Steroid-responsive aseptic meningitis with raised intracranial pressure syndrome associated with myelin oligodendrocyte glycoprotein autoantibodies.
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ABSTRACT:
SUBMITTER: Wong WK
PROVIDER: S-EPMC10087128 | biostudies-literature | 2022 Dec
REPOSITORIES: biostudies-literature
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Steroid-responsive aseptic meningitis with raised intracranial pressure syndrome associated with myelin oligodendrocyte glycoprotein autoantibodies.
Wong Wui-Kwan WK Troedson Christopher C Peacock Ken K Brilot-Turville Fabienne F Menezes Manoj P MP Dale Russell C RC Webster Richard R
Journal of paediatrics and child health 20220824 12
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Project description:BackgroundThe autoantibody to myelin oligodendrocyte glycoprotein (MOG), a component of the central nervous system myelin, has been identified in a subset of demyelinating diseases. However, there is no convincing evidence to support the direct pathogenic contribution of this autoantibody.ObjectiveTo elucidate the role of anti-MOG autoantibodies in human demyelinating disorders, we assessed the effect of autoantibodies on MOG-expressing cells.MethodsMammalian cells expressing the human MOG protein reacted with human anti-MOG autoantibodies in the presence or absence of complement. Sera from 86 patients and 11 healthy sera were used. We analyzed anti-MOG antibody titers, IgG subclass, and their cytotoxic ability in sera from patients with various neurological diseases. Membrane attack complex (MAC) formation was examined by detection of complement C9 or C9neo with western blot or flow cytometry.ResultsAmong 86 patients, 40 were determined to be MOG-IgG-positive and 46 were negative. Anti-MOG-positive sera, but not -negative sera, caused cell death in MOG-expressing cells. This cytotoxic effect was disappeared after heat inactivation of sera. Importantly, anti-MOG IgG and externally added complement were necessary for sufficient cytotoxic effects. Anti-MOG autoantibodies were histologically colocalized with complement and formed a membrane attack complex consisting of anti-MOG IgG and complement factors.ConclusionThe human MOG antibody specifically killed MOG-expressing cells in vitro in the presence of externally added complement. Membrane attack complexes were formed on the cells, indicating that this autoantibody activated complement-mediated cytotoxicity. Further studies in larger numbers of patients are needed to characterize the role of complement in MOGAD.
| S-EPMC9930155 | biostudies-literature
Project description:Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) have recently been established to define a new disease entity, MOG-antibody-associated disease (MOGAD), which is clinically overlapping with multiple sclerosis. MOG-specific antibodies (Abs) from patients are pathogenic, but the precise effector mechanisms are currently still unknown and no therapy is approved for MOGAD. Here, we determined the contributions of complement and Fc-receptor (FcR)-mediated effects in the pathogenicity of MOG-Abs. Starting from a recombinant anti-MOG (mAb) with human IgG1 Fc, we established MOG-specific mutant mAbs with differential FcR and C1q binding. We then applied selected mutants of this MOG-mAb in two animal models of experimental autoimmune encephalomyelitis. First, we found MOG-mAb-induced demyelination was mediated by both complement and FcRs about equally. Second, we found that MOG-Abs enhanced activation of cognate MOG-specific T cells in the central nervous system (CNS), which was dependent on FcR-, but not C1q-binding. The identification of complement-dependent and -independent pathomechanisms of MOG-Abs has implications for therapeutic strategies in MOGAD.
| S-EPMC10068779 | biostudies-literature
Project description:BackgroundMyelin-oligodendrocyte-glycoprotein (MOG)-IgG-positivity in patients with typical MS lesions on MRI may lead to diagnostic/therapeutic uncertainty.Objective and methodsWe reviewed reports of cases with MS phenotype on MRI and MOG-IgG-positivity published in Pubmed between 01/2012-06/2021.ResultsSixteen patients were included (median age [range], 37,5 [25-66] years; 60% female). Three patients initially tested negative for MOG-IgG. Disease course was: relapsing-remitting, 10; or progressive, 6. Intrathecal IgG-synthesis was common (79%). Low and high-efficacy MS-targeted agents prevented relapses in 30% and 100%, respectively. None of the patients showed resolution of MRI T2-lesions over time.ConclusionsMOG-IgG-positivity is unlikely to alter the expected treatment response and outcomes in patients with otherwise typical MS phenotype on MRI.
| S-EPMC8606934 | biostudies-literature
Project description:Myelin Oligodendrocyte Glycoprotein Antibody Disease (MOGAD) is a spectrum of diseases, including optic neuritis, transverse myelitis, acute disseminated encephalomyelitis, and cerebral cortical encephalitis. In addition to distinct clinical, radiological, and immunological features, the infectious prodrome is more commonly reported in MOGAD (37-70%) than NMOSD (15-35%). Interestingly, pediatric MOGAD is not more aggressive than adult-onset MOGAD, unlike in multiple sclerosis (MS), where annualized relapse rates are three times higher in pediatric-onset MS. MOGAD pathophysiology is driven by acute attacks during which T cells and MOG antibodies cross blood brain barrier (BBB). MOGAD lesions show a perivenous confluent pattern around the small veins, lacking the radiological central vein sign. Initial activation of T cells in the periphery is followed by reactivation in the subarachnoid/perivascular spaces by MOG-laden antigen-presenting cells and inflammatory CSF milieu, which enables T cells to infiltrate CNS parenchyma. CD4+ T cells, unlike CD8+ T cells in MS, are the dominant T cell type found in lesion histology. Granulocytes, macrophages/microglia, and activated complement are also found in the lesions, which could contribute to demyelination during acute relapses. MOG antibodies potentially contribute to pathology by opsonizing MOG, complement activation, and antibody-dependent cellular cytotoxicity. Stimulation of peripheral MOG-specific B cells through TLR stimulation or T follicular helper cells might help differentiate MOG antibody-producing plasma cells in the peripheral blood. Neuroinflammatory biomarkers (such as MBP, sNFL, GFAP, Tau) in MOGAD support that most axonal damage happens in the initial attack, whereas relapses are associated with increased myelin damage.
| S-EPMC10011114 | biostudies-literature
Project description:Multiple sclerosis is a chronic disease of the central nervous system (CNS) characterized by inflammation, demyelination, and axonal loss. The immunopathogenesis of demyelination in multiple sclerosis involves an autoantibody response to myelin oligodendrocyte glycoprotein (MOG), a type I transmembrane protein located at the surface of CNS myelin. Here we present the crystal structures of the extracellular domain of MOG (MOGIgd) at 1.45-A resolution and the complex of MOGIgd with the antigen-binding fragment (Fab) of the MOG-specific demyelinating monoclonal antibody 8-18C5 at 3.0-A resolution. MOGIgd adopts an IgV like fold with the A'GFCC'C" sheet harboring a cavity similar to the one used by the costimulatory molecule B7-2 to bind its ligand CTLA4. The antibody 8-18C5 binds to three loops located at the membrane-distal side of MOG with a surprisingly dominant contribution made by MOG residues 101-108 containing a strained loop that forms the upper edge of the putative ligand binding site. The sequence R101DHSYQEE108 is unique for MOG, whereas large parts of the remaining sequence are conserved in potentially tolerogenic MOG homologues expressed outside the immuno-privileged environment of the CNS. Strikingly, the only sequence identical to DHSYQEE was found in a Chlamydia trachomatis protein of unknown function, raising the possibility that Chlamydia infections may play a role in the MOG-specific autoimmune response in man. Our data provide the structural basis for the development of diagnostic and therapeutic strategies targeting the pathogenic autoantibody response to MOG.
| S-EPMC170938 | biostudies-literature
Project description:ImportanceMyelin oligodendrocyte glycoprotein-IgG1-associated disorder (MOGAD) is a distinct central nervous system-demyelinating disease. Positive results on MOG-IgG1 testing by live cell-based assays can confirm a MOGAD diagnosis, but false-positive results may occur.ObjectiveTo determine the positive predictive value (PPV) of MOG-IgG1 testing in a tertiary referral center.Design, setting, and participantsThis diagnostic study was conducted over 2 years, from January 1, 2018, through December 31, 2019. Patients in the Mayo Clinic who were consecutively tested for MOG-IgG1 by live cell-based flow cytometry during their diagnostic workup were included. Patients without research authorization were excluded.Main outcomes and measuresMedical records of patients who were tested were initially reviewed by 2 investigators blinded to MOG-IgG1 serostatus, and pretest probability was classified as high or low (suggestive of MOGAD or not). Testing of MOG-IgG1 used a live-cell fluorescence-activated cell-sorting assay; an IgG binding index value of 2.5 or more with an end titer of 1:20 or more was considered positive. Cases positive for MOG-IgG1 were independently designated by 2 neurologists as true-positive or false-positive results at last follow-up, based on current international recommendations on diagnosis or identification of alternative diagnoses; consensus was reached for cases in which disagreement existed.ResultsA total of 1617 patients were tested, and 357 were excluded. Among 1260 included patients tested over 2 years, the median (range) age at testing was 46 (0-98) years, and 792 patients were female (62.9%). A total of 92 of 1260 (7.3%) were positive for MOG-IgG1. Twenty-six results (28%) were designated as false positive by the 2 raters, with an overall agreement on 91 of 92 cases (99%) for true and false positivity. Alternative diagnoses included multiple sclerosis (n = 11), infarction (n = 3), B12 deficiency (n = 2), neoplasia (n = 2), genetically confirmed adrenomyeloneuropathy (n = 1), and other conditions (n = 7). The overall PPV (number of true-positive results/total positive results) was 72% (95% CI, 62%-80%) and titer dependent (PPVs: 1:1000, 100%; 1:100, 82%; 1:20-40, 51%). The median titer was higher with true-positive results (1:100 [range, 1:20-1:10000]) than false-positive results (1:40 [range, 1:20-1:100]; P < .001). The PPV was higher for children (94% [95% CI, 72%-99%]) vs adults (67% [95% CI, 56%-77%]) and patients with high pretest probability (85% [95% CI, 76%-92%]) vs low pretest probability (12% [95% CI, 3%-34%]). The specificity of MOG-IgG1 testing was 97.8%.Conclusions and relevanceThis study confirms MOG-IgG1 as a highly specific biomarker for MOGAD, but when using a cutoff of 1:20, it has a low PPV of 72%. Caution is advised in the interpretation of low titers among patients with atypical phenotypes, because ordering MOG-IgG1 in low pretest probability situations will increase the proportion of false-positive results.
| S-EPMC8077043 | biostudies-literature
Project description:ObjectivesGlobal brain volume changes in patients with myelin oligodendrocyte glycoprotein antibody-associated disease compared with healthy controls (HC) could be revealed by magnetic resonance imaging, but specific atrophy patterns of cortical structures and relation to cognitive impairment are not yet comprehensively known. Thus, we aimed to investigate cortical thickness differences in patients with myelin oligodendrocyte glycoprotein antibody-associated disease compared with HC.Methods3-Tesla brain magnetic resonance imaging was performed in 23 patients with myelin oligodendrocyte glycoprotein antibody-associated disease and 49 HC for voxel-wise group comparisons and neuropsychological testing in patients. Surface-based morphometry with region of interest-based surface analysis and region of interest-based extraction of cortical thickness was performed in patients compared with HC and in patient subgroups with and without cognitive impairment.ResultsComparing patients with myelin oligodendrocyte glycoprotein antibody-associated disease with HC, exploratory surface-based morphometry demonstrated cortical volume reduction in pericalcarine and lingual cortical regions. Region of interest-based surface analysis specified reduced cortical thickness in the adjacent pericalcarine and orbitofrontal regions in myelin oligodendrocyte glycoprotein antibody-associated disease, as well as reduced temporal cortical thickness in patients with cognitive impairment (n = 10). Patients without cognitive impairment (n = 13) showed only circumscribed cortical brain volume loss compared with HC in the pericalcarine region.InterpretationIn conclusion, cortical atrophy in myelin oligodendrocyte glycoprotein antibody-associated disease was characterized by cortical thickness reduction in the adjacent pericalcarine and orbitofrontal regions, with a tendency of temporal thickness reduction in cognitively impaired patients.
| S-EPMC11330211 | biostudies-literature
Project description:Myelin oligodendrocyte glycoprotein (MOG), a member of the immunoglobulin (Ig) superfamily, is a myelin protein solely expressed at the outermost surface of myelin sheaths and oligodendrocyte membranes. This makes MOG a potential target of cellular and humoral immune responses in inflammatory demyelinating diseases. Due to its late postnatal developmental expression, MOG is an important marker for oligodendrocyte maturation. Discovered about 30 years ago, it is one of the best-studied autoantigens for experimental autoimmune models for multiple sclerosis (MS). Human studies, however, have yielded controversial results on the role of MOG, especially MOG antibodies (Abs), as a biomarker in MS. But with improved detection methods using different expression systems to detect Abs in patients' samples, this is meanwhile no longer the case. Using cell-based assays with recombinant full-length, conformationally intact MOG, several recent studies have revealed that MOG Abs can be found in a subset of predominantly pediatric patients with acute disseminated encephalomyelitis (ADEM), aquaporin-4 (AQP4) seronegative neuromyelitis optica spectrum disorders (NMOSD), monophasic or recurrent isolated optic neuritis (ON), or transverse myelitis, in atypical MS and in N-methyl-d-aspartate receptor-encephalitis with overlapping demyelinating syndromes. Whereas MOG Abs are only transiently observed in monophasic diseases such as ADEM and their decline is associated with a favorable outcome, they are persistent in multiphasic ADEM, NMOSD, recurrent ON, or myelitis. Due to distinct clinical features within these diseases it is controversially disputed to classify MOG Ab-positive cases as a new disease entity. Neuropathologically, the presence of MOG Abs is characterized by MS-typical demyelination and oligodendrocyte pathology associated with Abs and complement. However, it remains unclear whether MOG Abs are a mere inflammatory bystander effect or truly pathogenetic. This article provides deeper insight into recent developments, the clinical relevance of MOG Abs and their role in the immunpathogenesis of inflammatory demyelinating disorders.
| S-EPMC5420591 | biostudies-literature
Project description:Thymic B cells represent a numerically minor cell population located primarily at the cortico-medullary junction. Their biological role is unclear. B cell-deficient ?MT mice exhibited reduced medullary thymic epithelial cell (mTEC) numbers and reduced MOG and insulin mRNA expression. Lymphotoxin produced by B cells was critical for normal tissue restricted antigen (TRA) expression, suggesting that B cells regulate self-antigens through their production of LT. These results reveal an unexpected role of B cells in mTEC maintenance and expression of TRAs through their production of LT.
| S-EPMC3157307 | biostudies-literature
Project description:Cerebral cortical encephalitis (CCE) is a recently described myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) phenotype. In this observational retrospective study, we characterized 19 CCE patients (6.7% of our MOGAD cohort). Headache (n = 15, 79%), seizures (n = 13, 68%), and encephalopathy (n = 12, 63%) were frequent. Magnetic resonance imaging revealed unilateral (n = 12, 63%) or bilateral (n = 7, 37%) cortical T2 hyperintensity and leptomeningeal enhancement (n = 17, 89%). N-Methyl-D-aspartate receptor autoantibodies coexisted in 2 of 15 tested (13%). CCE pathology (n = 2) showed extensive subpial cortical demyelination (n = 2), microglial reactivity (n = 2), and inflammatory infiltrates (perivascular, n = 1; meningeal, n = 1). Most received high-dose steroids (n = 17, 89%), and all improved, but 3 had CCE relapses. This study highlights the CCE spectrum and provides insight into its pathogenesis. ANN NEUROL 2023;93:297-302.
| S-EPMC10107670 | biostudies-literature