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Anti-aquaporin-1 autoantibodies in patients with neuromyelitis optica spectrum disorders.

ABSTRACT: Autoantibodies against aquaporin-4 (AQP4), a water channel in CNS astrocytes, are detected in ?50-80% of patients with neuromyelitis optica spectrum disorders (NMOsd), characterized by longitudinally extensive transverse myelitis (LETM) and/or optic neuritis. Although these autoantibodies present an invaluable biomarker for NMOsd and for the differential diagnosis of multiple sclerosis (MS), diagnosis of anti-AQP4-seronegative NMOsd remains challenging. We hypothesized that seronegative NMOsd patients might have autoantibodies against aquaporin-1 (AQP1), another water channel in CNS astrocytes. We initially developed a radioimmunoprecipitation assay to search for anti-AQP1 antibodies in sera from 632 individuals. Anti-AQP1 or anti-AQP4 autoantibodies were detected in 16.7% and 12%, respectively, of 348 patients with suspected NMOsd. Anti-AQP1 specificity was confirmed by competition, protein immunoblotting and ELISA assays, whereas epitope localization was studied by immunoadsorption on intact cells expressing AQP1 and peptide mapping experiments. Most anti-AQP1 autoantibodies were of the complement-activating IgG1 subclass and the majority bound to the extracellular domain of AQP1, suggesting a possible pathogenic role. Five out of 42 MS patients had anti-AQP1 antibodies, but 2 of them also had spinal cord lesions, while the anti-AQP1 antibodies in the other 3 bound to the cytoplasmic domain of AQP1. Anti-AQP1 antibodies were not detected in 100 healthy individuals or 142 patients with non-demyelinating neuroimmune diseases. Analysis of 17 anti-AQP1+/anti-AQP4- patients with suspected NMOsd showed that 5 had NMO and 11 had LETM. 12/17 of these sera bound predominantly to the extracellular AQP1 loop-?. Overall, we found that anti-AQP1 autoantibodies are present in a subgroup of patients with chronic demyelination in the CNS and similarities with anti-AQP4-seronegative NMOsd, offering a novel potential biomarker for CNS demyelination disorders.

SUBMITTER: Tzartos JS

PROVIDER: S-EPMC3781161 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Anti-aquaporin-1 autoantibodies in patients with neuromyelitis optica spectrum disorders.

Tzartos John S JS Stergiou Christos C Kilidireas Konstantinos K Zisimopoulou Paraskevi P Thomaidis Thomas T Tzartos Socrates J SJ

PloS one 20130923 9

Autoantibodies against aquaporin-4 (AQP4), a water channel in CNS astrocytes, are detected in ∼50-80% of patients with neuromyelitis optica spectrum disorders (NMOsd), characterized by longitudinally extensive transverse myelitis (LETM) and/or optic neuritis. Although these autoantibodies present an invaluable biomarker for NMOsd and for the differential diagnosis of multiple sclerosis (MS), diagnosis of anti-AQP4-seronegative NMOsd remains challenging. We hypothesized that seronegative NMOsd pa ...[more]

PMID: 24086369

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Project description:Neuromyelitis optica spectrum disorders (NMOSD) are central nervous system inflammatory disorders causing significant morbidities and mortality. The majority of NMOSD patients have autoimmunity against aquaporin-4 (AQP4), evidenced by seropositivity for autoantibodies against aquaporin-4 (AQP4-IgG). AQP4-IgG is pathogenic with neuroinflammation initiated upon binding of AQP4-IgG to astrocytic AQP4. Complement activation contributes to astrocytic cytotoxicity, neuroinflammation, and tissue necrosis in NMOSD, but the role of complement-independent mechanisms is uncertain. We studied the complement-independent pathogenic effects of AQP4-IgG by passive transfer of IgG from NMOSD patients to mice with breached blood-brain barrier (BBB). Mice, pretreated with bacterial proteins, received daily intraperitoneal injections of IgG purified from AQP4-IgG-seropositive NMOSD patients [IgG(AQP4+)], or IgG from AQP4-IgG-seronegative patients [IgG(AQP4-)] or healthy subjects [IgG(Healthy)] for 8 days. Motor function was tested by walking across narrow beams, and spinal cords were collected for immunofluorescent analysis. We found that human IgG infiltrated into cord parenchyma of mice with breached BBB without deposition of complement activation products. Spinal cord of mice that received IgG(AQP4+) demonstrated loss of AQP4 and glial fibrillary acidic protein (suggestive of astrocyte loss), decrease in excitatory amino acid transporter 2, microglial/macrophage activation, neutrophil infiltration, patchy demyelination, and loss in axonal integrity. Mice that received IgG(AQP4+) required longer time with more paw slips to walk across narrow beams indicative of motor slowing and incoordination. Our findings suggest that AQP4-IgG induces complement-independent cord pathologies, including astrocytopathy, neuroinflammation, demyelination, and axonal injuries/loss, which are associated with subtle motor impairments. These complement-independent pathophysiologies likely contribute to early NMOSD lesion development.

Project description:Objective Neuromyelitis optica and its spectrum disorders (NMOSD) are inflammatory demyelinating diseases (IDD) with a specific biomarker, aquaporin-4-IgG. Prior NMO/NMOSD epidemiological studies are limited by lack of aquaporin-4-IgG seroprevalence assessment, absence of population-based USA studies and under-representation of blacks. To overcome these limitations, we sought to compare NMO/NMOSD seroepidemiology across two ethnically divergent populations. Methods We performed a population-based comparative study of the incidence (2003-2011) and prevalence (on December 31, 2011) of NMO/NMOSD and aquaporin-4-IgG seroincidence and seroprevalence (sera collected in 80-84% of IDD) among patients with IDD diagnosis in Olmsted County, USA (82% white [Caucasian]) and Martinique (90% black [Afro-Caribbean]). Aquaporin-4-IgG was measured by M1-isoform-fluorescent-activated-cell-sorting assays. Results The age and sex adjusted incidence (7.3 vs 0.7/1,000,000 person-years [p<0.01]) and prevalence (10 vs 3.9/100,000[p=0.01]) in Martinique exceeded that in Olmsted County. The AQP4-IgG age and sex-adjusted seroincidence (6.5 vs 0.7/1,000,000 person-years [p<0.01]) and seroprevalence (7.9 vs 3.3/100,000[p=0.04]) were also higher in Martinique than Olmsted County. The ethnicity-specific prevalence was similar in Martinique and Olmsted County: 11.5 and 13/100,000 in blacks, and 6.1 and 4.0/100,000 in whites, respectively. NMO/NMOSD represented a higher proportion of IDD in Martinique than Olmsted County (16% vs 1.4%; p<0.01). The onset age (median, 35-37 years) and female:male distribution (8-9:1) were similar across both populations; 60% of prevalent cases were either blind in one eye, dependent on a gait aid or both. Interpretation This study reports the highest prevalence of NMO/NMOSD in any population (10/100,000 in Martinique), estimates it affects 16,000-17,000 in the USA (higher than previous predictions) and demonstrates it disproportionately affects blacks. This article is protected by copyright. All rights reserved.

Project description:BackgroundRecognizing the predictors of disease relapses in patients with anti-aquaporin-4 antibody (AQP4-ab)-positive neuromyelitis optica spectrum disorder (NMOSD) is essential for individualized treatment strategy. We aimed to identify the factors that predicted relapses among patients with AQP4-ab-positive NMOSD, develop outcome prediction models, and validate them in a multicenter validation cohort.MethodsBetween January 2015 and December 2020, 820 patients with NMOSD were registered at Huashan Hospital. We retrospectively reviewed their medical records, and included 358 AQP4-ab-positive patients with 1135 treatment episodes. Univariate and multivariate analyses were used to explore the predictors of relapse, severe visual or motor disability during follow-up. A model predicting the 1- and 2-year relapse-free probability was developed and validated in an external validation cohort of 92 patients with 213 treatment episodes.ResultsLower serum AQP4-ab titer (< 1:100), higher Expanded Disability Status Scale (EDSS) score at onset (≥ 2.5), and use of intravenous methylprednisolone (IVMP) at the first attack predicted an overall lower annualized relapse rate. Older age (> 48 years), optic neuritis at onset, and higher onset EDSS score (≥ 2.5) significantly increased the risk for blindness, while IVMP at the first attack and maintenance therapy reduced the risk for blindness. Myelitis at onset increased the possibility of motor disability (EDSS ≥ 6.0), severe motor disability or death (EDSS ≥ 8.0), while maintenance therapy reduced these possibilities. Anderson and Gill model identified that the risk factors predicting recurrent relapses under certain treatment status were female gender, high AQP4-ab titer (≥ 1:100), previous attack under same therapy, lower EDSS score at treatment initiation (< 2.5), and no maintenance therapy or oral prednisone lasting less than 6 months. A nomogram using the above factors showed good discrimination and calibration abilities. The concordance indexes in the primary and validation cohort were 0.66 and 0.65, respectively.ConclusionThis study reports the demographic, clinical and therapeutic predictors of relapse, and severe visual or motor disability in NMOSD. Early identification of patients at risk of unfavorable outcomes is of paramount importance to inform treatment decisions.

Project description:BackgroundNeuromyelitis optica spectrum disorders are severe autoimmune inflammatory diseases of the central nervous system associated with the presence of immunoglobulin G antibodies against the water channel protein aquaporin-4. During exacerbation, specific aquaporin-4 immunoglobulin G may be produced intrathecally. We measured extracellular aquaporin-4 microparticles in the cerebrospinal fluid of a patient who later developed the typical symptoms and signs of a neuromyelitis optica spectrum disorder.Case presentationA 17-year-old South American girl developed acute severe motor and vocal tics and difficulties in walking, peripheral numbness, muscle pain, and bilateral headache. At age 22, she had a multitude of motor and psychiatric symptoms. Over the years, she fulfilled the diagnostic criteria for anorexia nervosa, depression, sleep disorder, obsessive-compulsive disorder, generalized anxiety disorder, panic disorder, agoraphobia, social anxiety disorder, development coordination disorder, attention-deficit/hyperactivity disorder, hypomania, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, conversion disorder, psychosis, and schizotypal personality syndrome. At age 24, she was found to have elevated titers of aquaporin-4 antibodies in serum, suggestive of probable neuromyelitis optica. She subsequently developed visual impairment, and swollen optic nerves were verified by magnetic resonance imaging. She was thus treated with a chimeric monoclonal antibody targeted against the pan-B-cell marker CD20 (rituximab), and almost all symptoms, including the psychiatric symptoms, rapidly decreased. We found a significant increase of extracellular microparticles of aquaporin-4 in cerebrospinal fluid sampled from our patient when she was 22 years old, 2 years before the full clinical development of neuromyelitis optica.ConclusionsMicroparticles of aquaporin-4 represent subcellular arrangements that may influence the pathogenesis of neuromyelitis optica spectrum disorders and may serve as biomarkers for the underlying cellular disturbances. The increase of aquaporin-4 microparticles in cerebrospinal fluid may be used for early diagnostic purposes; for prevention; and for evaluation of effective treatment, long-term follow-up studies, and elucidating the pathophysiology in neuromyelitis optica spectrum disorders. Further studies of aquaporin-4 microparticles in cerebrospinal fluid of patients with neuromyelitis optica and similar neuropsychiatric disorders are thus called for.

Dataset Information

Anti-aquaporin-1 autoantibodies in patients with neuromyelitis optica spectrum disorders.

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Anti-aquaporin-1 autoantibodies in patients with neuromyelitis optica spectrum disorders.

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