Pathogenesis Of Neuromyelitis Optica Research Articles

Astrocyte-secreted C3 signaling impairs neuronal development and cognition in autoimmune diseases

Neuromyelitis optica (NMO) arises from primary astrocytopathy induced by autoantibodies targeting the astroglial protein aquaporin 4 (AQP4), leading to severe neurological sequelae such as vision loss, motor deficits, and cognitive decline. Mounting evidence has shown that dysregulated activation of complement components contributes to NMO pathogenesis. Complement C3 deficiency has been shown to protect against hippocampal neurodegeneration and cognitive decline in neurodegenerative disorders (e.g., Alzheimer's disease, AD) and autoimmune diseases (e.g., multiple sclerosis, MS). However, whether inhibiting the C3 signaling can ameliorate cognitive dysfunctions in NMO remains unclear. In this study, we found that the levels of C3a, a split product of C3, significantly correlate with cognitive impairment in our patient cohort. In response to the stimulation of AQP4 autoantibodies, astrocytes were activated to secrete complement C3, which inhibited the development of cultured neuronal dendritic arborization. NMO mouse models exhibited reduced adult hippocampal newborn neuronal dendritic and spine development, as well as impaired learning and memory functions, which could be rescued by decreasing C3 levels in astrocytes. Mechanistically, we found that C3a engaged with C3aR to impair neuronal development by dampening β-catenin signalling. Additionally, inhibition of the C3-C3aR-GSK3β/β-catenin cascade restored neuronal development and ameliorated cognitive impairments. Collectively, our results suggest a pivotal role of the activation of the C3-C3aR network in neuronal development and cognition through mediating astrocyte and adult-born neuron communication, which represents a potential therapeutic target for autoimmune-related cognitive impairment diseases.

Early involvement of peripherally derived monocytes in inflammation in an NMO-like mouse model

Neuromyelitis optica (NMO) is an autoimmune inflammatory disease that primarily affects the optic nerve and spinal cord within the central nervous system (CNS). Acute astrocyte injury caused by autoantibodies against aquaporin 4 (NMO-IgG) is a well-established key factor in the pathogenesis, ultimately leading to neuronal damage and patient disability. In addition to these humoral immune processes, numerous innate immune cells were found in the acute lesions of NMO patients. However, the origin and function of these innate immune cells remain unclear in NMO pathogenesis. Therefore, this study aims to analyze the origin and functions of these innate immune cells in an NMO-like mouse model and evaluate their role in the pathophysiology of NMO. The expression of Tmem119 on Iba1 + cells in brain tissue disappeared immediately after the injection of NMO-IgG + human complement mixture, while the expression of P2ry12 remained well-maintained at 1 day after injection. Based on these observations, it was demonstrated that monocytes infiltrate the brain during the early stages of the pathological process and are closely associated with the inflammatory response through the expression of the proinflammatory cytokine IL-1β. Understanding the variations in the expression patterns of P2ry12, Tmem119, and other markers could be helpful in distinguishing between these cell types and further analyzing their functions. Therefore, this research may contribute to a better understanding of the mechanisms and potential treatments for NMO.

Neuromyelitis Optica Spectrum Disorders: Clinical Perspectives, Molecular Mechanisms, and Treatments

Neuromyelitis optica (NMO) is a rare autoimmune inflammatory disorder affecting the central nervous system (CNS), specifically the optic nerve and the spinal cord, with severe clinical manifestations, including optic neuritis (ON) and transverse myelitis. Initially, NMO was wrongly understood as a condition related to multiple sclerosis (MS), due to a few similar clinical and radiological features, until the discovery of the AQP4 antibody (NMO-IgG/AQP4-ab). Various etiological factors, such as genetic-environmental factors, medication, low levels of vitamins, and others, contribute to the initiation of NMO pathogenesis. The autoantibodies against AQP4 target the AQP4 channel at the blood–brain barrier (BBB) of the astrocyte end feet, which leads to high permeability or leakage of the BBB that causes more influx of AQP4-antibodies into the cerebrospinal fluid (CSF) of NMO patients. The binding of AQP4-IgG onto the AQP4 extracellular epitopes initiates astrocyte damage through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Thus, a membrane attack complex is formed due to complement cascade activation; the membrane attack complex targets the AQP4 channels in the astrocytes, leading to astrocyte cell damage, demyelination of neurons and oligodendrocytes, and neuroinflammation. The treatment of NMOSD could improve relapse symptoms, restore neurological functions, and alleviate immunosuppression. Corticosteroids, apheresis therapies, immunosuppressive drugs, and B cell inactivating and complement cascade blocking agents have been used to treat NMOSD. This review intends to provide all possible recent studies related to molecular mechanisms, clinical perspectives, and treatment methodologies of the disease, particularly focusing on recent developments in clinical criteria and therapeutic formulations.

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 circadian rhythms regulated by Cx43-signaling in the pathogenesis of Neuromyelitis Optica.

Neuromyelitis Optica (NMO) is an inflammatory demyelinating disease of the central nervous system (CNS). NMO manifests as selective and severe attacks on axons and myelin of the optic nerve and spinal cord, resulting in necrotic cavities. The circadian rhythms are well demonstrated to profoundly impact cellular function, behavior, and disease. This study is aimed to explore the role and molecular basis of circadian rhythms in NMO. We used an Aquaporin 4(AQP4) IgG-induced NMO cell model in isolated astrocytes. The expression of Cx43 and Bmal1 were detected by real-time PCR and Western Blot. TAT-Gap19 and DQP-1105 were used to inhibit Cx43 and glutamate receptor respectively. The knockdown of Bmal1 were performed with the shRNA containing adenovirus. The levels of glutamate, anterior visual pathway (AVP), and vasoactive intestinal peptide (VIP) were quantified by ELISA kits. We found that Bmal1 and Clock, two essential components of the circadian clock, were significantly decreased in NMO astrocytes, which were reversed by Cx43 activation (linoleic acid) or glutamate. Moreover, the expression levels of Bmal1 and Clock were also decreased by Cx43 blockade (TAT-Gap19) or glutamate receptor inhibition (DQP-1105). Furthermore, adenovirus-mediated Bmal1 knockdown by shRNA (Ad-sh-Bmal1) dramatically decreased the levels of glutamate, AVP, and VIP from neurons, and significantly down-regulated the protein level of Cx43 in NMO astrocytes with Cx43 activation (linoleic acid) or glutamate treatment. However, Bmal1 knockdown did not alter these levels in normal astrocytes with Cx43 blockade (TAT-Gap19) or glutamate receptor inhibition (DQP-1105). Collectively, these results suggest that Cx43-glutamate signaling would be a critical upstream regulator that contributes to the NMO-induced rhythmic damage in SCN astrocytes.

Correlation between ERα gene polymorphism and multiple sclerosis and neuromyelitis optica.

Objective:To study the polymorphism distribution of estrogen receptor (ER) α gene and the correlation between different types of polymorphism in multiple sclerosis (MS) and neuromyelitis optica (NMO) patients.Methods:Forty-six cases of MS and NMO diagnosed from June 2018 to December 2019 were collected. Peripheral venous blood samples were collected. The patient’s gender, age of onset, course of disease, and other clinical data were recorded. Fifty-eight healthy volunteers of the same age and sex were selected. By means of Pvu II and Xba I restriction fragment length polymorphism enzyme recognition sites of ER α gene, polymerase chain reaction-restriction fragment length polymorphism analysis was conducted.Results:There was no significant difference in the frequency distribution of ER α gene’s PP, Pp, and pp genotype between MS and NMO case group and control group (P = .598). Frequency distribution of ER α gene’s XX, Xx, and xx was statistically significant between MS and NMO case group and control group (P = .021). Among them, distribution of Xx and Xx gene frequency between patient group and the control group was statistically significant (P = .001, OR = 4.622, 95% CI: 1.803–11.852). There was no significant correlation between ER α genotypes and the onset age in patient group (P > .05). The difference was statistically significant in disease duration of XX and Xx genotype (P = .006). The comparison of Xx and xx genotype frequency distribution in gender exists a difference(P = .047, OR = 7.500, 95% CI: 1.023–54.996).Conclusions:Xba I gene polymorphisms in the ER α gene have correlation with MS and NMO. Xba I gene could be a risk factor of MS and NMO pathogenesis, especially the women with Xx genotype are more vulnerable. Xba I gene polymorphisms in the ER α gene may impact the disease duration of MS and NMO, or rather, the disease duration of Xx genotype persists longer than Xx genotype. Pvu II gene polymorphisms in the ER α gene has no correlation with MS and NMO.

Effects of C5a and Receptor CD88 on Glutamate and N-Methyl-D-Aspartic Acid Receptor Expression in the Mouse Model of Optic Neuromyelitis

Objective To analyze the role of C5a, C5a receptor (CD88), glutamic acid, and N-methyl-D-aspartic acid receptors (NMDAR1 and NMDAR2B) in the onset of neuromyelitis optica (NMO) disease in mice. Method To select C57BL/6 wild-type (WT) mice and C5a receptor gene knockout (C5aR-/-) mice, use NMO-IgG and hemolytic complement to intervene in spinal cord tissue sections and optic nerves to establish an NMO model in vitro. The experiment was carried out with five groups (control group, WT group, C5aR-/- group, C5a group, and C5a+C5aRA group), with six mice in each group. The differences of American spinal cord injury (ASIA) motor scores were compared among all groups. The expressions of aquaporin (AQP4), glial fibrillary acidic protein (GFAP), NMDAR1, and NMDAR2B in spinal cord and optic nerve tissues were detected. The difference of glutamic acid (Glu) concentrations in culture solutions of the spinal cord and optic nerves was compared. Result The ASIA motor score of the control group was significantly lower than that of the other four groups. The C5a-/- group was significantly higher than the WT group. The C5a+C5aRA group was significantly higher than the C5a group in terms of ASIA motor score. In the control group, AQP4 and GFAP showed expression loss. The C5aR-/- group's loss rate was significantly higher than that of the WT group. The loss rate of the C5a+C5aRA group was significantly higher than that of the C5a group. In the control group, the protein expressions of NMDAR1 and NMDAR2B were significantly lower than that of the other four groups. The C5aR-/- group was significantly higher than the WT group. The C5a+C5aRA group was significantly higher than the C5a group in protein expression. In the control group, the concentration of Glu in the C5aR-/- group was significantly higher than that in the WT group, and the C5a group was significantly lower than the C5a+C5aRA group. Conclusion The deletion of the C5a receptor promotes NMDAR activity, which affects the toxic excitatory effect of NMDAR in NMO and regulates the neurotoxic effect of glutamic acid, thus participating in the pathogenesis of NMO.

FTY720 Exacerbates Blood-Brain Barrier Dysfunction Induced by IgG Derived from Patients with NMO and MOG Disease.

Neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein (MOG) antibody-related disease (MOG disease) are inflammatory demyelinating diseases of the central nervous system (CNS). The disruption of the blood-brain barrier (BBB) is considered a key step in the pathogenesis of NMO and MOG disease. Although a previous report indicated that circulating immunoglobulin G (IgG) from NMO patients disrupts the BBB, the effect of IgG from patients with MOG disease has not been elucidated. In addition, it has been reported that some disease-modifying drugs for multiple sclerosis are harmful to NMO by an unknown mechanism. This study aimed to examine the effects of IgG from patients with NMO or MOG disease on BBB integrity. We also examined the effects of disease-modifying drugs (fingolimod [FTY720] and dimethyl fumarate [DMF]) on IgG-treated brain capillary endothelial cells. We used in vitro BBB models constructed with rat brain capillary endothelial cells (RBECs) to examine the effects on BBB function. The integrity of the RBECs was assessed by measuring transendothelial resistance (TEER) and cell viability. NMO or MOG-IgG treatment decreased TEER and cell viability in the endothelial monolayer model. Although FTY720 and DMF did not affect barrier function or cell viability under normal conditions, disease IgG-induced barrier dysfunctions were worsened by the presence of FTY720. These data indicate that circulating IgG in patients with NMO or MOG disease worsens BBB function. Furthermore, in patients with NMO or MOG disease treated with FTY720, changes in the integrity of the BBB were found to exacerbate the disease.

The Emerging Role of Microglia in Neuromyelitis Optica.

Neuromyelitis optica (NMO) is an autoantibody-triggered neuro-inflammatory disease which preferentially attacks the spinal cord and optic nerve. Its defining autoantibody is specific for the water channel protein, aquaporin‐4 (AQP4), which primarily is localized at the end-feet of astrocytes. Histopathology studies of early NMO lesions demonstrated prominent activation of microglia, the resident immune sentinels of the central nervous system (CNS). Significant microglial reactivity is also observed in NMO animal models induced by introducing AQP4-IgG into the CNS. Here we review the potential roles for microglial activation in human NMO patients as well as different animal models of NMO. We will focus primarily on the molecular mechanisms underlying microglial function and microglia-astrocyte interaction in NMO pathogenesis. Understanding the role of microglia in NMO pathology may yield novel therapeutic approaches for this disease.

Identification of geraldol as an inhibitor of aquaporin‑4 binding by NMO‑IgG.

Neuromyelitis optica (NMO) is a severe neurological demyelinating autoimmune disease that affects the optic nerves and spinal cord. There is currently no effective cure or therapy. Aquaporin-4 (AQP4) is a known target of the autoimmune antibody NMO-IgG. Therefore, binding of NMO-IgG to AQP4, and subsequent activation of antibody-mediated and complement-dependent cytotoxicity (CDC), are thought to underlie the pathogenesis of NMO. In the present study, a cell-based high-throughput screening approach was developed to identify molecular inhibitors of NMO-IgG binding to AQP4. Using this approach, extracts from the herb Petroselinum crispum were shown to have inhibitory effects on NMO-IgG binding to AQP4, and the natural compound geraldol was purified from the herb extracts. Analytical high performance liquid chromatography, electrospray ionization-mass spectrometry and nuclear magnetic resonance analyses confirmed the identity of the isolated compound as geraldol, a flavonoid. Geraldol effectively blocked binding of NMO-IgG to AQP4 in immunofluorescence assays and decreased CDC in NMO-IgG/complement-treated FRTL-AQP4 cells and primary astrocytes. Geraldol exhibited low cytotoxicity, with no effect on proliferation or apoptosis of FRTL-AQP4 cells and primary astrocytes. Permeability assays indicated that geraldol did not alter the water transport function of AQP4 in either cell system. The present study suggests the potential therapeutic value of geraldol for NMO drug development.

Protein spectrum changes in exosomes after therapeutic plasma exchange in patients with neuromyelitis optica.

Neuromyelitis optica (NMO) is an autoimmune disease with a high rate of blindness and positive for the detection of aquaporin-4 antibody (AQP4) in most patients. NMO acute attacks are managed by high-doses of intravenous methylprednisolone followed by oral taper, and if symptoms fail to resolve, therapeutic plasma exchange (TPE) is added. TPE can remove pathological antibodies and inflammatory factors leading to clinical improvement. A total of 40 TPE fluid collections from the first to fifth TPE treatments were obtained from eight patients. Exosomes were isolated by ultracentrifugation. Mass spectrometry analyses were used to compare protein change in TPE fluid collection exosomes after the first to the fifth TPE treatments in these patients. We detected 647 exosome proteins through data-independent acquisition analysis. It was found that some unknown functional antibody fragments and complement pathway proteins decreased after TPE treatment. The results revealed a significant involvement of the following two key pathways: the primary immunodeficiency and systemic lupus erythematosus that may be associated with NMO pathophysiology and TPE treatment efficacy (P < .05). A series of complement proteins may contribute to NMO; in addition, the following proteins increased with plasma exchange: complement factor H-related protein 5, bridging integrator 2, neuroplastin, pigment epithelium-derived factor, ficolin-1, extracellular matrix protein 1, and fatty acid-binding protein 5. Our study may provide a new perspective on the pathogenesis and treatment efficacy of NMO.

Elevated serum level of IL-4 in neuromyelitis optica and multiple sclerosis patients

ABSTRACTMediators have important roles in the pathogenesis of autoimmune diseases. Interleukin 4 (IL-4) is one of the most important cytokines that has a regulatory effect on immune cells. In the current study, the serum level of IL-4 was assessed in the newly diagnosed neuromyelitis optica (NMO) and multiple sclerosis (MS) patients compared to healthy subjects. ELISA technique was used for assessment of the serum level of IL-4, and data analysis was performed by SPSS software. Serum level of IL-4 was elevated in both NMO and MS patients compared with healthy individuals (P < .001), but no statistically significant difference was identified between MS and NMO patients (P = .071). Furthermore, gender (female) and AQP4-Ab had significant impacts on the level of IL-4 in NMO patients (P < .001). These data show the crucial role of IL-4 in the pathogenesis of NMO and MS diseases. However, we suggest future studies to investigate the serum level of IL-4 in NMO and MS patients to clarify more roles of this cytokine in the pathogenesis of both diseases.

Current Status and Prospects of Complement-Targeting Therapy for Neuromyelitis Optica

Neuromyelitis optica (NMO) is clinically characterized by severe optic neuritis and long myelitis; and is associated with aquaporin-4 immunoglobulin-G (AQP4-IgG), an autoantibody directed against aquaporin-4 (AQP4), which is an astrocytic water channel protein. Until recent years, the treatment of NMO has mainly focused on the suppression of lymphocytes and depletion of autoantibodies. However, several studies on the pathogehesis of the disease in human pathology, cultured cells, and animal models have revealed that astrocyte injury in NMO is mainly caused by the complement-dependent cytotoxicity following AQP4-IgG binding to AQP4. Moreover, complement-targeting therapy has recently been translated into practical applications in several hematological disorders. and similary, also in the cases of NMO. In this article, we review the relevance of the complement system in the pathogenesis of NMO. Additionally, we review the current status and prospects of the complement-targeting therapy for NMO, including the clinical trials of eculizumab and C1 inhibitor for NMO, and the experimental studies on C1 inhibition by monoclonal antibodies.

The role of complement signaling pathway in the pathogenesis of neuromyelitis optica

Neuromyelitis optica (NMO) is a kind of demyelinating disorder that preferentially affects the optic nerves and spinal cord and results in permanent vision loss. NMO pathogenesis is thought to involve binding of anti-aquaporin-4 (AQP4) auto-antibodies to astrocytes, which causes complement-dependent cytotoxicity (CDC) and downstream inflammation leading to oligodendrocyte and neuronal injury. Vasculocentric deposition of activated complement is a prominent feature of NMO pathology. In recent years, a number of groups have found complements play an important role in the pathogenesis of NMO, and basic researches in NMO therapy due to its specificity and uniformity. Its inhibition would protect against proteins in the classical complement pathway so that cure the disease. This review will expound the the role of complement signaling pathway in the pathogenesis of NMO, and provide reference for a more in-depth understanding and clinical treatments of NMO. Key words: Neuromyelitis optica; Complement C1; Complement C3; Complement C5; Review

Repetitive intrathecal injection of human NMO-IgG with complement exacerbates disease severity with NMO pathology in experimental allergic encephalomyelitis mice

Neuromyelitis optica (NMO) is recognized as a different CNS autoimmune disease from multiple sclerosis (MS). Whether NMO-IgG contributes directly to the pathogenesis of NMO or is just a serologic marker of autoimmune responses of the disease needs to be clarified. We created MOG-induced experimental autoimmune encephalomyelitis (EAE) mice by passively transferring NMO-IgG to model the pathogenic findings in NMO patients. The mice were divided into three groups and administered intrathecal PBS, human complement with IgG from normal subjects, or IgG from AQP4(+) patients on days 8 and 11 after immunization. The EAE scores of EAE mice with intrathecal NMO-IgG injection were significantly elevated 14 days post-immunization. All of the mice were sacrificed for brain and spinal cord pathology analysis on day 21 post-immunization. Compared to mice given normal human IgG, EAE mice injected with NMO-IgG had markedly decreased AQP4 and glial fibrillary acidic protein (GFAP) expression and fluorescent intensity in the brain and spinal cord but more scattered deposition of complement (C9neo). Thus, our studies not only support the pathogenic role of NMO-IgG with complement in NMO disease but also provide a platform for the development of future therapeutics.

Treatment strategies for neuromyelitis optica.

Neuromyelitis optica (NMO) is an autoimmune demyelinating disease with pathogenic autoantibodies that act against the astrocyte water channel protein, i.e. aquaporin-4: the disease is associated with recurrent episodes of optic neuritis (ON) and transverse myelitis, often resulting in severe disability. The main goals in treatment of NMO include acute symptomatic therapy and long-term stabilization of symptoms by preventing relapse. In recent years, ongoing randomized controlled trials in NMO patients have studied evidence for treatment. Briefly, acute-stage management (with pulse therapy using corticosteroids and/or plasmapheresis) and maintenance therapy (including rituximab, mycophenolate mofetil, and azathioprine) have been recommended in some case series and retrospective studies. Because of the high prevalence of liver disease, all NMO patients in Taiwan should be screened for hepatitis B and C before treatment is initiated. Although immunosuppression and plasma exchange are the mainstays of therapy for NMO ON, several selective and potentially therapeutic strategies targeting specific steps in NMO pathogenesis including blockers of NMO-IgG binding and inhibitors of granulocyte function have been evaluated in recent years.

Combination Treatment of C16 Peptide and Angiopoietin-1 Alleviates Neuromyelitis Optica in an Experimental Model.

Neuromyelitis optica (NMO) is an autoimmune inflammatory demyelinating disease that mainly affects the spinal cord and optic nerve, causing blindness and paralysis in some individuals. Moreover, NMO may cause secondary complement-dependent cytotoxicity (CDC), leading to oligodendrocyte and neuronal damage. In this study, a rodent NMO model, showing typical NMO pathogenesis, was induced with NMO-IgG from patient serum and human complement. We then tested whether the combination of C16, an αvβ3 integrin-binding peptide, and angiopoietin-1 (Ang1), a member of the endothelial growth factor family, could alleviate NMO in the model. Our results demonstrated that this combination therapy significantly decreased disease severity, inflammatory cell infiltration, secondary demyelination, and axonal loss, thus reducing neural death. In conclusion, our study suggests a possible treatment that can relieve progressive blindness and paralysis in an animal model of NMO through improvement of the inflammatory milieu.

The single nucleotide polymorphism site of aquaporin-4 gene in patients with neuromyelitis optica.

The single nucleotide polymorphism (SNP) site within the aquaporin (AQP)-4 gene exons and its possible role in the pathogenesis of neuromyelitis optica (NMO) were studied. From March 2010 to June 2012, 72 patients with NMO from Xiangyang No. 1 People's Hospital, Hubei University of Medicine were enrolled in the NMO group. At the same time, 80 patients with multiple sclerosis (MS) were enrolled in our study as the MS group. Blood samples were collected and DNA was extracted for analysis of SNP sites of AQP4 gene. Specific site-directed mutagenesis method was used for site-directed mutagenesis on plasmid enhanced green fluorescence protein carrying AQP4 gene. Mutant plasmids were constructed and used for transfecting cell lines. The differences of anti-AQP4 antibody level in the cell line were analyzed. The possible correlation between AQP4 gene SNP sites and the pathogenesis of NMO were analyzed. In the NMO group, 6 SNP sites in AQP4 gene were located in exons 2 and 5. These included R108T, I110N, E280R, D281R, P295R and E317M. There was no SNP site in exons 1, 3 and 4. In the MS group, no SNP site was found in AQP4 gene. R108T, I110N, R108T/I110N, E280R/D281R, P295R and E317M cell lines were constructed in the NMO group, and anti-AQP4 antibody in the serum was compared between R108T/I110N, E280R/D281R and E317M cell lines and the original HEK293T cell line. The difference was statistically significant (P<0.05). The positive rate of anti-AQP4 antibody titer in serum was compared between R108T, I110N, R108T/I110N, E280R/D281R, P295R and E317M cell lines in the NMO group and the original cell line in the MS group. In conclusion, SNP sites in AQP4 gene in patients with NMO may lead to some conformational changes in AQP4 protein. This affects the antigenicity of AQP4 protein. The different intensity of antigen-antibody reaction may cause the differences of titer observed between the different mutant cell lines.

Complexity and wide range of neuromyelitis optica spectrum disorders: more than typical manifestations.

Neuromyelitis optica (NMO), considered to be mediated by autoantibodies, often cause severely disabling disorders of the central nervous system, and predominantly cause optic nerve damage and longitudinally extensive transverse myelitis. Remarkable progress has been made in deciphering NMO pathogenesis during the past decade. In 2015, the International Panel for NMO Diagnosis proposed the unifying term “NMO spectrum disorders” (NMOSD) and the updated NMOSD criteria reflects a wide range of disease and maintains reasonable specificity. Moreover, cumulative findings have indicated that NMOSD are frequently associated with multiple autoimmune diseases, thereby presenting complex clinical symptoms that make this disease more difficult to recognize. Notably, most neurologists do not heed these symptoms or comorbid conditions in patients with NMOSD. Whereas previous reviews have focused on pathogenesis, treatment, and prognosis in NMOSD, we summarize the present knowledge with particular emphasis on atypical manifestations and autoimmune comorbidities in patients with NMOSD. Furthermore, we emphasized the identification of these atypical characteristics to enable a broader and better understanding of NMOSD, and improve early accurate diagnosis and therapeutic decision making.

Induction of Paralysis and Visual System Injury in Mice by T Cells Specific for Neuromyelitis Optica Autoantigen Aquaporin-4

While it is recognized that aquaporin-4 (AQP4)-specific T cells and antibodies participate in the pathogenesis of neuromyelitis optica (NMO), a human central nervous system (CNS) autoimmune demyelinating disease, creation of an AQP4-targeted model with both clinical and histologic manifestations of CNS autoimmunity has proven challenging. Immunization of wild-type (WT) mice with AQP4 peptides elicited T cell proliferation, although those T cells could not transfer disease to naïve recipient mice. Recently, two novel AQP4 T cell epitopes, peptide (p) 135-153 and p201-220, were identified when studying immune responses to AQP4 in AQP4-deficient (AQP4-/-) mice, suggesting T cell reactivity to these epitopes is normally controlled by thymic negative selection. AQP4-/- Th17 polarized T cells primed to either p135-153 or p201-220 induced paralysis in recipient WT mice, that was associated with predominantly leptomeningeal inflammation of the spinal cord and optic nerves. Inflammation surrounding optic nerves and involvement of the inner retinal layers (IRL) were manifested by changes in serial optical coherence tomography (OCT). Here, we illustrate the approaches used to create this new in vivo model of AQP4-targeted CNS autoimmunity (ATCA), which can now be employed to study mechanisms that permit development of pathogenic AQP4-specific T cells and how they may cooperate with B cells in NMO pathogenesis.