RESUMEN
Analogs of immunodominant myelin peptides involved in multiple sclerosis (MS: the most common autoimmune disease) have been extensively used to modify the immune response over the progression of the disease. The immunodominant 35-55 epitope of myelin oligodendrocyte glycoprotein (MOG35-55 ) is an autoantigen appearing in MS and stimulates the encephalitogenic T cells, whereas mannan polysaccharide (Saccharomyces cerevisiae) is a carrier toward the mannose receptor of dendritic cells and macrophages. The conjugate of mannan-MOG35-55 has been extensively studied for the inhibition of chronic experimental autoimmune encephalomyelitis (EAE: an animal model of MS) by inducing antigen-specific immune tolerance against the clinical symptoms of EAE in mice. Moreover, it presents a promising approach for the immunotherapy of MS under clinical investigation. In this study, a competitive enzyme-linked immunosorbent assay (ELISA) was developed to detect the MOG35-55 peptide that is conjugated to mannan. Intra- and inter-day assay experiments proved that the proposed ELISA methodology is accurate and reliable and could be used in the following applications: (i) to identify the peptide (antigen) while it is conjugated to mannan and (ii) to adequately address the alterations that the MOG35-55 peptide may undergo when it is bound to mannan during production and stability studies.
Asunto(s)
Epítopos Inmunodominantes , Esclerosis Múltiple , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Péptidos , Animales , Ratones , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/terapia , Ensayo de Inmunoadsorción Enzimática , Epítopos Inmunodominantes/análisis , Mananos/química , Ratones Endogámicos C57BL , Glicoproteína Mielina-Oligodendrócito/análisis , Fragmentos de Péptidos/análisis , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/terapiaRESUMEN
BACKGROUND: The clinical phenotypes of myelin oligodendrocyte glycoprotein (MOG) antibody disease, its disease course, and treatment are poorly understood and much work needs to be done towards this. OBJECTIVE: To characterize the clinico-radiologic spectrum and treatment outcomes of MOG antibody disease and differentiate it from aquaporin-4 (AQP-4) antibody positive neuromyelitis optica spectrum disorders (NMO-SD). METHODS: A single-center, observational study from Western India during 2017-2019, of 48 patients with either MOG antibody positive (21 patients) or AQP-4 antibody positive (27 patients) central nervous system demyelination. RESULTS: MOG antibody group had median age 32.2 years, no gender bias, median disease duration 40 months, relapses in 9 patients (43%), and median 2.5 (1-16) episodes per patient. Onset phenotypes included isolated bilateral optic neuritis (ON) (43%), isolated unilateral ON (19%), acute brainstem syndrome (19%), simultaneous ON with myelitis (9%), isolated myelitis (5%), and acute disseminated encephalomyelitis optic neuritis (ADEM-ON) (5%). Characteristic neuroimaging abnormalities were anterior segment longitudinally extensive ON, upper brainstem, and thoracic cord involvement (both short and long segment lesions). Most patients (86%) responded well to steroids, only 3/21 required rescue immunotherapy. In total, 6 out of 46 eyes affected developed permanent visual disability, while one patient had motor disability. The features differentiating MOG from AQP-4 antibody group were: no female predilection, preferential optic nerve involvement, characteristic neuroimaging abnormalities, and favorable therapeutic response and outcome. CONCLUSIONS: MOG disease commonly presents as severe ON, myelitis, acute brainstem syndrome, ADEM or their combinations. Early identification, treatment, and maintenance immunosuppression are necessary. It can easily be differentiated from NMO-SD using clinico-radiological features and therapeutic response.
Asunto(s)
Personas con Discapacidad , Trastornos Motores , Glicoproteína Mielina-Oligodendrócito , Neuromielitis Óptica , Adulto , Acuaporina 4 , Autoanticuerpos , Humanos , India , Glicoproteína Mielina-Oligodendrócito/análisis , Neuromielitis Óptica/diagnóstico por imagenRESUMEN
BACKGROUND: Investigations of myelin oligodendrocyte glycoprotein (MOG) antibodies are usually focused on demyelinating syndromes, but the entire spectrum of MOG antibody-associated syndromes in children is unknown. In this study, we aimed to determine the frequency and distribution of paediatric demyelinating and encephalitic syndromes with MOG antibodies, their response to treatment, and the phenotypes associated with poor prognosis. METHODS: In this prospective observational study, children with demyelinating syndromes and with encephalitis other than acute disseminated encephalomyelitis (ADEM) recruited from 40 secondary and tertiary centres in Spain were investigated for MOG antibodies. All MOG antibody-positive cases were included in our study, which assessed syndromes, treatment and response to treatment (ie, number of relapses), outcomes (measured with the modified Rankin scale [mRS]), and phenotypes associated with poor prognosis. We used Fisher's exact and Wilcoxon rank sum tests to analyse clinical features, and survival Cox regression to analyse time to antibody negativity. FINDINGS: Between June 1, 2013, and Dec 31, 2018, 239 children with demyelinating syndromes (cohort A) and 296 with encephalitis other than ADEM (cohort B) were recruited. 116 patients had MOG antibodies, including 94 (39%) from cohort A and 22 (7%) from cohort B; 57 (49%) were female, with a median age of 6·2 years (IQR 3·7-10·0). Presenting syndromes in these 116 patients included ADEM (46 [68%]), encephalitis other than ADEM (22 [19%]), optic neuritis (20 [17%]), myelitis (13 [11%]), neuromyelitis optica spectrum disorders (six [5%]), and other disorders (nine [8%]). Among the patients with autoimmune encephalitis in cohort B (n=64), MOG antibodies were more common than all neuronal antibodies combined (22 [34%] vs 21 [33%]). After a median follow-up of 42 months (IQR 22-67), 33 (28%) of the 116 patients had relapses, including 17 (17%) of 100 diagnosed at first episode. Steroids, intravenous immunoglobulin, or plasma exchange were used in 100 (86%) patients at diagnosis, and 32 (97%) of 33 at relapses. Rituximab was mainly used at relapses (11 [33%]). 99 (85%) of 116 patients had substantial recovery (mRS <2) and 17 (15%) moderate to severe deficits (mRS >2; one died). Phenotypes of poor prognosis included ADEM-like relapses progressing to leukodystrophy-like features, and extensive cortical encephalitis evolving to atrophy. Time to antibody negativity was longer in patients with relapses (HR 0·18, 95% CI 0·05-0·59). INTERPRETATION: The spectrum of paediatric MOG antibody-associated syndromes is wider than previously reported and includes demyelinating syndromes and encephalitis. Recognition of these disorders has important clinical and prognostic implications. FUNDING: Mutua Madrileña Foundation; ISCIII-Subdirección General de Evaluación y Fomento de la Investigación Sanitaria; Fondo Europeo de Desarrollo Regional; Pediatrics Spanish Society; Departament de Salut, Generalitat de Catalunya; Marato TV3 Foundation; Red Española de Esclerosis Múltiple; La Caixa Foundation; and Fundació CELLEX.
Asunto(s)
Enfermedades Desmielinizantes/inmunología , Encefalitis/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Autoanticuerpos/sangre , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulinas Intravenosas , Imagen por Resonancia Magnética , Masculino , Glicoproteína Mielina-Oligodendrócito/análisis , Neuromielitis Óptica/sangre , Neuromielitis Óptica/diagnóstico , Neuromielitis Óptica/inmunología , Pediatría , Estudios Prospectivos , España , SíndromeRESUMEN
AIM: To evaluate the diagnostic value of MOG-IgG antibodies in multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM). MATERIAL AND METHODS: Twenty-nine patients with definitive MS according to the criteria of McDonald, 2010 (21 with relapse-remitting MS and 8 with secondary progressive MS), 7 patients with ADEM confirmed by clinical and instrumental data and 27 healthy volunteers were included in the study. Serum MOG-IgG levels were evaluated in all patients. MOG-IgG levels in the cerebrospinal fluid (CSF) were evaluated in 22 cases with MS, 6 cases with ADEM, and 8 healthy volunteers using ELISA. RESULTS AND CONCLUSIONS: Serum MOG-IgG levels are significantly higher in patients with MS and ADEM compared to the control group. No statistically significant differences in the serum MOG-IgG levels were found between MS and ADEM groups. When analyzing the level of MOG-IgG in CSF, no statistically significant between-group differences were obtained. The sensitivity and specificity of the determination of MOG-IgG in serum in patients with MS are 75,8% and 92.59%, respectively. MOG-IgG is detected in serum and CSF in patients with demyelinating diseases that indicates its pathogenetic significance in the development of MS and ADEM. Serum MOG-IgG may be a valuable biomarker for demyelinating diseases. Further research in a large population of patients is required.
Asunto(s)
Encefalomielitis Aguda Diseminada , Esclerosis Múltiple , Glicoproteína Mielina-Oligodendrócito , Autoanticuerpos , Estudios de Casos y Controles , Sistema Nervioso Central , Encefalomielitis Aguda Diseminada/diagnóstico , Humanos , Esclerosis Múltiple/diagnóstico , Glicoproteína Mielina-Oligodendrócito/análisisRESUMEN
BACKGROUND: Myelin oligodendrocyte glycoprotein antibodies (MOG Abs) are frequently detected in pediatric acquired demyelinating syndrome (ADS), and MOG-Ab-positive ADS differs from multiple sclerosis (MS) and aquaporin-4 (AQP4)-Ab-positive neuromyelitis optica spectrum disorder (NMOSD) in terms of age distribution, therapeutic response, and prognosis. METHODS: Based on medical records, we retrospectively evaluated patients with MOG-Ab-positive NMOSD treated in the acute phase who were followed up in the chronic phase at our hospital from January 2011 to December 2017. RESULTS: The patients comprised two boys and two girls aged 3-12 (median, 8) years. Peak MOG-Ab titers were 1:2048 to 1:32768 (median, 1:10240), and the relapse rate ranged from 0 to 1.25 times/year (median, 0.59 times/year); no sequelae were observed in any cases. Lesions other than those of optic neuritis were distributed at the cortex in one patient, subcortical white matter in four, deep white matter in three, and brainstem in one, all of which were disseminated lesions. No lesions were found in the corpus callosum, periventricular white matter, diencephalon, and regions adjacent to the third and fourth ventricles. The lesions tended to be asymptomatic, and two patients aged >5â¯years had well-demarcated lesions. CONCLUSION: All the patients showed disseminated lesions in the subcortical region to deep white matter, which were different from those found in MS and AQP4-Ab-positive NMOSD and were consistent with the characteristics of brain lesions in MOG-Ab-positive ADS, including other disease types.
Asunto(s)
Glicoproteína Mielina-Oligodendrócito/análisis , Glicoproteína Mielina-Oligodendrócito/inmunología , Neuromielitis Óptica/diagnóstico por imagen , Autoanticuerpos , Encéfalo , Tronco Encefálico , Niño , Preescolar , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Neuritis Óptica/fisiopatología , Estudios RetrospectivosRESUMEN
Neuromyelitis optica (NMO) is an autoimmune, demyelinating disorder of the central nervous system (CNS) with typical clinical manifestations of optic neuritis and acute transverse myelitis attacks. Previously believed to be a variant of multiple sclerosis (MS), it is now considered an independent disorder which needs to be differentiated from MS. The discovery of autoantibodies against aquaporin-4 (AQP4-IgGs) changed our understanding of NMO immunopathogenesis and revolutionized the diagnostic process. AQP4-IgG is currently regarded as a specific biomarker of NMO and NMO spectrum disorders (NMOsd) and a key factor in its pathogenesis. Nevertheless, AQP4-IgG seronegativity in 10%-25% of NMO patients suggests that there are several other factors involved in NMO immunopathogenesis, i.e., autoantibodies against aquaporin-1 (AQP1-Abs) and antibodies against myelin oligodendrocyte glycoprotein (MOG-IgGs). This manuscript reviews current knowledge about NMO immunopathogenesis, pointing out the controversial issues and showing potential directions for future research. Further efforts should be made to broaden our knowledge of NMO immunology which could have important implications for clinical practice, including the use of potential novel biomarkers to facilitate an early and accurate diagnosis, and modern treatment strategies improving long-term outcome of NMO patients.
Asunto(s)
Neuromielitis Óptica/inmunología , Neuromielitis Óptica/patología , Nervio Óptico/patología , Médula Espinal/patología , Animales , Acuaporina 4/análisis , Acuaporina 4/inmunología , Autoanticuerpos/análisis , Autoanticuerpos/inmunología , Biomarcadores/análisis , Humanos , Inmunoglobulina G/análisis , Inmunoglobulina G/inmunología , Glicoproteína Mielina-Oligodendrócito/análisis , Glicoproteína Mielina-Oligodendrócito/inmunología , Neuromielitis Óptica/diagnóstico , Neuromielitis Óptica/terapia , Nervio Óptico/inmunología , Médula Espinal/inmunologíaRESUMEN
BACKGROUND: DRα1-mouse(m)MOG-35-55, a novel construct developed in our laboratory as a simpler and potentially less immunogenic alternative to two-domain class II constructs, was shown previously to target the MIF/CD74 pathway and to reverse clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) in DR*1501-Tg mice in a manner similar to the parent DR2ß1-containing construct. METHODS: In order to determine whether DRα1-mMOG-35-55 could treat EAE in major histocompatibility complex (MHC)-mismatched mice and to evaluate the treatment effect on central nervous system (CNS) inflammation, C57BL/6 mice were treated with DRα1-mMOG-35-55. In addition, gene expression profile was analyzed in spinal cords of EAE DR*1501-Tg mice that were treated with DRα1-mMOG-35-55. RESULTS: We here demonstrate that DRα1-mMOG-35-55 could effectively treat EAE in MHC-mismatched C57BL/6 mice by reducing CNS inflammation, potentially mediated in part through an increased frequency of M2 monocytes in the spinal cord. Microarray analysis of spinal cord tissue from DRα1-mMOG-35-55-treated vs. vehicle control mice with EAE revealed decreased expression of a large number of pro-inflammatory genes including CD74, NLRP3, and IL-1ß and increased expression of genes involved in myelin repair (MBP) and neuroregeneration (HUWE1). CONCLUSION: These findings indicate that the DRα1-mMOG-35-55 construct retains therapeutic, anti-inflammatory, and neuroprotective activities during treatment of EAE across MHC disparate barriers.