Myelin Oligodendrocyte Glycoprotein Research Articles

Delimiting MOGAD as a disease entity using translational imaging.

The first formal consensus diagnostic criteria for myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) were recently proposed. Yet, the distinction of MOGAD-defining characteristics from characteristics of its important differential diagnoses such as multiple sclerosis (MS) and aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorder (NMOSD) is still obstructed. In preclinical research, MOG antibody-based animal models were used for decades to derive knowledge about MS. In clinical research, people with MOGAD have been combined into cohorts with other diagnoses. Thus, it remains unclear to which extent the generated knowledge is specifically applicable to MOGAD. Translational research can contribute to identifying MOGAD characteristic features by establishing imaging methods and outcome parameters on proven pathophysiological grounds. This article reviews suitable animal models for translational MOGAD research and the current state and prospect of translational imaging in MOGAD.

An engineered Fc fusion protein that targets antigen-specific T cells and autoantibodies mitigates autoimmune disease

Current effective therapies for autoimmune diseases rely on systemic immunomodulation that broadly affects all T and/or B cell responses. An ideal therapeutic approach would combine autoantigen-specific targeting of both T and B cell effector functions, including efficient removal of pathogenic autoantibodies. Albeit multiple strategies to induce T cell tolerance in an autoantigen-specific manner have been proposed, therapeutic removal of autoantibodies remains a significant challenge. Here, we devised an approach to target both autoantigen-specific T cells and autoantibodies by producing a central nervous system (CNS) autoantigen myelin oligodendrocyte glycoprotein (MOG)-Fc fusion protein. We demonstrate that MOG-Fc fusion protein has significantly higher bioavailability than monomeric MOG and is efficient in clearing anti-MOG autoantibodies from circulation. We also show that MOG-Fc promotes T cell tolerance and protects mice from MOG-induced autoimmune encephalomyelitis. This multipronged targeting approach may be therapeutically advantageous in the treatment of autoimmunity.

Quantification of Autoreactive Antibodies in Mice upon Experimental Autoimmune Encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is a disease model that recapitulates the autoimmune disorder multiple sclerosis (MS) at histopathological and molecular levels. EAE is induced by immunizing experimental animals via subcutaneous injection of short myelin peptides together with specific adjuvants to boost the immune response. Like the human counterpart, EAE mice develop demyelinating lesions, immune cell infiltration into the central nervous system (CNS), glia activation and neuronal injury. A consistent body of evidence also supports a mechanistic role for B cell dysfunction in the etiology of both MS and EAE. B cells can serve as antigen-presenting cells as well as a primary source of pro-inflammatory cytokines and autoantibodies. In EAE, antibodies are generated against the myelin peptides that were employed to induce the disease. Such autoantibodies have been shown to mediate either myelin loss or pathogenic T cell reactivation into the CNS. This article describes an efficient ELISA-based protocol to quantify autoantibodies in the serum of C57BL/6J mice immunized with the myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) peptide. The proposed method serves as a powerful tool to investigate the specificity and magnitude of the aberrant humoral response in the context of autoimmune demyelination.

Systematic review exploring the clinical features of optic neuritis after SARS-CoV infection and vaccination

BackgroundThis study aims to characterise the symptoms and clinical features of optic neuritis (ON) following SARS-CoV-2 infection and vaccination.MethodA literature search was conducted in four databases (PubMed, Medline, Embase and...

Upbeat Nystagmus and Ataxia in a Case of Myelin Oligodendrocyte Glycoprotein (MOG)-IgG-Associated Disease

Upbeat Nystagmus and Ataxia in a Case of Myelin Oligodendrocyte Glycoprotein (MOG)-IgG-Associated Disease

Characteristics of Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease Patients at Cleveland Clinic Abu Dhabi: A Case Series

Characteristics of Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease Patients at Cleveland Clinic Abu Dhabi: A Case Series

Evolution of Brain MRI Lesions in Paediatric Myelin-Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD) and Its Relevance to Disease Course

Evolution of Brain MRI Lesions in Paediatric Myelin-Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD) and Its Relevance to Disease Course

Myelin-Oligodendrocyte Glycoprotein Antibody-Associated Disease and Intracranial Hypertension: A Case Report

Myelin-Oligodendrocyte Glycoprotein Antibody-Associated Disease and Intracranial Hypertension: A Case Report

Acute Optic Neuritis: An Update on Approach and Management.

This review discusses the physical examination and diagnostic tests necessary to diagnose optic neuritis (ON) and provides an update on the approach and management of acute ON. A comprehensive search of the PubMed database was conducted, limited to English-language journals and recent publications. A total of 160 articles were initially screened by title, of which 73 articles were included in the narrative synthesis. ON is an inflammation of the optic nerve that can be caused by different systemic and neurological disorders. It is commonly presented as a subacute unilateral painful vision loss, and based on its clinical manifestation, it can be classified as typical or atypical. Atypical ON is bilateral with visual acuity of worse than 20/200 or has an atypical demographic presentation for demyelination, such as a non-Caucasian male with optic disc swelling, for which neuromyelitis optica spectrum disorder (NMOSD), myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD), or other etiologies should be considered. Steroids and immunosuppressants are the main treatment options for ON, and timely treatment initiation is critical to preventing irreversible vision loss, especially in atypical cases.

A longitudinal analysis of brain volume changes in myelin oligodendrocyte glycoprotein antibody-associated disease.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a relapsing demyelinating condition. There are several cross-sectional studies showing evidence of brain atrophy in people with MOGAD (pwMOGAD), but longitudinal brain volumetric assessment is still an unmet need. Current recommendations do not include monitoring with MRI and assume distinct attacks. Evidence of ongoing axon loss will have diagnostic and therapeutic implications. In this study, we assessed brain volume changes in pwMOGAD over a mean follow-up period of 2years and compared this to changes in people with multiple sclerosis (pwMS). This is a retrospective single-center study over a 7-year period from 2014 to 2021. MRI brain scans at the time of diagnosis and follow-up in remission were collected from 14 Caucasian pwMOGAD, confirmed by serum myelin oligodendrocyte glycoprotein immunoglobulin G antibody presence, detected by live cell-based assays. Total brain volume (TBV), white matter (WM), gray matter (GM), and demyelinating lesion volumes were assessed automatically using the Statistical Parametric Mapping and FMRIB automated segmentation tools. MRI brain scans at diagnosis and follow-up on remission were collected from 32-matched pwMS for comparison. Statistical analysis was done using analysis of variance. There is evidence of TBV loss, affecting particularly GM, over an approximately 2-year follow-up period in pwMOGAD (p<.05), comparable to pwMS. WM and lesion volume change over the same period were not statistically significant (p>.1). We found evidence of loss of GM and TBV over time in pwMOGAD, similar to pwMS, although the WM and lesion volumes were unchanged.

Longitudinal evaluation of serum MOG-IgG titers in MOGAD after initiation of maintenance immunoglobulin: A case series.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a distinct demyelinating disease of the central nervous system. Immunoglobulin (Ig) has been used as a maintenance therapy to prevent relapses in MOGAD, but the impact of Ig on serum MOG-IgG titers is unclear. To characterize the variation in serum MOG-IgG titers after initiation of Ig treatment in people with MOGAD. We conducted a retrospective study of 10 patients with a diagnosis of MOGAD and available serum MOG-IgG titers before and after initiation of maintenance Ig treatment. We found that most of the patients remained MOG-IgG seropositive while on Ig treatment with a reduced or unchanged titer, despite a lack of disease activity. This case series suggests that the mechanism of action of Ig therapy in MOGAD is not exclusively dependent on MOG-IgG titer reduction.

Optic neuritis in Turkish children and adolescents: A multicenter retrospective study

BackgroundVarious etiologies may underlie optic neuritis, including autoantibody-mediated disorders described in the last decade. We re-examined demographic, clinical, laboratory features and prognostic factors in pediatric patients with autoimmune optic neuritis according to current knowledge. MethodsCases of pediatric ON from 27 centers in Türkiye diagnosed between 2009 and 2022 were included for retrospective evaluation. ResultsThe study included 279 patients, 174 females and 105 males, with a female-to-male ratio of 1.65. The average age at onset was 12.8 ± 3.4 years, and mean follow-up, 2.1 years (range: 1–12.1 years). Patients <10 years old were grouped as "prepubertal" and those ≥10 years old as "others”. The diagnoses made at the end of follow-up were multiple sclerosis associated optic neuritis (n = 90, 32.3 %), single isolated optic neuritis (n = 86, 31 %), clinically isolated syndrome (n = 41, 14.7 %), myelin oligodendrocyte glycoprotein antibody associated optic neuritis (n = 22, 7.9 %), and relapsing isolated optic neuritis (n = 18, 6.5 %). Predominant diagnoses were myelin oligodendrocyte glycoprotein antibody associated optic neuritis and acute disseminated encephalomyelitis associated optic neuritis in the prepubertal group and multiple sclerosis associated optic neuritis in the older group. Recurrences were observed in 67 (24 %) patients, including 28 with multiple sclerosis associated optic neuritis, 18 with relapsing isolated optic neuritis, 11 with myelin oligodendrocyte glycoprotein antibody associated optic neuritis, 8 with aquaporin-4 antibody related optic neuritis, and 2 with chronic relapsing inflammatory optic neuropathy. Recurrences were more common among female patients. Findings supporting the diagnosis of multiple sclerosis included age of onset ≥ 10 years (OR=1.24, p = 0.027), the presence of cranial MRI lesions (OR=26.92, p<0.001), and oligoclonal bands (OR=9.7, p = 0.001). Treatment in the acute phase consisted of intravenous pulse methylprednisolone (n = 46, 16.5 %), pulse methylprednisolone with an oral taper (n = 212, 76 %), and combinations of pulse methylprednisolone, plasmapheresis, or intravenous immunoglobulin (n = 21, 7.5 %). Outcome at 12 months was satisfactory, with 247 out of 279 patients (88.5 %) demonstrating complete recovery. Thirty-two patients exhibited incomplete recovery and further combination treatments were applied. Specifically, patients with relapsing isolated optic neuritis and aquaporin-4 antibody related optic neuritis displayed a less favorable prognosis. ConclusionOur results suggest optic neuritis is frequently bilateral in prepubertal and unilateral in peri‑ or postpubertal patients. Age of onset 10 or older, presence of oligoclonal bands, and brain MRI findings reliably predict the development of multiple sclerosis. The risk of developing multiple sclerosis increases mostly during the second and third years of follow-up. Relapsing isolated optic neuritis remains a separate group where the pathogenesis and outcome remain unclear. Investigation of predisposing and diagnostic biomarkers and long follow-up could help to define this group.

Big Data Analysis of Inflammatory Conditions Associated With Optic Neuritis.

Previous studies in the United States established multiple sclerosis (MS) as the most common cause of optic neuritis (ON). ON can be associated with other systemic inflammatory conditions including sarcoidosis, neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and lupus; however, prospective studies to establish risk of ON associated with these diseases are lacking. Furthermore, appropriate workup for ON is still debated. A deidentified electronic medical record of a tertiary care academic center was searched for ON and rheumatologic/neuro-inflammatory diseases in the medical history, diagnoses, and laboratory results; followed by the intersection of ON with each condition. We calculated frequency of systemic conditions among patients with ON and prevalence of ON in those conditions. We also calculated relative risk (RR) of underlying systemic conditions among patients with ON compared with the study patient population. In 6.7 million charts, 5,344 cases of ON were identified. Among those, MS occurred most commonly (20.6%), followed by NMOSD (10.5%). Conversely, ON occurred in 98.4% of NMOSD cases, 53.3% of MOGAD, and 10.0% of MS. NMOSD (RR = 1,233), MOGAD (RR = 688), and MS (RR = 126) had the highest RR among the conditions we evaluated. The subset analysis showed similar findings. The high RR for ON among patients with NMOSD and MOGAD suggests that clinical suspicion for ON should be high among patients with these conditions presenting with vision changes. Conversely, MS and NMOSD should initially be high on the differential diagnosis for any patient presenting with optic neuritis.

Prevalence of serum MOG antibody and AQP4 antibody in optic neuritis after SARS-CoV-2 infection.

To evaluate the prevalence of serum myelin oligodendrocyte glycoprotein antibody (MOG-Ab) and aquaporin-4 antibody (AQP4-Ab) in optic neuritis (ON) patients after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by cell-based indirect immunofluorescence assay (CBA). In this prospective case series study, 35 patients clinically diagnosed as ON and laboratory-confirmed SARS-CoV-2 infection from 8 December 2022 to 8 February 2023 were included. All patients' clinical and laboratory data were collected and analyzed. The mean age of the 35 patients (46 eyes) was 38.2 years (ranging from 6 to 69 years), and 17 cases were female patients. Thirty-three and two cases showed positive SARS-CoV-2 RNA test results before or shortly after ON onset, respectively. ON occurred unilaterally in 24 cases and bilaterally in 11 cases. Ophthalmic examination revealed swollen optic disc in 37 eyes, normal optic disc in 6 eyes, and temporally or wholly paled optic disc in 3 eyes. CBA revealed seropositive MOG-Ab in 10 cases and AQP4-Ab in 2 cases, respectively, of which 2 AQP4-Ab-seropositive cases and 1 MOG-Ab-seropositive case had a past medical history of ON. Most ON patients showed a rapid and dramatic response to pulse steroid therapy. The median of BCVA at the onset and at the last follow-up was 20/500 (ranging from light perception to 20/20) and 20/67 (ranging from counting fingers to 20/20), respectively. Serum MOG-Ab and AQP4-Ab were detected in 28.6% (10/35) and 5.7% (2/35) ON cases after SARS-CoV-2 infection. SARS-CoV-2 infection may trigger an onset or a relapse of ON, as well as the production of MOG-Ab.

Evolution of brain MRI lesions in paediatric myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and its relevance to disease course

BackgroundLesion resolution is often observed in children with myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and asymptomatic lesions are less commonly reported in MOGAD than in multiple sclerosis (MS).ObjectiveWe aimed to evaluate...

Timing of MOG-IgG Testing Is Key to 2023 MOGAD Diagnostic Criteria.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is a recently identified autoimmune demyelinating disorder of the CNS affecting both adults and children. Diagnostic criteria for MOGAD have recently been published. We aimed to validate the 2023 MOGAD diagnostic criteria in a real-world cohort of patients with atypical CNS inflammation. All patients referred to the National neuromyelitis optica spectrum disorder (NMOSD) specialized service at The Walton Center NHS Foundation Trust between 2012 and 2023 with an atypical demyelinating syndrome were evaluated. We systematically applied the 2023 MOGAD diagnostic criteria and previous 2018 International Diagnostic Recommendations for MOG encephalomyelitis to our retrospective cohort. 474 patients were screened and 66 were excluded for lack of clinical information. Preexisting diagnoses within our cohort included the following: MOGAD, n = 127; AQP4-IgG NMOSD, n = 125; seronegative NMOSD, n = 33; multiple sclerosis (MS), n = 10; and other diagnoses, n = 113. Of patients with preexisting MOGAD, 97% (123/127) fulfilled the 2023 MOGAD diagnostic criteria. Three patients with a low-positive MOG-IgG did not meet supportive features though 2/3 had insufficient investigations. Alternative diagnoses could not be excluded in 1 patient with MS-MOGAD overlap. No patients with a non-MOGAD diagnosis were found to fulfill the 2023 diagnostic criteria. The sensitivity and specificity of the 2023 MOGAD diagnostic criteria were 97% and 100% with no false positives, improving on 2018 International Diagnostic Recommendations for MOG encephalomyelitis. Low-positive MOG-IgG results were more often associated with a longer time from disease onset to sampling (p < 0.001). In addition, in patients with a MOG-IgG1 test within 6 months of clinical onset, approximately 25% can become low positive by 6 months. Of patients with preexisting MOGAD, 9% (12/127) had insufficient investigations and examinations to fully evaluate additional supportive features. However, in those who were completely evaluated, supportive features were fulfilled in 97% (111/115). The 2023 MOGAD diagnostic criteria were highly sensitive and specific and closely align with historically established cases of MOGAD. However, because additional supportive features are stipulated for patients with a low-positive MOG-IgG result, missed diagnoses may occur due to delayed testing or insufficient investigations.

Diagnostic Value of Multiparameter MRI-Based Radiomics in Pediatric Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disorders.

Myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD) have a higher prevalence among children. For children undergoing the initial manifestation of MOGAD, prompt diagnosis has paramount importance. This study assessed the performance of multiparameter MRI-based radiomics in distinguishing patients with and without MOGAD with idiopathic inflammatory demyelinating diseases. We enrolled a cohort of 121 patients diagnosed with idiopathic inflammatory demyelinating diseases, including 68 children with MOGAD and 53 children without MOGAD. Radiomics models (T1WI, T2WI, FLAIR, and compound model) using features extracted from demyelinating lesions within the brain parenchyma were developed in the training set. The performance of these models underwent validation within the internal testing set. Additionally, we gathered clinical factors and MRI features of brain parenchymal lesions at their initial presentation. Subsequently, these variables were used in the construction of a clinical prediction model through multivariate logistic regression analysis. The areas under the curve for the radiomics models (T1WI, T2WI, FLAIR, and the compound model) in the training set were 0.781 (95% CI, 0.689-0.864), 0.959 (95% CI, 0.924-0.987), 0.939 (95% CI, 0.898-0.979), and 0.989 (95% CI, 0.976-0.999), respectively. The areas under the curve for the radiomics models (T1WI, T2WI, FLAIR, and the compound model) in the testing set were 0.500 (95% CI, 0.304-0.652), 0.833 (95% CI, 0.697-0.944), 0.804 (95% CI, 0.664-0.918), and 0.905 (95% CI, 0.803-0.979), respectively. The areas under the curve of the clinical prediction model in the training set and testing set were 0.700 and 0.289, respectively. Multiparameter MRI-based radiomics helps distinguish MOGAD from non-MOGAD in patients with idiopathic inflammatory demyelinating diseases.

Antibody Investigations in 2,750 Children With Suspected Autoimmune Encephalitis.

To assess the frequency and types of neuronal and glial (neural) antibodies in children with suspected autoimmune encephalitis (AE). Patients younger than 18 years with suspected AE other than acute disseminated encephalomyelitis, whose serum or CSF samples were examined in our center between January 1, 2011, and April 30, 2022, were included in this study. Samples were systematically examined using brain immunohistochemistry; positive immunostaining was further investigated with cell-based assays (CBA), immunoblot, or live neuronal immunofluorescence. Of 2,750 children, serum or CSF samples of 542 (20%) showed brain immunoreactivity, mostly (>90%) against neural cell surface antigens, and 19 had antibodies only identified by CBA. The most frequent targets were N-methyl-d-aspartate receptor (NMDAR, 76%) and myelin oligodendrocyte glycoprotein (MOG, 5%), followed by glutamic acid decarboxylase 65 (2%) and γ-aminobutyric acid A receptor (2%). Antibodies against other known cell surface or intracellular neural antigens (altogether 6% of positive cases) and unknown antigens (9%) were very infrequent. The repertoire of antibodies in children with AE is different from that of the adults. Except for NMDAR and MOG antibodies, many of the antibodies included in diagnostic panels are rarely positive and their up-front testing in children seems unneeded.

Clinical and radiological features, treatment responses and prognosis in pediatric patients with co-existing anti-N-methyl-D-aspartate receptor and myelin oligodendrocyte glycoprotein antibody-associated encephalitis: A single center study

To characterize the clinical and radiological features, treatment responses and outcomes of children with co-existing anti-N-methyl-D-aspartate receptor(NMDAR) and myelin oligodendrocyte glycoprotein(MOG) antibody-associated encephalitis. Clinical manifestations, imaging features, effectiveness of treatment and outcomes of patients who were cerebral spinal fluid(CSF)-positive for NMDAR-antibody(NMDAR-ab) and seropositive for MOG-antibody(MOG-ab) were analyzed. Twelve patients including 8 females and 4 males were enrolled. The median onset age was 9 years, ranging from 2.2 to 12.8 years. Behavioral changes and/or psychiatric symptoms (n=8/12), seizures (n=8/12), encephalopathy (n=7/12) were 3 of the most common symptoms. Brain magnetic resonance imaging(MRI) of all the patients showed T2/fluid attenuation inversion recovery(FLAIR) abnormal signal in the cerebral white matter at least once in the courses of disease, 2 of whom developed new brain lesions which were asymptomatic. All of the patients had supratentorial lesions. Spinal cord MRI was performed in 7 patients. Only 1 patient showed related abnormalities with increased T2 signal in the spinal cord C1-5. Nine patients underwent optic nerve MRI; 5 patients demonstrated abnormal results, among whom 4 exhibited T2 abnormal signal (2 were symptom-free) and 1 showed a little effusion in bilateral optic nerve sheats. Intravenous immunoglobulin (IVIG) and intravenous methylprednisolone (IVMP) were the most common used therapies in those patients. Nine patients were treated with second-line therapy to prevent relapses. For total 29 clinical attacks, the median modified Rankin Scale (mRS) before treatment and after therapy of acute stage was 1 and 0, respectively. Seven of 12 patients(58.3%) experienced clinical relapses. In terms of outcome, all of the patients' mRS of last follow-up (≥6 months) was ≤2. Behavioral changes and/or psychiatric symptoms, seizures and encephalopathy were common in children with co-existing anti-NMDAR and MOG antibody-associated encephalitis. A minority of subjects may develop asymptomatic lesions on brain and optic nerve MRI. The relapse rate of this disease is relatively high. The majority of patients responded well to the immunotherapies and had a good outcome(mRS of last follow-up≤2).

A B cell-driven EAE mouse model reveals the impact of B cell-derived cytokines on CNS autoimmunity.

In multiple sclerosis (MS), pathogenic T cell responses are known to be important drivers of autoimmune inflammation. However, increasing evidence suggests an additional role for B cells, which may contribute to pathogenesis via antigen presentation and production of proinflammatory cytokines. However, these B cell effector functions are not featured well in classical experimental autoimmune encephalomyelitis (EAE) mouse models. Here, we compared properties of myelin oligodendrocyte glycoprotein (MOG)-specific and polyclonal B cells and developed an adjuvant-free cotransfer EAE mouse model, where highly activated, MOG-specific induced germinal center B cells provide the critical stimulus for disease development. We could show that high levels of MOG-specific immunoglobulin G (IgGs) are not required for EAE development, suggesting that antigen presentation and activation of cognate T cells by B cells may be important for pathogenesis. As our model allows for B cell manipulation prior to transfer, we found that overexpression of the proinflammatory cytokine interleukin (IL)-6 by MOG-specific B cells leads to an accelerated EAE onset accompanied by activation/expansion of the myeloid compartment rather than a changed T cell response. Accordingly, knocking out IL-6 or tumor necrosis factor α in MOG-specific B cells via CRISPR-Cas9 did not affect activation of pathogenic T cells. In summary, we generated a tool to dissect pathogenic B cell effector function in EAE development, which should improve our understanding of pathogenic processes in MS.