RESUMO
OBJECTIVE: To analyze serum immunoglobulin G (IgG) antibodies to major isoforms of myelin oligodendrocyte glycoprotein (MOG-alpha 1-3 and beta 1-3) in patients with inflammatory demyelinating diseases. METHODS: Retrospective case-control study using 378 serum samples from patients with multiple sclerosis (MS), patients with non-MS demyelinating disease, and healthy controls with MOG alpha-1-IgG positive (n = 202) or negative serostatus (n = 176). Samples were analyzed for their reactivity to human, mouse, and rat MOG isoforms with and without mutations in the extracellular MOG Ig domain (MOG-ecIgD), soluble MOG-ecIgD, and myelin from multiple species using live cell-based, tissue immunofluorescence assays and ELISA. RESULTS: The strongest IgG reactivities were directed against the longest MOG isoforms alpha-1 (the currently used standard test for MOG-IgG) and beta-1, whereas the other isoforms were less frequently recognized. Using principal component analysis, we identified 3 different binding patterns associated with non-MS disease: (1) isolated reactivity to MOG-alpha-1/beta-1 (n = 73), (2) binding to MOG-alpha-1/beta-1 and at least one other alpha, but no beta isoform (n = 64), and (3) reactivity to all 6 MOG isoforms (n = 65). The remaining samples were negative (n = 176) for MOG-IgG. These MOG isoform binding patterns were associated with a non-MS demyelinating disease, but there were no differences in clinical phenotypes or disease course. The 3 MOG isoform patterns had distinct immunologic characteristics such as differential binding to soluble MOG-ecIgD, sensitivity to MOG mutations, and binding to human MOG in ELISA. CONCLUSIONS: The novel finding of differential MOG isoform binding patterns could inform future studies on the refinement of MOG-IgG assays and the pathophysiologic role of MOG-IgG.
Assuntos
Autoanticorpos/metabolismo , Doenças Desmielinizantes/metabolismo , Encefalite/metabolismo , Glicoproteína Mielina-Oligodendrócito/metabolismo , Estudos de Casos e Controles , Doenças Desmielinizantes/imunologia , Encefalite/imunologia , Feminino , Humanos , Masculino , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Glicoproteína Mielina-Oligodendrócito/imunologia , Ligação Proteica , Isoformas de Proteínas/metabolismo , Estudos RetrospectivosRESUMO
Limited data exist on isolated optic neuritis in children. We report the clinical features and treatment of pediatric subjects with monophasic and recurrent idiopathic optic neuritis. This retrospective cohort study of patients with isolated optic neuritis identified 10 monophasic and 7 recurrent optic neuritis cases. Monophasic optic neuritis patients were older (mean 13.3 ± 4.22) than those with recurrent idiopathic optic neuritis (9.86 ± 3.63). Females represented 50% of monophasic and 85.7% of recurrent idiopathic optic neuritis cases. Patients with monophasic optic neuritis were less likely to have a bilateral onset than recurrent idiopathic optic neuritis (40% vs 57.1%). Only 1 case had oligoclonal bands in the cerebrospinal fluid CSF. Most recurrent idiopathic optic neuritis cases had evidence of anti-myelin oligodendrocyte glycoprotein (MOG) antibodies (5/7). Treatment of recurrent idiopathic optic neuritis cases included intravenous pulse glucocorticosteroids and immunotherapy. We observed differences between recurrent and monophasic idiopathic optic neuritis. Immunosuppression appeared to prevent further relapses in recurrent idiopathic optic neuritis patients. Weaning immunotherapies after several years of quiescence in recurrent idiopathic optic neuritis may be possible, but larger studies are needed.
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Autoanticorpos , Glucocorticoides/uso terapêutico , Imunoterapia/métodos , Glicoproteína Mielina-Oligodendrócito/imunologia , Neurite Óptica/diagnóstico , Adolescente , Criança , Feminino , Humanos , Masculino , Neurite Óptica/tratamento farmacológico , Neurite Óptica/imunologia , Recidiva , Estudos RetrospectivosRESUMO
It is well established that the binding of pathogenic aquaporin-4 (AQP4)-specific autoantibodies to astrocytes may initiate a cascade of events culminating in the destruction of these cells and in the formation of large tissue-destructive lesions typical for patients with neuromyelitis optica spectrum disorders (NMOSD). To date, not a single experimental study has shown that the systemic presence of the antibody alone can induce any damage to the central nervous system (CNS), while pathological studies on brains of NMOSD patients suggested that there might be ways for antibody entry and subsequent tissue damage. Here, we systemically applied a highly pathogenic, monoclonal antibody with high affinity to AQP4 over prolonged period of time to rats, and show that AQP4-abs can enter the CNS on their own, via circumventricular organs and meningeal or parenchymal blood vessels, that these antibodies initiate the formation of radically different lesions with AQP4 loss, depending on their mode and site of entry, and that lesion formation is much more efficient in the presence of encephalitogenic T-cell responses. We further demonstrate that the established tissue-destructive lesions trigger the formation of additional lesions by short and far reaching effects on blood vessels and their branches, and that AQP4-abs have profound effects on the AQP4 expression in peripheral tissues which counter-act possible titer loss by antibody absorption outside the CNS. Cumulatively, these data indicate that directly induced pathological changes caused by AQP4-abs inside and outside the CNS are efficient drivers of disease evolution in seropositive organisms.
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Aquaporina 4/imunologia , Autoanticorpos/farmacologia , Autoantígenos/imunologia , Neuromielite Óptica/imunologia , Animais , Autoanticorpos/imunologia , Ratos , Ratos Endogâmicos Lew , Ratos NusRESUMO
BACKGROUND: The presence of circulating anti-myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) has been described in sera of patients with different inflammatory conditions of the central nervous system. In adults the core clinical feature is usually characterised by acute myelitis and/or optic neuritis. We here report an atypical case with serum and cerebrospinal fluid MOG-Abs and a clinical picture suggestive for acute encephalitis. CASE PRESENTATION: A 31-year-old Indian man presented with altered mental status, slight fever, and ataxia. Brain magnetic resonance imaging noted a widespread involvement of the white matter associated with slight cortical and subcortical damage in absence of contrast enhancement. An extensive infectious screening resulted negative while autoimmune analysis revealed the presence of MOG-Abs, detected with live cell-based assay. After treatment with intravenous immunoglobulins a marked and prompt clinical and radiological improvement was observed. CONCLUSIONS: To date, several areas of uncertainty still remain regarding clinical features and prognosis of subjects with MOG-Abs. The description of atypical cases is crucial, since recognition of this condition leads to prompt treatment and better prognosis, as in the case here reported.
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Encefalite/imunologia , Imunoglobulinas Intravenosas/administração & dosagem , Glicoproteína Mielina-Oligodendrócito/imunologia , Adulto , Autoanticorpos/sangue , Humanos , Imageamento por Ressonância Magnética , Masculino , Neurite Óptica/etiologia , PrognósticoRESUMO
BACKGROUND: Antibodies 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. METHODS: We 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. RESULTS: Overall, 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. CONCLUSION: This 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.
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Anticorpos/metabolismo , Cerebelo/metabolismo , Proteínas do Sistema Complemento/metabolismo , Doenças Desmielinizantes/metabolismo , Glicoproteína Mielina-Oligodendrócito/metabolismo , Adolescente , Adulto , Idoso , Animais , Cerebelo/patologia , Criança , Pré-Escolar , Doenças Desmielinizantes/patologia , Feminino , Células HEK293 , Humanos , Lactente , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Neuromielite Óptica/metabolismo , Neuromielite Óptica/patologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Endogâmicos Lew , Adulto JovemRESUMO
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.
RESUMO
Acute disseminated encephalomyelitis (ADEM) is a rare autoimmune-mediated demyelinating disease affecting mainly children and young adults. Differentiation to multiple sclerosis is not always possible, due to overlapping clinical symptoms and recurrent and multiphasic forms. Until now, immunoglobulins reactive to myelin oligodendrocyte glycoprotein (MOG antibodies) have been found in a subset of patients with ADEM. However, there are still patients lacking autoantibodies, necessitating the identification of new autoantibodies as biomarkers in those patients. Therefore, we aimed to identify novel autoantibody targets in ADEM patients. Sixteen ADEM patients (11 seronegative, 5 seropositive for MOG antibodies) were analysed for potential new biomarkers, using a protein microarray and immunohistochemistry on rat brain tissue to identify antibodies against intracellular and surface neuronal and glial antigens. Nine candidate antigens were identified in the protein microarray analysis in at least two patients per group. Immunohistochemistry on rat brain tissue did not reveal new target antigens. Although no new autoantibody targets could be found here, future studies should aim to identify new biomarkers for therapeutic and prognostic purposes. The microarray analysis and immunohistochemistry methods used here have several limitations, which should be considered in future searches for biomarkers.
Assuntos
Autoanticorpos/imunologia , Encefalomielite Aguda Disseminada/diagnóstico , Encefalomielite Aguda Disseminada/imunologia , Imuno-Histoquímica , Análise Serial de Proteínas , Animais , Autoantígenos/imunologia , Biomarcadores , Criança , Análise por Conglomerados , Reações Cruzadas/imunologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Proteínas de Membrana/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Proteínas do Tecido Nervoso/imunologia , Proteínas/imunologia , Proteoma , Proteômica/métodos , RatosRESUMO
The aim of this study was to report the clinical spectrum associated with antibodies to myelin oligodendrocyte glycoprotein (MOG) in adult patients, and to assess whether phenotypic variants are dependent on recognition of rodent MOG epitopes. We retrospectively analyzed the features, course and outcome of 56 patients whose samples were investigated by brain tissue immunohistochemistry and cell-based assays using human and rodent MOG. The median age at symptom onset was 37 years (range 18-70); 35 patients (63 %) were female. After a median follow-up of 43 months (range 4-554), only 14 patients (25 %) developed a neuromyelitis optica spectrum disorder (NMOSD), 27 patients (47 %) retained the initial diagnosis of isolated optic neuritis, 7 (12 %) of longitudinally extensive transverse myelitis, and 2 (4 %) of acute disseminated encephalomyelitis; 6 patients (11 %) developed atypical demyelinating syndromes (4 had relapsing episodes of short myelitis lesions which in one occurred with optic neuritis; 1 had relapsing brainstem symptoms, and 1 relapsing demyelinating encephalomyelitis). The course was frequently associated with relapses (71 %) and good outcome. Twenty-seven patients (49 %) had antibodies that recognized rodent MOG epitopes, and 9 of them (16 %) showed a myelin staining pattern in rodent tissue. Only the myelin staining pattern was linked to NMOSD (p = 0.005). In conclusion, MOG autoimmunity in adult patients associates with a clinical spectrum wider than the one expected for patients with suspected NMOSD and overall good outcome. Antibodies to rodent MOG epitopes do not associate with any phenotypic variant.
Assuntos
Autoanticorpos/sangue , Autoimunidade/fisiologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Neuromielite Óptica/sangue , Neuromielite Óptica/fisiopatologia , Adolescente , Adulto , Idoso , Animais , Aquaporina 4/imunologia , Encéfalo/metabolismo , Avaliação da Deficiência , Feminino , Seguimentos , Células HEK293 , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/patologia , Estudos Retrospectivos , Estatísticas não Paramétricas , Adulto JovemRESUMO
N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune neurological disease, diagnosed by a specific autoantibody against NMDAR. Antibody testing using commercially available cell-based assays (CBA) or immunohistochemistry on rat brain tissue has proven high specificity and sensitivity. Here we compare an immunofluorescence live CBA to a flow cytometry (FACS) based assay to detect NMDAR antibodies by their binding to the surface of HEK293A cells functionally expressing NMDAR. Both assays were first established using a discovery group of 76 individuals and then validated in a group of 32 patients in a blinded manner. In the CBA, 23 of 23 patients with NMDAR encephalitis were positive for NMDAR antibodies and 0 of 85 controls (32 healthy controls and 53 patients with other neurological diseases), resulting in a sensitivity and specificity of 100% (95% confidence intervals (CI) 85.1-100.0 and 95.7-100.0, respectively). The FACS based assay detected NMDAR antibodies in 20 of 23 patients and in 0 of 85 controls. Therefore, with an equally high specificity (95% CI 95.7-100.0) the sensitivity of the FACS based assay was 87% (95% CI 66.4-97.2). Comparing antibody titers from CBA with delta median fluorescence intensities from FACS showed a high concordance (kappa = 0.943, p<0.0001) and correlation (r = 0.697, p<0.0001). In conclusion, evaluation of the FACS based assay revealed a lower sensitivity and high inter-assay variation, making the CBA a more reliable detection method.
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Encefalite Antirreceptor de N-Metil-D-Aspartato/sangue , Autoanticorpos/sangue , Testes Sorológicos/métodos , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Feminino , Citometria de Fluxo/métodos , Células HEK293 , Humanos , Masculino , Microscopia de Fluorescência/métodos , Receptores de N-Metil-D-Aspartato/imunologia , Sensibilidade e EspecificidadeRESUMO
We have recently demonstrated the safety and tolerability of a novel therapeutic regimen employing autologous blood cells chemically coupled with seven myelin peptides to induce antigen-specific tolerance in MS (ETIMS study). The aim of the current study was an extended safety analysis to assess the effect of the ETIMS approach on antibodies to common autoantigens, the myelin peptides used and common recall antigens. None of the patients showed induction of autoantibody responses. One patient had a measurable myelin peptide-specific response at baseline, which was reduced after treatment. Total immunoglobulins and recall antibody responses showed no significant change.