Neuromyelitis Optica Immunoglobulin Research Articles

Electrochemical Biosensing Strategy for Ultrasensitive Detection of Aquaporin-4 Antibody as Neuromyelitis Optica Autoimmune Disease Biomarker Using Aquaporin-4 Extracellular Loop

Neuromyelitis optica (NMO) is a severe and disabling neurodegenerative disorder of the central nervous system (CNS). Neuromyelitis optica-Immunoglobulin G (NMO-IgG) is a serum IgG autoantibody almost exclusively present in NMO patients, which helps to differentiate NMO from other CNS disorders. Developing standardized and user-friendly assays remains a significant challenge in making NMO-IgG testing widely available. Label-free methods are simpler and faster, without additional reagents and procedures. Here, we present a peptide-based label-free electrochemical biosensor for detecting aquaporin-4 antibodies (AQP4-Abs) using extracellular AQP4 to diagnose NMO disease via the DPV electrochemical method. We have developed a novel approach in which the E loop of extracellular AQP4 is bemployed to detect NMO. 3 phenylalanines (Phe) were annexed to the C terminal, and because phenylalanine has a benzene ring, it can have π-π interaction with the benzene ring of carbon nanotube (CNT). In the designated platform, instead of using functional groups with complex and multi-step processes for immobilizing on the electrode surface, we used Nickel-Metal−organic framework /CNT as a novel modifier for measuring AQP4 antibodies with a simple, cheap, and accessible synthesis method. The developed sensor can detect antibodies with detection limit and quantification of 6.2 and 10.0 pg ml−1, respectively (S/N = 3). Also, superb sensitivity of the biosensor was attained as 28.8 μA mL ng−1 cm−2, confirming that the sensor has great potential for clinical application as a diagnostic test.

Efficacy and Safety of the Natural Killer T Cell-Stimulatory Glycolipid OCH-NCNP1 for Patients With Relapsing Multiple Sclerosis: Protocol for a Randomized Placebo-Controlled Clinical Trial.

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that causes myelin sheath damage and axonal degeneration. The glycolipid (2S, 3S, 4R)-1-O-(α-d-galactosyl)-2-tetracosanoylamino-1,3,4-nonaetriol (OCH-NCNP1 or OCH) exerts an immunoregulatory action that suppresses T helper (Th)1 cell-mediated immune responses through natural killer T cell activation, selective interleukin-4 production, and Th2 bias induction in human CD4-positive natural killer T cells. This trial aims to investigate the efficacy and safety of the immunomodulator OCH in patients with relapsing MS through 24-week repeated administration. This protocol describes a double-blind, multicenter, placebo-controlled, randomized phase II clinical trial that was initiated in September 2019. The participants were randomly assigned to either a placebo control group or an OCH-NCNP1 group and the investigational drug (3.0 mg) was orally administered once weekly for the 24-week duration. Major inclusion criteria are as follows: patients had been diagnosed with relapsing MS (relapsing-remitting and/or secondary progressive MS) based on the revised McDonald criteria or were diagnosed with MS by an attending physician as noted in their medical records; patients with at least two medically confirmed clinical exacerbations within 24 months prior to consent or one exacerbation within 12 months prior to consent; patients with at least one lesion suspected to be MS on screening magnetic resonance imaging (MRI); and patients with 7 points or less in the Expanded Disability Status Scale during screening. Major exclusion criteria are as follows: diagnosis of neuromyelitis optica and one of optic neuritis, acute myelitis, and satisfying at least two of the following three items: (1) spinal cord MRI lesion extending across at least three vertebral bodies, (2) no brain MRI lesions during onset (at least four cerebral white matter lesions or three lesions, one of which is around the lateral ventricle), and (3) neuromyelitis optica-immunoglobulin G or antiaquaporin-4 antibody-positive. Outcome measures include the primary outcome of MRI changes (the percentage of subjects with new or newly expanded lesions at 24 weeks on T2-weighted MRI) and the secondary outcomes annual relapse rate (number of recurrences per year), relapse-free period (time to recurrence), sustained reduction in disability (SRD) occurrence rate, period until SRD (time to SRD occurrence), no evidence of disease activity, and exploratory biomarkers from phase I trials (such as gene expression, cell frequency, and intestinal and oral microbiome). We plan to enroll 30 patients in the full analysis set. Enrollment was closed in June 2021 and the study analysis was completed in March 2023. This randomized controlled trial will determine whether OCH-NCNP1 is effective and safe in patients with MS as well as provide evidence for the potential of OCH-NCNP1 as a therapeutic agent for MS. ClinicalTrials.gov NCT04211740; https://clinicaltrials.gov/study/NCT04211740. DERR1-10.2196/46709.

Anti-aquaporin-4 immunoglobulin G/anti-myelin oligodendrocyte glycoprotein immunoglobulin G double-positive paraneoplastic neurological syndrome in a patient with triple-negative breast cancer.

We report a rare case of paraneoplastic neurological syndrome with dual seropositivity of anti-aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies in a 40 year-old woman with metastatic triple-negative breast cancer. She received multiple lines of anti-neoplastic treatment, including immunotherapy with pembrolizumab, as well as cytotoxic chemotherapy. Paraneoplastic meningoencephalomyelitis developed 2 years after diagnosis of breast cancer and 1 year after discontinuation of immunotherapy with pembrolizumab. She first developed longitudinally extending transverse myelitis followed by left optic neuritis and meningoencephalitis with new enhancing lesions in the brain and spinal leptomeninges. Cerebrospinal fluid analysis during both episodes showed normal glucose and protein, and elevated white blood cell count. Cytology was negative for malignancy. Cerebrospinal fluid was positive for neuromyelitis optica immunoglobulin G antibody anti-aquaporin-4, and autoimmune myelopathy panel was positive for myelin oligodendrocyte glycoprotein antibody. The patient had significant clinical and radiographic improvement after completion of five cycles of plasmapheresis followed by intravenous immunoglobulin. She did not have recurrence of paraneoplastic syndrome with maintenance rituximab every 6 months and daily low-dose prednisone. She succumbed to progressive systemic metastatic disease 4.5 years after her breast cancer diagnosis. This case shows that these antibodies can occur concurrently and cause clinical features, such as both neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody disease, in a patient with a singular type of cancer. We highlight the importance of testing for paraneoplastic etiology in cancer patients with radiographic menigoencephalomyelitis or meningitis with atypical symptoms of meningeal carcinomatosis and/or cerebrospinal fluid profile negative for leptomeningeal carcinomatosis.

Neuromyelitis Optica Spectrum Disorder (Device’s Disease): - A Case Report Of Full Recovery With Corticosteroids, Therapeutic Plasmapheresis And Immunotherapy

Neuromyelitis optica is a severely disabling inflammatory disorder of autoimmune etiology of the central nervous system, mainly affecting the optic nerves and spinal cord. Here, we present a case report of neuromyelitis optica in a 28-year-old Indian woman who presented with sudden painless loss of vision with tingling followed by weakness of all four limbs with bowel involvement that developed over a period of one week, with a significant history of recent vaccination with COVISHIELD (ChAdOx1 nCoV- 19) vaccine . Clinical evaluation showed diminished vision in both eyes, which progressed to loss of power across all major muscle groups in all limbs and bowel involvement. Magnetic resonance imaging of brain with contrast was done which showed T2W/FLAIR hyperintense non enhancing signal in bilateral thalami extending caudally in mid brain on left side and in midline anterior medulla with subtle T2 hyperintense signal in body of corpus callosum, similar foci are seen in bilateral frontoparietal white matter suggestive of ADEM or demyelination. Also T2 hyperintense signal in both optic nerves [left> right] in posterior part of orbit suggestive of optic neuritis. MRI whole spine showed multiple patchy hyperintense signals on T2 and hypointensity on T1 all over cervical and dorsal vertebrae through whole segment in contiguous manner. The patient was immediately started on intravenous methylprednisolone pulse therapy followed by plasmapheresis and immunomodulator therapy. The diagnosis of neuromyelitis optica was later confirmed with strongly positive neuromyelitis optica immunoglobulin G. Since, treatment was started early patient responded very well and made full recovery. Hence, early initiation of aggressive immunosuppressive treatment is essential in such cases.

Teaching Neuro Images : Longitudinally extensive transverse myelitis in neuro-Behçet disease

A 25-year-old man presented with subacute spastic paraparesis. He reported 2 previous episodes of spastic paraparesis with partial recovery. Recurrent oral and genital ulceration, pustular skin eruptions, and fever coexisted. Profound motor weakness, a sensory level at T10, oral ulceration, and a pustular eruption on the anterior abdominal wall were noted. Marked neutrophilia was noted in both blood and CSF. Neuromyelitis optica–immunoglobulin G autoantibody was negative. MRI (figure) demonstrated marked inflammatory changes. IV and oral steroids, followed by 6 months of pulsed IV cyclophosphamide, resulted in marked clinical improvement. Neuro-Behçet disease lies within the clinical differential for longitudinally extensive transverse myelitis.1,2

Inhibition of Neuromyelitis Optica Immunoglobulin G Binding to Aquaporin-4 by the Small Molecule Blocker Melanthioidine.

Neuromyelitis optica (NMO) is a severe neurological demyelinating autoimmune disease affecting the optic nerves and spinal cord. The binding of neuromyelitis optica immunoglobulin G (NMO-IgG) and aquaporin-4 (AQP4) on the surface of astrocytes in the serum and cerebrospinal fluid is the main pathogenesis of NMO. Currently, therapeutic strategies for NMO include a reduction of the secondary inflammation response and the number of NMO-IgG, which can only alleviate clinical symptoms rather than fundamentally preventing a series of pathological processes caused by NMO-IgG binding to AQP4. The purpose of this study was to investigate the blocking effect of melanthioidine on the binding of NMO-IgG to AQP4 and its potential cytotoxicity. The current study developed a cell-based high-throughput screening approach to identify a molecular blocker of NMO-IgG binding to AQP4 using the Chinese hamster lung fibroblast (V79) cells expressing M23-AQP4. By screening ~400 small molecules, we identified melanthioidine with blocking effects without affecting AQP4 expression or its water permeability. Melanthioidine effectively blocked the binding of NMO-IgG to AQP4 in immunofluorescence assays and reduced complement-dependent cytotoxicity against both NMO-IgG/complement-treated Fischer rat thyroid-AQP4 cells and primary astrocytes. The docking computations identified the putative sites of blocker binding at the extracellular surface of AQP4. This study serves as proof of a potential NMO therapy by using a small-molecule blocker to target NMO pathogenesis.

The association between body mass index, demographic and clinical characteristics with cognitive performance in patients with neuromyelitis optica spectrum disorder.

Background: Cognitive dysfunction is one of the problems that patients with neuromyelitis optica spectrum disorder (NMOSD) suffer from. We aimed to assess the association between demographic and clinical features as well as body mass index (BMI) and cognitive function in patients with NMOSD. Methods: A cross-sectional study was performed on 41 patients with definite diagnosis of NMOSD. Serum status of neuromyelitis optica immunoglobulin G (NMO-IgG) was determined using enzyme-linked immunosorbent assay (ELISA) method. Cognitive function was assessed by Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) battery which is validated for Persian people before and North American Adult Reading Test (NAART). Results: The mean score of NAART test was higher in participants with normal weight compared with overweight patients (40.47 ± 3.51 vs. 36.00 ± 5.74, P = 0.02). Current age was negatively correlated with Delis-Kaplan Executive Function System (D-KEFS)-Sorting (P = 0.05, r = -0.30). The correlation of duration of disease and cognitive performance was not significant (P > 0.05). Higher physical disability based on Expanded Disability Status Scale (EDSS) was correlated with lower results in Brief Visuospatial Memory Test-Revised (BVMT-R) (P < 0.01, r = -0.50), California Verbal Learning Test-second edition (CVLT-II)-Delayed Recall (P = 0.02, r = -0.35), and Symbol Digit Modalities Test (SDMT) (P = 0.03, r = -0.33) subtests of MACFIMS. Annual relapse rate was indirectly correlated with CVLT-II (P = 0.03, r = -0.34) and CVLT-II-Delayed Recall (P = 0.01, r = -0.38). Male participants obtained better scores in Paced Auditory Serial Addition Test (PASAT) subtest (P = 0.05). NMO-IgG seropositive patients had poorer performance in terms of CVLT-II-Delayed Recall, Controlled Oral Word Association Test (COWAT), and D-KEFS-Descriptive (P < 0.05). Participants with bachelor and master education degrees showed significantly better results compared to those with high school degree (P < 0.05). Conclusion: Investigating the clinical and demographic factors affecting cognitive impairment can increase the awareness of health care providers for early diagnosis of cognitive impairment in patients with NMOSD and increase the quality of health services.

Atypical presentation of multiple sclerosis – A few points to ponder

The article by Dr. Aishwarya Angadi has brilliantly highlighted how multiple sclerosis can present as unilateral internuclear ophthalmoplegia. The author has meticulously examined the patient and presented it along with the detailed neurological findings. Early detection of multiple sclerosis can go a long way in reducing the morbidity of the disease through timely treatment and intervention. From an academic point of view, there are a few points that I would like to contribute. Since the patient complained of visual blurring, subclinical optic neuritis should have been ruled out with a visually evoked potential test.[1] In the cerebrospinal fluid study, the number of oligoclonal bands is significant for the prognosis of multiple sclerosis.[2] In a case of multiple sclerosis, NeuroMyelitis Optica Immunoglobulin G (NMOIgG) and anti-Myelin Oligodendrocyte Glycoprotein (anti-MOG) antibody should be tested.[345] Lesions on Magnetic Resonance Imaging (MRI) should fulfil McDonald's criteria to qualify as those of multiple sclerosis. MRI orbit is relevant in this case. Also, MRI brainstem should show lesions in the medial longitudinal fasciculus to explain the internuclear ophthalmoplegia. As this patient was positive for Anti Neutrophil Cytoplasmic Antibodies (ANCA), autoimmune vasculitis should also be ruled out. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

New BBB Model Reveals That IL-6 Blockade Suppressed the BBB Disorder, Preventing Onset of NMOSD.

Background and ObjectivesTo evaluate the pathophysiology of neuromyelitis optica spectrum disorder (NMOSD) and the therapeutic mechanism and levels of interleukin-6 (IL-6) blockade (satralizumab), especially with respect to blood-brain barrier (BBB) disruption with the new in vitro and ex vivo human BBB models and in vivo model.MethodsWe constructed new static in vitro and flow-based ex vivo models for evaluating continued barrier function, leukocyte transmigration, and intracerebral transferability of neuromyelitis optica-immunoglobulin G (NMO-IgG) and satralizumab across the BBB using the newly established triple coculture system that are specialized to closely mimic endothelial cell contact of pericytes and endfeet of astrocytes. In the in vivo study, we assessed the effects of an anti–IL-6 receptor antibody for mice (MR16-1) on in vivo BBB disruption in mice with experimental autoimmune encephalomyelitis in which IL-6 concentration in the spinal cord dramatically increases.ResultsIn vitro and ex vivo experiments demonstrated that NMO-IgG increased intracerebral transferability of satralizumab and NMO-IgG and that satralizumab suppressed the NMO-IgG–induced transmigration of T cells and barrier dysfunction. In the in vivo study, the blockade of IL-6 signaling suppressed the migration of T cells into the spinal cord and prevented the increased BBB permeability.DiscussionThese results suggest that (1) our triple-cultured in vitro and in ex vivo BBB models are ideal for evaluating barrier function, leukocyte transmigration, and intracerebral transferability; (2) NMO-IgG increased the intracerebral transferability of NMO-IgG via decreasing barrier function and induced secretion of IL-6 from astrocytes causing more dysfunction of the barrier and disrupting controlled cellular infiltration; and (3) satralizumab, which can pass through the BBB in the presence of NMO-IgG, suppresses the BBB dysfunction and the infiltration of inflammatory cells, leading to prevention of onset of NMOSD.

Low Frequency Ultrasound With Injection of NMO-IgG and Complement Produces Lesions Different From Experimental Autoimmune Encephalomyelitis Mice.

Neuromyelitis optica spectrum disorder (NMOSD), a relapsing autoimmune disease of the central nervous system, mainly targets the optic nerve and spinal cord. To date, all attempts at the establishment of NMOSD animal models have been based on neuromyelitis optica immunoglobulin G antibody (NMO-IgG) and mimic the disease in part. To solve this problem, we developed a rodent model by opening the blood-brain barrier (BBB) with low frequency ultrasound, followed by injection of NMO-IgG from NMOSD patients and complement to mice suffering pre-existing neuroinflammation produced by experimental autoimmune encephalomyelitis (EAE). In this study, we showed that ultrasound with NMO-IgG and complement caused marked inflammation and demyelination of both spinal cords and optic nerves compared to blank control group, as well as glial fibrillary acidic protein (GFAP) and aquaporin-4 (AQP4) loss of spinal cords and optic nerves compared to EAE mice and EAE mice with only BBB opening. In addition, magnetic resonance imaging (MRI) revealed optic neuritis with spinal cord lesions. We further demonstrated eye segregation defects in the dorsal lateral geniculate nucleus (dLGN) of these NMOSD mice.

Factors Associated with Changes in Retinal Layers Following Acute Optic Neuritis: A Longitudinal Study Using Optical Coherence Tomography.

This study aimed to analyze longitudinal changes in retinal microstructures following acute optic neuritis and to identify the factors that affect those changes using spectral-domain optical coherence tomography (OCT). Forty-eight eyes of 37 patients with a first episode of optic neuritis and 48 eyes of 48 healthy controls were enrolled. Patients underwent serial OCT and visual function testing for more than six months. Individual layers from macular OCT were segmented with an automated algorithm. The total retinal layer (TRL), nerve fiber layer (NFL), ganglion cell layer (GCL) and inner plexiform layer (IPL) of optic neuritis eyes showed significant thinning with time over 6–15 months (p < 0.001 for all). The outer nuclear layer (ONL) showed a later decrease in thickness (p = 0.007). The outer retinal layer (ORL) showed an increase (p = 0.007) in thickness at two to five months which was sustained over time. Low visual acuity and neuromyelitis optica (NMO) immunoglobulin (Ig) G were associated with changes in the thickness of the GCL, IPL, and ONL over time (p < 0.05 for all). Low visual acuity was also associated with changes in the thickness of the NFL over time (p = 0.033). Dynamic changes of retinal microstructures varied according to the retinal layer examined after an optic neuritis attack. Initial visual acuity and NMO-IgG were found to be significant factors affecting the changes in thickness of each retinal layer. These results will lead to a better understanding of the pathologic changes that occur in eyes with optic neuritis.

Experimental mouse model of NMOSD produced by facilitated brain delivery of NMO-IgG by microbubble-enhanced low-frequency ultrasound in experimental allergic encephalomyelitis mice

Although optic neuritis and myelitis are the core clinical characteristics of neuromyelitis optica spectrum disorders (NMOSD), appropriate animal models of NMOSD with myelitis and optic neuritis are lacking. we developed a mouse model of NMOSD by intravenously injecting 100 µg neuromyelitis optica immunoglobulin G antibody (NMO-IgG) and complement into experimental allergic encephalomyelitis (EAE) mice after reversible blood-brain barrier (BBB) opening by microbubble-enhanced low-frequency ultrasound (MELFUS). Animals were assessed by histopathology. We found noticeable inflammation and demyelination concomitant with the loss of aquaporin-4 (AQP4) and glial fibrillary acidic protein (GFAP) expression in the spinal cord, brain and optic nerve, as well as human IgG and C9neo deposition. Thus, with the help of MELFUS, we established an NMOSD mouse model with the core lesions of NMOSD by applying a considerably lower dose of human NMO-IgG, which may help identify the pathogenesis and facilitate the development of other neuroimmune disease models in the future.

Incidence and timing of recurrence of optic neuritis.

To describe the incidence and timing of recurrence in patients with optic neuritis (ON). Medical documents of adult patients with ON were retrospectively reviewed. The incidence and timing of recurrence of an ON episode were analyzed. One hundred eleven patients with ON were included in this study. Their mean follow-up duration was 4.1 ± 3.1years. Seven relapses occurred after intravenous methylprednisolone treatment. The estimated cumulative incidence of recurrence in either eye was 26% at 1year, 33% at 3years, 37% at 5years, and 50% at 10years after the first episode of ON. If there was no recurrence until 6months after the first episode of ON, the next 5-year recurrence-free survival probability was 67%. If there was no recurrence until 1year, the next 5-year survival probability was 72%. If there was no recurrence until 2years, the next 5-year survival probability was 81%. Relapse within 1month and the presence of neuromyelitis optica-immunoglobulin G were factors that increased the recurrence rate over time. We evaluated the incidence and timing of the recurrence in patients with ON after the first episode. Lower probability of recurrence was observed in patients with longer recurrence-free follow-up period. However, monitoring for recurrence is needed even in patients with a single episode of ON due to the increasing tendency of the estimated cumulative incidence of recurrence over many years.

Open-label, add-on trial of cetirizine for neuromyelitis optica.

ObjectiveThis pilot study preliminarily examined the efficacy and tolerability of cetirizine as an add-on to standard therapy for neuromyelitis optica (NMO).MethodsEligible participants met the Wingerchuk 2006 diagnostic criteria or had a single typical episode along with positive NMO immunoglobulin G. After baseline clinical and laboratory assessments, participants began treatment with cetirizine 10 mg orally daily, in addition to their usual disease-modifying therapy for NMO, and continued for 1 year. The primary end point was the annualized relapse rate (ARR) while on the same disease-modifying therapy before starting cetirizine compared with after taking cetirizine. Additional end points included disability (Expanded Disability Status Scale [EDSS]), relapse severity, tolerability, especially with respect to drowsiness measured by the Epworth Sleepiness Scale (ESS), and laboratory parameters.ResultsThe ARR before cetirizine was 0.4 ± 0.80 and after cetirizine was 0.1 ± 0.24 (p = 0.047). There was no statistically significant difference in the EDSS (mean 3.9 ± 2.18 before the start of the study and 3.2 ± 2.31 at the conclusion of the study, p = 0.500). The ESS remained fairly consistent throughout the study (mean 6.5 ± 5.33 at baseline and 6.9 ± 4.50 at month 12, p = 0.740). Laboratory studies were unrevealing.ConclusionsIn this pilot study, cetirizine was well tolerated, and the prespecified primary efficacy end point was satisfied. However, the open-label design and the small sample size of this pilot study preclude definitive conclusions. Further research is needed.Classification of evidenceThis study provides Class IV evidence that in patients with NMO, the addition of cetirizine to standard therapy is safe, well tolerated, and reduces relapses.

Inhibition of RGMa alleviates symptoms in a rat model of neuromyelitis optica

Neuromyelitis optica (NMO) is an autoimmune disease associated with NMO immunoglobulin G (NMO-IgG), an antibody that selectively binds to the aquaporin-4. Here, we established a localized NMO model by injecting NMO-IgG into the spinal cord, and assessed the efficacy of treating its NMO-like symptoms by blocking repulsive guidance molecule-a (RGMa), an axon growth inhibitor. The model showed pathological features consistent with NMO. Systemic administration of humanized monoclonal anti-RGMa antibody delayed the onset and attenuated the severity of clinical symptoms. Further, it preserved astrocytes and reduced inflammatory-cell infiltration and axonal damage, suggesting that targeting RGMa is effective in treating NMO.

Complement regulator CD59 prevents peripheral organ injury in rats made seropositive for neuromyelitis optica immunoglobulin G

Pathogenesis in aquaporin-4 immunoglobulin G (AQP4-IgG) seropositive neuromyelitis optica spectrum disorders (herein called NMO) involves complement-dependent cytotoxicity initiated by AQP4-IgG binding to astrocyte AQP4. We recently reported that rats lacking complement inhibitor protein CD59 were highly susceptible to development of NMO pathology in brain and spinal cord following direct AQP4-IgG administration (Yao and Verkman, Acta Neuropath Commun 2017, 5:15). Here, we report evidence that CD59 is responsible for protection of peripheral, AQP4-expressing tissues in seropositive NMO. Rats made seropositive by intraperitoneal injection of AQP4-IgG developed marked weakness by 24 h and died soon thereafter. Serum creatine phosphokinase at 24 h was >900-fold greater in seropositive CD59−/− rats than in seropositive CD59+/+ (or control) rats. AQP4-expressing cells in skeletal muscle and kidney, but not in stomach, of seropositive CD59−/− rats showed injury with deposition of AQP4-IgG and activated complement C5b-9, and inflammation. Organ injury in seropositive CD59−/− rats was prevented by a complement inhibitor. Significant pathological changes in seropositive CD59−/− rats were not seen in optic nerve, spinal cord or brain, including circumventricular tissue. These results implicate a major protective role of CD59 outside of the central nervous system in seropositive NMO, and hence offer an explanation as to why peripheral, AQP4-expressing cells are largely unaffected in NMO.

Marked central nervous system pathology in CD59 knockout rats following passive transfer of Neuromyelitis optica immunoglobulin G

Neuromyelitis optica spectrum disorders (herein called NMO) is an inflammatory demyelinating disease of the central nervous system in which pathogenesis involves complement-dependent cytotoxicity (CDC) produced by immunoglobulin G autoantibodies targeting aquaporin-4 (AQP4-IgG) on astrocytes. We reported evidence previously, using CD59−/− mice, that the membrane-associated complement inhibitor CD59 modulates CDC in NMO (Zhang and Verkman, J. Autoimmun. 53:67–77, 2014). Motivated by the observation that rats, unlike mice, have human-like complement activity, here we generated CD59−/− rats to investigate the role of CD59 in NMO and to create NMO pathology by passive transfer of AQP4-IgG under conditions in which minimal pathology is produced in normal rats. CD59−/− rats generated by CRISPR/Cas9 technology showed no overt phenotype at baseline except for mild hemolysis. CDC assays in astrocyte cultures and cerebellar slices from CD59−/− rats showed much greater sensitivity to AQP4-IgG and complement than those from CD59+/+ rats. Intracerebral administration of AQP4-IgG in CD59−/− rats produced marked NMO pathology, with astrocytopathy, inflammation, deposition of activated complement, and demyelination, whereas identically treated CD59+/+ rats showed minimal pathology. A single, intracisternal injection of AQP4-IgG in CD59−/− rats produced hindlimb paralysis by 3 days, with inflammation and deposition of activated complement in spinal cord, optic nerves and brain periventricular and surface matter, with most marked astrocyte injury in cervical spinal cord. These results implicate an important role of CD59 in modulating NMO pathology in rats and demonstrate amplification of AQP4-IgG-induced NMO disease with CD59 knockout.

Müller cells and retinal axons can be primary targets in experimental neuromyelitis optica spectrum disorder

Recent work from our laboratory, using different models of experimental neuromyelitis optica spectrum disorder (NMOSD), has led to a number of observations that might be highly relevant for NMOSD patients. For example: (i) in the presence of neuromyelitis optica immunoglobulin G, astrocyte‐destructive lesions can be initiated by CD4+ T cells when these cells recognize aquaporin 4 (AQP4), but also when they recognize other antigens of the central nervous system. The only important prerequisite is that the T cells have to be activated within the central nervous system by “their” specific antigen. Recently activated CD4+ T cells with yet unknown antigen specificity are also found in human NMOSD lesions. (ii) The normal immune repertoire might contain AQP4‐specific T cells, which are highly encephalitogenic on activation. (iii) The retina might be a primary target of AQP4‐specific T cells and neuromyelitis optica immunoglobulin G: AQP4‐specific T cells alone are sufficient to cause retinitis with low‐grade axonal pathology in the retinal nerve fiber/ganglionic cell layer. A thinning of these layers is also observed in NMOSD patients, where it is thought to be a consequence of optic neuritis. Neuromyelitis optica immunoglobulin G might target cellular processes of Müller cells and cause their loss of AQP4 reactivity, when AQP4‐specific T cells open the blood–retina barrier in the outer plexiform layer. Patchy loss of AQP4 reactivity on Müller cells of NMOSD patients has been recently described. Cumulatively, our findings in experimental NMOSD suggest that both CD4+ T cell and antibody responses directed against AQP4 might play an important role in the pathogenesis of tissue destruction seen in NMOSD.

Seropositive Neuromyelitis Optica (Devic’s Disease): A Rare Case Report

Neuromyelitis optica or Devic’s disease is a rare inflammatory demyelinating autoimmune disease of the central nervous system which affects the spinal cord and optic nerves and usually associated with increased disability and morbidity. The purpose of this case report is to present this rare disease and focus on diagnostic criteria. NMO is often misdiagnosed as Multiple Sclerosis. The discovery of neuromyelitis optica (NMO) immunoglobulin G (IgG), directed against aquaporin-4 (AQP4), has dramatically changed the clinical definition of NMO and is important in the diagnostic criteria of this disease. Also longitudinally extensive spinal cord lesions (3 or more spinal segments) are characteristic of NMO. Here we report a case of a 14 year old girl presented with weakness of all four limbs with left sided complete blindness. NMO was diagnosed because of characteristic MRI finding and positive Aquaporin 4 IgG positive.J MEDICINE July 2016; 17 (2) : 122-124

Complement-independent retinal pathology produced by intravitreal injection of neuromyelitis optica immunoglobulin G.

BackgroundNeuromyelitis optica (NMO), an autoimmune inflammatory disease of the central nervous system, is often associated with retinal abnormalities including thinning of the retinal nerve fiber layer and microcystic changes. Here, we demonstrate that passive transfer of an anti-aquaporin-4 autoantibody (AQP4-IgG) produces primary retinal pathology.MethodsAQP4-IgG was delivered to adult rat retinas by intravitreal injection. Rat retinas and retinal explant cultures were assessed by immunofluorescence.ResultsImmunofluorescence showed AQP4-IgG deposition on retinal Müller cells, with greatly reduced AQP4 expression and increased glial fibrillary acidic protein by 5 days. There was mild retinal inflammation with microglial activation but little leukocyte infiltration and loss of retinal ganglion cells by 30 days with thinning of the ganglion cell complex. Interestingly, the loss of AQP4 was complement independent as seen in cobra venom factor-treated rats and in normal rats administered a mutated AQP4-IgG lacking complement effector function. Exposure of ex vivo retinal cultures to AQP4-IgG produced a marked reduction in AQP4 expression by 24 h, which was largely prevented by inhibitors of endocytosis or lysosomal acidification.ConclusionsPassive transfer of AQP4-IgG results in primary, complement-independent retinal pathology, which might contribute to retinal abnormalities seen in NMO patients.