Immune-mediated Demyelination Research Articles

OPTIC NEUROMYELITIS DEVICIS: IMMUNOPATHOGENESIS AND RISK FACTORS (literature review and clinical case)

Background. Neuromyelitis optical spectrum disorders (NMOSD) or neuromyelitis optical (NMO) are inflammatory central nervous system disorders characterized by severe immune-mediated demyelination and axon destruction, with predominantly optic nerve and spinal cord damage. Previously, NMO and multiple sclerosis were thought to be a single disease with different phenotypes and expression. However, the results of studies in recent decades have revealed differences between these diseases in terms of pathogenesis, clinical features, neuroimaging findings, biomarkers, and treatment response. Aim: to summarize the current views of scientists on the basis of studies on the mechanisms of immunopathogenesis of optic neuromyelitis, to identify differences in immunological markers from other demyelinating diseases of the central nervous system, to assess possible risk factors for the occurrence of Devick's disease. Materials and methods. A literature review was conducted using the medical search databases “PubMed”, “Web of Science”, “Scopus”, as well as the service “Google Scholar” and more than 30 articles describing clinical, immunological and genomic studies on the immunopathogenesis and risk factors for the occurrence of optic neuromyelitis of Davick were selected for analysis (focusing on studies over the past decade). A clinical case of this pathology was analyzed. Results. As a result of our review of current literature, it was confirmed that autoimmune processes play an important role in the pathogenesis of optic neuromyelitis. Protein aquaporin-4 (AQP4) was identified as a target antigen in optic neuromyelitis, to which self-reactive Ig (immunoglobulins) G are synthesized. After binding of AQP4-IgG, the complement-dependent cytotoxicity (CDC) pathway is initiated, leading to the formation of necrotic lesions through the activation of the membrane-attacking complement complex. Chemotoxins enhance the effects of CDC through cellular infiltration and cytokine production. After cellular infiltration, anti-AQP4 Ig interacts with natural killer (NK) cells and leads to antibody-dependent cellular cytotoxicity (ADCC), which results in astrocyte death. It has been proven that in addition to humoral immunity, cellular immunity, especially T helper 17 lymphocytes (Th-17), as well as proinflammatory interleukins (Il) - Il-6, Il-17, Il-21, Il-1β - play an important role in the pathogenesis of optic neuromyelitis. The Th-17 subtype enhances the production of antibodies in naive B cells, and the cytokines produced by these cells have a crucial impact on pathogenesis. Certain studies in the world suggest the following risk factors for the development of optic neuromyelitis: genetic predispositions, viral and bacterial infections (Helicobacter pylori, Clostridium perfringens), vitamin D hypovitaminosis, and oxidative stress. Conclusion. Studies of recent decades have shown that both the humoral (IgG) and cellular (Th17) immune systems are involved in the immunopathogenesis of Devick's disease. It has been shown that the risk factors for its occurrence include both genetic prerequisites and past viral and bacterial infections, vitamin D hypovitaminosis, and oxidative stress. It is noted that today it is important to develop targeted therapy using highly selective monoclonal antibodies.

Comprehensive analysis of ocrelizumab's efficacy across different forms of multiple sclerosis: a multi-dimensional approach

BackgroundMultiple sclerosis (MS) is the most common immune-mediated inflammatory demyelinating disease of the central nervous system. MS usually affects individuals between the ages of 20 and 40 and is 3 times more common among women than among men. This disease presents with a vast range of neurological symptoms and, in some cases, cognitive impairment. Aim of the studyThe purpose of this review was to assess whether the anti-CD20 antibody ocrelizumab has proven effective in treating MS since its introduction.Material and methodsThe PubMed database was searched for original papers on the effects of ocrelizumab in the treatment of MS. The inclusion criterion was a comparison of the clinical or radiological effectiveness of ocrelizumab versus placebo or other MS therapies. For this purpose, the phrase "Ocrelizumab AND Multiple Sclerosis" was used, marking only studies such as "Randomised Clinical Trial" and "Clinical Trial". The cut-off point for publishing the work was 2016.Results43 works were found, of which 15 met the conditions for inclusion in the work. The analysed studies investigated the efficacy and safety of ocrelizumab in Relapsing Multiple Sclerosis, Primary Progressive Multiple SclerosisConclusionsThe effectiveness of ocrelizumab treatment shows that the use of newly developed targeted factors may significantly improve the clinical status of MS patients. Preliminary real-world data on the efficacy of ocrelizumab are promising and align with clinical trial findings. Although ocrelizumab is generally well tolerated, it is essential to monitor and assess its long-term safety.

Cystatin F attenuates neuroinflammation and demyelination following murine coronavirus infection of the central nervous system

BackgroundCystatin F is a secreted lysosomal cysteine protease inhibitor that has been implicated in affecting the severity of demyelination and enhancing remyelination in pre-clinical models of immune-mediated demyelination. How cystatin F impacts neurologic disease severity following viral infection of the central nervous system (CNS) has not been well characterized and was the focus of this study. We used cystatin F null-mutant mice (Cst7-/-) with a well-established model of murine coronavirus-induced neurologic disease to evaluate the contributions of cystatin F in host defense, demyelination and remyelination.MethodsWildtype controls and Cst7-/- mice were intracranially (i.c.) infected with a sublethal dose of the neurotropic JHM strain of mouse hepatitis virus (JHMV), with disease progression and survival monitored daily. Viral plaque assays and qPCR were used to assess viral levels in CNS. Immune cell infiltration into the CNS and immune cell activation were determined by flow cytometry and 10X genomics chromium 3’ single cell RNA sequencing (scRNA-seq). Spinal cord demyelination was determined by luxol fast blue (LFB) and Hematoxylin/Eosin (H&E) staining and axonal damage assessed by immunohistochemical staining for SMI-32. Remyelination was evaluated by electron microscopy (EM) and calculation of g-ratios.ResultsJHMV-infected Cst7-/- mice were able to control viral replication within the CNS, indicating that cystatin F is not essential for an effective Th1 anti-viral immune response. Infiltration of T cells into the spinal cords of JHMV-infected Cst7-/- mice was increased compared to infected controls, and this correlated with increased axonal damage and demyelination associated with impaired remyelination. Single-cell RNA-seq of CD45 + cells enriched from spinal cords of infected Cst7-/- and control mice revealed enhanced expression of transcripts encoding T cell chemoattractants, Cxcl9 and Cxcl10, combined with elevated expression of interferon-g (Ifng) and perforin (Prf1) transcripts in CD8 + T cells from Cst7-/- mice compared to controls.ConclusionsCystatin F is not required for immune-mediated control of JHMV replication within the CNS. However, JHMV-infected Cst7-/- mice exhibited more severe clinical disease associated with increased demyelination and impaired remyelination. The increase in disease severity was associated with elevated expression of T cell chemoattractant chemokines, concurrent with increased neuroinflammation. These findings support the idea that cystatin F influences expression of proinflammatory gene expression impacting neuroinflammation, T cell activation and/or glia cell responses ultimately impacting neuroinflammation and neurologic disease.

The fluctuations of expression profiles of critical genes in the miRNA maturation process and pro-and anti-inflammatory cytokines in the pathogenesis and progression of multiple sclerosis.

Multiple sclerosis (MS) is a central nervous system disease known for immune-mediated demyelination, inflammatory, and neurodegeneration symptoms. Discovering molecular biomarkers to classify RRMS and SPMS patients, monitor the disease activity, and response to particular treatments is one area that has received notable attraction. MicroRNA (miRNA), a single-stranded non-coding RNA molecule, is a significant regulator of gene expression recruited in pathogenic mechanisms in diverse diseases, especially cancer and MS. Also, the relapsing-remitting features of MS exhibit that both inflammatory and anti-inflammatory cytokines are effective in the progression of the disease over time. It was assessed the expression patterns of the genes (Drosha, Pasha(DGCR8), and Dicer) encoding the critical enzymes in the processing steps of miRNA maturation and major pro-inflammatory and anti-inflammatory cytokines (IFN-α, IFN-β, and IL-6) in blood cells of 40 MS patients (two groups of 10 men and women in both clinical courses of RR and SPMS patients) in comparison with 20 healthy control group (10 males and 10 females). The highest transcription activity of Drosha was observed for RRMS patients (4.2 and 3.6-fold, respectively), and the expression ratio was down regulated in male and female patients with SPMS (3.9- and 3.1-fold, respectively). Considering the studied cytokines, the increase in expression ratio of IL-6 in SPMS patients and the decrease in transcript abundance of INF-α, and INF-β cytokines are consistent with the progression of the disease. Our findings showed that the high and low transcriptional levels of the considered genes seem to be effective in the pathogenesis and progression of MS.

Clinical characteristics and long-term follow-up outcomes of myelin oligodendrocyte glycoprotein antibody-associated disease in Han Chinese participants.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an immune-mediated inflammatory demyelinating disease of the central nervous system. This study aimed to delineate the clinical manifestations, imaging features, and long-term outcomes in Chinese patients with MOGAD and analyze the recurrence-associated factors. The phenotypic and neuroimaging characteristics of 15 Han Chinese patients with MOGAD were retrospectively analyzed. Demyelinating attacks, MOG antibodies in the cerebrospinal fluid/serum, response to immunotherapy, follow-up outcomes, and recurrence-associated factors were recorded. The median age at disease onset was 34 years (range, 4-65 years). The most common initial presentations included vision loss (10/15, 66.7%) and seizures (5/15, 33.3%). Serum MOG-Ab titers in 14/15 cases were higher than those in the cerebrospinal fluid and were detected in 3/6 relapsed patients. Brain magnetic resonance imaging during acute attacks showed lesions in 10/15 patients (66.7%), mostly in the cortex/subcortical white matter (5/15, 33.3%). Recurrence occurred in 6/15 patients (40.0%); in 4 patients, recurrence occurred shortly after immunotherapy discontinuation. Residual neurological deficits were present in 5/15 patients (33.3%), including visual impairment, incapacitation, cognitive impairment, and speech reduction. Optic neuritis was the most common clinical manifestation of MOGAD. magnetic resonance imaging findings were heterogeneous and the cerebral cortex/subcortical white matter was the most susceptible brain region. Although patients in the acute phase responded well to methylprednisolone pulse therapy, the long-term recurrence rate was high. Consistently detected serum MOG antibodies and inappropriate maintenance immunotherapy may be associated with recurrence, and residual neurological deficits should not be ignored.

Fibroblast growth factor 9 (FGF9)-mediated neurodegeneration: Implications for progressive multiple sclerosis?

Fibroblast growth factor (FGF) signalling is dysregulated in multiple sclerosis (MS) and other neurological and psychiatric conditions, but there is little or no consensus as to how individual FGF family members contribute to disease pathogenesis. Lesion development in MS is associated with increased expression of FGF1, FGF2 and FGF9, all of which modulate remyelination in a variety of experimental settings. However, FGF9 is also selectively upregulated in major depressive disorder (MDD), prompting us to speculate it may also have a direct effect on neuronal function and survival. Transcriptional profiling of myelinating cultures treated with FGF1, FGF2 or FGF9 was performed, and the effects of FGF9 on cortical neurons investigated using a combination of transcriptional, electrophysiological and immunofluorescence microscopic techniques. The in vivo effects of FGF9 were explored by stereotactic injection of adeno-associated viral (AAV) vectors encoding either FGF9 or EGFP into the rat motor cortex. Transcriptional profiling of myelinating cultures after FGF9 treatment revealed a distinct neuronal response with a pronounced downregulation of gene networks associated with axonal transport and synaptic function. In cortical neuronal cultures, FGF9 also rapidly downregulated expression of genes associated with synaptic function. This was associated with a complete block in the development of photo-inducible spiking activity, as demonstrated using multi-electrode recordings of channel rhodopsin-transfected rat cortical neurons in vitro and, ultimately, neuronal cell death. Overexpression of FGF9 in vivo resulted in rapid loss of neurons and subsequent development of chronic grey matter lesions with neuroaxonal reduction and ensuing myelin loss. These observations identify overexpression of FGF9 as a mechanism by which neuroaxonal pathology could develop independently of immune-mediated demyelination in MS. We suggest targeting neuronal FGF9-dependent pathways may provide a novel strategy to slow if not halt neuroaxonal atrophy and loss in MS, MDD and potentially other neurodegenerative diseases.

Mimicry of Two Disease Guillain-Barre Syndrome and Japanese encephalitis: A Case Report

Guillian-Barre syndrome (GBS) is an acute immune-mediated inflammatory demyelinating polyneuropathy characterized by symmetrical limb weakness and areflexia preceded by an infection while Japanese encephalitis (JE) virus is a neurotropic RNA virus belonging to Flaviviridae family. GBS can have different clinical manifestations which overlaps JE. GBS secondary to JE has been reported earlier though in the incidence is low.Involvement of the peripheral nerve, areflexic paralysis, electrophysiological nerve examination and JE IgM in CSF were consistent with a diagnosis of GBS with JE. Prompt detection and diagnosis can reduce morbidity and mortality.

Assessment of Multiple Sclerosis Patients' Knowledge and Behavioral Practice Regarding COVID-19 in Saudi Arabia.

Background Coronavirus disease 2019 (COVID-19) is caused by a coronavirus subtype called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is crucial to control the spread of coronavirus by understanding the disease and practicing the measures adopted during the COVID-19 pandemic. Multiple sclerosis (MS) is a central nervous system immune-mediated inflammatory demyelinating disease. COVID-19 infection may exacerbate the MS disease and its relapses. Therefore, MS patients are more susceptible to infection because of their immunosuppressive or immunomodulatory medications. Objective We aimed to evaluate the knowledge, attitude, and behaviors of patients with MS in Saudi Arabia regarding the COVID-19 pandemic. Method A quantitative observational cross-sectional study was conducted. MS patients in Saudi Arabia were included in the study population. Data were collected via an online self-reported questionnaire from 214 participants from November 2020 to June 2021. Results A total of 214 MS patients participated in this study. The gender distribution showed that the male participants represented 38.3% (n = 82), while female participants accounted for 61.7% (n = 132).Most MS patients understood the COVID-19 preventive measures. The mean knowledge score was 15.7 (SD = 2.34, range: 1-20), showing an appropriate level of knowledge. While the mean behaviors score was 6.1 (SD = 1.2, range: 2-9), showing good behaviors. The mean score for attitude was 5.4 (SD = 1.77, range: 1-8), showing optimistic attitudes. However, a closer analysis of the participants' answers showed that 74.3% of the patients agreed that the treatment plan should be discussed with their doctors during the pandemic. In addition, almost half of the participants (49.1%) agreed that being an MS patient means they are at higher risk of getting infected by the virus. Data also showed that 17% of patients continued to attend social events involving many people. Also, 28.0% of the patients reported being in crowded places. Conclusion MS patients' risk of COVID-19 might be linked to their knowledge, attitude, and behaviors. Our results suggest that although MS patients have a high knowledge and good attitude and behaviors, it is still essential to have health education programs among MS patients to reduce the risk of SARS-CoV-2 infection and the impact of the COVID-19 pandemic on MS patients' care. Knowledge, attitude, and behaviors toward the COVID-19 pandemic can highlight the importance of education programs and translate the findings into action to minimize the disease risk.

Consensus opinion on the management of patients with neuromyelitis optica spectrum diseases: issues of terminology and therapy

Neuromyelitis optica spectrum disorders (NMOSD) are a group of inflammatory diseases of the central nervous system characterized by episodes of immune-mediated astrocytopathy, inflammatory demyelination and axonal damage, predominantly affecting the optic nerves and spinal cord. Currently, there are several unresolved issues that make it difficult to provide medical care to patients with NMOSD. The objective of this publication is to present the results of the work of the Russian experts panel, held in September 2022. The consensus council of experts adopted the main definitions and terms for NMOSD, proposed a therapeutic algorithm to prevent exacerbations in patients with NMOSD with serum IgG antibodies to aquaporin-4 (AQP4-IgG). The experts formulated profiles of patients with NMOSD to whom eculizumab may be recommended, and proposed a risk management plan during the treatment with this drug. The experts worked out the next steps, which are necessary for the improvement of medical care for these patients: development of unified electronic register of patients with NMOSD in the Russian Federation, development and approval of clinical guidelines.

Thermoregulatory dynamics reveal sex-specific inflammatory responses to experimental autoimmune encephalomyelitis in mice: Implications for multiple sclerosis-induced fatigue in females

The course of multiple sclerosis (MS) is characterized by striking sex differences in symptoms such as fatigue and impaired thermal regulation, which are associated with aggravated systemic pro-inflammatory processes. The purpose of this study was to replicate these symptoms in experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice in the quest to advance the preclinical study of non-motor symptoms of MS. Male and female C57BL/6 mice exposed to a mild form of EAE were evaluated for the progression of clinical, behavioural, thermal, and inflammatory processes. We show higher susceptibility in females to EAE than males based on greater clinical score and cumulative disease index (CDI), fatigue-like and anxiety-like behaviours. Accordingly, infrared (IR) thermography indicated higher cutaneous temperatures in females from post-induction days 12–23. Females also responded to EAE with greater splenic and adrenal gland weights than males as well as sex-specific changes in pro- and anti-inflammatory cytokines. These findings provide the first evidence of a sex-specific thermal response to immune-mediated demyelination, thus proposing a non-invasive assessment approach of the psychophysiological dynamics in EAE mice. The results are discussed in relation to the thermoregulatory correlates of fatigue and how endogenously elevated body temperature without direct heat exposure may be linked to psychomotor inhibition in patients with MS.

Comparative Profiling of TG2 and Its Effectors in Human Relapsing Remitting and Progressive Multiple Sclerosis.

Multiple Sclerosis (MS) is a chronic CNS autoimmune disease characterized by immune-mediated demyelination, axon loss, and disability. Dysregulation of transglutaminase-2 (TG2) has been implicated in disease initiation and progression. Herein, TG2 expression in post-mortem human brain tissue from Relapsing Remitting MS (RRMS) or Progressive MS (PMS) individuals were examined and correlated with the presence of TG2 binding partners and effectors implicated in the processes of inflammation, scar formation, and the antagonism of repair. Tissues from Relapsing-Remitting Multiple Sclerosis (RRMS; n = 6), Progressive Multiple Sclerosis (PMS; n = 5), and non-MS control (n = 6) patients underwent immunohistochemistry for TG2, PLA2, COX-2, FN, CSPG, and HSPG. TG2 was strongly upregulated in active RRMS and PMS lesions, within blood vessels and the perivascular tissue of sclerotic plaques. TG2 colocalization was observed with GFAP+ astrocytes and ECM, including FN, HSPG, and CSPG, which also increased in either RRMS or PMS lesions. Although TG2 was not colocalized with inflammatory mediators COX-2 and PLA2, or the macrophage-microglia marker Iba1, its increased expression correlated with their elevation in active RRMS and PMS lesions. In summary, the correlation of strong TG2 induction in either RRMS or PMS with some of its binding partners but not others implicates potentially different roles for TG2 in disparate MS forms that may warrant further investigation.

Magnolol prevented brain injury through the modulation of Nrf2-dependent oxidative stress and apoptosis in PLP-induced mouse model of multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated chronic inflammatory demyelinating disease of the central nervous system (CNS). The aim of the current study was to investigate the effects of magnolol in an experimental autoimmune encephalomyelitis (EAE) model of MS in female mice. Magnolol (0.1, 1, and 10 mg/kg) was administered once daily for 21 days after immunization of mice. Magnolol post-immunization treatment significantly reversed clinical scoring, EAE-associated pain parameters, and motor dysfunction in a dose-dependent manner. Magnolol treatment significantly inhibited oxidative stress by reducing malondialdehyde (MDA), nitric oxide (NO) production, and myeloperoxidase (MPO) activity while enhancing the level of antioxidants such as reduced glutathione (GSH), glutathione-S-transferase (GST), catalase, and superoxide dismutase (SOD) in the brain and spinal cord. It reduced cytokine levels in the brain and spinal cord. It suppressed CD8+ T cells frequency in the spleen tissue. Magnolol remarkably reversed the EAE-associated histopathology of the brain and spinal cord tissue. Magnolol significantly intensifies the antioxidant defense system by enhancing the expression level of nuclear factor erythroid 2-related factor (Nrf2) while decreasing the expression of inducible nitric oxide synthase (iNOS) and cleaved-caspase-3 in the brain. Molecular docking results showed that magnolol possesses a better binding affinity for Nrf2, iNOS, and caspase-3 proteins. Taken together, the present study demonstrated that magnolol has significant neuroprotective properties in EAE via inhibition of oxidative stress.

Acute disseminated encephalomyelitis with bilateral optic neuritis following ChAdOx1 COVID-19 vaccination

BackgroundAcute disseminated encephalomyelitis (ADEM) is a rare immune-mediated inflammatory demyelinating disease of the central nervous system. We report a case of ADEM presenting with bilateral optic neuritis temporally associated with the ChAdOx1 vaccine against SARS-COVID19 virus.Case presentationA 36-year-old female presented with bilateral optic neuritis following her first dose of the ChAdOx1 vaccine. Initial MRI Brain showed evidence of demyelination within the subcortical white matter, with no radiological involvement of the optic nerves. Visual evoked potentials were consistent with bilateral optic neuritis which was confirmed radiologically on follow up MRI. She was treated with intravenous steroids with improvement both in symptoms and radiological appearance. A pseudo-relapse occurred which was treated with a further course of intravenous steroids followed by an oral taper. The clinical, radiological and serological results were most consistent with diagnosis of ADEM.ConclusionsADEM is an exceedingly rare complication of ChAdOx1 vaccine despite millions of doses. While it is imperative clinicians remain aware of neurological complications of vaccines, the importance of vaccination to control a pandemic should not be undermined.

Comparison of Clinical and Radiological Features of Aquaporin4 (AQP-4) Antibody Positive Neuromyelitis Optica Spectrum Disorder (NMOSD) and Anti Myelin Oligodendrocyte Glycoprotein (Anti-MOG) Syndrome-Our Experience from Northwest India.

Background:More and more cases of myelin oligodendrocyte glycoprotein (MOG) antibody are being diagnosed with the availability of laboratory tests helping us to know the differing patterns from AQP-4 antibody disease and we need to understand the natural course, treatment, and prognosis in a better way.Objectives:Neuromyelitis optica spectrum disorder (NMOSD) and anti-MOG syndromes are immune-mediated inflammatory demyelinating conditions of the central nervous system (CNS) that mainly involve the optic nerves and the spinal cord. We conducted this study to compare demographic, clinical, laboratory, and radiological features of AQP-4 antibody and MOG antibody positive patients.Methods:A single-centre retrospective observational study from a large tertiary care university centre of Northwest India conducted during 2019--2021. We screened all patients presenting with acute CNS demyelinating attacks and recruited total 47 patients of which 25 were positive for AQP4 antibody and 22 were positive for MOG antibody. No patient tested positive for both antibodies. Data were collected using a standardized format including demographic, clinical, laboratory, and neuroimaging data.Results:In our study, total 47 patients were included, amongst which 25 patients were AQP4 antibody and 22 patients were MOG antibody positive. Though there was no gender preponderance, pediatric patients were more frequently affected in MOG antibody positive group. In AQP-4 antibody positive patients, myelitis was most common presenting clinical feature followed by optic neuritis (ON), simultaneous ON with myelitis, and brainstem syndrome. In MOG antibody positive group, myelitis was the commonest phenotype followed by ON, brainstem syndrome, and cerebral syndrome. The neuroimaging revealed involvement of medulla mainly area postrema, cervicodorsal spinal cord and extension of cervical lesion up to brainstem more commonly in AQP4 antibody group, on the other hand involvement of upper brainstem (midbrain and pons), cortex, and conus was more common in MOG antibody group.Conclusion:We have made an attempt to find differentiating features in AQP-4 vs. MOG antibody positive cases but they were of no statistically significance value as the numbers were small. Further larger studies may prove helpful in planning better strategies in two groups.

Relaxometry and brain myelin quantification with synthetic MRI in MS subtypes and their associations with spinal cord atrophy

Immune-mediated demyelination and neurodegeneration are pathophysiological hallmarks of Multiple Sclerosis (MS) and main drivers of disease related disability. The principal method for evaluating qualitatively demyelinating events in the clinical context is contrast-weighted magnetic resonance imaging (MRI). Moreover, advanced MRI sequences provide reliable quantification of brain myelin offering new opportunities to study tissue pathology in vivo. Towards neurodegenerative aspects of the disease, spinal cord atrophy – besides brain atrophy – is a powerful and validated predictor of disease progression. The etiology of spinal cord volume loss is still a matter of research, as it remains unclear whether the impact of local lesion pathology or the interaction with supra- and infratentorial axonal degeneration and demyelination of the long descending and ascending fiber tracts are the determining factors.Quantitative synthetic MR using a multiecho acquisition of saturation recovery pulse sequence provides fast automatic brain tissue and myelin volumetry based on R1 and R2 relaxation rates and proton density quantification, making it a promising modality for application in the clinical routine. In this cross sectional study a total of 91 MS patients and 31 control subjects were included to investigate group differences of global and regional measures of brain myelin and relaxation rates, in different MS subtypes, using QRAPMASTER sequence and SyMRI postprocessing software. Furthermore, we examined associations between these quantitative brain parameters and spinal cord atrophy to draw conclusions about possible pathophysiological relationships.Intracranial myelin volume fraction of the global brain exhibited statistically significant differences between control subjects (10.4%) and MS patients (RRMS 9.4%, PMS 8.1%). In a LASSO regression analysis with total brain lesion load, intracranial myelin volume fraction and brain parenchymal fraction, the intracranial myelin volume fraction was the variable with the highest impact on spinal cord atrophy (standardized coefficient 4.52). Regional supratentorial MRI metrics showed altered average myelin volume fraction, R1, R2 and proton density in MS patients compared to controls most pronounced in PMS. Interestingly, quantitative MRI parameters in supratentorial regions showed strong associations with upper cord atrophy, suggesting an important role of brain diffuse demyelination on spinal cord pathology possibly in the context of global disease activity. R1, R2 or proton density of the thalamus, cerebellum and brainstem correlated with upper cervical cord atrophy, probably reflecting the direct functional connection between these brain structures and the spinal cord as well as the effects of retrograde and anterograde axonal degeneration.By using Synthetic MR-derived myelin volume fraction, we were able to effectively detect significant differences of myelination in relapsing and progressive MS subtypes. Total intracranial brain myelin volume fraction seemed to predict spinal cord volume loss better than brain atrophy or total lesion load. Furthermore, demyelination in highly myelinated supratentorial regions, as an indicator of diffuse disease activity, as well as alterations of relaxation parameters in adjacent infratentorial and midbrain areas were strongly associated with upper cervical cord atrophy.

Long Non-Coding RNA- Associated Competing Endogenous RNA Axes in T-Cells in Multiple Sclerosis.

Multiple sclerosis (MS) is an immune-mediated demyelinating and degenerative disease with unknown etiology. Inappropriate response of T-cells to myelin antigens has an essential role in the pathophysiology of MS. The clinical and pathophysiological complications of MS necessitate identification of potential molecular targets to understand the pathogenic events of MS. Since the functions and regulatory mechanisms of long non-coding RNAs (lncRNAs) acting as competing endogenous RNAs (ceRNAs) in MS are yet uncertain, we conducted a bioinformatics analysis to explain the lncRNA-associated ceRNA axes to clarify molecular regulatory mechanisms involved in T-cells responses in MS. Two microarray datasets of peripheral blood T-cell from subjects with relapsing-remitting MS and matched controls containing data about miRNAs (GSE43590), mRNAs and lncRNAs (GSE43591) were downloaded from the Gene Expression Omnibus database. Differentially expressed miRNAs (DEmiRNAs), mRNAs (DEmRNAs), and lncRNAs (DElncRNAs) were identified by the limma package of the R software. Protein-protein interaction (PPI) network and module were developed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and the Molecular Complex Detection (MCODE) Cytoscape plugin, respectively. Using DIANA-LncBase and miRTarBase, the lncRNA-associated ceRNA axes was constructed. We conducted a Pearson correlation analysis and selected the positive correlations among the lncRNAs and mRNAs in the ceRNA axes. Lastly, DEmRNAs pathway enrichment was conducted by the Enrichr tool. A ceRNA regulatory relationship among Small nucleolar RNA host gene 1 (SNHG1), hsa-miR-197-3p, YOD1 deubiquitinase (YOD1) and zinc finger protein 101 (ZNF101) and downstream connected genes was identified. Pathway enrichment analysis showed that DEmRNAs were enriched in “Protein processing in endoplasmic reticulum” and “Herpes simplex virus 1 infection” pathways. To our knowledge, this would be the first report of a possible role of SNHG1/hsa-miR-197-3p/YOD1/ZNF101 axes in the pathogenesis of MS. This research remarks on the significance of ceRNAs and prepares new perceptions for discovering the molecular mechanism of MS.

Consensus of expert advices on routing, diagnosis, and management of patients with neuromyelitis optica spectrum disorders

Neuromyelitis optica spectrum disorders (NMOSDs) are autoimmune inflammatory disorders accompanied by central nervous system damage, widespread immunemediated demyelination, and axonal damage, involving mainly the optic nerves, spinal cord, and area postrema. The diagnostic capabilities, administration and routing of patients, and therapeutic approaches to this disease need to be improved. During several expert councils held in 2019–2021 in different regions of the Russian Federation, we discussed multiple issues related to various aspects of medical care for patients with NMOSDs. As a result, the experts developed further steps necessary to improve the medical care to these patients: to write and publish clinical guidelines for the diagnosis and treatment of NMOSDs; to consider the possibility of optimizing the NMOSDs diagnostic program including the aquaporin-4 antibodies (AQP4-IgG) testing; to evaluate the implementation of a set of measures aimed at including the corresponding laboratory investigations into the system of state guarantees (together with the institutions of the Ministry of Health of Russia), if there is clinical and economic feasibility; to include the issues of timely NMOSDs evaluation in educational programs initiated by the scientific medical community, in order to raise awareness of primary care neurologists in relation to the clinical and neuroimaging signs of probable NMOSDs; to assess the possibility of introducing routing schemes for patients with NMOSDs at the regional level; to work out a decision on the collection of NMOSDs epidemiological and clinical data in the Russian Federation.

CD200 -dependent and -independent immune-modulatory functions of neural stem cells

Neural stem/precursor cells (NPC) exhibit powerful immune-modulatory properties. Attenuation of neuroinflammation by intra-cerebroventricular transplantation of NPC, protects from immune-mediated demyelination and axonal injury. The immune modulatory properties of NPC are mediated by a non-species-specific, multiple bystander effect, mediated by both direct cell-cell contact, and by soluble factor(s). CD200 is a cell-surface molecule, with important roles in regulating diverse immune responses, and shown also to limit neuroinflammatory processes. We hypothesized that CD200 may play a role in mediating immune-modulatory effects of NPC.We used wild type and CD200-deficient NPC to examine the role of CD200 in mediating two vital aspects of NPC -immune modulatory properties: (1) Attenuation of autoimmune neuroinflammation; and (2) Suppression of immune rejection response towards transplanted allogeneic NPC from the host CNS.We found that CD200 is dispensable for attenuating acute experimental autoimmune neuroinflammation, but is required for protecting transplanted allogeneic NPC from immune rejection by the host tissue. CD200 deficient NPC showed similar growth, differentiation and survival properties as wild type NPC. CD200-deficient NPC attenuated efficiently T cell activation and proliferation, but exhibited reduced ability to inhibit macrophages. We conclude that CD200 plays a partial role in mediating the immune-modulatory properties of NPC. The differential effect on T cells versus macrophages may underlie the observed discrepancy in their function in vivo.

AZD8055 ameliorates experimental autoimmune encephalomyelitis via the mTOR/ROS/NLRP3 pathway

AimsExperimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), is characterized by immune-mediated demyelination and neurodegeneration. NOD-like receptor protein 3 (NLRP3) inflammasome activation aggravates spinal cord inflammation in EAE. Autophagy is associated with alleviation of systemic inflammation, including that encountered in EAE. However, the effects of autophagy on NLRP3 in EAE are still unclear. Here, we evaluated the effects of the autophagy activator AZD8055 on EAE. MethodsEAE model mice were established, histological examination was performed to assess the degree of inflammatory cell infiltration and demyelination. And the levels of autophagy and NLRP3-mediated pyroptosis in spinal cords were assessed. Western blotting and immunofluorescence analyses were performed to evaluate protein expression and localization. ResultsAZD8055 significantly enhanced autophagy in the spinal cords of EAE model mice, coupled with decreased abnormal clinical behavior scores and increased body weights. The degree of inflammatory cell infiltration and demyelination was mild in AZD8055-treated EAE model mice.Meanwhile, the pathway of ROS/NLRP3 was downregulated, and LC3 and NLRP3 were colocalized. ConclusionsAZD8055 ameliorated EAE through anti-inflammatory and anti-pyroptosis effects via the mammalian target of mTOR/ROS/NLRP3 pathway. These findings provide insights into the interactions between autophagy and pyroptosis and may facilitate the development of novel treatments for MS.

New Insights into Multiple Sclerosis Mechanisms: Lipids on the Track to Control Inflammation and Neurodegeneration.

Multiple sclerosis (MS) is a central nervous system disease with complex pathogenesis, including two main processes: immune-mediated inflammatory demyelination and progressive degeneration with axonal loss. Despite recent progress in our understanding and management of MS, availability of sensitive and specific biomarkers for these both processes, as well as neuroprotective therapeutic options targeted at progressive phase of disease, are still being sought. Given their abundance in the myelin sheath, lipids are believed to play a central role in underlying immunopathogenesis in MS and seem to be a promising subject of investigation in this field. On the basis of our previous research and a review of the literature, we discuss the current understanding of lipid-related mechanisms involved in active relapse, remission, and progression of MS. These insights highlight potential usefulness of lipid markers in prediction or monitoring the course of MS, particularly in its progressive stage, still insufficiently addressed. Furthermore, they raise hope for new, effective, and stage-specific treatment options, involving lipids as targets or carriers of therapeutic agents.