Dynamic Homeostasis
State: Stable immune and neural regulation within an energetically open but coherently maintained CNS
Key Cellular Systems: Microglia, Resident macrophages of CNS, Oligodendrocytes, Astrocytes
- Microglia: In a surveillant mode, expressing CX3CR1 and TREM2, enabling debris clearance and synaptic sculpting (via complement C1q) without triggering inflammation.
- Oligodendrocytes: Modulate myelin thickness in response to neuronal activity and support axons metabolically via MCT1-mediated lactate shuttling.
- Astrocytes: Buffer glutamate (via EAAT1/2), maintain K⁺ balance, and reinforce BBB tight junctions by releasing Sonic Hedgehog and angiotensin.
System Level Integrity:
- BBB Selectivity: Maintained by claudin/occludin proteins, pericytes, and astrocytic endfeet.
- Treg Dominance: IL-10 and TGF-β suppress autoimmunity and peripheral infiltration.
- Myelin Antigen Sequestration: Proteins like MBP, PLP, and MOG are compartmentalized and immunologically hidden from adaptive immunity.
Energetic & Thermodynamic Stablity:
- Predominant OXPHOS metabolism maintains high ΔG (~–58 kJ/mol)
- Heat and waste removed via CSF and vasculature
- Minimal internal entropy; low-cost structural renewal
Preclinical Symptoms:
- Sensory: Transient tingling, Uhthoff-like heat sensitivity
- Visual: Mild, fatigue-related blurring
- Cognitive/Affective: Subthreshold attention or mood shifts
- Systemic: Infection-linked fatigue; early mitochondrial strain
Therapeutic Goal: Preserve glial balance, energetic efficiency, and immune silence to delay or prevent entry into autoimmune priming.
Clinical Application:
- Vitamin D → ↑ Treg, IL-10 production
- Omega-3s → microglial modulation, cytokine suppression
- Exercise (Moderate) → ↑ BDNF, mitochondrial biogenesis
- Sleep Hygiene → circadian/BBB stabilization
- Stress Regulation (CBT/mindfulness) → ↓ HPA-driven Th17 bias
Genetic Predisposition:
- MRI screening for subclinical lesions
- Biomarkers: sNfL, IL-6, IFN-γ
- EBV-targeted strategies (future): e.g. vaccine, B cell depleters
Disruption
State: Immune privilege breaks as autoreactive T cells enter CNS, triggering a misdirected immune response against myelin. Glial cells amplify inflammation in a self-sustaining feedback loop.
Key Cellular Events:
- Microglia: Shift to M1 → release IL-1β, TNF-α, ROS
Oligodendrocytes: Recognized by cross-reactive CD4⁺ T cells → stress, demyelination - Astrocytes: Shift to A1 → ↑ GFAP, secrete C3, VCAM-1, promote leukocyte adhesion
Pathophysiology:
- Peripheral Immune Activation
- EBV/HHV-6 infect epithelial or B cells; antigens mimic CNS myelin proteins (MBP, PLP, MOG)
- Dendritic cells/monocytes present viral peptides on MHC-II to CD4⁺ T cells
- Cross-reactive CD4⁺ T cells are activated, proliferate, and differentiate (Th1/Th17)
- Systemic Inflammation and BBB Disruption
Cytokines from T cells/monocytes:- IL-6 → ↓ claudin-5, BBB junction weakening
- TNF-α → endothelial apoptosis, ↑ permeability
- IFN-γ → primes microglia, ↑ MHC expression
- IL-17 → chemokine release, neutrophil attraction
- MMPs degrade BBB basement membrane
- Glial Activation:
- Astrocytes (A1): ↑ GFAP, complement, pro-inflammatory cytokines
- Microglia (M1): Antigen-presenting, ROS production, T cell recruitment
- CNS Infiltration and Antigen Recognition
- CD4⁺ T cells recognize MBP/MOG/PLP on MHC-II (from microglia/APCs)
- If TCR binds → cytokine release → local immune amplification
- T cell help activates B cells, which:
- Class-switch and mature
- Produce autoantibodies against myelin
- Amplification Loop
- Cytokines: IL-1β, TNF-α, IL-6, IL-17, IFN-γ
- ↑ Oligodendrocyte stress and death
- Myelin debris builds, feeding inflammation
- Astrocyte–microglia loop sustains response
Symptoms arise primarily from neuroinflammation, cytokine effects, and early glial dysfunction:
- Sensory Overload / Flooding
Cause: Cytokine-driven thalamic dysregulation and astrocyte dysfunction
Mechanism: ↑ IL-1β, IL-6 disrupt sensory filtering → cortex receives excess, unfiltered input - Anxiety or Paranoia (Early Affective Dysregulation)
Cause: Cytokine effects on limbic system (amygdala, hippocampus)
Mechanism: ↑ IL-6, TNF-α alter emotional salience → threat perception increases without external cause - Cognitive Fog / Attention Fluctuation
Cause: Astrocytic dysfunction and microglial activation in PFC
Mechanism: ↑ IL-1β, IFN-γ impair synaptic regulation and network coherence → reduced executive clarity - Visual Discomfort or Transient Blur (Pre-Optic Neuritis)
Cause: Cytokine spillover into optic pathway (no axonal loss yet)
Mechanism: Inflammatory edema or astrocyte swelling → signal conduction is slowed or distorted - Fatigue During Immune Stress
Cause: Systemic cytokines (IL-6, TNF-α) affect hypothalamic and mitochondrial function
Mechanism: Altered energy metabolism and circadian disruption → reduced cognitive/physical stamina
Therapeutic Goal: Interrupt the immune feedback loop, restore glial balance, and reduce infiltration and cytokine burden.
Clinical Application:
- Steroids (e.g., methylprednisolone): suppresses cytokine storms by altering gene transcription in immune and glial cells, inhibiting key inflammatory pathways (like NF-κB), reducing leukocyte recruitment, and stabilizing the BBB
- Omega-3s/Curcumin: modulate microglia, reduce IL-1β/TNF-α
- Disease-modifying therapies (DMTs): e.g., interferon-β, glatiramer acetate (reduce antigen presentation, T cell trafficking)
- Stress management / CBT: prevent neuroendocrine relapse triggers
- Vitamin D, sleep, exercise: continue to stabilize systemic immune tone
Reaction
State: Acutely inflamed CNS attempts to contain disruption. Glial cells, cytokines, and infiltrating immune cells launch high-cost, short-term containment strategies, but risk overwhelming local regulatory capacity.
Key Cellular Events:
- Microglia: M1 → release IL-1β, TNF-α, ROS (reaction)
- Astrocytes: A1 -> upregulate GFAP, VCAM-1, C3 (reaction)
- Oligodendrocytes: direact to cytokine overburst (disruption) -> react to immune signals with metabolic stress, impaired myelin maintenance
Pathophysiology:
- T cells recruit B cells -> once inside, maturation into plasma cells, production of anti-myelin antibodies
- Autoantibody binding leads to complement activation and Fc-receptor–driven microglial phagocytosis
- Together, this initiates a maladaptive containment loop:
- Inflammation (Phase 1) → Disruption (Phase 2) → Phagocytosis (Phase 3) → Maladaptation (Phase 4) → Sustained immune drive (Phase 5)
Energetic and Thermodynamic Consequences:
- ATP demand ↑ (ion transport, cytokine production, repair attempts)
- Mitochondrial Δψ collapse → inefficient ATP regeneration
- NAD⁺ depletion from PARP1 activation and ROS stress
- Local ΔG of ATP hydrolysis becomes less negative (~–45 kJ/mol)
This leads to bioenergetic exhaustion in vulnerable cells like oligodendrocytes and axons.
Symptoms:
- Sensory Flooding: ↑ IL-1β/IL-6 → thalamic disinhibition, cortical overload
Anxiety / Paranoia: ↑ IL-6/TNF-α → limbic system dysregulation - Cognitive Fog:↑ IFN-γ, IL-1β → PFC signaling disruption
- Transient Visual Blur: Astrocyte swelling, inflammatory edema in optic pathway
- Fatigue: IL-6/TNF-α → hypothalamic and mitochondrial energy imbalance
Therapeutic Goal: Suppress the neuroimmune cascade, contain glial overactivation, and restore CNS filtering thresholds before irreversible damage or structural demyelination begins.
Clinical Application:
- Methylprednisolone (IV): Genomic suppression of NF-κB/AP-1, ↑ IL-10, ↓ IL-1β/IL-6/TNF-α → BBB stabilization, glial modulation
- Omega-3s / Curcumin: Inhibit microglial NF-κB, reduce oxidative stress and cytokine production
- DMTs (e.g., IFN-β, glatiramer): ↓ Antigen presentation, ↓ leukocyte CNS trafficking, ↑ Treg tone
- CBT / Stress Management: Reduce HPA overdrive and peripheral Th17 activation
- Lifestyle Interventions: Vitamin D, sleep, moderate exercise → stabilize immune tone, NAD⁺ levels, and redox balance
Reaction is a phase of acute, unsustainable containment — biologically expensive, temporarily effective, and potentially damaging if not resolved. It reflects the CNS’s attempt to maintain order under conditions of escalating internal entropy and immune infiltration.
Adaptation
State: Following acute immune disruption, the CNS initiates repair-oriented processes : remyelination, synaptic reorganization, and energetic recalibration. However, under persistent cytokine burden or continued immune cell infiltration, these adaptations may become structurally maladaptive, reinforcing dysfunction rather than recovery.
Key Cellular Events:
- Oligodendrocytes: Attempt remyelination, but differentiation is blocked by inflammatory milieu (e.g., TNF-α, IL-6, IFN-γ); surviving oligodendrocytes downregulate MBP, PLP synthesis.
- Astrocytes: Transition toward A2 phenotype in areas of low inflammation (neuroprotective), but remain A1-reactive near persistent immune infiltrates.
- Microglia: Polarization becomes mixed (M1/M2); regions of repair coexist with zones of ongoing oxidative damage
- B cells: Infiltrate meninges, form ectopic lymphoid follicles, contribute to sustained autoantibody production.
Pathophysiology:
- Synaptic and axonal plasticity is initiated as a compensatory mechanism following structural disruption. However, remodeling often becomes maladaptive, reinforcing inefficient circuitry and contributing to chronic network dysfunction.
- Myelin debris may persist, inhibiting OPC maturation (via LINGO-1, MAG signaling).
- Chronic presence of IL-1β, IL-6, and IFN-γ alters epigenetic regulation in glial cells, promoting long-term phenotype shifts.
- Astrocytic scars limit regeneration by releasing chondroitin sulfate proteoglycans (CSPGs)
- Neuronal metabolic strain persists due to inefficient conduction across demyelinated axons → mitochondrial fragmentation and axonal degeneration (especially in spinal tracts and optic pathways)
Energetic Adaptation:
- Gradual re-establishment of mitochondrial function via AMPK-PGC-1α pathway
- ↑ Autophagy and mitophagy in surviving cells to clear damaged organelles
- Partial recovery of NAD⁺ pools, driven by SIRT1 activation and reduced PARP1 stress
- If adaptation is incomplete: ΔG of ATP hydrolysis remains suboptimal (~–50 kJ/mol) → energy cost of conduction stays elevated
Symptoms:
- Residual fatigue: High ATP demand in demyelinated axons, persistent cytokine tone
- Mild memory or processing delay: Synaptic rewiring, hippocampal glial stress
- Visual ghosting / diplopia: Axonal signal delay across partially remyelinated tracts
- Sensorimotor stiffness: Aberrant circuit remodeling in motor tracts, glial scar interference
- Emotional Flattening / apathy: Limbic demyelination and monoaminergic imbalance
Therapeutic Goal: Support neuroregeneration, restore metabolic resilience, and reverse maladaptive glial phenotypes before long-term consolidation of dysfunction occurs.
Clinical Application:
- Clemastine: Promotes OPC differentiation, remyelination (via muscarinic receptor blockade)
- Exercise / BDNF-enhancement: ↑ PGC-1α, ↑ neurogenesis, supports mitochondrial recovery
- NAD⁺ boosters (e.g., NR, NMN): Restore redox balance, improve axonal energy metabolism
- Anti-LINGO-1 (experimental): Relieves inhibition of remyelination
- CBT / Metacognitive therapy: Supports cognitive flexibility, PFC–hippocampus network stability
- SIRT1 activation (resveratrol, fasting): Improves mitochondrial biogenesis, epigenetic plasticity
- IL-1β / IL-6 pathway modulation: Reduces inflammation-driven remyelination block (experimental)
If successful → transition to Refined Homeostasis
If maladaptive → reinforcement of structural damage, lesion expansion, and cognitive decline
Refined Pathological Homeostasis
State: Following repeated or unresolved cycles of disruption and maladaptive adaptation, the CNS enters a dysregulated but stable condition
Key Cellular Events:
- Oligodendrocytes: Remyelination capacity exhausted; OPCs fail to differentiate due to inhibitory environment (e.g., LINGO-1, Notch, Jagged1)
- Astrocytes: A1-scar-forming, secrete chondroitin sulfate proteoglycans (CSPGs) → inhibit synaptic remodeling and OPC migration
- Microglia: Chronically primed (“M1-biased”) → low-level ROS, cytokine release, impaired debris clearance, antigen presentation persists
- B cells: Reside in meningeal follicles, sustain antibody production → chronic complement activation, epitope spreading
- Neurons: Axonal degeneration, mitochondrial fragmentation, impaired firing precision
Pathophysiology:
- Structural consolidation: Synaptic networks and glial scars harden
- Energy economy drops: ΔG of ATP hydrolysis may stabilize at ~–45 kJ/mol → high cost per unit conduction
- Neuroplasticity is restricted: BDNF signaling is suppressed, long-term potentiation (LTP) is reduced
- Inflammation persists: Low-level but chronic release of IL-1β, TNF-α, IFN-γ
- Epigenetic lock-in: Glial and neuronal gene expression patterns stabilize into a pro-inflammatory or hypoactive profile (e.g., ↑ HDAC activity, ↓ histone acetylation)
Therapeutic Goal: Support residual neuroplasticity, maintain quality of life, and prevent further degenerative regression by targeting metabolic, cognitive, and structural resilience.
Clinical Application:
- Cognitive Remediation: Engages dormant circuits, supports executive function, promotes frontal network activity
- Exercise (Structured): ↑ BDNF, supports mitochondrial function, delays progression
- NAD⁺ precursors (NR/NMN): Support axonal energetics and redox buffering in low-functioning circuits
- DMTs (e.g., ocrelizumab): B cell depletion → reduces subclinical inflammation, slows progression
- HDAC inhibitors (experimental): Reverse epigenetic silencing of neuroprotective genes
- Sleep + circadian repair: Supports glymphatic clearance, redox resetting, neuroimmune modulation
MS Subtypes
- Relapsing-Remitting MS (RRMS)
- Pattern: Clear episodes (relapses) of disruption and reaction → followed by periods of partial adaptation or repair
- CNS re-engages repair after each flare, but never fully resets
- Triggers: Stress, infection, immune shifts
- Immunology: Dominated by Th1/Th17 T cells, with evolving B cell contribution
- Glial behavior: M1/A1 states dominate during relapse; partial return to quiescence in remission
- Remyelination: Possible but gradually less efficient over time
This form cycles between “Reaction” and partial “Adaptation,” but rarely returns to full dynamic homeostasis.
2. Secondary Progressive MS (SPMS)
- Begins as RRMS, but over time the adaptive mechanisms fail
- Neurodegeneration becomes independent of immune flares
- B cells, plasma cells, and microglia sustain low-level, chronic inflammation (even without new relapses)
- Remyelination capacity is lost, replaced by axonal loss, glial scarring, and metabolic exhaustion
- Neuroplasticity becomes rigid (PFC–hippocampal dysfunction)
This form reflects a transition into Refined Pathological Homeostasis, where the system resists further adaptation and becomes structurally locked.
3. Primary Progressive MS (PPMS)
- No clear relapses; instead, gradual functional decline from disease onset
- Innate immune activation (especially microglia and astrocytes) plays a larger role than peripheral adaptive immunity
- Often less lesion activity on MRI, but more diffuse neurodegeneration
- Early mitochondrial dysfunction, axonopathy, and white matter atrophy
This form seems to go over “Reaction” and sustain in a chronic, low-grade form of maladaptive adaptation — possibly due to distinct glial and metabolic vulnerabilities.
4. Progressive-Relapsing MS (PRMS)
- A rare pattern of baseline progression with superimposed attacks
- Suggests coexisting systemic immune instability (relapses) and CNS-localized degeneration (progression)
- Often evolves rapidly toward fixed neurological loss
Conclusion
Multiple Sclerosis is not a linear degeneration, but a temporally staggered and spatially compartmentalized breakdown of multiscale homeostasis. Each biological layer—peripheral immune system, CNS glial networks, and intracellular metabolic machinery—undergoes its own phase progression, governed by localized regulatory loops and constrained by energetic thresholds.
Crucially, these phases are temporally desynchronized but interdependent. Peripheral immune activation may resolve into a new pathological baseline before the CNS even enters its own disruption phase. Within the CNS, the loss of immune privilege initiates its own cascade—from microglial and astrocytic activation to oligodendrocyte stress and neuronal adaptation failure. Each tissue, each cell type, engages its own bounded response loop, shaped by its structural barriers, temporal delays, and thermodynamic limits.
This layered unfolding reveals MS not simply as an autoimmune attack, but as a failure of coordinated phase regulation across compartments. The progression from dynamic coherence to pathological homeostasis emerges not from a singular insult, but from misaligned cycles of disruption, reaction, and maladaptive adaptation — where spatial compartmentalization, temporal asynchrony, and energetic constraint converge to trap the system in a rigid, low-functioning state.
Understanding MS through this lens of phase disintegration across systems opens the door to a new therapeutic logic: one that moves beyond immunosuppression toward dynamic realignment of immune-glial communication, energetic resilience, and temporal coherence across compartmental boundaries
Abbreviations List
A1 / A2 – Neurotoxic astrocyte phenotype (pro-inflammatory, GFAP↑, C3↑ / Neuroprotective astrocyte phenotype (repair-supportive)
AMPK – AMP-activated protein kinase
APC – Antigen-presenting cell
BBB – Blood–brain barrier
BDNF – Brain-derived neurotrophic factor
CBT – Cognitive behavioral therapy
CD4⁺ – Cluster of Differentiation 4 positive (helper T cell)
CNS – Central nervous system
CSPG – Chondroitin sulfate proteoglycan
CSF – Cerebrospinal fluid
CX3CR1 – CX3C chemokine receptor 1
DMT – Disease-modifying therapy
EAAT1/2 – Excitatory amino acid transporter 1/2 (glutamate transporters)
EBV – Epstein–Barr virus
GFAP – Glial fibrillary acidic protein
HDAC – Histone deacetylase
HHV-6 – Human herpesvirus 6
HPA – Hypothalamic–pituitary–adrenal (axis)
IFN-γ – Interferon gamma
IL-1β, IL-6, IL-10, IL-17 – Interleukin 1 beta, 6, 10, 17
LINGO-1 – Leucine-rich repeat and Ig domain–containing Nogo receptor–interacting protein 1
MAG – Myelin-associated glycoprotein
MBP – Myelin basic protein
MCT1 – Monocarboxylate transporter 1
MHC – Major histocompatibility complex
MMP – Matrix metalloproteinase
MOG – Myelin oligodendrocyte glycoprotein
NF-κB – Nuclear factor kappa-light-chain-enhancer of activated B cells
OXPHOS – Oxidative phosphorylation
OPC – Oligodendrocyte progenitor cell
PARP1 – Poly (ADP-ribose) polymerase 1
PLP – Proteolipid protein
ROS – Reactive oxygen species
RRMS – Relapsing-remitting multiple sclerosis
sNfL – Serum neurofilament light chain
SIRT1 – Sirtuin 1 (NAD⁺-dependent deacetylase)
SPMS – Secondary progressive multiple sclerosis
TGF-β – Transforming growth factor beta
TREM2 – Triggering receptor expressed on myeloid cells 2
Treg – Regulatory T cell
VCAM-1 – Vascular cell adhesion molecule 1
References
Biernacki, T., Sandi, D., Bencsik, K., & Vécsei, L. (2020). Kynurenines in the pathogenesis of multiple sclerosis: Therapeutic perspectives. Cells, 9(6), 1564. https://doi.org/10.3390/cells9061564
De Kleijn, K. M. A., & Martens, G. J. M. (2020). Molecular effects of FDA-approved MS drugs on glial cells and neurons. International Journal of Molecular Sciences, 21(12), 4229. https://doi.org/10.3390/ijms21124229
Dziedzic, A., Saluk-Bijak, J., & Bijak, M. (2019). Antioxidant compounds in multiple sclerosis therapy. Nutrients, 11(7), 1528. https://doi.org/10.3390/nu11071528
Michaličková, D., Martin, Š., & Slanař, O. (2019). Redox signaling and inflammation in multiple sclerosis. Physiological Research, 69(Suppl 1), S73–S87. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8565962/
Aharoni, R., Eilam, R., & Arnon, R. (2021). Astrocytes in multiple sclerosis: Star-shaped conductors of neuroinflammation. International Journal of Molecular Sciences, 22(11), 5904. https://doi.org/10.3390/ijms22115904
Ghaffary, E. M., & Bjørklund, G. (2025). Adipokines in multiple sclerosis: Immune dysregulation and therapeutics. Autoimmunity Reviews, 24(3), 103158. https://pubmed.ncbi.nlm.nih.gov/40311722/
Wang, P. F., Jiang, F., Zeng, Q. M., & Hu, Y. Z. (2024). Peripheral immune metabolism and CNS autoimmunity in multiple sclerosis. Journal of Neuroinflammation, 21, 1–14. https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-024-03016-8
Comments:
IL-6 disrupts the blood–brain barrier by weakening tight junctions (e.g., claudin-5): Wang et al. (2024) in Neuroscience confirm IL-6 involvement in BBB disruption via downstream signaling that affects endothelial tight junction proteins like claudin-5.
TNF-α promotes endothelial apoptosis and increases BBB permeability: Mohammadipour et al. (2023, Cell Mol Neurobiol) also report that TNF-α, via NF-κB activation, increases oxidative stress and endothelial barrier permeability in MS-like models.
Cytokine overload (IL-6, TNF-α) triggers microglial activation and astrocytic reactivity: Gao et al. (2021, J Neuroinflammation) highlight cytokine-induced astrocytic Notch1 activation and neuroinflammation in EAE models.
MMPs degrade the BBB basement membrane during inflammation: Multiple studies over the past decade (notably in Journal of Neuroinflammation) have shown that MMP-9 levels correlate with BBB degradation in active MS lesions.