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Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease

What is MOGAD?

Everyone knows electrical cables: They are provided with insulation that separates the individual conductors in the cable bundle from each other so that the signals in them do not interfere with each other and get from A to B unaltered.
The spinal cord contains a whole strand of many such cable bundles. They conduct the nerve signals from the brain to the various organs, muscles, tissues, etc. in the body. While the insulation of the cable is made of plastics, textiles or special materials, the insulating layer Myelin layer.

What is going wrong at MOGAD?

In the case of MOGAD, the body's own immune system makes a serious mistake: it mistakenly produces Antibodies against a specific protein on the outside of this insulating layer, the so-called. MOG-protein. Antibodies are actually the body's guardians that recognize, mark and destroy pathogens such as viruses and bacteria. In MOGAD, however, they are mistakenly directed against the body's own healthy tissue, the insulation of its own nerve fibers.

Compared to a cable, it's like scratching, grinding or corroding the insulation, causing it to become perforated and the electrical signals no longer reach their destination cleanly or even at all.

Where in the body does this happen?

MOGAD relates exclusively to the Central nervous system, i.e. the brain, spinal cord and optic nerves. Depending on which area is affected, different symptoms arise:

• Optic nerve - Sudden loss of vision, blurred vision, eye pain (often only in one eye, sometimes in both eyes at the same time - this is more common in MOGAD than in other similar diseases)
• Spinal cord - Symptoms of paralysis, numbness, problems urinating
• Brain : Confusion, epileptic seizures, coordination disorders

How does the disease progress?

MOGAD typically proceeds in Pushes. There are phases in which the inflammation is active and symptoms occur, intermittently with quieter phases in between.
After an attack, many patients recover surprisingly well, better than in MS, for example. This is because the nerve fibers themselves are often less likely to be permanently damaged than the insulating layer, which can partially regenerate.

Around half of those affected only experience a single flare-up in their lifetime. The other half have recurrent episodes, which can lead to permanent impairment if left untreated.

How common is MOGAD?

MOGAD is rare, only estimated 1-2 out of 100,000 people fall ill. Unlike many other autoimmune diseases of the nervous system, it affects women and men in roughly equal numbers. Children can also develop the disease, which often manifests itself as extensive inflammation of the brain with confusion and fever.

What triggers MOGAD?

The first episode is often followed by infection ahead. The body fights against a pathogen and mistakenly confuses the body's own structures with the enemy. The immune system learns to attack the wrong target, so to speak, and never stops. The exact cause is not yet fully understood.

How is MOGAD treated?

There is currently no specifically approved medication for MOGAD. One acute attack is treated with high doses of Cortisone infusions, which quickly reduce the inflammation. If this is not sufficient Blood washing (Plasmapheresis) the harmful antibody can be removed directly from the blood.

To the Prevention of further relapses Various drugs are used to calm the immune system, for example with substances that reduce antibody-producing cells. Several new, more targeted drugs are currently being tested in clinical trials and could be approved in the next few years.

Scientific introduction and definition

The MOG antibody-associated disease (MOGAD) English: Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease is a rare, inflammatory autoimmune disease of the central nervous system (CNS) that has been recognized as an independent entity with its own diagnostic criteria since 2018. It was previously considered a variant of multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD).

The core element of the disease is the pathological production of autoantibodies (IgG) against the Myelin oligodendrocyte glycoprotein (MOG), a transmembrane protein on the outermost layer of the myelin sheath of oligodendrocytes in the CNS. These antibodies damage myelin sheaths and lead to a characteristic perivenular demyelination.

The main clinical manifestations of MOGAD are optic neuritis, transverse myelitis and acute disseminated encephalomyelitis (ADEM). The disease is usually relapsing and affects the optic nerve, spinal cord and, more rarely, the brain. The median age of onset is between 30 and 35 years; in contrast to NMOSD, women and men are affected almost equally often.

Differentiation between MOGAD, NMOSD and MS

Feature	MOGAD	AQP4+ NMOSD	multiple sclerosis
Target antigen	MOG (oligodendrocytes)	Aquaporin-4 (astrocytes)	No specific autoantibody
Antibody isotype	IgG1 (prew.)	IgG1 (prew.)	Oligoclonal IgG (CSF)
Primary cell damage	Oligodendrocytes/myelin	Astrocytes (primary)	Oligodendrocytes
Histology	Perivenular demyelination, CD4+	Astrocyte lesions, granulocytes	Periaxial plaques
Gender (F:M)	~1:1	~9:1	~3:1
Complement activation	Moderate (less MAC)	Strong (MAC formation)	Low
OKB in cerebrospinal fluid	Rare (<10%)	Occasionally	Frequent (>90%)
Course	Relapsing; often well recovered	Thrust-shaped; accumulates disability	Often progedient
Approved therapies	None (as of 2026)	Eculizumab, ublituximab, satralizumab	Many DMTs

MOG protein - structure and physiological function

MOG (myelin oligodendrocyte glycoprotein) is a Type I transmembrane protein with a total length of 218 amino acids, which is expressed exclusively in the CNS. It is a member of the immunoglobulin superfamily and, with a proportion of around 0.01-0.05 % of the total myelin protein, represents a quantitatively small but immunologically highly relevant component of the myelin sheath.

Structural domains

• Extracellular Ig-V-like domain (AS 1-120): Single exposed domain, highly immunogenic; contains the critical CC‘ loop region (Pro42, His103, Ser104) as the major epitope binding site for MOG-IgG
• Single-pass transmembrane helix: Anchors the protein in the myelin membrane
• Short cytoplasmic C-terminal domain: possibly interacts with the cytoskeleton

Physiological functions

• Adhesion molecule: Mediates structural integrity of the myelin sheath, possibly by compacting the myelin lamellae
• Interaction with C1q of the complement system (physiological)
• Interaction with nerve growth factor (NGF)
• Receptor for rubella virus (clinically relevant for post-infectious ADEM)
• Stabilization of microtubules in oligodendrocytes
• Expression: Late in oligodendrocyte differentiation; only after initial myelination

MOG-IgG autoantibodies primarily recognize Conformational epitopes of the extracellular domain. As MOG is exposed on the outermost surface of the myelin sheath, it is directly accessible to circulating antibodies and immune complexes - a decisive difference to intracellular antigens.

Pathogenesis and immunopathology

MOGAD pathogenesis is a multistep process involving peripheral immune activation, migration across the blood-brain barrier (BBB) and CNS-local effector mechanisms. Neither T cells nor B cells alone are sufficiently pathogenic; it is the synergistic interaction of both arms of the adaptive immune system that causes the disease.

Trigger and initial activation

The main initial triggers are Infections discussed: An infectious prodrome has been documented in 37-70 % of MOGAD patients (more frequent than in NMOSD with 15-35 %). The mechanisms include:

• Molecular mimicry - pathogen epitopes are structurally similar to the CC‘ loop region of the MOG, e.g. SARS-CoV-2 sequences or rubella viruses
• Bystander activation - non-specific inflammatory reaction activates dormant autoreactive lymphocytes
• Polyclonal B-cell activation by microbial superantigens

Genetic predisposition plays a role, but specific risk haplotypes have not been conclusively identified. In contrast to MS, no consistent HLA associations have been described.

T-cell mediated pathogenesis

MOG-specific CD4+ T cells are essential for MOGAD pathogenesis. In animal models (EAE), antibodies alone are not pathogenic and require encephalitogenic T cells as co-effectors. The CD4+ pathway comprises several phases:

Phase 1 - Peripheral activation

MOG peptides are produced by antigen-presenting cells (APC) via MHC-II molecules to naïve CD4+ T cells. Noteworthy: MOG peptides can bind directly to peripheral MHC II molecules, without further processing. This could explain the involvement of the peripheral nervous system.

Effector cell subsets that can induce EAE independently of each other are Th1, Th17 and Th9. Th17 cells are particularly relevant for MOGAD, as Th17 cytokines (IL-17, IL-21) are markedly elevated in shearing episodes.

Phase 2 - BHS penetration

Activated CD4+ T cells express specific adhesion molecules (integrins, selectins) and chemokine receptors (in particular CCR6), which enable them to enter the CNS. CCR6+ Th17 cells bind to CCL20, which is constitutively expressed in the choroid plexus, and enter the subarachnoid space via it.

• Matrix metalloproteinases (MMP-2, MMP-9)
  Degradation of the basement membrane of the BBB
• Neutrophil NETs (Neutrophil Extracellular Traps)
  Provide costimulatory signals for T cells in the initiation phase
• Thrombocytes
  Promote CD4+ T cell proliferation and differentiation to Th1/Th17 through cytokines and adhesion molecules

Phase 3 - Perivascular reactivation

In the perivascular space and subarachnoid space, MOG-specific T cells are reactivated by local MOG-loaded APCs (microglia, dendritic cells). This reactivation triggers the actual inflammatory cascade: Secretion of proinflammatory cytokines, recruitment of further leukocytes and oligodendrocyte damage.

B-cell and antibody-mediated pathogenesis

MOG-specific B cells and plasma cells are the main producers of pathogenic IgG1 autoantibodies. However, the B cell role goes beyond antibody production:

• Antigen presentation - B cells can bind MOG conformational epitopes via their BCR (pro42, his103, ser104 of the CC‘ loop) and act as APCs for T cells
• Promotion of Th17 differentiation - B cells secrete IL-6, which together with TGF-β drives Th17 differentiation
• MAPK and AKT signaling activation - BCR binding to MOG activates these signaling pathways intracellularly
• Increase in intracellular calcium - Leads to activation of stress-associated signaling cascades

Most MOG-IgG antibodies are produced in the periphery (oligoclonal bands in CSF only in ~10 % of cases, in comparison: MS ~90 %). The antibodies are bivalent-binding to MOG, both Fab arms bind simultaneously to two neighboring MOG molecules. This leads to less efficient C1q recruitment compared to monovalent binding of AQP4-IgG in NMOSD.

Molecular signaling pathways and effector mechanisms

Signaling pathway 1 - classical complement pathway (CDC)

When MOG-IgG1 (and MOG-IgG3) bind to oligodendrocyte MOG, the classic complementary route are activated. However, complement activation is weaker in MOGAD than in AQP4+ NMOSD:

• C1q binding to the Fc part of bound IgG1 antibodies → Activation of C1r and C1s
• Cleavage of C4 → C4a + C4b; C4b + C2 → C3 convertase (C4b2a)
• Cleavage of C3 → C3a (anaphylatoxin) + C3b (opsonin)
• C3b → C5 convertase → Cleavage of C5 → C5a (potent anaphylatoxin) + C5b
• C5b + C6, C7, C8, C9 → membrane attack complex (MAC, C5b-9): Direct lysis of the oligodendrocytes

Important: In the CSF of MOGAD patients, C3a and C5a are significantly elevated (comparable to AQP4+ NMOSD), but the MAC complex (C5b-9) is not significantly elevated. significantly lower than in NMOSD. This is due to bivalent IgG binding, which is less efficient for C1q clustering, and the relatively low density of complement regulators on oligodendrocytes (less CR1, MCP, HRF than on other cell types).

Signaling pathway 2 - Fcγ receptor pathway (FcR-mediated)

LMU research (Mader, Kawakami, Meinl, 2024 PNAS) showed that Fcγ receptor (FcγR)-mediated mechanisms to about 50 % of myelin damage and are therefore on a par with complement activation:

• FcγRIII (CD16) on NK cells and macrophages
  Binds the Fc part of MOG-bound IgG1 → ADCC (antibody-dependent cellular cytotoxicity)
• FcγRI/II/III on macrophages and monocytes
  Phagocytosis of MOG-opsonized oligodendrocyte fragments (ADCP)
• Crucial: The second FcR pathomechanism
  Enhancement of T cell activation, runs exclusively via Fc receptors, NOT via the complement pathway
• FcγR on dendritic cells
  Facilitate the processing and presentation of MOG-IgG-loaded oligodendrocyte antigens to MOG-specific T cells

Clinical implication: Since two independent pathogenic pathways exist, therapeutic approaches must be Both mechanisms in order to achieve maximum effectiveness.

Signaling pathway 3 - IL-6/JAK-STAT3 pathway

IL-6 is a central mediator of MOGAD immunopathogenesis and acts on several levels:

IL-6 binds to its receptor (IL-6Rα/gp130 complex), which leads to the JAK1/2 phosphorylation leads. This primarily activates STAT3, which serves as a transcription factor for:

• Th17 differentiation
  IL-6 + TGF-β → RORγt expression → IL-17A/F production; IL-6 + IL-23 → maintenance of the Th17 phenotype
• Folicular T helper cells (Tfh)
  IL-6 → STAT3 → Bcl6 expression → Germinal center B cell maturation and IgG class switch
• B-cell maturation to plasma cells
  IL-6 promotes differentiation via STAT3/Blimp-1 axis
• Suppression of Treg function
  IL-6 inhibits FoxP3 expression, which shifts the Treg/Th17 balance towards inflammation

Therapeutic relevance: IL-6 blockade (e.g. tocilizumab, satralizumab) breaks this cycle. Satralizumab (anti-IL-6R) is currently being investigated in the Phase 3 METEOROID study for MOGAD.

Signaling pathway 4 - MAPK and AKT signaling pathways (B cells)

BCR binding to MOG conformational epitopes activated in B cells:

• MAPK path (MEK/ERK)
  Promotion of B-cell proliferation and differentiation
• PI3K/AKT path
  Cell survival and differentiation of B cells into plasma cells
• Calcium influx
  Activation of calcineurin/NFAT axis → Cytokine production
• NK cell activation
  BCR-MOG binding induces NK cell-mediated cytotoxicity

Signaling pathway 5 - Th17 cytokine network in the CNS

In the CNS, Th17 cells maintain an inflammatory environment through multiple mediators:

• IL-17A and IL-17F
  Activate astrocytes and microglia; induce release of chemokines (CXCL-1/5/8) that recruit neutrophils
• IL-21 (auto- and paracrine)
  Enhances Th17 differentiation; promotes B-cell differentiation and IgG class switch (especially IgG1)
• IL-22
  Dysregulation of BBB integrity
• GM-CSF (via IL-23)
  Activates microglia and macrophages, increases local demyelination
• CXCL13
  Chemotaxis of B cells in perivascular spaces → local antibody production

Signal paths - overview

Signal path	Key molecules	Effect	Therapeutic targets
Classic complementary route	C1q, C3, C5, MAC (C5b-9)	Direct oligodendrocyte lysis	C5 inhibitors (eculizumab), C3 inhibitors
FcγR path (ADCC/ADCP)	FcγRI/II/III, NK cells, macrophages	Cytotoxicity, phagocytosis, T-cell potentiation	FcRn inhibitors (IgG degradation), FcR blockade
IL-6/JAK-STAT3	IL-6, IL-6Rα, gp130, JAK1/2, STAT3, RORγt	Th17 differentiation, B-cell maturation, IgG production	Anti-IL-6R (tocilizumab, satralizumab)
PI3K/AKT/MAPK (B cells)	BTK, PI3K, AKT, ERK, NFAT	B-cell activation, plasma cell maturation	BTK inhibitors (ibrutinib, tolebrutinib)
Th17 cytokine network	IL-17, IL-21, IL-22, GM-CSF, CXCL13	BBB damage, leukocyte recruitment, demyelination	Anti-IL-17, Anti-IL-21
FcRn-IgG recycling	FcRn (neonatal Fc receptor)	Prolonged IgG half-life	Anti-FcRn (rozanolixizumab)

Relevant receptors and target molecules

MOG itself as a target structure (not a classic receptor)

In MOGAD, the MOG protein acts as an antigen, not as a signal receptor. Nevertheless, the following interactions are pathophysiologically significant:

• C1q binding
  MOG can physiologically bind C1q, which leads to complement activation in the case of pathological antibody coverage
• DC-SIGN (CD209)
  Lectin receptor on dendritic cells; can bind MOG and contribute to antigen presentation
• Rubella virus receptor_
  MOG serves as an entry molecule for rubella viruses, which could explain post-infectious ADEM in children

Fcγ receptors (FcγR)

Fcγ receptors on immune cells are central effectors of IgG1-mediated damage:

• FcγRI (CD64)
  High affinity, on macrophages and dendritic cells; mediation of ADCP and antigen presentation
• FcγRIII (CD16)
  Low affinity, on NK cells; main mediator of ADCC against MOG-opsonized oligodendrocytes
• FcγRIIA/B (CD32A/B)
  Activating or inhibiting; modulation of B-cell activation and phagocytosis

Neonatal Fc receptor (FcRn)

FcRn (β2m/FcRn-α complex) is responsible for the intracellular recycling of IgG antibodies. It binds IgG in acidified endosomes (pH 6.0) and prevents its lysosomal degradation, thereby extending the IgG half-life to approx. 21 days.

• In MOGAD, FcRn causes the persistent circulation of pathogenic MOG-IgG1
• Therapeutic blockage due to Rozanolixizumab (anti-FcRn IgG4): Forces lysosomal IgG degradation and lowers plasma IgG by ~50%
• FcRn expression - epithelial cells, endothelial cells, monocytes, hepatocytes

IL-6 receptor (IL-6Rα / gp130)

The IL-6 receptor consists of the ligand-binding α-subunit (IL-6Rα, CD126) and the signal transduction co-receptor gp130 (IL-6Rβ, CD130). Two signaling modes:

• Classic signaling
  Membrane-bound IL-6Rα on T cells, B cells, monocytes → IL-6/IL-6Rα/gp130 complex → JAK1/2 → STAT3, STAT1, MAPK, PI3K/AKT
• Trans signaling
  Soluble IL-6Rα (sIL-6R) binds IL-6 and activates gp130 even on cells without membrane-bound IL-6Rα (e.g. endothelial cells of the BBB)

Relevant downstream effects: RORγt expression (Th17), Bcl-6 (Tfh and germinal centers), Blimp-1 (plasma cells), suppression of FoxP3 (Treg).

T-cell receptor (TCR) and costimulation molecules

• TCR/MHC-II-MOG peptide complex
  Central activation axis for MOG-specific CD4+ T cells
• CD28/B7
  Costimulation during T-cell activation
• CCR6/CCL20 axis
  CCR6 on Th17 cells binds CCL20 at the choroid plexus → CNS entry
• CXCR3/CXCL10
  Chemotaxis of Th1 cells in areas of inflammation

Complement receptors

• C1qR
  Mediates C1q binding to immune complexes on oligodendrocyte membranes
• C3aR and C5aR1 (CD88)
  Anaphylatoxin receptors on microglia/macrophages → Proinflammatory activation
• Complement regulators on oligodendrocytes
  CR1 (CD35), MCP (CD46), HRF (CD59) are lowly expressed on oligodendrocytes, which makes them more susceptible to complement damage than astrocytes, for example

Histopathology and CNS lesion pattern

MOGAD lesions are histopathologically fundamentally different from MS and NMOSD:

• Perivenous demyelination
  Lesions form concentrically around small veins (perivenous pattern), not periaxially as in MS. The typical ‚central vein sign‘ of MS is absent on MRI
• CD4+ T-cell infiltrate
  Dominant inflammatory cell pattern are CD4+ T cells and macrophages, fewer neutrophils and hardly any eosinophil granulocytes (unlike AQP4+ NMOSD)
• Oligodendrocyte damage (primary)
  In contrast to NMOSD, where astrocytes are primarily damaged, MOGAD focuses on oligodendrocyte degeneration
• C9neo deposition
  Detection of MAC (terminal complement complex) in lesions, albeit weaker than in NMOSD
• Relative axon conservation
  In acute attacks, axonal damage is often less severe than in MS, which explains the often good clinical recovery
• Cortical lesions
  Leptomeningeal inflammation and cortical demyelination (common in the ADEM variant)

Clinical manifestations and phenotypes

MOGAD is clinically heterogeneous. Important phenotypes:

Phenotype	Frequency	Clinical features	MRI special features
Optic neuritis (ON)	Most common (approx. 50%)	Often bilateral, loss of vision, retrobulbar, painful eye movements. eye movements	Long optic nerve involvement, perinervous contrast medium accumulation
Transverse myelitis	Approx. 30%	Longitudinal myelitis (LETM), sensory/motor, bladder disorders	Longitudinal T2 lesions, H2 syndrome (‚lenticular‘)
ADEM	Most common manifestation in children	Encephalopathy, polyfocal neurolog. deficits	Bilateral, large-volume T2 lesions, also basal ganglia
Brain stem encephalitis	Approx. 15%	Diplopia, ataxia, area postrema syndrome (hiccup, vomiting)	Brain stem / cerebellar T2 lesions
Cortical encephalitis	Rarer	Epileptic seizures, confusion	Cortical FLAIR signal changes
CRION	Rarer	Chronic recurrent inflam. Optic neuropathy	Persistent optic nerve involvement

Diagnostics

Diagnostic criteria (Banwell et al, Lancet Neurology 2023) are required:

(1) Detection of MOG-IgG in serum or cerebrospinal fluid using a cell-based assay (CBA)
(2) appropriate clinical phenotype
(3) Exclusion of alternative diagnoses.

• Cell-based immunofluorescence test (CBA)
  with naturally folded, membrane-bound MOG (HEK293 cells transfected with human MOG); detects conformation-dependent epitopes
• ELISA and line/strip blots
  Unreliable for MOGAD, as linear epitopes are recognized
• IgG subclasses
  Primarily IgG1; occasionally IgG2, IgG3, IgG4. Exclusive IgG3 positivity is a diagnostic pitfall (Jarius 2024)
• Titre kinetics
  Persistently high titers correlate with relapse risk; often decreasing in monophasic course
• Liquor
  Pleocytosis possible; oligoclonal bands rare (<10 %), intrathecal IgG synthesis rare
• Biomarkers
  sNfL (serum neurofilament light chain) as a disease activity marker; sGFAP (glial fibrillary acidic protein) as a marker of astrocytic involvement

Therapeutic strategies

Acute therapy (relapse treatment)

Standard treatment of a MOGAD relapse:

• High-dose Methylprednisolone (HDMP)
  1000 mg i.v. daily for 5 days - first line
• Plasmapheresis / immunoadsorption
  In case of insufficient HDMP response; removes MOG-IgG from plasma; 5-7 cycles (retrospective data show efficacy in approx. 50-70% of cases)
• Intravenous immunoglobulins (IVIG)
  2 g/kg over 5 days; in the absence of a response to HDMP and as an option after plasmapheresis; possibly effective via FcRn saturation and FcγR competition
• Taper off corticosteroids
  Particularly important in MOGAD (frequent steroid dependence) - rapid reduction can trigger rebound episodes

Prophylactic long-term therapy

(off-label, no approved preparation - status 2026)

The indication for long-term therapy is individual - not all patients need it. Factors: Relapse rate, severity of relapses, persistent MOG-IgG titres, phenotypic risk factors.

Substance	Mechanism of action	Data situation	Level of evidence
Azathioprine	Purine synthesis blockade (TPMT-dependent); inhibits T and B cell proliferation	Retrospective studies; national RCT ongoing (France, TOMATO study)	IIb-III (off-label)
Mycophenolate mofetil (MMF)	Inosine monophosphate dehydrogenase inhibitor; inhibits lymphocyte proliferation	Case series; possibly effective, lower relapse prevention than rituximab	III (off-label)
Rituximab	Anti-CD20 → B-cell depletion; inhibits MOG-IgG production	Largest retrospective cohort; effective, not for everyone; increased risk of infection	IIb (off-label)
Tocilizumab	Anti-IL-6Rα (iv); blocks IL-6 signaling pathway (JAK/STAT3); inhibits Th17/plasma cells	Positive retrospective data; RCT results for NMOSD positive (TANGO)	IIb (off-label)
IVIG (iv/subcutaneous)	Fc receptor saturation; MOG-IgG neutralization; FcRn saturation	Retrospective data positive; option in case of desire to have children, pregnancy, infection	IIb (off-label)

Clinical studies - 2024-2026

For the first time, several randomized, placebo-controlled phase 3 studies are underway for MOGAD, which are expected to provide class I evidence:

study	Substance	Mechanism	Target group	status
cosMOG	Rozanolixizumab (UCB7665)	Anti-FcRn IgG4-mAb: blocks IgG recycling → accelerates IgG degradation, lowers MOG IgG titre ~50 %	Adults (≥18 years), relapsing, ≥1 relapse/12 months	Phase 3, international; first ever MOGAD Phase 3 study
METEOROID	Satralizumab (anti-IL-6R sc.)	Anti-IL-6R (subcutaneous); inhibits JAK/STAT3 → Th17 differentiation, B-cell maturation, IgG production	Adults + adolescents (≥12 yrs); relapsing, preceded by ≥1 relapse	Phase 3, international, ongoing
TOMATO	Azathioprine	Purine synthesis inhibition; broadly immunosuppressive	French multicenter study; adults with MOGAD	National RCT, phase 3
MOGwAI	Not specified (Observational)	Biomarker study: validation of MOG-IgG titer, sNfL, sGFAP, sCD83 as progression markers	International cohort study	Ongoing

New and future therapy concepts

Based on the molecular findings of recent years, the following approaches for MOGAD are discussed:

BTK inhibitors (Bruton's tyrosine kinase)

BTK is a central kinase in the B-cell receptor signaling cascade (PI3K/AKT/MAPK). Tolebrutinib and other BTK inhibitors are in MS and NMOSD research; clinical trials are pending for MOGAD. Oral application would be an advantage. Inhibition of both B-cell activation and myeloid cells (microglia-BTK).

Tolerance induction (MOG tolerization)

Antigen-specific tolerance induction (e.g. via MOG peptides or nanoparticle-based approaches) is a promising concept. The Guthy-Jackson Charitable Foundation promotes research into curative approaches. Advantage: No global immunosuppression, Selective elimination of MOG autoreactivity.

Complement inhibitors

Since complement activation (C3a, C5a, MAC) is detectable in MOGAD lesions, it would be Eculizumab (Anti-C5) or a C3 inhibitor is theoretically effective. However, as the MAC complex (C5b-9) is formed to a much lesser extent in MOGAD than in NMOSD (where Eculizumab is approved), the clinical relevance is uncertain.

Anti-neonatal Fc receptor strategies

Besides Rozanolixizumab will also Efgartigimod (an IgG-Fc fragment that competitively blocks FcRn) for other IgG-mediated diseases. Since the pathomechanism of FcRn blockade directly lowers MOG IgG levels, this is a particularly target-oriented approach.

Autologous hematopoietic stem cell transplantation (aHSCT)

For severe, refractory courses, aHSCT is a potentially curative concept: deep immunoablation and reconstitution of the immune system could eliminate the autoreactive T and B cell clones. Data for MOGAD very limited; use only in specialized centers.

Biomarkers and follow-up monitoring

Biomarker-based therapy decisions are the goal of current research:

• MOG-IgG titer (serum)
  Persistence correlates with relapse risk; in monophasic course often spontaneous drop in titer; therapy decision co-determinant
• Serum Neurofilament Light (sNfL)
  Marker for axonal damage; elevated during relapse; normalization as therapy response marker
• Serum GFAP (sGFAP)
  Astrocytic activation; lower in MOGAD than in NMOSD; can provide complementary information
• sCD83
  New candidate biomarker (under validation); possibly marker for dendritic cell activation and immune activity
• Cerebrospinal fluid cell count and protein
  Pleocytosis during episodes of thrust; normalization after therapy

Forecast and special features

Compared to AQP4+ NMOSD, MOGAD tends to show a More favorable forecast, especially better visual recovery after ON. However, the following aspects are important:

• Monophasic progression
  Approx. 50% of patients; often spontaneous drop in titer; no long-term therapy may be necessary
• Thrust-shaped progression
  Approx. 50%; higher titer persists; cumulative disability build-up possible, but slower than NMOSD
• No progressive course
  In contrast to MS, no gradual progression without relapses has been described
• Steroid sensitivity and steroid dependence
  Many patients respond very well to corticosteroids, but: rapid withdrawal often triggers relapses
• Special pediatric feature
  ADEM most common first manifestation in children (<10 years); prognosis often good, but note risk of recurrence
• Pregnancy: thin data
  No generally increased risk of relapse during pregnancy, but puerperium could be a risk factor (analogous to MS)

Summary and outlook

MOGAD is an independent, antibody-mediated autoimmune disease of the CNS that is characterized by the following key features:

• The MOG protein on the outside of oligodendrocytes and myelin sheaths is the target antigen
• Pathogenic MOG-IgG1 autoantibodies damage myelin via two parallel effector pathways: complement activation (CDC, ca. 50%) and FcγR binding (ADCC/ADCP, ca. 50%)
• In addition, the antibodies strengthen T-cell activation via FcγR mechanisms
• The IL-6/JAK/STAT3 signaling pathway promotes Th17 differentiation and plasma cell maturation and is a key therapeutic target
• There are currently no approved therapies (as of Feb. 2026); first phase 3 RCTs are underway (cosMOG with rozanolixizumab, METEOROID with satralizumab)
• Therapy is moving towards risk-adapted, biomarker-based strategies

The most important research progress in recent years has been the precise decoding of effector mechanisms (complement vs. FcR pathway) by research groups such as that of Meinl, Mader, Kawakami (LMU Munich), which has direct implications for therapy development: An optimal therapeutic approach must address IgG production (anti-CD20, FcRn inhibitors) as well as effector mechanisms (complement, FcγR) and the Th17/IL-6 axis.

Tolerance induction strategies and BTK inhibitors represent future, mechanistically based therapeutic principles that are likely to be clinically tested in the coming years.

Essential oils - active ingredients arranged according to signaling pathways

The active substances can be clustered according to their points of attack in MOGAD pathophysiology. This is crucial because MOGAD has three main axes:

• Th17/IL-6
• Complement system/oligodendrocyte protection
• Remyelination/OPC differentiation.

Frankincense (Boswellia serrata) - AKBA and incensol acetate

According to BCP, this is the most scientifically substantiated candidate for MOGAD and is exceptional in its range of effects.

AKBA (3-O-acetyl-11-keto-β-boswellic acid) is the main active principle. AKBA has multiple physiological effects, including anti-infectious, anti-tumor and antioxidant effects as well as proven neuroprotective effects. It promotes nerve repair and regeneration, protects against ischemic brain damage, inhibits neuroinflammation and improves memory deficits. European Academy of Neurology

AKBA inhibits STAT3 dose-dependent, a key mechanism as STAT3 is the main effector transcription factor of the IL-6/JAK signaling pathway that drives Th17 differentiation and plasma cell maturation in MOGAD. Moreover, activation of the Nrf2/HO-1 pathway by AKBA provides a direction for the reduction of oxidative damage, prevention of demyelination and promotion of remyelination. ACS Publications

AKBA acts as a molecular switch that blocks leukotriene formation through allosteric modulation of 5-LOX and 15-LOX, but at the same time stimulates the production of SPM (Specialized Pro-Resolving Mediators). This actively shifts the immune response in the direction of Resolution of the inflammation, not just their damping. PubMed

Incensol acetate (volatile component of frankincense essential oil, happens BHS) activates TRPV3 channels in neurons as well as PPAR-γ - Frankincense components can significantly reduce IL-6, TNF-α and GFAP (marker for astrocyte activation) in the brain after induced inflammation. Neurology

Important quality note: There are considerable differences in quality between Boswellia products, some products (e.g. H15 Ayurmedica®) contained only trace amounts of the characteristic boswellic acids (0.31 mg AKBA) in analyses. In contrast, products such as BOSWELLIASAN® (7.51 mg) and Sallaki® Tablets (7.88 mg) showed substantial amounts of AKBA and correspondingly potent pharmacological effects. Analysis of Boswellic Acid Contents and Related Pharmacological Activities of Frankincense-Based Remedies That Modulate Inflammation and Frontiers.

The doTERRA product Frankincense Boswellic Acid Complex contains 37.5 mg AKBA*

Therapeutically relevant AKBA target doses

The following picture emerges from clinical and preclinical research:

Application goal	AKBA daily dose	source
Anti-inflammatory (general)	100-200 mg	Human studies joint/intestine
NF-κB / STAT3 inhibition (neuroinflammation)	200-400 mg	Animal models, cell culture
Optimal CNS effect (barrier passage)	200-300 mg	Experimental data
Upper well-tolerated daily dose	400-600 mg	Tolerance studies

Conversion to 37.5 mg AKBA per capsule

Target AKBA daily dose	Units/day	Practical scheme
150 mg	4 units	2 × in the morning + 2 × in the evening
200 mg	5-6 units	3 × in the morning + 2-3 × in the evening
300 mg	8 units	4 × in the morning + 4 × in the evening
400 mg	10-11 units	3 × 3-4 units daily

Recommended entry: 4 units daily (= 150 mg AKBA), divided into 2 gifts.

After 2 weeks - if well tolerated - increase to 6 units (= 225 mg).

Important instructions for use

Fat is crucial: AKBA is highly lipophilic, the Bioavailability increases by 2-3 times, when taken with a fatty meal. Olive oil, avocado or a main meal are ideal. Taking it on an empty stomach drastically reduces absorption.

Timing: AKBA has a half-life of approx. 6 hours, therefore 2-3 doses daily This makes more sense than a single dose in order to maintain an even level of effectiveness.

Combination with BCP: AKBA (STAT3/NF-κB axis) and BCP (CB2/Th17 axis) address different signaling pathways in MOGAD and act synergistically. There are no known pharmacological interactions.

Gastric tolerance: Boswellia is generally very well tolerated. Slight stomach irritation rarely occurs with higher doses. Therefore, always take with a meal or reduce the dose temporarily if necessary.

Black pepper (oral)

The main active ingredient β-caryophyllene (BCP) in black pepper oil (Piper nigrum) causes a decrease in the inflammatory cytokines IL-6, TNF-α, IL-17, IFN-γ and the transcription factors of Th17 (ROR-γt) and Th1 (T-bet), as well as a significant increase in the anti-inflammatory cytokines TGF-β1, IL-10, IL-4 and the transcription factors of Th2 (GATA3) and Treg (Foxp3). These effects are strictly linked to CB2 receptor activation.

CB2 receptors and remyelination are directly linked mechanistically: CB2 agonism promotes the maturation of OPCs - a next-generation CB2 agonist (Yhhu4952) significantly increased the expression of myelin basic protein (MBP) and the proportion of mature oligodendrocytes in the corpus callosum.

Dosage for black pepper: 20 ... 200 mg/d - corresponding to 20 tr./d - so it is best to take 7 trp. every 8 hours (preferably 5 trp. every 6 hours for higher plasma levels) in carrier oil in capsule. As lipophilic together with high-fat food/drink.

Black pepper (inhalation)

Dosage: Inhale 3 trp. every 4 hours during the day (half-life is 2-4 hours) onto the Liqui-Pad of the heated diffuser for 20 minutes and hold your breath for about 5-8 seconds after each deep breath, leave the diffuser running in the room at night, no direct inhalation.

Black pepper may have a stimulating effect and impair sleep. In this case, do not diffuse at night.

If the respiratory tract becomes irritated (dryness) or a headache develops: Reduce dose or increase intervals.

Copaiba oil (oral) - doTERRA ONLY

52.6 % BCP - corresponds to 14.7 mg BCP/drop - as BCP is lipophilic, always take with high-fat food/drink!

According to clinical safety studies, this results in the following dosage recommendation based on body weight:

MOGAD-specific dosage table (doTERRA Copaiba 52.5 % BCP)

Body weight	Conservation (0.4 mg/kg)	Active thrust (1.0 mg/kg)	Intensive therapy (1.5 mg/kg)
50 kg	20 mg = 1-2 drops	50 mg = 3-4 drops	75 mg = 5 drops
60 kg	24 mg = 2 drops	60 mg = 4 drops	90 mg = 6 drops
70 kg	28 mg = 2 drops	70 mg = 5 drops	105 mg = 7 drops
80 kg	32 mg = 2 drops	80 mg = 5-6 drops	120 mg = 8 drops
90 kg	36 mg = 2-3 drops	90 mg = 6 drops	135 mg = 9 drops
100 kg	40 mg = 3 drops	100 mg = 7 drops	150 mg = 10 drops

MOGAD phase-adapted dosing

Phase 1: Acute flare-up (first 2-4 weeks)

Target: Aggressive Th17 suppression, IL-6 reduction

• Dosage: 1.0-1.5 mg/kg daily
• Allocation: 3× daily (optimal for continuous CB2 receptor activation)
• Example 70 kg: 5-7 drops daily, distributed as 2+2+3 drops
• Combination: With AKBA (200-300 mg/day for STAT3 inhibition) + high-dose cortisone (standard)

Phase 2: relapse remission / maintenance (long-term)

Target: Relapse prevention, constant anti-inflammatory tone

• Dosage: 0.4-0.7 mg/kg daily
• Allocation: 2× daily
• Example 70 kg: 2-3 drops daily, distributed as 1+2 or 2+2
• Combination: With AKBA (150 mg/day) optional

Phase 3: Monophasic course (titer decreasing)

Target: Neuroprotection, remyelination

• Dosage: 0.2-0.4 mg/kg daily
• Allocation: 1-2× daily
• Example 70 kg: 1-2 drops daily
• Balancing possible after 6-12 months of stable seronegativity

Sources

• Toxicology (700 mg/kg NOAEL)
  https://pubmed.ncbi.nlm.nih.gov/27358239/
• EAE model (2.5-5 mg/kg effective)
  https://pmc.ncbi.nlm.nih.gov/articles/PMC10377147/
• Human study (100 mg safe)
  https://pmc.ncbi.nlm.nih.gov/articles/PMC9104399/
• Clinical study (126 mg/day effective)
  https://accurateclinic.com/accurate-education-terpenes-caryophyllene/

Copaiba oil (inhalation)

In addition to black pepper with a maximum of 38% BCP, copaiba oil with up to 87% BCP is far more potent and therefore the best choice for inhalation.
Diffusers generally work with cold ultrasonic (US) atomization. However, BCP only vaporizes from around 130 °C and burns at temperatures above 180 °C. For this reason, heatable, temperature-controlled diffusers must be used (e.g. Volcano Classic, Volcano Hybrid or Mighty+) in the price segment of approx. 270 - 415 euros and the temperature should be set as precisely as possible (check with an IR thermometer) to 160 °C.

Recommended dosage for Copaiba oil (doTERRA) with 69 % BCP content - 1 drop contains 18.6 mg BCP.

BCP has a half-life of 2-4 hours. In order to achieve as constant a level of active ingredient as possible, inhalation - as described above - should be carried out with 4 drops (equivalent to approx. 200 mg BCP) every 4 hours. A diffuser can be left running near the bed during the night.

Target doses and required number of drops

Target BCP dose	Drops of Copaiba oil	Total oil (mg)
20 mg BCP (starting dose)	~1 drop	~29 mg
50 mg BCP	~3 drops	~72 mg
100 mg BCP (therapeutic)	~5-6 drops	~145 mg
120 mg BCP (upper daily dose)	~6-7 drops	~174 mg

Target-inhaled BCP	Quantity of oil on liquid pad	Drops
~20 mg BCP inhaled	~40 mg oil (~78 mg/0.69)	2-3 drops
~50 mg BCP inhaled	~100 mg oil	4-5 drops

Synergistic MOGAD strategy (multi-target)

Since MOGAD has three pathomechanisms, this evidence-based combination results:

Active ingredient	dose	Signal path	MOGAD relevance
BCP (oral)	0.4-1.5 mg/kg	CB2 → Th17↓, IL-6↓, Nrf2/HO-1↑	★★★★★
AKBA (oral)	200-400 mg/day	STAT3↓, NF-κB↓, 5-LOX↓	★★★★★
BCP (inhaled, 160 °C)	2-3 drops, 2×/day	Limbic, rapid CNS penetration	★★★
Frankincense oil (inhaled)	3-4 drops, 2×/day	Incensol acetate → TRPV3, PPAR-γ	★★★

This four-pillar strategy addresses:

• Th17/IL-6 (BCP oral + AKBA)
• STAT3 (AKBA)
• Oligodendrocyte protection (BCP Nrf2 activation)
• Limbic modulation (inhalation)

Important MOGAD-specific information

1. No monotherapy - BCP/AKBA are Add-ons to conventional therapy
   (cortisone acute, if necessary rituximab/MMF/IVIG prophylactic) - never as a substitute
2. Biomarker monitoring:
   • MOG-IgG titer every 3-6 months
   • sNfL (Neurofilament Light) as an activity marker
   • Consider reducing the dose if titres fall permanently
3. Observe thrust trigger - Infections are the main trigger
   In case of infection, dose if necessary temporarily increase to 1.5 mg/kg (preventive)
4. Liver values for Copaiba - If >1 mg/kg for >3 months
   Check ALT/AST every 3 months
5. Black pepper alternative - For Copaiba concerns: Black pepper oil (25-38 % BCP)
   Then calculate the number of drops × 2

α-Asarone (calamus oil, Acorus calamus) - directly oligodendrocyte-protective

One of the few active ingredients with direct remyelination effect is α-Asaron. It improves dysmyelination due to loss of mature oligodendrocytes after hypoxia-ischemia by upregulation and activation of PPAR-γ in astrocytes. This increases the expression of the glutamate transporter GLT-1 and removes excessive glutamate from the extracellular space, which would otherwise cause glutamate-mediated excitotoxicity in OPCs, inhibit their differentiation and induce cell death. Heidelberg University Hospital

PPARy in Neurology - Frontiers Editorial 2022

Attention: Depending on its origin, calamus oil contains varying amounts of β-asarone, which is classified as mutagenic. Only β-Asarone-free qualities (Acorus calamus var. americanus).

According to the current status (02.2026), market availability is not given.

Geranium oil (Pelargonium graveolens) - Neuroinflammation and NO

Geranium oil may be useful in neurodegenerative diseases where neuroinflammation is part of the pathophysiology.
Main active ingredient Citronellol showed excellent inhibitory activity on NO production at higher concentrations, whereby synergistic interactions between the components are crucial.
Citronellol also inhibits NF-κB - directly relevant for microglial activation in MOGAD.

Tea tree oil (Melaleuca alternifolia) - Microglia modulation

Tea tree oil and its main components inhibit AChE and BChE as well as LOX. The optimization of oxidative stress through antioxidant properties, neuroinflammation inhibition and AChE/BChE inhibition can effectively contribute to the prevention of neuronal cell death as an overall strategy.
Terpinen-4-ol (main active ingredient) also specifically inhibits microglia M1 polarization.

---

Overview of active substances according to MOGAD signaling pathways

Active ingredient	Oil source	MOGAD signal pathway	Strength of the evidence
β-Caryophyllene (BCP)	Black pepper, Copaiba	CB2 → Nrf2/HO-1, PPAR-γ; Th17↓, IL-6↓	★★★★ (EAE model)
AKBA	Frankincense (Boswellia serrata)	STAT3↓, NF-κB↓, 5-LOX↓, SPM↑, Nrf2/HO-1↑	★★★★ (CNS studies)
Incensol acetate	Frankincense (volatile portion)	TRPV3, PPAR-γ, IL-6↓, GFAP↓	★★★ (animal model)
α-Asaron	Calamus (Acorus calamus)	PPAR-γ → GLT-1↑ → OPC protection, direct remyelination	★★★ (hypoxia model)
Linalool	Lavender, lemon balm	NMDA modulation, SERT, neuroprotection	★★★
1,8-Cineole	Eucalyptus, rosemary	AChE inhibition, antioxidant	★★★ (proven in the brain)
Citronellol	Geranium	NO↓, NF-κB↓, synergy effects	★★
Terpinen-4-ol	Tea tree	Microglia M1↓, LOX↓, AChE↓	★★

Sources and further reading

• Banwell B et al - Lancet Neurol. 2023;22:268-282 Diagnostic criteria MOGAD
  PubMed (free): https://pubmed.ncbi.nlm.nih.gov/36706773/
  ScienceDirect (Abstract free, full text with costs): https://www.sciencedirect.com/science/article/abs/pii/S1474442222004318
  DOI: https://doi.org/10.1016/S1474-4422(22)00431-8
• Mader S et al - PNAS 2023 (Note: referred to as „PNAS 2024" in our document - the correct publication year is March 2023) Complement vs. FcR pathomechanism, LMU Munich
  PNAS full text (free): https://www.pnas.org/doi/10.1073/pnas.2300648120
  LMU press release (with explanation): https://www.med.lmu.de/bmc/en/news/latest-news/news-overview/news/autoimmune-disease-mogad-insights-into-pathomechanisms.html
  EAN commentary: https://www.ean.org/research/resources/neurology-updates/detail/complement-dependent-and-independent-pathomechanisms-of-myelin-oligodendrocyte-glycoprotein-mog-abs-implications-for-therapeutic-strategies-in-mog-antibody-associated-disease-mogad
• Kaneko K et al - Neurol Neuroimmunol Neuroinflamm. 2024;11(5):e200293 CSF complement activation
  The article e200293 is cannot be found directly - However, the related MOGAD review article from the same issue (e200275 by Moseley/Zamvil) is available:
  Neurology NXI (e200275, same issue): https://www.neurology.org/doi/10.1212/NXI.0000000000200275
  PubMed search for Kaneko 2024 MOGAD CSF: https://pubmed.ncbi.nlm.nih.gov/38996203/ (leads to e200275 - direct PubMed search recommended for e200293)
• Cho EB et al - Front Immunol. 2024;15:1320094 Complementary pattern MOGAD vs. NMOSD
  Frontiers (Full text free): https://doi.org/10.3389/fimmu.2024.1320094 (DOI directly accessible)
• Frontiers Immunol. 2025 - EAE models, MOGAD pathogenesis (Generally referred to in the document - this refers to the overview article on signaling pathways/pathomechanisms)
  Frontiers Immunol. 2025 (Sun et al., PMID 40406135): https://doi.org/10.3389/fimmu.2025.1535571
• PMC 2023 - Comprehensive Review Pathophysiology MOGAD
  PMC Full text (free): https://pmc.ncbi.nlm.nih.gov/articles/PMC9597055/
• PMC 2024 - Updated Review Clinical Spectrum, Pathogenesis, Treatment
  PubMed/PMC (Trewin et al., Autoimmun Rev 2025): https://pubmed.ncbi.nlm.nih.gov/39577549/
  PMC full text: https://pmc.ncbi.nlm.nih.gov/articles/PMC9294102/ (Monoclonal Antibody Therapies NMOSD/MOGAD)
• Stögbauer J et al - Autoimmunity Reviews 2025;103970 Therapeutic Approaches Adults MOGAD
  ScienceDirect (Open Access, full text free): https://www.sciencedirect.com/science/article/pii/S1568997225002319
  DOI: https://doi.org/10.1016/j.autrev.2025.103970
  German summary: https://www.reine-nervensache.de/therapieansaetze-bei-mogad-von-der-akutbehandlung-zur-langfristigen-strategie/
• Expert Opinion on Emerging Drugs 2025 - Clinical Trial Landscape
  Tandfonline (Abstract free, full text with costs): https://www.tandfonline.com/doi/full/10.1080/14728214.2025.2565189
  DOI: https://doi.org/10.1080/14728214.2025.2565189
  
• NEMOS study group https://www.nemos-net.de
  
• Patient-oriented study overview (cosMOG/METEOROID):
  The MOG project - https://mogproject.org/clinical-trials/
  ClinicalTrials.gov - cosMOG - https://clinicaltrials.gov/study/NCT05063162

All contents have been conscientiously researched and reflect the current (02.2026) published state of knowledge. It is for information purposes only and does not replace a professional medical consultation.
All dosage recommendations must be agreed with the attending physician.
Linked studies provide the practitioner with further medical and scientific information.