Identification of neurotransmitter imbalances in the cingulate cortex of NMOSD patients using magnetic resonance spectroscopy.

Cognitive impairment affects 29-67% of patients with neuromyelitis optica spectrum disorder. Previous studies have reported glutamate homeostasis disruptions in astrocytes, leading to imbalances in gamma-aminobutyric acid levels. However, the association between these neurotransmitter changes and cognitive deficits remains inadequately elucidated. Point RESolved Spectroscopy and Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy techniques were utilized to evaluate gamma-aminobutyric acid, glutamate, glutathione levels, and excitation/inhibition balance in the anterior cingulate cortex, posterior cingulate cortex, and occipital cortex of 39 neuromyelitis optica spectrum disorder patients and 41 healthy controls. Cognitive function was assessed using neurocognitive scales. Results showed decreased gamma-aminobutyric acid levels alongside increased glutamate, glutathione, and excitation/inhibition ratio in the anterior cingulate cortex and posterior cingulate cortex of neuromyelitis optica spectrum disorder patients. Specifically, within the posterior cingulate cortex of neuromyelitis optica spectrum disorder patients, decreased gamma-aminobutyric acid levels and increased excitation/inhibition ratio correlated significantly with anxiety scores, whereas glutathione levels predicted diminished executive function. The results suggest that neuromyelitis optica spectrum disorder patients exhibit dysregulation in the GABAergic and glutamatergic systems in their brains, where the excitation/inhibition imbalance potentially acts as a neuronal metabolic factor contributing to emotional disorders. Additionally, glutathione levels in the posterior cingulate cortex region may serve as predictors of cognitive decline, highlighting the potential benefits of reducing oxidative stress to safeguard cognitive function in neuromyelitis optica spectrum disorder patients.

B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4.

Neuromyelitis optica is a paradigmatic autoimmune disease of the central nervous system, in which the water-channel protein AQP4 is the target antigen1. The immunopathology in neuromyelitis optica is largely driven by autoantibodies to AQP42. However, the T cell response that is required for the generation of these anti-AQP4 antibodies is not well understood. Here we show that B cells endogenously express AQP4 in response to activation with anti-CD40 and IL-21 and are able to present their endogenous AQP4 to T cells with an AQP4-specific T cell receptor (TCR). A population of thymic B cells emulates a CD40-stimulated B cell transcriptome, including AQP4 (in mice and humans), and efficiently purges the thymic TCR repertoire of AQP4-reactive clones. Genetic ablation of Aqp4 in B cells rescues AQP4-specific TCRs despite sufficient expression of AQP4 in medullary thymic epithelial cells, and B-cell-conditional AQP4-deficient mice are fully competent to raise AQP4-specific antibodies in productive germinal-centre responses. Thus, the negative selection of AQP4-specific thymocytes is dependent on the expression and presentation of AQP4 by thymic B cells. As AQP4 is expressed in B cells in a CD40-dependent (but not AIRE-dependent) manner, we propose that thymic B cells might tolerize against a group of germinal-centre-associated antigens, including disease-relevant autoantigens such as AQP4.

A novel rare variant of CNPY3 from familial NMOSD impairs the TLR-mediated immune response.

Toll-like receptors (TLRs) are a class of proteins that play essential roles in innate and adaptive immune responses. Recently, accumulating evidence has demonstrated that impairments in the TLR signalling pathway contribute to the development and progression of neuroimmune diseases, such as neuromyelitis optica spectrum disorder (NMOSD). However, the cellular and molecular mechanisms are still largely unknown. In this study, we report a novel variant, C52Y, of canopy FGF signalling regulator 3 (CNPY3) from patients with familial NMOSD and demonstrate that this variant shows a stronger interaction with GP96 and TLRs than with wild-type CNPY3. We find that C52Y has dominant negative effects on TLR4 surface expression. Importantly, the TLR4 surface expression level is decreased in RAW264.7 cells infected with the C52Y virus upon LPS stimulation. We further demonstrate that bone marrow-derived macrophages (BMDMs) from CNPY3C52Y/+ transgenic mice secrete less tumour necrosis factor (TNF) and interleukin (IL)-6 than BMDMs from wild-type mice upon stimulation with LPS. These data suggest that impairment of TLR trafficking may contribute to the development of neuroimmune disorders.

Olamkicept(sgp130Fc): The missing trial in Neuromyelitis Optica Spectrum Disorder.

Satralizumab, an antibody against IL-6R, has been recently approved in Neuromyelitis optica spectrum disorder(NMOSD). Targeting IL-6 or IL-6 Receptor(like Satralizumab does) results in inhibition of both pro and anti-inflammatory pathways of IL-6. Sgp130FC(Olamkicept) is a monoclonal antibody that prevents only the proinflammatory pathway of IL-6 to be activated, and could represent a better way to target IL-6 pathway in Neuromyelitis optica spectrum disorder.

Dynamics of AQP4 upon exposure to seropositive patient serum before and after Rituximab therapy in Neuromyelitis Optica: A cell-based study.

Neuromyelitis Optica (NMO) is an autoimmune inflammatory disease that affects the optic nerves and spinal cord. The autoantibody is generated against the abundant water channel protein of the brain, Aquaporin 4 (AQP4). Of the two isoforms of AQP4, the shorter one (M23) often exists as a supramolecular assembly known as an orthogonal array of particles (OAPs). There have been debates about the fate of these AQP4 clusters upon binding to the antibody, the exact mechanism of its turnover, and the proteins associated with the process. Recently several clinical cases of NMO were reported delineating the effect of Rituximab (RTX) therapy. Extending these reports at the cell signaling level, we developed a glioma based cellular model that mimicked antibody binding and helped us track the subsequent events including a variation of AQP4 levels, alterations in cellular morphology, and the changes in downstream signaling cascades. Our results revealed the extent of perturbations in the signaling pathways related to stress involving ERK, JNK, and AKT1 together with markers for cell death. We could also decipher the possible routes of degradation of AQP4, post-exposure to antibody. We further investigated the effect of autoantibody on AQP4 transcriptional level and involvement of FOXO3a and miRNA-145 in the regulation of transcription. This study highlights the differential outcome at the cellular level when treated with the serum of the same patient pre and post RTX therapy and for the first time mechanistically describes the effect of RTX.

B-Cell Compartmental Features and Molecular Basis for Therapy in Autoimmune Disease.

BACKGROUND AND OBJECTIVES: To assess the molecular landscape of B-cell subpopulations across different compartments in patients with neuromyelitis optica spectrum disorder (NMOSD). METHODS: We performed B-cell transcriptomic profiles via single-cell RNA sequencing across CSF, blood, and bone marrow in patients with NMOSD. RESULTS: Across the tissue types tested, 4 major subpopulations of B cells with distinct signatures were identified: naive B cells, memory B cells, age-associated B cells, and antibody-secreting cells (ASCs). NMOSD B cells show proinflammatory activity and increased expression of chemokine receptor genes (CXCR3 and CXCR4). Circulating B cells display an increase of antigen presentation markers (CD40 and CD83), as well as activation signatures (FOS, CD69, and JUN). In contrast, the bone marrow B-cell population contains a large ASC fraction with increased oxidative and metabolic activity reflected by COX genes and ATP synthase genes. Typically, NMOSD B cells become hyperresponsive to type I interferon, which facilitates B-cell maturation and anti-aquaporin-4 autoantibody production. The pool of ASCs in blood and CSF were significantly elevated in NMOSD. Both CD19- and CD19+ ASCs could be ablated by tocilizumab, but not rituximab treatment in NMOSD. DISCUSSION: B cells are compartmentally fine tuned toward autoreactivity in NMOSD and become hyperreactive to type I interferon. Inhibition of type I interferon pathway may provide a new therapeutic avenue for NMOSD.

Anti-AQP4 autoantibodies promote ATP release from astrocytes and induce mechanical pain in rats.

BACKGROUND: Intractable neuropathic pain is a common symptom of neuromyelitis optica spectrum disorder (NMOSD). However, the underlying mechanism of NMOSD pain remains to be elucidated. In this study, we focused on ATP, which is one of the damage-associated molecular patterns, and also a well-recognized molecule involved in peripheral neuropathic pain. METHODS: We assessed the development of pain symptoms by injecting anti-AQP4 recombinant autoantibodies (rAQP4 IgG) into rat spinal cords. We incubated HEK293 cells expressing AQP4 (HEK-AQP4) and rat astrocytes with rAQP4 IgG and assessed the level of ATP in the supernatant. We performed transcriptome analysis of the spinal cords injected with rAQP4 IgG. Pharmacological inhibition was also applied to investigate the involvement of ATP in the development of neuropathic pain in our rat model. The ATP concentration within the cerebrospinal fluid was examined in patients with NMOSD and other neurological diseases. RESULTS: Development of mechanical allodynia was confirmed in rAQP4 IgG-treated rats. AQP4-Ab-mediated extracellular ATP release from astrocytes was observed in vitro, and pharmacological inhibition of ATP receptor reversed mechanical allodynia in the rAQP4 IgG-treated rats. Furthermore, transcriptome analysis revealed elevation of gene expressions related to several ATP receptors including P2rx4 and IL1B in the spinal cord of rAQP4 IgG-treated rats. In patients, CSF ATP concentration was significantly higher in the acute and remission phase of NMOSD than in multiple sclerosis or other neurological disorders. CONCLUSION: Anti-AQP4 antibody was shown to induce the release of extracellular ATP from astrocytes. The ATP-mediated development of mechanical allodynia was also suggested in rats treated with anti-AQP4 antibody. Our study indicates the pivotal role of ATP in the pain mechanism of NMOSD.

The immune regulatory effects of tetrahedral framework nucleic acid on human T cells via the mitogen-activated protein kinase pathway.

OBJECTIVES: Autoimmune diseases are a heterogeneous group of diseases which lose the immunological tolerance to self-antigens. It is well recognized that irregularly provoked T cells participate in the pathological immune responses. As a novel nanomaterial with promising applications, tetrahedral framework nucleic acid (TFNA) nanostructure was found to have immune regulatory effects on T cells in this study. MATERIALS AND METHODS: To verify the successful fabrication of TFNA, the morphology of TFNA was observed by atomic force microscopy (AFM) and dynamic light scattering. The regulatory effect of TFNA was evaluated by flow cytometry after cocultured with CD3+ T cells isolated from healthy donors. Moreover, the associated signaling pathways were investigated. Finally, we verified our results on the T cells from patients with neuromyelitis optica spectrum disorder (NMOSD), which is a typical autoimmune disease induced by T cells. RESULTS: We revealed the alternative regulatory functions of TFNA in human primary T cells with steady status via the JNK signaling pathway. Moreover, by inhibiting both JNK and ERK phosphorylation, TFNA exhibited significant suppressive effects on IFNγ secretion from provoking T cells without affecting TNF secretion. Similar immune regulatory effects of TFNA were also observed in autoreactive T cells from patients with NMOSD. CONCLUSIONS: Overall, our results revealed a potential application of TFNA in regulating the adaptive immune system, as well as shed a light on the treatment of T cell-mediated autoimmune diseases.

Investigating the Presence of Interattack Astrocyte Damage in Neuromyelitis Optica Spectrum Disorder: Longitudinal Analysis of Serum Glial Fibrillary Acidic Protein.

OBJECTIVES: Information on subclinical astrocyte damage can provide further insight into neuromyelitis optica spectrum disorder (NMOSD) pathophysiology and disease-monitoring strategies. To investigate whether astrocyte and neuroaxonal damage occurs during interattack periods in individuals with NMOSD through longitudinal measurement of serum glial fibrillary acidic protein (sGFAP) and neurofilament light chain (sNfL) at multiple time points. METHODS: sGFAP and sNfL levels were measured in 187 serum samples from 20 participants with NMOSD treated with rituximab (median follow-up: 24 months) and 19 age-/sex-matched healthy controls using a highly sensitive single-molecule array assay. From the NMOSD cohort of National Cancer Center, Korea, 14 clinically stable participants were randomly selected for focused investigation of interattack periods, and 6 participants with clinical attacks despite treatment were enrolled for attack-related measurements. RESULTS: Significant elevations of sGFAP levels were observed in all clinical attacks, and 95% (19/20) of patients showed reduction of sGFAP levels below the cutoff value (3 SDs above mean levels in age-/sex-matched healthy controls) within 3 months of their clinical attacks. The sGFAP levels were consistently low during interattack periods in 90% (17/19) of patients whose sGFAP levels returned to below the cutoff value. Changes in sNfL levels were similar to but slower than those in sGFAP levels. CONCLUSIONS: Subclinical astrocyte damage represented by increasing sGFAP levels rarely occurred during interattack periods in individuals with NMOSD; however, a certain degree of astrocyte damage did occur at the time of clinical attacks without exception, but it was not evident within 3 months of the attack.

Prognostic factors for relapse and outcome in pediatric acute transverse myelitis.

OBJECTIVE: It may be difficult for clinicians to estimate the prognosis of pediatric acute transverse myelitis (ATM). The aim of this study was to define prognostic factors for relapsing disease and poor outcome in pediatric ATM. METHODS: This prospective cohort study included 49 children, 18 boys and 31 girls (median age 13.1 years, IQR 6.5-16.2) with a first episode of ATM. Factors associated with relapsing disease and poor outcome (Expanded Disability Status Scale (EDSS) ≥ 4) were assessed during a median follow-up of 37 months (IQR 18-75). RESULTS: In total, 14 patients (29%) experienced ≥ 1 relapse(s) and nine patients (18%) had a poor outcome. Factors at onset associated with relapsing disease included higher age (16.1 vs. 11.6 years, p = 0.002), longer time to maximum severity of symptoms (5.5 vs. 3 days, p = 0.01), lower maximum EDSS score (4.0 vs. 6.5, p = 0.003), short lesion on spinal MRI (64 vs. 21%, p = 0.006), abnormalities on brain MRI (93 vs. 44%, p = 0.002) and presence of oligoclonal bands in cerebrospinal fluid (67 vs. 14%, p = 0.004). The only factor associated with poor outcome was presence of a spinal cord lesion on MRI without cervical involvement (56 vs. 14%, p = 0.02). CONCLUSION: Pediatric ATM patients presenting with clinical, radiological and laboratory features associated with multiple sclerosis (MS) are at risk for relapsing disease. In absence of these known MS risk factors at onset of disease these patients are at low risk for relapses. Only a minority of pediatric ATM patients in this cohort have a poor outcome.

Distinct microglial and macrophage distribution patterns in the concentric and lamellar lesions in Baló's disease and neuromyelitis optica spectrum disorders.

TMEM119 and purinergic receptor P2Y12 (P2RY12), which are not expressed by recruited peripheral blood macrophages, are proposed to discriminate microglia from macrophages. Therefore, we investigated the distribution patterns of microglia and macrophages in 10 concentric lesions from four autopsied Baló's disease cases and one neuromyelitis optica spectrum disorder (NMOSD) case, using quantitative immunohistochemistry for the markers TMEM119, P2RY12, CD68, CD163 and GLUT5. Three cases with Baló's disease had distal oligodendrogliopathy (DO) showing preferential loss of myelin-associated glycoprotein and early active demyelination in the outermost demyelinating layer (termed DMY-MO). In DMY-MO with DO, TMEM119-positive activated microglia expressing upregulated GLUT5 but markedly downregulated P2RY12 were significantly increased. These activated microglia expressed inducible nitric oxide synthase. Oligodendrocytes and their precursors showed apoptotic-like nuclear condensation in DMY-MO. TMEM119-negative and CD68/CD163-positive macrophages were distributed throughout the lesion center of DMY-MO with DO and these cells demonstrated foamy morphology only in the inner portion but not in the outer portion. In concentric demyelinating lesions from another Baló's case and lamellar demyelinating lesions in an NMOSD case, which had late active demyelination without DO, the densities of TMEM119-, GLUT5- and P2RY12-positive microglia with ramified morphology were significantly increased in myelinated layers but not in demyelinating layers. In particular, in the NMOSD case, TMEM119-positive microglia were confined to the outer portion of the myelinated layers. CD68-positive macrophages with foamy morphology also expressing CD163 accumulated in myelinated as well as in demyelinated layers. These findings suggest that activated microglia expressing TMEM119 and GLUT5, but not P2RY12, are associated with apoptosis of oligodendrocytes in the leading edge of Baló's concentric lesions with DO, whereas TMEM119-, GLUT5- and P2RY12-positive microglia with ramified morphology are associated with myelin preservation in concentric lesions without DO in Baló's disease and NMOSD. These two types of microglia appear to play distinct roles in the formation of concentric lesions.

Interleukin-6 in neuromyelitis optica spectrum disorder pathophysiology.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder that preferentially affects the spinal cord and optic nerve. Most patients with NMOSD experience severe relapses that lead to permanent neurologic disability; therefore, limiting frequency and severity of these attacks is the primary goal of disease management. Currently, patients are treated with immunosuppressants. Interleukin-6 (IL-6) is a pleiotropic cytokine that is significantly elevated in the serum and the CSF of patients with NMOSD. IL-6 may have multiple roles in NMOSD pathophysiology by promoting plasmablast survival, stimulating the production of antibodies against aquaporin-4, disrupting blood-brain barrier integrity and functionality, and enhancing proinflammatory T-lymphocyte differentiation and activation. Case series have shown decreased relapse rates following IL-6 receptor (IL-6R) blockade in patients with NMOSD, and 2 recent phase 3 randomized controlled trials confirmed that IL-6R inhibition reduces the risk of relapses in NMOSD. As such, inhibition of IL-6 activity represents a promising emerging therapy for the management of NMOSD manifestations. In this review, we summarize the role of IL-6 in the context of NMOSD.

Deep Gray Matter Iron Content in Neuromyelitis Optica and Multiple Sclerosis.

BACKGROUND: Neuromyelitis optica (NMO) and multiple sclerosis (MS) are often presenting with overlapping symptoms. The aim of this study was to determine whether and how NMO and MS differ regarding cerebral iron deposits in deep gray matter (DGM) and the correlation between iron deposition and clinical severity as well as to regional atrophy of the DGM. METHODS: We analyzed 20 patients with NMO, 40 patients with a relapsing-remitting (RR) form of MS, and 20 healthy controls with 1.5T MRI. Quantitative susceptibility mapping (QSM) was performed to estimate iron concentration in the DGM. RESULTS: Patients with NMO have higher magnetic susceptibility values in the substantia nigra compared to healthy controls. RRMS patients have lower magnetic susceptibility values in the thalamus compared to healthy controls and NMO patients. Atrophy of the thalamus, pulvinar, and putamen is significant both in RRMS compared to NMO patients and healthy controls. A correlation was found between the disability score (EDSS) and magnetic susceptibility in the putamen in RRMS. CONCLUSIONS: This study confirms that a disturbed cerebral iron homeostasis in patients with NMO occurs in different structures than in patients with RRMS. Increased magnetic susceptibility in substantia nigra in NMO and decreased magnetic susceptibility within the thalamus in RRMS were the only significant differences in the study sample. We could confirm that iron concentration in the thalami is decreased in RRMS compared to that in the HC group. Positive association was found between putaminal iron and EDSS in RRMS.

Decreased mRNA Expressions of CD40L in Patients with Neuromyelitis Optica Spectrum Disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease that preferentially affects central nerve system. Herein, we evaluated changes of CD40L and CD40 mRNA expressions in NMOSD and controls to explore their potential roles in development of NMOSD. The expressions of CD40L and CD40 mRNA in peripheral blood mononuclear cells (PBMCs) from patients with NMOSD and healthy controls were detected by quantitative real-time PCR (qPCR). Kruskal-Wallis tests were used to compare expression levels of CD40L and CD40 mRNA between groups, and Spearman correlation analysis was performed to evaluate correlation between mRNA expression levels and annual relapse rate (ARR) of NMOSD. A total of 71 patients with NMOSD and 42 gender- and age-matched healthy volunteers were recruited in our study. Compared with healthy controls, expression of CD40L mRNA was significantly decreased in untreated patients with NMOSD, and similar trends were observed also in CD40 mRNA expression although the difference was not significant. Other than that, immunosuppressants not only successfully increased CD40L and CD40 mRNA levels during remission of NMOSD, but also corrected the negative correlation between CD40L mRNA expression and annual relapse rate (ARR) of patients NMOSD. These results favored the long-term prognosis of NMOSD patients. Our results suggest that decreased expressions of CD40L mRNA may be involved in developing of NMOSD and the proper CD40L mRNA levels benefit to prevent attacks of NMOSD. Nevertheless, the relationship between protein and mRNA expressions of CD40L and their underlying roles in the pathogenesis of NMOSD remains to be further studied.

A comparison between spinal cord infarction and neuromyelitis optica spectrum disorders: Clinical and MRI studies.

This study aims to investigate the clinical features and magnetic resonance imaging (MRI) findings in patients with spinal cord infarction (SCI) and neuromyelitis optica spectrum disorders (NMOSDs). Over a period of 16 years, we retrospectively analyzed 39 patients with SCI and 21 patients with NMOSD. The demographic features and clinical presentations of both diseases were carefully documented. Etiology-specific MRI features, such as the length and distribution of the lesions, the owl's eyes sign and bright spotty lesions, were recorded and analyzed regarding their association with the clinical signs/symptoms. Patients with SCI were older than patients with NMOSD and had sudden onset of clinical symptoms with focal pain adjacent to the lesions. Concomitant spinal cord and vertebral body infarctions were frequently associated with aortic pathology (p = 0.04). In addition, artery dissection was highly associated with combined ASA and unilateral PSA infarctions and long segments of SCI (all p < 0.05). In contrast, patients with NMOSD had a relatively younger age of onset, female predominance and subacute progression of limbs weakness. As observed by MRI, the length and location of the lesions demonstrated significant differences between the two diseases (P < 0.01). The owl's eyes sign showed more frequently in patients with SCI than NMOSD (p < 0.01). The predicted prognoses in SCI and NMOSD were significantly associated with initial motor function (muscle power), after adjustments for age and gender (p < 0.01 and p = 0.02, respectively). Along with patient demographic characteristics, lesion features on MRI can help clinicians differentiate acute noncompressive myelopathy due to SCI from that due to NMOSD, which may lead to immediate initiation of adequate therapeutic measures.

Paraneoplastic neuromyelitis optica and ovarian teratoma: A case series.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare inflammatory disease of the central nervous system, characterized by the presence of auto-antibodies directed against aquaporin-4 (AQP4) expressed on astrocyte end-feet. Despite NMOSD does not primarily belong to the spectrum of paraneoplastic neurological syndromes, rare cases of association with neoplasia have been outlined. Here, we report the association of NMOSD with ovarian teratoma in 3 cases. Pathological analysis of teratomas revealed glial component strongly expressing AQP4 and closely localized to immune infiltrates. Our series highlight the rare association of teratoma with NMOSD and the possible paraneoplastic mechanism.

Simulating the Impact of Elevated Levels of Interleukin-6 on the Pharmacokinetics of Various CYP450 Substrates in Patients with Neuromyelitis Optica or Neuromyelitis Optica Spectrum Disorders in Different Ethnic Populations.

A physiologically based pharmacokinetic (PBPK) model was used to simulate the impact of elevated levels of interleukin (IL)-6 on the exposure of several orally administered cytochrome P450 (CYP) probe substrates (caffeine, S-warfarin, omeprazole, dextromethorphan, midazolam, and simvastatin). The changes in exposure of these substrates in subjects with rheumatoid arthritis (and hence elevated IL-6 levels) compared with healthy subjects were predicted with a reasonable degree of accuracy. The PBPK model was then used to simulate the change in oral exposure of the probe substrates in North European Caucasian, Chinese, and Japanese population of patients with neuromyelitis optica (NMO) or NMO spectrum disorder with elevated plasma IL-6 levels (up to 100 pg/mL). Moderate interactions [mean AUC fold change, ≤ 2.08 (midazolam) or 2.36 (simvastatin)] was predicted for CYP3A4 probe substrates and weak interactions (mean AUC fold change, ≤ 1.29-1.97) were predicted for CYP2C19, CYP2C9, and CYP2D6 substrates. No notable interaction was predicted with CYP1A2. Although ethnic differences led to differences in simulated exposure for some of the probe substrates, there were no marked differences in the predicted magnitude of the change in exposure following IL-6-mediated suppression of CYPs. Decreased levels of serum albumin (as reported in NMO patients) had little impact on the magnitude of the simulated IL-6-mediated drug interactions. This PBPK modeling approach allowed us to leverage knowledge from different disease and ethnic populations to make predictions of cytokine-related DDIs in a rare disease population where actual clinical studies would otherwise be difficult to conduct.

CD55 upregulation in astrocytes by statins as potential therapy for AQP4-IgG seropositive neuromyelitis optica.

BACKGROUND: Neuromyelitis optica spectrum disorder (herein called NMO) is an inflammatory demyelinating disease that can be initiated by binding of immunoglobulin G autoantibodies (AQP4-IgG) to aquaporin-4 on astrocytes, causing complement-dependent cytotoxicity (CDC) and downstream inflammation. The increased NMO pathology in rodents deficient in complement regulator protein CD59 following passive transfer of AQP4-IgG has suggested the potential therapeutic utility of increasing the expression of complement regulator proteins. METHODS: A cell-based ELISA was developed to screen for pharmacological upregulators of endogenous CD55 and CD59 in a human astrocyte cell line. A statin identified from the screen was characterized in cell culture models and rodents for its action on complement regulator protein expression and its efficacy in models of seropositive NMO. RESULTS: Screening of ~ 11,500 approved and investigational drugs and nutraceuticals identified transcriptional upregulators of CD55 but not of CD59. Several statins, including atorvastatin, simvastatin, lovastatin, and fluvastatin, increased CD55 protein expression in astrocytes, including primary cultures, by three- to four-fold at 24 h, conferring significant protection against AQP4-IgG-induced CDC. Mechanistic studies revealed that CD55 upregulation involves inhibition of the geranylgeranyl transferase pathway rather than inhibition of cholesterol biosynthesis. Oral atorvastatin at 10-20 mg/kg/day for 3 days strongly increased CD55 immunofluorescence in mouse brain and spinal cord and reduced NMO pathology following intracerebral AQP4-IgG injection. CONCLUSION: Atorvastatin or other statins may thus have therapeutic benefit in AQP4-IgG seropositive NMO by increasing CD55 expression, in addition to their previously described anti-inflammatory and immunomodulatory actions.

Study of the cytological features of bone marrow mesenchymal stem cells from patients with neuromyelitis optica.

Neuromyelitis optica (NMO) is a refractory autoimmune inflammatory disease of the central nervous system without an effective cure. Autologous bone marrow­derived mesenchymal stem cells (BM­MSCs) are considered to be promising therapeutic agents for this disease due to their potential regenerative, immune regulatory and neurotrophic effects. However, little is known about the cytological features of BM­MSCs from patients with NMO, which may influence any therapeutic effects. The present study aimed to compare the proliferation, differentiation and senescence of BM­MSCs from patients with NMO with that of age­ and sex­matched healthy subjects. It was revealed that there were no significant differences in terms of cell morphology or differentiation capacities in the BM­MSCs from the patients with NMO. However, in comparison with healthy controls, BM­MSCs derived from the Patients with NMO exhibited a decreased proliferation rate, in addition to a decreased expression of several cell cycle­promoting and proliferation­associated genes. Furthermore, the cell death rate increased in BM­MSCs from patients under normal culture conditions and an assessment of the gene expression profile further confirmed that the BM­MSCs from patients with NMO were more vulnerable to senescence. Platelet­derived growth factor (PDGF), as a major mitotic stimulatory factor for MSCs and a potent therapeutic cytokine in demyelinating disease, was able to overcome the decreased proliferation rate and increased senescence defects in BM­MSCs from the patients with NMO. Taken together, the results from the present study have enabled the proposition of the possibility of combining the application of autologous BM­MSCs and PDGF for refractory and severe patients with NMO in order to elicit improved therapeutic effects, or, at the least, to include PDGF as a necessary and standard growth factor in the current in vitro formula for the culture of NMO patient­derived BM­MSCs.

Blockade of IL-6 signaling in neuromyelitis optica.

Neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorder (NMOSD) are autoimmune diseases associated with a disease-specific autoantibody directed against the water channel protein aquaporin-4. Standard immunotherapy, immunosuppressive agents, and corticosteroids can prevent acute attacks and maintain remission in most patients with NMOSD. However, there is a strong need for additional options for patients who are refractory to standard treatments. Emerging therapies targeting specific molecules related to the pathogenicity of NMOSD are currently being developed. The review focuses on improving preventive treatments for NMOSD, including ongoing randomized clinical trials using biological drugs targeting CD19 and CD20 on B cells, interleukin-6, and complement protein C5. The anti-IL-6 receptor monoclonal antibody tocilizumab (TCZ), which can block IL-6 signaling, was shown to be highly effective for refractory patients with NMOSD. Notably, TCZ has marked effects on chronic neuropathic pain and general fatigue in patients refractory to standard medications. TCZ is a promising drug for preventing acute attacks in patients with NMOSD.