Myelin Oligodendrocyte Glycoprotein Research Articles

A Simple Score (MOG-AR) to Identify Individuals at High Risk of Relapse After MOGAD Attack.

To identify predictors for relapse in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and to develop and validate a simple risk score for predicting relapse. In China National Registry of Neuro-Inflammatory Diseases (CNRID), we identified patients with MOGAD from March 2023 and followed up prospectively to September 2023. The primary endpoint was MOGAD relapse, confirmed by an independent panel. Patients were randomly divided into model development (75%) and internal validation (25%) cohorts. Prediction models were constructed and internally validated using Andersen-Gill models. Nomogram and relapse risk score were generated based on the final prediction models. A total of 188 patients (comprising 612 treatment episodes) were included in cohorts. Female (HR: 0.687, 95% CI 0.524-0.899, p = 0.006), onset age 45 years or older (HR: 1.621, 95% CI 1.242-2.116, p < 0.001), immunosuppressive therapy (HR: 0.338, 95% CI 0.239-0.479, p < 0.001), oral corticosteroids >3 months (HR 0.449, 95% CI 0.326-0.620, p < 0.001), and onset phenotype (p < 0.001) were identified as factors associated with MOGAD relapse. A predictive score, termed MOG-AR (Immunosuppressive therapy, oral Corticosteroids, Onset Age, Sex, Attack phenotype), derived in prediction model, demonstrated strong predictive ability for MOGAD relapse. MOG-AR score of 13-16 indicates a higher risk of relapse (HR: 3.285, 95% CI 1.473-7.327, p = 0.004). The risk of MOGAD relapse seems to be predictable. Further validation of MOG-AR score developed from this cohort to determine appropriate treatment and monitoring frequency is warranted. CNRID, NCT05154370, registered December 13, 2021, first enrolled December 15, 2021.

High-yield production of recombinant human myelin oligodendrocyte glycoprotein in SHuffle bacteria without a refolding step

Experimental autoimmune encephalomyelitis (EAE) is a model for central nervous system (CNS) autoimmune demyelinating diseases such as multiple sclerosis (MS) and MOG antibody-associated disease (MOGAD). Immunization with the extracellular domain of recombinant human MOG (rhMOG), which contains pathogenic antibody and T cell epitopes, induces B cell-dependent EAE for studies in mice. However, these studies have been hampered by rhMOG availability due to its insolubility when overexpressed in bacterial cells, and the requirement for inefficient denaturation and refolding. Here, we describe a new protocol for the high-yield production of soluble rhMOG in SHuffle cells, a commercially available E. coli strain engineered to facilitate disulfide bond formation in the cytoplasm. SHuffle cells can produce a soluble fraction of rhMOG yielding >100 mg/L. Analytical size exclusion chromatography multi-angle light scattering (SEC-MALS) and differential scanning fluorimetry of purified rhMOG reveals a homogeneous monomer with a high melting temperature, indicative of a well-folded protein. An in vitro proliferation assay establishes that purified rhMOG can be processed and recognized by T cells expressing a T cell receptor (TCR) specific for the immunodominant MOG35–55 peptide epitope. Lastly, immunization of wild-type, but not B cell deficient, mice with rhMOG resulted in robust induction of EAE, indicating a B cell-dependent induction. Our SHuffle cell method greatly simplifies rhMOG production by combining the high yield and speed of bacterial cell expression with enhanced disulfide bond formation and folding, which will enable further investigation of B cell-dependent EAE and expand human research of MOG in CNS demyelinating diseases.

Overview of emerging therapies for demyelinating diseases.

This paper provides an overview of autoimmune disorders of the central nervous system, specifically those caused by demyelination. We explore new research regarding potential therapeutic interventions, particularly those aimed at inducing remyelination. Remyelination is a detailed process, involving many cell types-oligodendrocyte precursor cells (OPCs), astrocytes, and microglia-and both the innate and adaptive immune systems. Our discussion of this process includes the differentiation potential of neural stem cells, the function of adult OPCs, and the impact of molecular mediators on myelin repair. Emerging therapies are also explored, with mechanisms of action including the induction of OPC differentiation, the transplantation of mesenchymal stem cells, and the use of molecular mediators. Further, we discuss current medical advancements in relation to many myelin-related disorders, including multiple sclerosis, optic neuritis, neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein antibody-associated disease, transverse myelitis, and acute disseminated encephalomyelitis. Beyond these emerging systemic therapies, we also introduce the dimethyl fumarate/silk fibroin nerve conduit and its potential role in the treatment of peripheral nerve injuries. Despite these aforementioned scientific advancements, this paper maintains the need for ongoing research to deepen our understanding of demyelinating diseases and advance therapeutic strategies that enhance affected patients' quality of life.

In Silico Modeling of Myelin Oligodendrocyte Glycoprotein Disulfide Bond Reduction by Phosphine-Borane Complexes

Background: Neurodegenerative diseases can cause vision loss by damaging retinal ganglion cells in the optic nerve. Novel phosphine-borane compounds (PBs) can protect these cells from oxidative stress via the reduction of disulfide bonds. However, the specific targets of these compounds are unknown. Proteomic evidence suggests that myelin oligodendrocyte glycoprotein (MOG) is a potential target. MOG is of significant interest due to its role in anti-MOG optic neuritis syndrome. Methods: We used in silico modeling to explore the structural consequences of cleaving the extracellular domain MOG disulfide bond, both in isolation and in complex with anti-MOG antibodies. The potential binding of PBs to this bond was examined using molecular docking. Results: Cleaving the disulfide bond of MOG altered the structure of MOG dimers and reduced their energetic favorability by 46.13 kcal/mol. The energy profiles of anti-MOG antibody complexes were less favorable when the disulfide bond of MOG was reduced in the monomeric state by 55.21 kcal/mol, but the reverse was true in the dimeric state. PBs exhibited reducing capabilities with the MOG extracellular disulfide bond, with this best-scoring compound binding with an energy of −28.54 kcal/mol to the MOG monomer and −24.97 kcal/mol to the MOG dimer. Conclusions: These findings suggest that PBs can affect the structure of MOG dimers and the formation of antibody complexes by reducing the MOG disulfide bond. Structural changes in MOG could have implications for neurodegenerative diseases and anti-MOG syndrome.

MOG-specific CAR Tregs: a novel approach to treat multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS) with the immune system attacking myelin sheaths leading to neuronal death. While several disease-modifying therapies are available to treat MS, these therapies are not universally effective and do not stop disease progression. More personalized long-term treatment options that target specific aspects of the disease, such as reducing relapse frequency, delaying disability accumulation, and addressing symptoms that impact daily functioning, as well as therapies that can promote neuroprotection and repair are needed. Chimeric Antigen Receptor (CAR) Tcell therapies have revolutionized cancer treatment by intravenously (IV) administering a defined dose of T cells with high specificity provided by the CAR. An autologous CAR T cell therapy using suppressive regulatory T cells (Tregs) inducing long-lasting tolerance would be the ideal treatment for patients. Hence, we expanded the application of CAR-T cells by introducing a CAR into Tregs to treat MS patients. We developed a myelin oligodendrocyte glycoprotein (MOG)-specific CAR Treg cell therapy for patients with MS. MOG is expressed on the outer membrane of the myelin sheath, the insulating layer the forms around nerves, making it an ideal target for CAR Treg therapy. Our lead candidate is a 2nd generation CAR, composed of an anti-MOG scFv screened from a large human library. In vitro, we demonstrated CAR-dependent functionality and showed efficacy in vivo using a passive EAE mouse model. Additionally, the MOG-CAR Tregs have very low tonic signaling with a desirable signal-to-noise ratio resulting in a highly potent CAR. In summary our data suggest that MOG-CAR Tregs are a promising MS treatment option with the potential to induce long-lasting tolerance in patients.

Myelin oligodendrocyte glycoprotein antibody–associated disease with histopathologic features of primary CNS angiitis without demyelination: Case report and literature review

Primary angiitis of the central nervous system (PACNS) is a rare inflammatory disease that affects both small- and medium-sized vessels of the CNS, while myelin oligodendrocyte glycoprotein (MOG) antibody–associated disease (MOGAD) is a novel antibody-mediated inflammatory demyelinating disorder that causes damage to the myelin in CNS. We report a case diagnosed as MOGAD due to a history of recurrent myelitis, brain lesions, and positive anti-MOG, but the brain biopsy showed vasculitis without demyelination.

From Organotypic Mouse Brain Slices to Human Alzheimer’s Plasma Biomarkers: A Focus on Nerve Fiber Outgrowth

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by memory loss and progressive deterioration of cognitive functions. Being able to identify reliable biomarkers in easily available body fluids such as blood plasma is vital for the disease. To achieve this, we used a technique that applied human plasma to organotypic brain slice culture via microcontact printing. After a 2-week culture period, we performed immunolabeling for neurofilament and myelin oligodendrocyte glycoprotein (MOG) to visualize newly formed nerve fibers and oligodendrocytes. There was no significant change in the number of new nerve fibers in the AD plasma group compared to the healthy control group, while the length of the produced fibers significantly decreased. A significant increase in the number of MOG+ dots around these new fibers was detected in the patient group. According to our hypothesis, there are factors in the plasma of AD patients that affect the growth of new nerve fibers, which also affect the oligodendrocytes. Based on these findings, we selected the most promising plasma samples and conducted mass spectrometry using a differential approach and we identified three putative biomarkers: aldehyde-dehydrogenase 1A1, alpha-synuclein and protein S100-A4. Our method represents a novel and innovative approach for translating research findings from mouse models to human applications.

Amelioration of experimental autoimmune encephalomyelitis by exogenous soluble PD-L1 is associated with restraining dendritic cell maturation and CCR7-mediated migration

Dendritic cells (DCs) orchestrate both immune activation and immune tolerance in multiple sclerosis (MS). Manipulating the phenotypes and functions of DCs to boost their tolerogenic potential is an appealing strategy for treating MS and its animal model experimental autoimmune encephalomyelitis (EAE). Programmed cell death 1 (PD-1) delivers the immunoinhibitory signals by interacting with PD-1 ligand 1 (PD-L1), which plays a critical role in maintaining immune tolerance. So far, the effects of PD-1/PD-L1 signalling activation on DCs in EAE are poorly understood. Here, the administration of soluble PD-L1 (sPD-L1) protein significantly alleviated the clinical symptoms of myelin oligodendrocyte glycoprotein (MOG)-induced EAE, and inhibited the expression of cluster of differentiation (CD)86, C-C motif chemokine receptor 7 (CCR7) as well as CCR7-mediated trafficking of splenic DCs, accompanied by enhancing their phagocytosis. The impact of sPD-L1 on the surface morphology and mechanical properties of DCs was investigated at the nanoscale, using scanning electron microscope and atomic force microscope. The treatment of sPD-L1 was found to mitigate morphological maturation and biomechanical alterations, specifically in terms of adhesion and elasticity, in bone marrow-derived DCs from EAE. Taken together, our findings suggest that application of exogenous sPD-L1 has a marked suppressive effect on the maturation and migration of DCs in EAE. PD-L1 administration may be a promising therapy for EAE and for MS in the future.

Cognitive and academic outcomes in children with myelin oligodendrocyte glycoprotein antibody-associated disease.

To describe the impact of paediatric myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) on academic and cognitive outcomes. This was an observational, retrospective, and descriptive single-centre study, carried out on a paediatric case series of children with MOGAD. A total of 51 patients were included (22 females); their median age was 8 years and the median follow-up duration was 31.1 months (interquartile range 23.5). The most frequent clinical presentation was acute disseminated encephalomyelitis (54.9%), followed by optic neuritis (35.5%). At the last follow-up, regardless of the clinical phenotype at disease onset, 39.5% of patients with MOGAD received academic and educational interventions (p < 0.05 compared to before disease onset), including academic accommodations (p < 0.05) or the need for a learning support assistant (p < 0.05). Ten patients were evaluated with the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V). The overall IQ was calculated for six patients (mean = 92); two of these patients had an IQ lower than 85. No difference was found regarding prenatal and neonatal neurodevelopmental characteristics between this cohort and the general population. MOGAD was associated with a need for academic support; lower scores were found on the WISC-V. Patients with MOGAD should receive cognitive and academic assessments to inform educational planning and support academic success.

Oral corticosteroid dosage and taper duration at onset in myelin oligodendrocyte glycoprotein antibody-associated disease influences time to first relapse

BackgroundWe sought to identify an optimal oral corticosteroid regimen at the onset of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), which would delay time to first relapse while minimising cumulative corticosteroid...

Employment, work hours, and wages in adults with myelin oligodendrocyte glycoprotein antibody disease: An international cohort study.

The objectives were to understand the employment impacts of myelin oligodendrocyte glycoprotein-associated antibody disease (MOGAD) on adults in an international cohort by determining lost employment, work hours, and wages. Clinically, MOGAD can be associated with significant disability; however, its socioeconomic consequences for adults are barely reported. Participants of potential working age (18-70 years old) with neurologist-diagnosed MOGAD were recruited from clinical sites in 13 countries, April 2022 to August 2023. Each participant completed a one-time survey. Regression models assessed associations with post-MOGAD (1) unemployment and (2) work hours. A total of 117 participants (66.7% female), mean age 39.7 years, median disease duration 3 years (25th, 75th percentile: 1, 7) were analyzed. Employment post-MOGAD reduced from 74 (63.2%) to 57 (48.7%) participants. Participants employed pre-diagnosis reduced their work hours, on average, from 31.6 hours/week to 19.5 hours/week post-diagnosis. Residence in a high-income country was statistically significantly associated with post-diagnosis employment and higher weekly work hours. Depressed mood was associated with unemployment. MOGAD-related pain and history of myelitis were independently associated with lost work hours. MOGAD can have significant impacts on adult employment, particularly in non-high-income countries. Depressed mood and pain are potentially modifiable factors related to socioeconomic status in MOGAD.

Infections Combined With Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease: A Case Report and Systematic Review of the Literature

Infections Combined With Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease: A Case Report and Systematic Review of the Literature

Plasma proteome-wide analysis of cerebral small vessel disease identifies novel biomarkers and disease pathways.

Cerebral small vessel disease (SVD), as defined by neuroimaging characteristics such as white matter hyperintensities (WMHs), cerebral microhemorrhages (CMHs), and lacunar infarcts, is highly prevalent and has been associated with dementia risk and other clinical sequelae. Although conditions such as hypertension are known to contribute to SVD, little is known about the diverse set of subclinical biological processes and molecular mediators that may also influence the development and progression of SVD. To better understand the mechanisms underlying SVD and to identify novel SVD biomarkers, we used a large-scale proteomic platform to relate 4,877 plasma proteins to MRI-defined SVD characteristics within 1,508 participants of the Atherosclerosis Risk in Communities (ARIC) Study cohort. Our proteome-wide analysis of older adults (mean age: 76) identified 13 WMH-associated plasma proteins involved in synaptic function, endothelial integrity, and angiogenesis, two of which remained associated with late-life WMH volume when measured nearly 20 years earlier, during midlife. We replicated the relationship between 9 candidate proteins and WMH volume in one or more external cohorts; we found that 11 of the 13 proteins were associated with risk for future dementia; and we leveraged publicly available proteomic data from brain tissue to demonstrate that a subset of WMH-associated proteins was differentially expressed in the context of cerebral atherosclerosis, pathologically-defined Alzheimer's disease, and cognitive decline. Bidirectional two-sample Mendelian randomization analyses examined the causal relationships between candidate proteins and WMH volume, while pathway and network analyses identified discrete biological processes (lipid/cholesterol metabolism, NF-kB signaling, hemostasis) associated with distinct forms of SVD. Finally, we synthesized these findings to identify two plasma proteins, oligodendrocyte myelin glycoprotein (OMG) and neuronal pentraxin receptor (NPTXR), as top candidate biomarkers for elevated WMH volume and its clinical manifestations.

The Patient Journey in Myelin Oligodendrocyte Glycoprotein Antibody Disease (MOGAD): Results From Cross-sectional Patient and Physician Surveys

The Patient Journey in Myelin Oligodendrocyte Glycoprotein Antibody Disease (MOGAD): Results From Cross-sectional Patient and Physician Surveys

Employment and its Associations in an International Cohort of Myelin Oligodendrocyte Glycoprotein Antibody Disease

Employment and its Associations in an International Cohort of Myelin Oligodendrocyte Glycoprotein Antibody Disease

Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD) or Paraneoplastic Syndrome: A Diagnostic Conundrum

Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD) or Paraneoplastic Syndrome: A Diagnostic Conundrum

Efficacy of Rituximab and Inebilizumab in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD): A Real-World Study

Efficacy of Rituximab and Inebilizumab in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD): A Real-World Study

An Unusual Radiological Presentation of a Common Disorder: Cervical Spinal Cord Enhancement in Spondylotic Myelopathy, Mimicking Myelin Oligodendrocyte Glycoprotein Antibody Associated Disease

An Unusual Radiological Presentation of a Common Disorder: Cervical Spinal Cord Enhancement in Spondylotic Myelopathy, Mimicking Myelin Oligodendrocyte Glycoprotein Antibody Associated Disease

Case Report: Profound Cerebellar Mutism in a Child with Parainfectious Myelin Oligodendrocyte Glycoprotein Antibody-associated Disease (MOGAD) and Cerebellitis

Case Report: Profound Cerebellar Mutism in a Child with Parainfectious Myelin Oligodendrocyte Glycoprotein Antibody-associated Disease (MOGAD) and Cerebellitis

A Case of Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD) with Charcot Marie Tooth Disease (CMT) and Mitofusin 2 Gene (MFN2) Mutation

A Case of Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD) with Charcot Marie Tooth Disease (CMT) and Mitofusin 2 Gene (MFN2) Mutation