SMPDL3B-Shedding Mechanistic Chain (v2.4)

1. How to Read This Document

This document explains how the SMPDL3B-shedding phenotype operates, step by step, in biologically grounded terms.

• Not a diagnostic tool.
• Does not claim permanent damage or continuous inflammation.
• Describes a state-dependent instability: stress activation → partial resolution → recovery re-engagement → delayed PEM.

2. What Is SMPDL3B — and Why Shedding Matters

SMPDL3B in plain terms

• Membrane-anchored regulatory enzyme that stabilizes lipid rafts.
• Constrains innate immune receptors (especially TLR4).
• Supports orderly membrane signaling under stress.

Two fundamentally different failure modes

• SMPDL3B-Deficient: chronically low expression → persistent membrane instability → more continuous dysfunction.
• SMPDL3B-Shedding: expression intact → episodic membrane cleavage → burst-like instability.

The shedding phenotype explains why patients can appear near-normal at rest, crash disproportionately, and recover — but incompletely.

3. Core Principle of the Shedding Phenotype

• Stress activates proteolytic pathways.
• SMPDL3B is temporarily lost from the membrane.
• Membrane signaling becomes brittle.
• Recovery is delayed rather than absent.

This creates an oscillatory disease architecture, not a degenerative one.

4. Stage I — Baseline Priming Without Inflammation (Loops 1–2)

4.1 EV high-mannose signaling primes the system (Loop 1)

• ER–Golgi glycan processing becomes inefficient after infection or inflammatory stress.
• Cells release extracellular vesicles (EVs) with high-mannose glycans.
• These EVs engage lectin and innate sensing pathways and maintain immune alertness without chronic cytokine elevation.

Crucially, this does not suppress SMPDL3B expression; it biases the system toward stress-responsive cleavage when challenged.

4.2 ER–Golgi stress biases toward proteolysis (Loop 2)

• Ongoing secretory demand strains ER folding capacity.
• Shortens membrane protein residence time.
• Increases reliance on stress-activated proteases.

In shedding-dominant systems, SMPDL3B remains expressible but becomes more susceptible to cleavage during stress windows. This sets the stage for episodic membrane destabilization — not permanent loss.

5. Stage II — Shedding Execution (Loops 3–5)

5.1 Ion handling instability primes shedding execution (Loop 3)

• Transient membrane instability disrupts coordinated ion channel regulation.
• Promotes intracellular sodium accumulation and secondary calcium dysregulation.
• Calcium instability activates stress-responsive signaling, engages reversible microRNA stress programs, and amplifies inflammatory/metabolic signaling without fixation.

This produces state-dependent cellular fragility, not persistent dysfunction.

5.2 Lipid raft destabilization lowers innate activation thresholds (Loop 4)

• Episodic loss of membrane SMPDL3B destabilizes lipid raft organization.
• Increases lateral mobility and clustering of TLR4.
• Lowers activation thresholds without constitutive activation.

Minor ligands trigger exaggerated responses; inflammatory signaling becomes hypersensitive but fluctuating. This creates immune hyper-responsiveness without chronic inflammation.

5.3 PI-PLC activation executes SMPDL3B shedding (Loop 5)

• Calcium-dependent stress signaling and TLR4 sensitization activate PI-PLC.
• PI-PLC cleaves GPI-anchored proteins from the membrane, intermittently removing SMPDL3B from the cell surface.
• Because transcription is preserved, SMPDL3B can be re-expressed between episodes and membrane stability partially recovers.

This establishes episodic shedding, not sustained enzymatic loss.

6. Stage III — Systemic Expression (Loops 6–10)

6.1 Calcium-driven mitochondrial stress amplifies instability (Loop 6)

• Episodic membrane disruption and PI-PLC activation increase intracellular calcium flux.
• Calcium overload stresses mitochondrial function, increases ROS generation, and reduces ATP efficiency during stress.

These effects are episodic and load-dependent, with partial recovery between events.

6.2 Endothelial NO signaling becomes brittle under stress (Loop 7)

• Repeated calcium and oxidative stress disrupt endothelial membrane signaling platforms.
• Impairs eNOS coupling and NO bioavailability.
• Endothelial function may appear preserved at rest, but vasodilatory reserve fails under demand.

This produces stress-dependent endothelial dysfunction, not fixed vascular damage.

6.3 Perfusion distribution failure emerges without global hypotension (Loop 8)

• Brittle endothelial control impairs adaptive microvascular redistribution.
• Produces regional under-perfusion during stress.
• Leads to localized ischemia despite normal global hemodynamics and metabolic stress signaling from hypoxic tissues.

This mismatch is functionally invisible at rest but decisive under load.

6.4 Autonomic compensation locks in vascular instability (Loop 9)

• Perfusion instability triggers compensatory sympathetic activation.
• Increases heart rate and vascular tone heterogeneity.
• Sympathetic drive increases calcium flux and metabolic demand, reinforcing upstream shedding triggers.

6.5 Renal perfusion variability destabilizes volume regulation (Loop 10)

• Autonomic–vascular mismatch produces intermittent renal hypoperfusion and disrupts sodium/water handling during stress.
• Creates state-dependent volume instability and heightened sensitivity to posture, heat, and exertion.
• Volume dysregulation worsens orthostatic stress and amplifies sympathetic drive and ischemic signaling.

With systemic instability established, the defining feature of the shedding phenotype emerges during recovery rather than exertion.

7. Stage IV — Recovery Failure, Delayed PEM, and Relapse (Loops 11–16)

7.1 Hepatic metabolic buffering becomes intermittently constrained (Loop 11)

• Repeated systemic stress increases burst-like hepatic metabolic demand.
• Loads bile-acid, lipid, and inflammatory clearance pathways.
• Liver structure and enzymes can remain normal, while buffering capacity becomes state-limited under load.

This reduces recovery depth without implying intrinsic liver disease.

7.2 ATP buffering fails during recovery, not exertion (Loop 12)

• During recovery, ATP resynthesis demand peaks and ion rebalancing intensifies.
• Delayed ATP buffer failure produces post-exertional collapse and explains PEM latency (hours to days).

PEM is thus a recovery-phase failure, not an exertional crash.

7.3 Innate immune resolution remains incomplete (Loop 13)

• Episodic SMPDL3B loss repeatedly removes local restraint on innate receptors.
• Between episodes, inflammatory signaling partially resolves but full immune reset does not occur.
• This maintains a primed but non-inflamed immune state, lowering thresholds for future flares.

7.4 Tissue-level stress amplifies pain and neuroimmune coupling (Loop 14)

• Repeated ischemic and inflammatory stress sensitizes peripheral tissues and nociceptive pathways.
• Alters neuroimmune signaling, producing pain/sensory amplification during flares with partial improvement between episodes.

No fixed tissue injury is required.

7.5 Incomplete recovery lowers physiological thresholds (Loop 15)

• Each decompensation leaves residual membrane instability and lingering metabolic/autonomic stress.
• Tolerance narrows; smaller stressors trigger larger responses over time.

This produces progressive relapse susceptibility, not irreversible decline.

7.6 Final common pathway: delayed PEM maintenance (Loop 16)

• Membrane shedding + perfusion mismatch + metabolic recovery failure + immune priming converge.
• Results in delayed, multi-system PEM, partial/incomplete recovery, and high relapse probability.

The system remains oscillatory and theoretically reversible, but increasingly fragile.

8. End-of-Chain Summary (Shedding Phenotype)

• SMPDL3B expression is preserved.
• Instability is stress-triggered and reversible.
• Delayed PEM arises from recovery-phase overload.

This distinguishes the SMPDL3B-shedding phenotype from chronic inflammatory disease, fixed mitochondrial disorders, and primary autonomic failure. It also explains why baseline tests may appear normal, symptoms fluctuate, and pacing/recovery protection are decisive.