The landscape of PBMCs in AQP4-IgG seropositive NMOSD and MOGAD, assessed by high dimensional mass cytometry.

OBJECTIVES: Data on peripheral blood mononuclear cells (PBMCs) characteristics of aquaporin-4 (AQP4)-IgG seropositive neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are lacking. In this study, we describe the whole PBMCs landscape of the above diseases using cytometry by time-of-flight mass spectrometry (CyTOF). METHODS: The immune cell populations were phenotyped and clustered using CyTOF isolated from 27 AQP4-IgG seropositive NMOSD, 11 MOGAD patients, and 15 healthy individuals. RNA sequencing was employed to identify critical genes. Fluorescence cytometry and qPCR analysis were applied to further validate the algorithm-based results that were obtained. RESULTS: We identified an increased population of CD11b+ mononuclear phagocytes (MNPs) in patients with high expression of CCR2, whose abundance may correlate with brain inflammatory infiltration. Using fluorescence cytometry, we confirmed the CCR2+ monocyte subsets in a second cohort of patients. Moreover, there was a wavering of B, CD4+ T, and NKT cells between AQP4-IgG seropositive NMOSD and MOGAD. CONCLUSIONS: Our findings describe the whole landscape of PBMCs in two similar demyelinated diseases and suggest that, besides MNPs, T, NK and B, cells were all involved in the pathogenesis. The identified cell population may be used as a predictor for monitoring disease development or treatment responses.

MOG-specific T cell response amplified in para- and post-SAR-CoV-2 infection in myelin oligodendrocyte glycoprotein antibody-associated disease.

We describe clinical characteristics and deep immunophenotypes in two patients with myelin-oligodendrocyte-glycoprotein (MOG)-antibody-associated-disease after COVID-19. The para-COVID case was a 74-year-old man who developed optic neuritis two days after COVID-19. Immunological assays revealed reduced absolute CD8+ T- and B-cell counts with increased frequency of NK cells. Post-COVID case was a 63-year-old man with optic neuritis six months after COVID-19, a frequency of CD8+ T-cells was elevated with a relatively low fraction of naïve and a high fraction of effector memory CD8+ T-cells. There was increased frequency of CD8+CD38+HLA-DR+ T-cells in the para-COVID case; interestingly, CD4+CD38+HLA-DR+ T cell frequency was increased in the post-COVID case. Both had increased SARS-CoV-2-specific and MOG-specific T-cell responses.

Socioeconomic, Clinical, and Laboratory Parameters Differentiating Pediatric Patients With MOG Antibody-Associated Disease and Multiple Sclerosis.

Studies indicate differences in the clinical phenotypes and neuroimaging of children with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) compared to multiple sclerosis; however, there are limited data assessing the socioeconomic and paraclinical differences between these distinct disorders. This retrospective study identified patients aged <18 years at time of diagnosis with MOGAD or multiple sclerosis. Demographics, birth history, socioeconomic factors (insurance type, median income, parental education level), and paraclinical features (clinical manifestations, laboratory evaluation) were recorded for eligible participants. Seventy-eight patients (28 MOGAD, 50 multiple sclerosis) met inclusion criteria. Mothers of MOGAD children were more likely to have attended college compared to the mothers of children with multiple sclerosis (80% vs 49%; P = .02). Though MOGAD patients had greater rates of day care attendance (81% vs 57%), lower rates of birth complications (7% vs 21%), and higher rates of being breastfed (65% vs 46%), these findings did not meet predefined statistical significance. Clinically, children with MOGAD exhibited a lower body mass index percentile at presentation (58th ± 27th percentile vs 83rd ± 20th percentile; P = .0001) and were younger (7.6 ± 4.1 vs 14.8 ± 1.6 years; P < .0001) and more likely to exhibit an infectious prodrome (57% vs 10%; P < .0001). MOGAD patients were less likely to have evidence of remote Epstein-Barr virus infection (29% vs 100%; P < .0001) and less likely to have ≥3 unique oligoclonal bands in the cerebrospinal fluid (5% vs 87%; P < .001). Compared with multiple sclerosis, children with MOGAD exhibit lower body mass index percentiles at presentation, are more likely to have mothers with higher education levels, and are less likely to have had prior Epstein-Barr virus infection. Our data confirm that MOGAD patients are younger, more likely to exhibit infectious prodrome, and are less likely to exhibit intrathecal synthesis of oligoclonal bands. These features provide new insights into the differentiating pathobiology of MOGAD and may be helpful in differentiating these children from multiple sclerosis early in the diagnostic evaluation.

Marked central canal T2-hyperintensity in MOGAD myelitis and comparison to NMOSD and MS.

OBJECTIVE: To assess marked central canal T2-hyperintensity in patients with myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) myelitis compared to myelitis patients with aquaporin-4-antibody-positive neuromyelitis optica spectrum disorder (AQP4 + NMOSD) and multiple sclerosis (MS). MATERIAL/METHODS: Two blinded raters evaluated spinal cord magnetic resonance imaging (MRIs) of myelitis patients with MOGAD (n = 63), AQP4 + NMOSD (n = 37), and MS (n = 26), assessing for marked central canal T2-hyperintensity and its evolution. If there were conflicting results, a third neurologist assessed the MRI. RESULTS: Marked central canal T2-hyperintensity was more frequent in patients with MOGAD (18/63[29%]) than MS (1/26[4%]; p = 0.01) myelitis but did not differ from AQP4 + NMOSD (13/37[35%]; p = 0.49). Marked central canal T2-hyperintensity had completely resolved on follow-up axial MRI for most MOGAD (12/14[86%]) and AQP4 + NMOSD (10/10[100%]; p = 0.49) patients. CONCLUSIONS: Marked central canal T2-hyperintensity is a common transient radiologic accompaniment of MOGAD and AQP4 + NMOSD myelitis, but not MS myelitis.

High serum neurofilament levels are observed close to disease activity events in pediatric-onset MS and MOG antibody-associated diseases.

BACKGROUND: Serum neurofilament light chain (sNfL) is an emerging multiple sclerosis (MS) biomarker which measures neuro-axonal damage. However, understanding its temporal association with disease activity in pediatric-onset MS (POMS) and Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) remains limited. OBJECTIVE: To investigate the association of sNfL levels and time from disease activity in children with MS and MOGAD. METHODS: POMS and MOGAD cases with onset before 18 years of age were enrolled at the University of California San Francisco (UCSF) Regional Pediatric MS Center. Frequency-matched healthy subjects were recruited from general pediatric clinics. Serum samples were tested for MOG-IgG at Mayo Clinic using a live cell-based fluorescent activated cell sorting assay. sNfL levels were measured using single-molecule array (Simoa) technology measured in pg/mL. Data on demographics, clinical features, MRI, CSF, and treatment data were collected by chart review. RESULTS: We included 201 healthy controls healthy controls, 142 POMS, and 20 confirmed MOGAD cases with available sNfL levels. The median (IQR) age at the time of sampling was 15.6 (3.9), 15.5 (3.1), and 8.8 (4.1) years for controls, POMS, and MOGAD, respectively. Median sNfL levels (pg/ml) were higher in POMS (19.6) and MOGAD (32.7) cases compared to healthy controls (3.9) (p<0.001). sNfL levels ≥100 pg/ml were only detected within four months of a clinical event or MRI activity in both POMS and MOGAD cases. In addition, sNfL levels were higher in POMS patients with new/enlarged T2 and gadolinium-enhanced lesions than those without MRI activity within four months of sampling in POMS cases. CONCLUSION: High sNfL levels were observed close to clinical or MRI events in POMS and MOGAD. Our findings support sNfL as a biomarker of disease activity in pediatric demyelinating disorders.

Low mortality rate in a large cohort of myelin oligodendrocyte glycoprotein antibody disease (MOGAD).

The mortality rates of individuals with myelin oligodendrocyte glycoprotein antibody disease (MOGAD) are currently unknown. This study aimed to assess the mortality rate in a large cohort of patients with MOGAD. Since none of the patients in our cohort died, we estimated the upper limit of a 95% confidence interval of the crude mortality rate in the cohort to be 2.1%. These data suggest that mortality in MOGAD is lower than that reported in other neuroinflammatory diseases and comparable to the age-adjusted mortality rates of the general population in the United States. Additional studies are warranted to confirm this observation.

Tolerogenic Nanovaccine for Prevention and Treatment of Autoimmune Encephalomyelitis.

Herein, a tolerogenic nanovaccine is developed and tested on an animal model of multiple sclerosis. The nanovaccine is constructed to deliver the self-antigen, myelin oligodendrocyte glycoprotein (MOG) peptide, and dexamethasone on an abatacept-modified polydopamine core nanoparticle (AbaLDPN-MOG). AbaLDPN-MOG can target dendritic cells and undergo endocytosis followed by trafficking to lysosomes. AbaLDPN-MOG blocks the interaction between CD80/CD86 and CD28 in antigen-presenting cells and T cells, leading to decreased interferon gamma secretion. The subcutaneous administration of AbaLDPN-MOG to mice yields significant biodistribution to lymph nodes and, in experimental-autoimmune encephalomyelitis (EAE) model mice, increases the integrity of the myelin basic sheath and minimizes the infiltration of immune cells. EAE mice are treated with AbaLDPN-MOG before or after injection of the autoantigen, MOG. Preimmunization of AbaLDPN-MOG before the injection of MOG completely blocks the development of clinical symptoms. Early treatment with AbaLDPN-MOG at three days after injection of MOG also completely blocks the development of symptoms. Notably, treatment of EAE symptom-developed mice with AbaLDPN-MOG significantly alleviates the symptoms, indicating that the nanovaccine has therapeutic effects. Although AbaLDPN is used for MOG peptide delivery in the EAE model, the concept of AbaLDPN can be widely applied for the prevention and alleviation of other autoimmune diseases.

Longitudinal Retinal Changes in MOGAD.

OBJECTIVE: Patients with myelin oligodendrocyte glycoprotein antibody (MOG-IgG)-associated disease (MOGAD) suffer from severe optic neuritis (ON) leading to retinal neuro-axonal loss, which can be quantified by optical coherence tomography (OCT). We assessed whether ON-independent retinal atrophy can be detected in MOGAD. METHODS: Eighty patients with MOGAD and 139 healthy controls (HCs) were included. OCT data was acquired with (1) Spectralis spectral domain OCT (MOGAD: N = 66 and HCs: N = 103) and (2) Cirrus high-definition OCT (MOGAD: N = 14 and HCs: N = 36). Macular combined ganglion cell and inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) were quantified. RESULTS: At baseline, GCIPL and pRNFL were lower in MOGAD eyes with a history of ON (MOGAD-ON) compared with MOGAD eyes without a history of ON (MOGAD-NON) and HCs (p < 0.001). MOGAD-NON eyes had lower GCIPL volume compared to HCs (p < 0.001) in the Spectralis, but not in the Cirrus cohort. Longitudinally (follow-up up to 3 years), MOGAD-ON with ON within the last 6-12 months before baseline exhibited greater pRNFL thinning than MOGAD-ON with an ON greater than 12 months ago (p < 0.001). The overall MOGAD cohort did not exhibit faster GCIPL thinning compared with the HC cohort. INTERPRETATION: Our study suggests the absence of attack-independent retinal damage in patients with MOGAD. Yet, ongoing neuroaxonal damage or edema resolution seems to occur for up to 12 months after ON, which is longer than what has been reported with other ON forms. These findings support that the pathomechanisms underlying optic nerve involvement and the evolution of OCT retinal changes after ON is distinct in patients with MOGAD. ANN NEUROL 2022;92:476-485.

Bilateral parafalcine cortical and leptomeningeal impairment in MOG antibody disease and AQP4 neuromyelitis optica.

OBJECTIVE: Bilateral parafalcine cortical and leptomeningeal impairment (BPCLI) is a rare finding observed in cases of myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD). The failure to recognize BPCLI may lead to misdiagnosis and delayed treatment. This study aimed to delineate the clinical and imaging characteristics of patients with BPCLI. METHODS: Clinical data from a cohort of 366 patients diagnosed with NMOSD or MOGAD were retrospectively reviewed. Subsequently, the clinical features of the seven patients with BPCLI were analyzed. RESULTS: Of the 366 patients, 33 had MOGAD, whereas 264 were positive for antibodies (Abs) against aquaporin-4 (AQP4) and had NMOSD. BPCLI was detected in five patients (15.1%) with MOGAD and two patients (0.7%) with AQP4-Ab-positive NMOSD. All seven patients (four males) presented with meningoencephalitis-like symptoms at the time of BPCLI. Six patients had seizures, and three of them also presented with fever. Three patients were misdiagnosed with intracranial infection, and one was misdiagnosed with cerebral venous thrombosis. Analysis of the cerebrospinal fluid revealed elevated total protein levels in two patients and increased leukocyte counts in five. In addition to BPCLI, impairments in the hippocampus and corpus callosum were confirmed in one and four patients, respectively. Moreover, five patients exhibited meningeal enhancement, and two showed callosal enhancement. In all cases, BPCLI attacks responded well to high-dose methylprednisolone or immunoglobulin therapy. CONCLUSIONS: BPCLI can be observed in both MOGAD and AQP4 NMOSD. It appears to be characteristic of MOGAD but is relatively rare in AQP4 NMOSD. These findings should be noted to avoid misdiagnosis.

A Spontaneous Model of Experimental Autoimmune Encephalomyelitis Provides Evidence of MOG-Specific B Cell Recruitment and Clonal Expansion.

The key role of B cells in the pathophysiology of multiple sclerosis (MS) is supported by the presence of oligoclonal bands in the cerebrospinal fluid, by the association of meningeal ectopic B cell follicles with demyelination, axonal loss and reduction of astrocytes, as well as by the high efficacy of B lymphocyte depletion in controlling inflammatory parameters of MS. Here, we use a spontaneous model of experimental autoimmune encephalomyelitis (EAE) to study the clonality of the B cell response targeting myelin oligodendrocyte glycoprotein (MOG). In particular, 94% of SJL/j mice expressing an I-As: MOG92-106 specific transgenic T cell receptor (TCR1640) spontaneously develop a chronic paralytic EAE between the age of 60-500 days. The immune response is triggered by the microbiota in the gut-associated lymphoid tissue, while there is evidence that the maturation of the autoimmune demyelinating response might occur in the cervical lymph nodes owing to local brain drainage. Using MOG-protein-tetramers we tracked the autoantigen-specific B cells and localized their enrichment to the cervical lymph nodes and among the brain immune infiltrate. MOG-specific IgG1 antibodies were detected in the serum of diseased TCR1640 mice and proved pathogenic upon adoptive transfer into disease-prone recipients. The ontogeny of the MOG-specific humoral response preceded disease onset coherent with their contribution to EAE initiation. This humoral response was, however, not sufficient for disease induction as MOG-antibodies could be detected at the age of 69 days in a model with an average age of onset of 197 days. To assess the MOG-specific B cell repertoire we FACS-sorted MOG-tetramer binding cells and clonally expand them in vitro to sequence the paratopes of the IgG heavy chain and kappa light chains. Despite the fragility of clonally expanding MOG-tetramer binding effector B cells, our results indicate the selection of a common CDR-3 clonotype among the Igk light chains derived from both disease-free and diseased TCR1640 mice. Our study demonstrates the pre-clinical mobilization of the MOG-specific B cell response within the brain-draining cervical lymph nodes, and reiterates that MOG antibodies are a poor biomarker of disease onset and progression.

[A patient with multiple sclerosis who developed bilateral optic neuritis and central trigeminal myelin lesion].

A 70-year-old woman was admitted to our hospital due to bilateral optic neuritis and left facial sensory disturbance that became exacerbated over 10 days. Both serum and cerebrospinal fluid (CSF) were negative for aquaporin 4 antibody and myelin oligodendrocyte glycoprotein antibody. A high level of myelin basic protein (MBP) in her CSF was observed. Brain MRI showed a high T2 signal and contrast enhancement of the bilateral optic nerve, intramedullary tract and central myelin lesion in the trigeminal nerve. After intravenous methylprednisolone pulse therapy, her visual impairment and facial sensory disturbance gradually improved. She was diagnosed with clinically isolated syndrome, based on 2017 McDonald criteria. A diagnosis of multiple sclerosis (MS) was suspected due to the trigeminal myelin lesion confined to the central myelin portion and high level of MBP in the CSF. Treatment with dimethyl fumarate has been effective for preventing recurrence in 13 months in this patient. The central-peripheral myelin transitional zone at the trigeminal nerve is located 1-6 mm from the pons, where central myelin changes to the peripheral myelin. This patient showed a high T2 signal at the trigeminal nerve 3 mm from the pons on MRI, suggesting the involvement of a central trigeminal myelin lesion. Findings of a central trigeminal myelin lesion on MRI may aid in differentiating between MS and seronegative neuromyelitis optica spectrum disorder.

Safety and efficacy of rituximab for relapse prevention in myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG)-associated disorders (MOGAD): A systematic review and meta-analysis.

INTRODUCTION: Myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG)-associated disorders (MOGAD) is neuroimmunological disorder manifesting as episodes of ADEM, optic neuritis, transverse myelitis, brainstem encephalitis, and other CNS manifestations and notably, distinct from multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). Current treatment strategy is high-dose intravenous methylprednisolone followed by maintenance immunotherapy for relapse prevention. The purpose of this study is to systematically create compelling evidence addressing the role of rituximab in relapse prevention among patient with MOGAD. METHODS: This study follows the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline. We searched PubMed, Embase, and Google Scholar for English language papers published between 2010 and 2021. Individual study proportions were meta-analyzed to yield the pooled relapse-free patient proportion. Individual studies' mean pre- and post-treatment annualized relapse ratio (ARR) and Expanded Disability Status Scale (EDSS) were used to calculate the overall mean difference. RESULTS: Our meta-analysis includes 13 studies with 238 subjects. After rituximab treatment, 55% (95% CI: 0.49-0.61) of MOGAD patients remained relapse-free. Our study found that after rituximab therapy, ARR was lowered by 1.36 (95% CI 1.02-1.71, p < 0.001). Similarly, we detected a 0.52 (95% CI: 0.08 to 0.96, p = 0.02) difference in EDSS score after starting rituximab medication. Because only a handful of the included studies documented adverse events, the safety profile of rituximab for the treatment of MOGAD could not be effectively determined. CONCLUSION: Our meta-analysis shows that rituximab effectively prevents relapses in MOGAD patients.

Factors Associated With Relapse and Treatment of Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease in the United Kingdom.

Importance: Longer-term outcomes and risk factors associated with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are not well established. Objective: To investigate longer-term risk of relapse and factors associated with this risk among patients with MOGAD. Design, Setting, and Participants: This large, single-nation, prospective cohort study was conducted among 276 patients with MOGAD at 5 health care centers in the UK. Data from January 1973 to March 2020 were collected from 146 patients at Oxford and its outreach sites, 65 patients at Liverpool, 32 patients at a children's hospital in Birmingham, 22 patients at a children's hospital in London, and 11 patients at Cardiff, Wales. Data were analyzed from April through July 2020. Main Outcomes and Measures: Risk of relapse and annualized relapse rate were evaluated according to different baseline features, including onset age, onset phenotype, and incident vs nonincident group, with the incident group defined as patients diagnosed with antibodies against myelin oligodendrocyte glycoprotein before a second attack. Time to next relapse among patients experiencing relapse was measured and compared between the maintenance therapy subgroup and each first-line treatment group. The no-treatment group was defined as the off-treatment phase among patients who were relapsing, which could occur between any attack or between the last attack and last follow-up. Results: Among 276 patients with MOGAD, 183 patients were identified as being part of the incident group. There were no differences in mean (SD) onset age between total and incident groups (26.4 [17.6] years vs 28.2 [18.1] years), and female patients were predominant in both groups (166 [60.1%] female patients vs 106 [57.9%] female patients). The most common presentation overall was optic neuritis (ON) (119 patients among 275 patients with presentation data [43.3%]), while acute disseminated encephalomyelitis (ADEM), brain, or brainstem onset was predominant among 69 patients aged younger than 12 years (47 patients [68.1%]), including 41 patients with ADEM (59.4%). In the incident group, the 8-year risk of relapse was 36.3% (95% CI, 27.1%-47.5%). ON at onset was associated with increased risk of relapse compared with transverse myelitis at onset (hazard ratio [HR], 2.66; 95% CI, 1.01-6.98; P = .047), but there was no statistically significant difference with adjustment for a follow-on course of corticosteroids. Any TM at onset (ie, alone or in combination with other presentations [ie, ON or ADEM, brain, or brain stem]) was associated with decreased risk of relapse compared with no TM (HR, 0.41; 95% CI, 0.20-0.88; P = .01). Young adult age (ie, ages >18-40 years) was associated with increased risk of relapse compared with older adult age (ie, ages >40 years) (HR, 2.71; 95% CI, 1.18-6.19; P = .02). First-line maintenance therapy was associated with decreased risk of relapse when adjusted for covariates (prednisolone: HR, 0.33; 95% CI, 0.12-0.92; P = .03; prednisolone, nonsteroidal immunosuppressant, or combined: HR, 0.51; 95% CI, 0.28-0.92; P = .03) compared with the no-treatment group. Conclusions and Relevance: The findings of this cohort study suggest that onset age and onset phenotype should be considered when assessing subsequent relapse risk and that among patients experiencing relapse, prednisolone, first-line immunosuppression, or a combination of those treatments may be associated with decreased risk of future relapse by approximately 2-fold. These results may contribute to individualized treatment decisions.

Antineonatal Fc Receptor Antibody Treatment Ameliorates MOG-IgG-Associated Experimental Autoimmune Encephalomyelitis.

BACKGROUND AND OBJECTIVES: Myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD) is a rare, autoimmune demyelinating CNS disorder, distinct from multiple sclerosis and neuromyelitis optica spectrum disorder. Characterized by pathogenic immunoglobulin G (IgG) antibodies against MOG, a potential treatment strategy for MOGAD is to reduce circulating IgG levels, e.g., by interference with the IgG recycling pathway mediated by the neonatal Fc receptor (FcRn). Although the optic nerve is often detrimentally involved in MOGAD, the effect of FcRn blockade on the visual pathway has not been assessed. Our objective was to investigate effects of a monoclonal anti-FcRn antibody in murine MOG-IgG-associated experimental autoimmune encephalomyelitis (EAE). METHODS: We induced active MOG35-55 EAE in C57Bl/6 mice followed by the application of a monoclonal MOG-IgG (8-18C5) 10 days postimmunization (dpi). Animals were treated with either a specific monoclonal antibody against FcRn (α-FcRn, 4470) or an isotype-matched control IgG on 7, 10, and 13 dpi. Neurologic disability was scored daily on a 10-point scale. Visual acuity was assessed by optomotor reflex. Histopathologic hallmarks of disease were assessed in the spinal cord, optic nerve, and retina. Immune cell infiltration was visualized by immunohistochemistry, demyelination by Luxol fast blue staining and complement deposition and number of retinal ganglion cells by immunofluorescence. RESULTS: In MOG-IgG-augmented MOG35-55 EAE, anti-FcRn treatment significantly attenuated neurologic disability over the course of disease (mean area under the curve and 95% confidence intervals (CIs): α-FcRn [n = 27], 46.02 [37.89-54.15]; isotype IgG [n = 24], 66.75 [59.54-73.96], 3 independent experiments), correlating with reduced amounts of demyelination and macrophage infiltration into the spinal cord. T- and B-cell infiltration and complement deposition remained unchanged. Compared with isotype, anti-FcRn treatment prevented reduction of visual acuity over the course of disease (median cycles/degree and interquartile range: α-FcRn [n = 16], 0.50 [0.48-0.55] to 0.50 [0.48-0.58]; isotype IgG [n = 17], 0.50 [0.49-0.54] to 0.45 [0.39-0.51]). DISCUSSION: We show preserved optomotor response and ameliorated course of disease after anti-FcRn treatment in an experimental model using a monoclonal MOG-IgG to mimic MOGAD. Selectively targeting FcRn might represent a promising therapeutic approach in MOGAD.

Children suspected of having intracranial infection with normal brain magnetic resonance imaging may be associated with the myelin oligodendrocyte glycoprotein antibody.

PURPOSE: To confirm whether encephalitis due to unknown causes but with normal brain magnetic resonance imaging (MRI) may be associated with the myelin oligodendrocyte glycoprotein (MOG) antibody. METHODS: We retrospectively analyzed and summarized the characteristics of three patients initially suspected of having intracranial infections with normal brain MRI, and ultimately tested positive for anti-MOG antibody. RESULTS: The three patients mainly presented with long-term fever accompanied by headaches and drowsiness. Auxiliary examinations showed obvious leukocytosis in peripheral blood and leukocytosis and increased protein expression in cerebrospinal fluid (CSF); furthermore, brain MRI was normal. These findings suggested intracranial infection, especially bacterial meningitis. No patient showed a response to prolonged anti-bacterial therapy; however, they recovered with glucocorticoid therapy, which was prescribed after anti-MOG antibodies were detected in the serum and CSF samples. CONCLUSION: Anti-MOG antibody detection should be performed early for patients with suspected encephalitis due to unknown causes with normal brain MRI, to identify whether they have MOG antibody-associated diseases (MOGAD).

MOG-antibody-associated longitudinal extensive myelitis after ChAdOx1 nCoV-19 vaccination.

This case report describes a 59-year-old man with myelin oligodendrocyte glycoprotein (MOG)-positive longitudinal extensive transverse myelitis (LETM) after being vaccinated with the COVID-19 vaccine ChAdOx1 nCoV-19. He presented with urinary retention, gait disturbance, hypoesthesia and brisk reflexes in his lower extremities without paresis. Due to the ineffectiveness of high-dose intravenous methylprednisolone, therapeutic plasma exchange was performed, gradually improving the patient's condition. Vaccination as a trigger for an excessive immunological response seems plausible, though unspecific for the ChAdOx1 nCoV-19 vaccine.

GRP78 Antibodies Are Associated With Blood-Brain Barrier Breakdown in Anti-Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disorder.

BACKGROUND AND OBJECTIVES: To analyze (1) the effect of immunoglobulin G (IgG) from patients with anti-myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated disorder on the blood-brain barrier (BBB) endothelial cells and (2) the positivity of glucose-regulated protein 78 (GRP78) antibodies in MOG-Ab-associated disorders. METHODS: IgG was purified from sera with patients with MOG-Ab-associated disorder in the acute phase (acute MOG, n = 15), in the stable stage (stable MOG, n = 14), healthy controls (HCs, n = 9), and disease controls (DCs, n = 27). Human brain microvascular endothelial cells (BMECs) were incubated with IgG, and the number of nuclear NF-κB p65-positive cells in BMECs using high-content imaging system and the quantitative messenger RNA change in gene expression over the whole transcriptome using RNA-seq were analyzed. GRP78 antibodies from patient IgGs were detected by Western blotting. RESULTS: IgG in the acute MOG group significantly induced the nuclear translocation of NF-κB and increased the vascular cell adhesion molecule 1/intercellular adhesion molecule 1 expression/permeability of 10-kDa dextran compared with that from the stable MOG and HC/DC groups. RNA-seq and pathway analysis revealed that NF-κB signaling and oxidative stress (NQO1) play key roles. The NQO1 and Nrf2 protein amounts were significantly decreased after exposure to IgG in the acute MOG group. The rate of GRP78 antibody positivity in the acute MOG group (10/15, 67% [95% confidence interval, 38%-88%]) was significantly higher than that in the stable MOG group (5/14, 36% [13%-65%]), multiple sclerosis group (4/29, 14% [4%-32%]), the DCs (3/27, 11% [2%-29%]), or HCs (0/9, 0%). Removal of GRP78 antibodies from MOG-IgG reduced the effect on NF-κB nuclear translocation and increased permeability. DISCUSSION: GRP78 antibodies may be associated with BBB dysfunction in MOG-Ab-associated disorder.