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Characterization of the human myelin oligodendrocyte glycoprotein antibody response in demyelination.

ABSTRACT: Over recent years, human autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG Ab) have been associated with monophasic and relapsing central nervous system demyelination involving the optic nerves, spinal cord, and brain. While the clinical relevance of MOG Ab detection is becoming increasingly clear as therapeutic and prognostic differences from multiple sclerosis are acknowledged, an in-depth characterization of human MOG Ab is required to answer key challenges in patient diagnosis, treatment, and prognosis. Herein, we investigated the epitope, binding sensitivity, and affinity of MOG Ab in a cohort of 139 and 148 MOG antibody-seropositive children and adults (n?=?287 patients at baseline, 130 longitudinal samples, and 22 cerebrospinal fluid samples). MOG extracellular domain was also immobilized to determine the affinity of MOG Ab. MOG Ab response was of immunoglobulin G1 isotype, and was of peripheral rather than intrathecal origin. High affinity MOG Ab were detected in 15% paediatric and 18% adult sera. More than 75% of paediatric and adult MOG Ab targeted a dominant extracellular antigenic region around Proline42. MOG Ab titers fluctuated over the progression of disease, but affinity and reactivity to Proline42 remained stable. Adults with a relapsing course intrinsically presented with a reduced immunoreactivity to Proline42 and had a more diverse MOG Ab response, a feature that may be harnessed for predicting relapse. Higher titers of MOG Ab were observed in more severe phenotypes and during active disease, supporting the pathogenic role of MOG Ab. Loss of MOG Ab seropositivity was observed upon conformational changes to MOG, and this greatly impacted the sensitivity of the detection of relapsing disorders, largely considered as more severe. Careful consideration of the binding characteristics of autoantigens should be taken into account when detecting disease-relevant autoantibodies.

SUBMITTER: Tea F

PROVIDER: S-EPMC6724269 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Characterization of the human myelin oligodendrocyte glycoprotein antibody response in demyelination.

Tea Fiona F Lopez Joseph A JA Ramanathan Sudarshini S Merheb Vera V Lee Fiona X Z FXZ Zou Alicia A Pilli Deepti D Patrick Ellis E van der Walt Anneke A Monif Mastura M Tantsis Esther M EM Yiu Eppie M EM Vucic Steve S Henderson Andrew P D APD Fok Anthony A Fraser Clare L CL Lechner-Scott Jeanette J Reddel Stephen W SW Broadley Simon S Barnett Michael H MH Brown David A DA Lunemann Jan D JD Dale Russell C RC Brilot Fabienne F

Acta neuropathologica communications 20190903 1

Over recent years, human autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG Ab) have been associated with monophasic and relapsing central nervous system demyelination involving the optic nerves, spinal cord, and brain. While the clinical relevance of MOG Ab detection is becoming increasingly clear as therapeutic and prognostic differences from multiple sclerosis are acknowledged, an in-depth characterization of human MOG Ab is required to answer key challenges in patient diagnosi ...[more]

PMID: 31481127

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Project description:BackgroundAntibodies to the myelin oligodendrocyte glycoprotein (MOG) are associated with a subset of inflammatory demyelinating diseases of the central nervous system such as acute disseminated encephalomyelitis and neuromyelitis optica spectrum disorders. However, whether human MOG antibodies are pathogenic or an epiphenomenon is still not completely clear. Although MOG is highly conserved within mammals, previous findings showed that not all human MOG antibodies bind to rodent MOG. We therefore hypothesized that human MOG antibody-mediated pathology in animal models may only be evident using species-specific MOG antibodies.MethodsWe screened 80 human MOG antibody-positive samples for their reactivity to mouse and rat MOG using either a live cell-based assay or immunohistochemistry on murine, rat, and human brain tissue. Selected samples reactive to either human MOG or rodent MOG were subsequently tested for their ability to induce complement-mediated damage in murine organotypic brain slices or enhance demyelination in an experimental autoimmune encephalitis (EAE) model in Lewis rats. The MOG monoclonal antibody 8-18-C5 was used as a positive control.ResultsOverall, we found that only a subset of human MOG antibodies are reactive to mouse (48/80, 60%) or rat (14/80, 18%) MOG. Purified serum antibodies from 10 human MOG antibody-positive patients (8/10 reactive to mouse MOG, 6/10 reactive to rat MOG), 3 human MOG-negative patients, and 3 healthy controls were tested on murine organotypic brain slices. Purified IgG from one patient with high titers of anti-human, mouse, and rat MOG antibodies and robust binding to myelin tissue produced significant, complement-mediated myelin loss in organotypic brain slices, but not in the EAE model. Monoclonal 8-18-C5 MOG antibody caused complement-mediated demyelination in both the organotypic brain slice model and in EAE.ConclusionThis study shows that a subset of human MOG antibodies can induce complement-dependent pathogenic effects in a murine ex vivo animal model. Moreover, a high titer of species-specific MOG antibodies may be critical for demyelinating effects in mouse and rat animal models. Therefore, both the reactivity and titer of human MOG antibodies must be considered for future pathogenicity studies.

Project description:ImportanceDifferential diagnosis of patients with seronegative demyelinating central nervous system (CNS) disease is challenging. In this regard, evidence suggests that immunoglobulin (Ig) A plays a role in the pathogenesis of different autoimmune diseases. Yet little is known about the presence and clinical relevance of IgA antibodies against myelin oligodendrocyte glycoprotein (MOG) in CNS demyelination.ObjectiveTo investigate the frequency of MOG-IgA and associated clinical features in patients with demyelinating CNS disease and healthy controls.Design, setting, and participantsThis longitudinal study comprised 1 discovery and 1 confirmation cohort derived from 5 centers. Participants included patients with suspected or confirmed demyelinating diseases and healthy controls. MOG-IgA, MOG-IgG, and MOG-IgM were measured in serum samples and cerebrospinal fluid (CSF) of patients, who were assessed from September 2012 to April 2022.Main outcomes and measuresFrequency and clinical features of patients who were seropositive for MOG-IgA and double-seronegative for aquaporin 4 (AQP4) IgG and MOG-IgG.ResultsAfter the exclusion of 5 participants with coexisting AQP4-IgG and MOG-IgA, MOG-IgG, and/or MOG-IgM, 1339 patients and 110 healthy controls were included; the median follow-up time was 39 months (range, 0-227 months). Of included patients with isolated MOG-IgA, 11 of 18 were female (61%), and the median age was 31.5 years (range, 3-76 years). Among patients double-seronegative for AQP4-IgG and MOG-IgG (1126/1339; 84%), isolated MOG-IgA was identified in 3 of 50 patients (6%) with neuromyelitis optica spectrum disorder, 5 of 228 patients (2%) with other CNS demyelinating diseases, and 10 of 848 patients (1%) with multiple sclerosis but in none of the healthy controls (0/110). The most common disease manifestation in patients seropositive for isolated MOG-IgA was myelitis (11/17 [65%]), followed by more frequent brainstem syndrome (7/16 [44%] vs 14/75 [19%], respectively; P = .048), and infrequent manifestation of optic neuritis (4/15 [27%] vs 46/73 [63%], respectively; P = .02) vs patients with MOG-IgG. Among patients fulfilling 2017 McDonald criteria for multiple sclerosis, MOG-IgA was associated with less frequent CSF-specific oligoclonal bands (4/9 [44%] vs 325/351 [93%], respectively; P < .001) vs patients with multiple sclerosis who were MOG-IgG/IgA seronegative. Further, most patients with isolated MOG-IgA presented clinical attacks after recent infection or vaccination (7/11 [64%]).Conclusion and relevanceIn this study, MOG-specific IgA was identified in a subgroup of patients who were double-seronegative for AQP4-/MOG-IgG, suggesting that MOG-IgA may be a novel diagnostic biomarker for patients with CNS demyelination.

Dataset Information

Characterization of the human myelin oligodendrocyte glycoprotein antibody response in demyelination.

Publications

Characterization of the human myelin oligodendrocyte glycoprotein antibody response in demyelination.

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