully reset
To make this persistence logic explicit, the feedback loops underlying the SMPDL3B-shedding phenotype are organized into four interacting layers, progressing from root cellular stress to relapse architecture.
Relationship to companion documents
This architecture is intended to be read alongside the following related works:
GLA v2.1 — Gut–Liver–Autonomic Axis (Foundational Framework)
Provides the systems-level context in which the mechanisms discussed here operate,
including vascular, autonomic, hepatic, and metabolic regulation.
GLA v2.3 — Core Framework Addition
Extends the GLA framework with EV-glycome biology, ER–Golgi stress, hepatic load,
and SMPDL3B-centered membrane instability, establishing the upstream constraints
that shape the feedback-loop behavior described in this document.
SMPDL3B-Shedding Systems Framework v2.4
Defines what biological mechanisms are involved and where instability emerges
using a linear mechanistic specification. The present document explains
why those mechanisms fail to fully reset, producing persistence,
oscillation, and relapse.
How to interpret “loops” in this document
The loops described here are not linear steps or a temporal sequence.
They represent closed feedback structures that can remain latent,
become partially engaged, or dominate system behavior depending on state.
Key interpretive principles:
- Loops describe persistence logic, not disease initiation
- Engagement is state-dependent and load-sensitive
- Loops may weaken or disengage with sufficient recovery
- Not all loops are active in all patients or at all times
- This architecture is phenotype-specific (shedding ≠ deficient)
This document should therefore be read as a systems persistence map, not a diagnostic tool or treatment protocol. Mechanisms remain hypothesis-level and are intended to be evaluated, refined, or falsified as evidence advances.
The Four-Layer Feedback Architecture
Membrane & Cellular Stress
(Trigger readiness without continuous activation)
At baseline, the SMPDL3B-shedding system exists in a primed but not inflamed state.
Persistent ER–Golgi stress and altered extracellular vesicle (EV) glycosylation bias innate immune signaling toward alertness rather than activation. These signals do not drive sustained cytokine elevation or suppress SMPDL3B expression transcriptionally. Instead, they maintain a cellular environment that is stress-responsive and biased toward stress-activated proteolytic permissiveness.
Crucially, this layer explains why:
- patients may appear immunologically “quiet” at rest
- inflammatory markers fluctuate rather than remain elevated
- minor stressors repeatedly re-engage downstream cascades
Disease persistence begins with lowered activation thresholds, not constant immune activity.
Ion, Innate, and Proteolytic Amplification
(Episode escalation and threshold lowering)
When stress exceeds tolerance, episodic SMPDL3B shedding occurs via PI-PLC–linked GPI-anchor cleavage.
Transient loss of membrane-anchored SMPDL3B destabilizes lipid rafts, impairing tight regulation of ion channels and innate receptors. This produces:
- intracellular sodium accumulation
- secondary calcium dysregulation
- stress-responsive microRNA activation
- heightened TLR4 sensitivity through lowered activation thresholds rather than constitutive signaling
Calcium overload and mitochondrial stress generate reactive oxygen species (ROS), which feed back into ER stress, innate signaling, and protease permissiveness—closing short, fast feedback loops that rapidly amplify instability once shedding begins.
Because SMPDL3B expression is not permanently suppressed, partial recovery occurs. However, each episode leaves the system more easily destabilized during subsequent stress windows.
Once shedding is initiated, multiple reinforcing loops cooperate to lower future thresholds, explaining why one crash primes the next.
Functional Perfusion Failure
(System-level expression under demand)
Membrane and ion-level instability propagate downstream as brittle vascular control rather than fixed endothelial disease.
Endothelial nitric oxide (NO) signaling is typically preserved at rest but becomes unreliable under load due to calcium stress and oxidative uncoupling. The result is perfusion distribution failure:
- some microvascular beds are over-perfused
- others become ischemic
- global blood pressure and cardiac output may remain normal - particularly under resting conditions
Regional ischemia generates metabolic stress signals that further increase calcium dysregulation, mitochondrial strain, and innate activation—feeding back into the membrane-level shedding machinery.
Autonomic compensation initially stabilizes perfusion but does so at the cost of increased sympathetic tone, calcium flux, and metabolic demand, which worsen upstream instability.
Vascular failure in this phenotype is functional and load-dependent, not continuously measurable at rest.
Recovery Failure & Relapse Architecture
(Why the system does not reset)
The defining vulnerability of the SMPDL3B-shedding phenotype emerges during the recovery phase.
After exertion or stress, demands peak simultaneously across:
- ATP buffering
- ion rebalancing
- membrane repair
- inflammatory resolution
- metabolic clearance (including hepatic buffering)
In this window, delayed mitochondrial stress, calcium dysregulation, and oxidative signaling peak during the recovery phase, re-engaging PI-PLC activity and membrane instability after the stressor has ended, producing delayed PEM.
Because recovery is incomplete, each episode leaves residual instability:
- membrane repair is partial
- metabolic flexibility is reduced
- autonomic compensation remains sensitized
- immune resolution is incomplete
Over time, this produces threshold erosion—the characteristic shrinking envelope of tolerance and increasing relapse risk.
PEM is not an exertional failure but a recovery-phase failure, maintained by interacting feedback loops rather than irreversible damage.
Why This Matters
This architecture explains how ME/CFS in the SMPDL3B-shedding phenotype can:
- persist without continuous inflammation
- relapse without new infection
- worsen despite partial recovery
- evade detection by resting tests
- respond paradoxically to mistimed interventions
It also implies that preventing small crashes, stabilizing recovery windows, and respecting phase-dependent vulnerability may be as important as targeting any single downstream pathway.
The SMPDL3B-shedding phenotype is best understood as a membrane-gated, recovery-limited systems disorder, in which delayed PEM and relapse emerge from interacting feedback loops that lower physiological thresholds over time rather than from fixed structural damage.
Feedback Loop Families in the SMPDL3B-Shedding Phenotype
This section groups the canonical feedback loops underlying the SMPDL3B-shedding phenotype into five functional families, each answering a specific systems-level question about disease persistence, oscillation, and relapse.
Rather than replacing the formal loop definitions (Appendix A), this organization provides a conceptual scaffold that allows readers to understand how multiple reinforcing loops cooperate across biological scales.
Priming & Trigger Readiness
(Canonical Loops 1–2)
Systems question addressed:
Why does the system remain persistently trigger-ready without continuous inflammation or fixed dysfunction?
Core dynamics
The SMPDL3B-shedding phenotype is maintained in a primed baseline state by interacting cellular stress processes rather than by sustained immune activation.
ER–Golgi stress alters protein trafficking and glycan maturation, producing extracellular vesicles (EVs) enriched in high-mannose and immature N-glycan structures. These EVs function as low-grade danger signals, engaging lectin pathways and innate sensors in a contextual, non-saturating manner.
Crucially, this signaling:
- biases innate pathways toward alertness rather than activation
- does not chronically suppress SMPDL3B expression
- maintains stress-responsive cellular programs
- increases reliance on rapid membrane turnover and stress-activated proteolysis
ER–Golgi stress and altered EV signaling reinforce one another, closing a loop that keeps the system persistently susceptible to re-triggering without producing continuous inflammatory pathology.
What this family reinforces
- Persistent immune and cellular “readiness”
- Lowered activation thresholds across downstream pathways
- Fluctuating biomarkers rather than sustained abnormalities
- Apparent clinical quiescence punctuated by instability
The disease state is maintained by baseline priming, not ongoing activation.
Shedding Execution & Threshold Lowering
(Canonical Loops 3–6)
Systems question addressed:
Why does one shedding episode make subsequent episodes easier to trigger?
Core dynamics
When physiological stress exceeds tolerance, episodic SMPDL3B shedding occurs via PI-PLC–mediated GPI-anchor cleavage.
Loss of membrane-anchored SMPDL3B transiently destabilizes lipid rafts, impairing tight regulation of:
- ion channels
- innate receptors
- membrane signaling microdomains
This produces intracellular sodium accumulation with secondary calcium dysregulation, activating stress-responsive microRNA programs and sensitizing innate signaling pathways.
Calcium overload drives mitochondrial stress and ROS generation, which feed back into:
- ER stress
- innate signaling bias
- PI-PLC permissiveness
- renewed membrane instability
Because SMPDL3B transcription is preserved, membrane integrity can partially recover between episodes. However, each episode leaves residual instability, lowering the threshold for future shedding.
What this family reinforces
- Rapid escalation once shedding begins
- Progressive lowering of activation thresholds
- Oscillatory instability rather than fixed dysfunction
- Increasing crash susceptibility over time
Threshold erosion emerges from repeated execution-level feedback, not permanent molecular loss.
Functional Perfusion Failure
(Canonical Loops 7–8; GLA v2.1 integration)
Systems question addressed:
Why does vascular failure appear normal at rest yet collapse under demand?
Core dynamics
Membrane and ion instability propagate downstream into the vascular system as brittle endothelial control, not structural vessel disease.
Calcium stress and oxidative signaling disrupt endothelial membrane platforms required for stable eNOS regulation. Nitric oxide signaling is therefore:
- preserved or near-normal at rest
- unreliable during physiological demand
This produces perfusion distribution failure, in which regional microvascular beds become ischemic despite preserved global hemodynamics.
Regional ischemia generates metabolic stress signals that further increase calcium dysregulation, mitochondrial ROS, and innate signaling—feeding directly back into upstream membrane instability and shedding susceptibility.
What this family reinforces
- “Normal” resting vascular tests
- Severe exertional or orthostatic intolerance
- Regional hypoxia without systemic hypotension
- Hidden ischemia driving downstream stress signaling
Perfusion failure in this phenotype is functional, load-dependent, and state-dependent, not fixed or continuously measurable.
Autonomic & Renal Lock-In
(Canonical Loops 9–10)
Systems question addressed:
Why do compensatory responses worsen long-term stability rather than restore it?
Core dynamics
Autonomic compensation initially stabilizes perfusion during vascular brittleness via sympathetic activation. However, sustained sympathetic tone:
- increases intracellular calcium flux
- raises metabolic demand
- worsens microvascular flow heterogeneity
These changes directly amplify upstream membrane instability and PI-PLC activation, increasing the probability of renewed SMPDL3B shedding.
Simultaneously, unreliable microvascular perfusion produces state-dependent renal hypoperfusion, destabilizing sodium and water handling. Volume instability worsens orthostatic stress, further increasing sympathetic drive and closing a reinforcing loop between autonomic activation, vascular mismatch, and renal low-flow states.
What this family reinforces
- Persistent sympathetic bias
- Orthostatic intolerance without fixed hypotension
- Sensitivity to dehydration, heat, and posture
- Increasing reliance on compensatory mechanisms that amplify instability
Compensation becomes pathogenic when it increases demand and calcium flux in a threshold-lowered system.
Recovery Failure & Relapse Architecture
(Canonical Loops 11–16)
Systems question addressed:
Why does partial recovery fail to restore resilience, producing delayed PEM and relapse?
Core dynamics
The dominant vulnerability in the SMPDL3B-shedding phenotype occurs during the recovery phase, not during exertion itself.
Following stress, simultaneous demands peak across:
- ATP buffering
- ion rebalancing
- membrane repair
- inflammatory resolution
- metabolic clearance (including hepatic buffering)
In this window, delayed mitochondrial stress, calcium dysregulation, and oxidative signaling peak during recovery, re-engaging PI-PLC activity and membrane instability after the stressor has ended. This produces delayed PEM rather than immediate collapse.
Repeated stress episodes impose episodic hepatic metabolic load, reducing recovery depth and metabolic flexibility. Immune resolution remains incomplete between episodes, leaving the system primed for re-triggering.
Each crash leaves residual buffering loss—threshold erosion—making future crashes easier to provoke and harder to recover from.
What this family reinforces
- Delayed PEM (12–48+ hours)
- Prolonged recovery kinetics
- Shrinking activity tolerance envelope
- Progressive relapse susceptibility
PEM is a recovery-phase failure maintained by feedback loops, not an exertional injury or irreversible damage.
Synthesis Across Loop Families
Together, these five loop families explain how the SMPDL3B-shedding phenotype can:
- persist without continuous inflammation
- oscillate between relative stability and decompensation
- evade detection by resting tests
- worsen despite partial recovery
- respond paradoxically to mistimed interventions
The defining feature is state-dependent threshold lowering across membrane, vascular, autonomic, metabolic, and immune systems, producing an oscillatory but self-reinforcing disease architecture.
In the SMPDL3B-shedding phenotype, interacting feedback loop families convert transient stress into delayed, cumulative system failure by lowering recovery-phase thresholds rather than by producing fixed structural damage.
Why Post-Exertional Malaise (PEM) Is Delayed in the SMPDL3B-Shedding Phenotype
Key point:
In the SMPDL3B-shedding phenotype, PEM reflects a recovery-phase failure, not an immediate exertional injury.
Explanation
During exertion or stress, the system often appears to compensate adequately. Perfusion, autonomic tone, and metabolic output may be temporarily maintained through sympathetic activation, redistributed blood flow, and short-term buffering mechanisms.
However, the highest physiological demand occurs after the stressor has ended, during recovery, when multiple processes peak simultaneously:
- ATP replenishment and mitochondrial repair
- Ion rebalancing (Na⁺/Ca²⁺ homeostasis)
- Membrane repair and lipid raft re-stabilization
- Inflammatory resolution
- Metabolic clearance and hepatic buffering
In the SMPDL3B-shedding phenotype, this recovery window coincides with maximum vulnerability. Delayed mitochondrial stress, calcium dysregulation, and oxidative signaling peak during recovery, re-engaging PI-PLC activity and episodic SMPDL3B shedding after exertion has ceased.
This delayed membrane instability destabilizes immune regulation, endothelial signaling, ion handling, and metabolic buffering simultaneously, producing delayed, multi-system symptom exacerbation rather than immediate collapse.
Clinical implication
PEM timing reflects when repair demand exceeds system capacity, not when effort occurs. This explains why:
- symptoms worsen hours to days after activity
- patients may feel “fine” immediately after exertion
- repeated minor overexertion accumulates into severe relapse
PEM is a maintenance behavior of interacting feedback loops, centered on recovery-phase vulnerability, rather than a direct marker of exertional damage.
What This Model Does Not Claim (Interpretation Guardrails)
To prevent misapplication or over-interpretation, the SMPDL3B-shedding feedback-loop architecture explicitly does not claim the following:
-
❌ This model does not assume permanent structural damage
The architecture describes functional, state-dependent instability, not irreversible tissue injury. Partial recovery between episodes is expected and observed. -
❌ This model does not propose continuous immune activation
Innate signaling is primed and episodic, not constitutively elevated. Fluctuating biomarkers and normal resting tests are compatible with this framework. -
❌ This model does not imply that all patients express all loops
Feedback loops are probabilistic and context-dependent. Loop dominance varies by phenotype, illness stage, stress load, and intervention timing. -
❌ This model does not function as a diagnostic tool
The framework is intended for mechanistic reasoning, phenotype stratification, and hypothesis generation — not diagnosis or individual clinical decision-making. -
❌ This model does not claim universal causality
SMPDL3B shedding is positioned as a state-dependent gate and amplifier, not a singular cause of ME/CFS or related conditions.
What the model does claim
- Disease persistence can arise from threshold-lowering feedback loops without fixed pathology
- Delayed PEM can be explained mechanistically without invoking deconditioning or psychosomatic factors
- Recovery quality, not just activity level, is central to relapse risk
This framework explains how instability is maintained — not who has the disease, how severe it must be, or how it should be treated.
↑ Top
Appendix A
Canonical Framework Loops ↔ Feedback Loop Family Cross-Reference
SMPDL3B-Shedding Phenotype (v2.4)
Purpose of this table
This appendix maps the linear mechanistic loops defined in the SMPDL3B-Shedding Systems Framework v2.4 to the closed feedback loop families described in the main text.
It allows readers to move bidirectionally between:
- causal sequence (what happens)
- persistence logic (why it keeps happening)
without re-reading the full framework.
| Framework Loop | Primary Feedback Loop Family | Functional Role in Persistence Architecture |
|---|---|---|
| 1 | Family I — Priming & Trigger Readiness | EV high-mannose glycome signaling maintains innate alertness and lowers downstream activation thresholds without sustained inflammation |
| 2 | Family I — Priming & Trigger Readiness | ER–Golgi stress biases trafficking and proteolytic permissiveness, preparing membranes for episodic shedding rather than fixed suppression |
| 3 | Family II — Shedding Execution & Threshold Lowering | Ion handling instability (Na⁺ → Ca²⁺) links transient membrane loss to stress-responsive signaling and innate sensitization |
| 4 | Family II — Shedding Execution & Threshold Lowering | Lipid raft destabilization lowers TLR4 activation thresholds, enabling episodic innate hyper-responsiveness |
| 5 | Family II — Shedding Execution & Threshold Lowering | PI-PLC–mediated GPI-anchor cleavage executes SMPDL3B shedding, directly reinforcing membrane instability |
| 6 | Family II — Shedding Execution & Threshold Lowering | Calcium-dependent mitochondrial stress and ROS amplify ER stress and protease permissiveness, accelerating repeat shedding |
| 7 | Family III — Functional Perfusion Failure | Endothelial NO signaling becomes brittle under demand due to calcium and oxidative stress, impairing adaptive vasodilation |
| 8 | Family III — Functional Perfusion Failure | Perfusion distribution failure produces regional ischemia despite normal global hemodynamics, feeding back into metabolic stress |
| 9 | Family IV — Autonomic & Renal Lock-In | Sympathetic compensation stabilizes perfusion short-term but increases calcium flux and demand, promoting future shedding |
| 10 | Family IV — Autonomic & Renal Lock-In | State-dependent renal hypoperfusion destabilizes volume regulation, worsening orthostatic stress and autonomic drive |
| 11 | Family V — Recovery Failure & Relapse Architecture | Episodic hepatic metabolic load limits recovery depth, prolonging oxidative stress and increasing re-trigger susceptibility |
| 12 | Family V — Recovery Failure & Relapse Architecture | Delayed recovery-phase ATP buffer failure produces PEM timing and re-engages membrane instability after exertion |
| 13 | Family V — Recovery Failure & Relapse Architecture | Incomplete immune resolution lowers innate activation thresholds, enabling repeated flares without continuous inflammation |
| 14 | Family V — Recovery Failure & Relapse Architecture | Pain and sensory amplification increase autonomic load, indirectly promoting perfusion instability and renewed shedding |
| 15 | Family V — Recovery Failure & Relapse Architecture | Residual instability after each crash erodes thresholds over time, producing a relapse-prone system |
| 16 | Family V — Recovery Failure & Relapse Architecture | Final common pathway: load-dependent SMPDL3B shedding maintains delayed PEM as a system-level attractor |
- Not all patients express all loops simultaneously; dominance is state- and phase-dependent.
- Feedback loops describe probabilistic reinforcement, not inevitability.
- Absence of abnormal resting tests does not exclude this architecture.
- The table does not imply linear progression; loops interact bidirectionally.
- This appendix maps mechanistic lineage, not treatment targets.
How to Use This Appendix
- Main text: understand system behavior via loop families
- Appendix: verify mechanistic completeness and traceability
- Researchers: identify dominant loops for hypothesis generation
- Trial designers: align interventions with phase-specific vulnerability
One-Line Summary (Appendix)
This cross-reference table demonstrates that persistence, delayed PEM, and relapse in the SMPDL3B-shedding phenotype emerge from interacting feedback loops distributed across membrane, vascular, autonomic, metabolic, and immune systems, rather than from a single dominant defect.
Closing Perspective
This framework is not intended to define a single cause of ME/CFS, nor to replace existing vascular, autonomic, immune, or metabolic models. Instead, it offers a systems-level explanation for how delayed post-exertional malaise, oscillatory relapse, and apparent recovery failure can emerge from interacting feedback loops without requiring fixed structural damage or continuous inflammation.
By making membrane gating, threshold dynamics, and recovery-phase vulnerability explicit, the SMPDL3B-shedding architecture reframes ME/CFS as a recovery-limited, state-dependent systems disorder. In this view, symptom exacerbation reflects when physiological demand exceeds adaptive capacity during recovery, rather than when exertion occurs.
The value of this model lies not in definitive claims, but in its ability to generate testable predictions, guide phenotype stratification, and clarify why timing, load, and recovery quality so strongly shape clinical outcomes. As new data emerge, individual loops may be revised or replaced, but the core insight—that persistence and relapse arise from interacting feedback dynamics rather than isolated defects—remains a useful organizing principle.
Framework Context & Related Documents
-
Daniels, M. (2025).
GLA Disease Concept v2.1 — Foundational Systems Framework
Subsequent refinement: GLA v2.3 — EV-glycome, ER stress, and BA–GLA extensions -
Daniels, M. (2025).
SMPDL3B-Shedding Systems Framework v2.4 — Phenotype-Specific Mechanistic Specification