Inflammatory Demyelinating Disease Research Articles

Krebs von den Lungen-6 (KL-6) in cerebrospinal fluid from neurosarcoidosis patients.

Krebs von den Lungen-6 (KL-6) is a high molecular weight (MW) glycoprotein mainly secreted by type II pneumocytes because of lung damage or during regeneration. Neurosarcoidosis (NS), where sarcoid granulomas involve the nervous system, occurs in 5-20% of patients with sarcoidosis. No data is currently available on KL-6 in serum or CSF of NS patients. The present study compared KL-6 concentrations in serum and CSF of NS patients versus others with neurodegenerative (ND) or chronic inflammatory demyelinating (DM) diseases. Nine NS patients (mean age 46.2 years, range 16-61 years, M/F 5/4), nine patients with a chronic neurodegenerative disease (mean age 53.1 years, range 37-65 years, M/F 5/4) and nine patients with a chronic demyelinating disease (mean age 46.3 years, range 18-65 years, M/F 5/4) were retrospectively enrolled. Measurable CSF concentrations of KL-6 were detected in 7/9 NS patients but in no ND or DM patients. No significant differences in CSF concentrations of ACE were observed between the three groups (p=0.0819). In NS patients, CSF concentrations of KL-6 were directly correlated with CSF albumin index (r=0.98; p<0.0001), albumin (r=0.979, p=0.0001), IgG (r=0.928, p=0.0009) and total protein concentrations (r=0.945, p=0.0004). KL-6 is a high MW protein, under physiological conditions it is unlikely to cross the blood-brain barrier. We found KL-6 in CSF from NS and not from ND and DM patients. The finding sustains the specificity of changes in KL-6 in this granulomatous disease, suggesting it as a candidate biomarker for recognition of NS.

Characteristics of hypersomnia due to inflammatory demyelinating diseases of the central nervous system

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) diagnostic criteria for inflammatory demyelinating central nervous system diseases included symptomatic narcolepsy; however, no relevant case‐control studies exist. We aimed to examine the relationship among...

Dihydroartemisinin Promotes Neural Stem Cell Differentiation into Oligodendrocytes via STAT6/Chi3l3 Signaling Pathway in Microglia

Promoting the differentiation of neural stem cells (NSCs) into oligodendrocytes is crucial for maintaining myelin integrity in demyelinating diseases, which is regulated by the microglia-mediated inflammatory milieu in the central nervous system (CNS). In this research, we aimed to investigate whether dihydroartemisinin (DHA) could promote the differentiation of C17.2 neural stem cell into oligodendrocytes by regulating microglia, and elucidate the underlying molecular mechanisms. Moreover, DHA trimer self-assembled nanoparticles (DHA3NPs) were prepared to explore the efficacy on attenuating inflammation compared to free DHA. An in vitro microglia-NSCs co-culturing model was established. The level of inflammation and the differentiation of NSCs were accessed via RT-qPCR, ELISA and western blot methods. To inhibit STAT6 activation in microglia, AS1517499 was applied. The results found that DHA effectively rebalanced BV2-mediated inflammation and specifically induced the directed differentiation of NSC cell lines into oligodendrocytes (OLs), as represented by the expression of MBP and PLP. Mechanistically, it was demonstrated that the enhanced expression of Chi3l3 induced by DHA was significantly eliminated by the blockade of STAT6, suggesting that DHA served as a booster for OLs differentiation in a STAT6-depenent manner. In addition, DHA3NPs were more effective than free DHA in attenuating microglia-mediated inflammation stimulated by lipopolysaccharide. In conclusion, DHA attenuated microglia-mediated neuroinflammation and activated the STAT6/Chi3l3 signaling pathway in microglia, inducing C17.2 differentiation into oligodendrocytes. This study reveals the molecular mechanism and the functional impact of DHA in inhibiting inflammation of CNS, and provides preliminary suggestions for the clinical treatment of inflammatory demyelinating diseases.

Central nervous system demyelinating diseases: glial cells at the hub of pathology.

Inflammatory demyelinating diseases (IDDs) are among the main causes of inflammatory and neurodegenerative injury of the central nervous system (CNS) in young adult patients. Of these, multiple sclerosis (MS) is the most frequent and studied, as it affects about a million people in the USA alone. The understanding of the mechanisms underlying their pathology has been advancing, although there are still no highly effective disease-modifying treatments for the progressive symptoms and disability in the late stages of disease. Among these mechanisms, the action of glial cells upon lesion and regeneration has become a prominent research topic, helped not only by the discovery of glia as targets of autoantibodies, but also by their role on CNS homeostasis and neuroinflammation. In the present article, we discuss the participation of glial cells in IDDs, as well as their association with demyelination and synaptic dysfunction throughout the course of the disease and in experimental models, with a focus on MS phenotypes. Further, we discuss the involvement of microglia and astrocytes in lesion formation and organization, remyelination, synaptic induction and pruning through different signaling pathways. We argue that evidence of the several glia-mediated mechanisms in the course of CNS demyelinating diseases supports glial cells as viable targets for therapy development.

Involvement of Degenerating 21.5 kDa Isoform of Myelin Basic Protein in the Pathogenesis of the Relapse in Murine Relapsing-Remitting Experimental Autoimmune Encephalomyelitis and MS Autopsied Brain.

Multiple sclerosis (MS) is the chronic inflammatory demyelinating disease of the CNS. Relapsing-remitting MS (RRMS) is the most common type of MS. However, the mechanisms of relapse and remission in MS have not been fully understood. While SJL mice immunized with proteolipid protein (PLP) develop relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE), we have recently observed that some of these mice were resistant to the active induction of relapsing EAE after initial clinical and histological symptoms of EAE with a severity similar to the relapsing EAE mice. To clarify the mechanism of relapsing, we examined myelin morphology during PLP139-151-induced RR-EAE in the SJL mice. While RR-EAE mice showed an increased EAE severity (relapse) with CNS inflammation, demyelination with abnormal myelin morphology in the spinal cord, the resistant mice exhibited a milder EAE phenotype with diminished relapse. Compared with the RR-EAE mice, the resistant mice showed less CNS inflammation, demyelination, and abnormalities of the myelin structure. In addition, scanning electron microscopic (SEM) analysis with the osmium-maceration method displayed ultrastructural abnormalities of the myelin structure in the white matter of the RR-EAE spinal cord, but not in that of the resistant mice. While the intensity of myelin staining was reduced in the relapsing EAE spinal cord, immunohistochemistry and immunoblot analysis revealed that the 21.5 kDa isoform of degenerating myelin basic protein (MBP) was specifically induced in the relapsing EAE spinal cord. Taken together, the neuroinflammation-induced degenerating 21 kDa isoform of MBP sheds light on the development of abnormal myelin on the relapse of MS pathogenesis.

Co-modulation of TNFR1 and TNFR2 in an animal model of multiple sclerosis

BackgroundTumour necrosis factor (TNF) is a pleiotropic cytokine and master regulator of the immune system. It acts through two receptors resulting in often opposing biological effects, which may explain the lack of therapeutic potential obtained so far in multiple sclerosis (MS) with non-receptor-specific anti-TNF therapeutics. Under neuroinflammatory conditions, such as MS, TNF receptor-1 (TNFR1) is believed to mediate the pro-inflammatory activities associated with TNF, whereas TNF receptor-2 (TNFR2) may instead induce anti-inflammatory effects as well as promote remyelination and neuroprotection. In this study, we have investigated the therapeutic potential of blocking TNFR1 whilst simultaneously stimulating TNFR2 in a mouse model of MS.MethodsExperimental autoimmune encephalomyelitis (EAE) was induced with myelin oligodendrocyte glycoprotein (MOG35-55) in humanized TNFR1 knock-in mice. These were treated with a human-specific TNFR1-selective antagonistic antibody (H398) and a mouse-specific TNFR2 agonist (EHD2-sc-mTNFR2), both in combination and individually. Histopathological analysis of spinal cords was performed to investigate demyelination and inflammatory infiltration, as well as axonal and neuronal degeneration. Retinas were examined for any protective effects on retinal ganglion cell (RGC) degeneration and neuroprotective signalling pathways analysed by Western blotting.ResultsTNFR modulation successfully ameliorated symptoms of EAE and reduced demyelination, inflammatory infiltration and axonal degeneration. Furthermore, the combinatorial approach of blocking TNFR1 and stimulating TNFR2 signalling increased RGC survival and promoted the phosphorylation of Akt and NF-κB, both known to mediate neuroprotection.ConclusionThese results further support the potential of regulating the balance of TNFR signalling, through the co-modulation of TNFR1 and TNFR2 activity, as a novel therapeutic approach in treating inflammatory demyelinating disease.

The Role of C3 and C4 Complement Levels in the Differential Diagnosis of Central Nervous System Demyelinating Diseases (P14-3.016)

<h3>Objective:</h3> Predictive value of C3 and C4 complement levels at the time of the first attack for the definitive diagnosis aimed to be investigated. <h3>Background:</h3> Neuromyelitis Optica Spectrum Disorders (NMOSD) and Multiple Sclerosis (MS) are primary inflammatory demyelinating diseases of the central nervous system. Since they have similar clinical features, difficulties are experienced in the differential diagnosis and, accordingly, in the early decision for the appropriate treatment. It is thought that NMOSD is humoral immunity mediated and MS is T-lymphocyte-mediated. Seronegative and aquaporin-4 positive (AQP4-IgG+) groups are included in NMOSD and it is considered that complement-dependent cytotoxicity has different roles in the pathophysiology of these sub-groups. <h3>Design/Methods:</h3> Peripheral blood samples were obtained from naive patients. 14 Seronegative NMO, 28 AQP4-IgG+ NMO, 23 MOGAD and 15 MS patients were included. Serum C3 and C4 levels were evaluated retrospectively. <h3>Results:</h3> The mean age of the sample was 42±15 and the female ratio was 68.7%. While there was no difference in C3 levels in NMOSD and MS groups, it was determined that C4 levels were lower in NMOSD compared to MS (respectively <i>p</i> values 0.21; 0.035). C4 levels were lower in seronegative and AQP4-IgG+ NMO groups compared to MS (respectively <i>p</i> values 0.026; 0.035). It has been determined that 4.8 cut-off value for C3/C4 ratio can discriminate MS and NMOSD groups with 67% sensitivity and 70% specificity (AUC:0.786; <i>p</i>=0.002). <h3>Conclusions:</h3> While activation of the classical pathway more predominantly decreases the level of C4, alternative pathway decreases the level of C3. The classical pathway in NMOSD was thought to be more affected when compared with MS. Since the involvement of the pathways in the complement system at different levels may be presented with the C3/C4 ratio, it seems likely that this ratio may have value as a candidate marker in the differential diagnosis of neurodemyelinating diseases. <b>Disclosure:</b> Melike Cakan, MD has nothing to disclose. Dr. Cimen has nothing to disclose. Dr. Acar Ozen has nothing to disclose. Dr. Karabudak has nothing to disclose. Meryem Aslı Tuncer has nothing to disclose.

Influence of Epstein-Barr virus infection on developing multiple sclerosis

Multiple sclerosis (MS) is the most common inflammatory-demyelinating disease. MS leads to the multifocal damage of the central nervous system, which causes the gradual deterioration of sensory, motor and cognitive functions. The etiology of this disease is not fully understood, but genetic and environmental factors (including the EBV infection) are suspected. In this review, we would like to summarize the state of knowledge over the effect of Epstein-Barr virus infection on developing multiple sclerosis.&#x0D; Infectious mononucleosis (IM) which is caused by EBV and MS have similar epidemiology: both diseases mainly affect people at a young age, geographical prevalence is also identical. There are many theories that explain the mechanism of the EBV involvement in the development of MS including: the migration of EBV-infected B cells into the Central Nervous System, the theory of molecular mimicry, the induction of αB-crystallin by EBV in lymphoid cells or cooperation of the EBV and other viruses in the development of MS. Observations by physicians from around the world suggest that EBV infection is a strong factor in the development of multiple sclerosis. Epstein-Barr virus is prevalent in the population. There are a lot of evidences that suggest its involvement in the development of multiple sclerosis. Prevention of EBV infection could potentially reduce the amount of cases of MS. However, more researches are needed to clearly confirm the involvement of EBV in the etiopathogenesis of developing MS.

Critical role of TLR activation in viral replication, persistence, and pathogenicity of Theiler's virus.

Theiler's murine encephalomyelitis virus (TMEV) establishes persistent viral infections in the central nervous system and induces chronic inflammatory demyelinating disease in susceptible mice. TMEV infects dendritic cells, macrophages, B cells, and glial cells. The state of TLR activation in the host plays a critical role in initial viral replication and persistence. The further activation of TLRs enhances viral replication and persistence, leading to the pathogenicity of TMEV-induced demyelinating disease. Various cytokines are produced via TLRs, and MDA-5 signals linked with NF-κB activation following TMEV infection. In turn, these signals further amplify TMEV replication and the persistence of virus-infected cells. The signals further elevate cytokine production, promoting the development of Th17 responses and preventing cellular apoptosis, which enables viral persistence. Excessive levels of cytokines, particularly IL-6 and IL-1β, facilitate the generation of pathogenic Th17 immune responses to viral antigens and autoantigens, leading to TMEV-induced demyelinating disease. These cytokines, together with TLR2 may prematurely generate functionally deficient CD25-FoxP3+ CD4+ T cells, which are subsequently converted to Th17 cells. Furthermore, IL-6 and IL-17 synergistically inhibit the apoptosis of virus-infected cells and the cytolytic function of CD8+ T lymphocytes, prolonging the survival of virus-infected cells. The inhibition of apoptosis leads to the persistent activation of NF-κB and TLRs, which continuously provides an environment of excessive cytokines and consequently promotes autoimmune responses. Persistent or repeated infections of other viruses such as COVID-19 may result in similar continuous TLR activation and cytokine production, leading to autoimmune diseases.

Myelin olygodendrocyte glycoprotein - autoantigen in inflammatory demyelinating diseases of the central nervous system

Demyelinating diseases of the CNS are a result of an autoimmune attack to the myelin sheaths surrounding axons. Their structural proteins become antigenic and as a result, myelin lesions appear. The identification of specific antibodies directed against the components of myelin, using highly specialized methods of laboratory diagnostics, can significantly improve diagnostic approaches. Currently, myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) consists of demyelinating syndromes with an identified antigen. The pathogenic role of human MOG-IgG has been demonstrated, which makes it possible to isolate this disease into a separate nosological form. However, for the myelin oligodendrocyte glycoprotein (MOG) gene, alternative splicing can produce various isoforms, which hinders antigen detection even for the most advanced techniques of immunofluorescence analysis. On the other hand, MOG conformational changes provide the structural integrity of other myelin proteins and maintain immune autotolerance mechanisms that are unique to humans.

Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination.

Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS. Increasing evidence suggests that vulnerable neurons in MS exhibit fatal metabolic exhaustion over time, a phenomenon hypothesized to be caused by chronic hyperexcitability. Axonal Kv7 (outward-rectifying) and oligodendroglial Kir4.1 (inward-rectifying) potassium channels have important roles in regulating neuronal excitability at and around the nodes of Ranvier. Here, we studied the spatial and functional relationship between neuronal Kv7 and oligodendroglial Kir4.1 channels and assessed the transcriptional and functional signatures of cortical and retinal projection neurons under physiological and inflammatory demyelinating conditions. We found that both channels became dysregulated in MS and experimental autoimmune encephalomyelitis (EAE), with Kir4.1 channels being chronically downregulated and Kv7 channel subunits being transiently upregulated during inflammatory demyelination. Further, we observed that pharmacological Kv7 channel opening with retigabine reduced neuronal hyperexcitability in human and EAE neurons, improved clinical EAE signs, and rescued neuronal pathology in oligodendrocyte-Kir4.1-deficient (OL-Kir4.1-deficient) mice. In summary, our findings indicate that neuron-OL compensatory interactions promoted resilience through Kv7 and Kir4.1 channels and identify pharmacological activation of nodal Kv7 channels as a neuroprotective strategy against inflammatory demyelination.

The Postpartum Period Can Worsen Myelin Oligodendrocyte Glycoprotein Antibody-associated Encephalomyelitis: A Case Report.

Myelin oligodendrocyte glycoprotein (MOG) antibodies are associated with relapsing inflammatory demyelinating disease. Pregnancy complicates the disease course, potentially leading to either symptom improvement or worsening. A 28-year-old woman with MOG antibody-associated encephalomyelitis had 2 pregnancies; her disease worsened during both postpartum periods despite continuing prednisolone and levetiracetam. The umbilical cord blood was positive for MOG antibodies following her second pregnancy, but neither baby had MOG antibody-associated disease. This is the first case report of MOG antibody-associated demyelinating disease that worsened postpartum despite continuous medication. Furthermore, we observed the placental transfer of MOG antibodies for the first time.

Evolution in anti-myelin oligodendrocyte glycoprotein antibody detection and its clinical significance: a narrative review.

Myelin oligodendrocyte glycoprotein (MOG) is a protein exclusively expressing on the surface of myelin sheaths and oligodendrocyte plasma membrane in the central nervous system of mammals, and it has a highly conserved nucleotide and amino acid structure between species. Evidence from animal research support that anti-MOG antibodies (MOG-Abs) are pathogenic antibodies rather than a bystander secondary to myelin destruction. Similarly, immunoglobulin-G against myelin oligodendrocyte glycoprotein (MOG-IgG) is considered a demyelinating disease-associated autoantibody in human beings. In clinical studies, several detection methods, including ELISA, immunoblot, radio immunoprecipitation assays and Cell-based assays (CBAs), have been applied in identifying MOG-Abs in idiopathic inflammatory demyelinating diseases (IIDDs) of human beings. CBAs method is recommended by many proposed diagnostic criterions for MOG-Abs-associated disorders (MOGAD). This method involves transfection of mammalian cells with MOG antigen, binding of MOG-Abs to MOG antigen, binding of secondary antibodies to MOG-Abs and quantification method. However, the reliability for CBAs systems of MOG-Abs detection can be influenced by numerous factors, such as length of MOG antigen, expression vectors, cell lines, secondary antibodies, and read-out systems. In addition, there are controversial results on the studies of IIDDs with MOG-IgG positive. Nowadays, more and more evidence suggests that patients positive for MOG-IgG share common features, but further clinical and laboratory researches are needed to clarify if MOGAD is an independent disease entity. In this review, we intend to summarize the detection methods of MOG-Abs and their sensitivity and specificity to MOGAD in human.

Comparing Two Protocols of Exercise on Physical Fitness and Psychological Factors of Mild to Moderate Multiple Sclerosis Patients

Background: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Previous studies have shown that aerobic activity is inversely related to MS symptoms and may be restorative and possibly protective. Objectives: This study aimed to compare the effects of high-intensity functional training (HIFT) protocols and aerobic exercise on functional fitness as well as the cognitive aspect of female patients with multiple sclerosis. Methods: This quasi-experimental and applied clinical trial study consisted of all patients with MS registered in an MS clinic. Among eligible individuals, 30 female RRMS patients were randomly and equally divided into three groups high-intensity functional training (n = 10); aerobic exercise (n = 10), and control group (n = 10). The forearm test, the 30-second standing test, and single leg stance test (SLST), the timed up and go (TUG), Expanded Disability Status Scale (EDSS) were performed to assess physical factors as well as the 21-DAS questionnaire to assess cognitive aspects. Results: This study showed a meaningful difference between the intervention groups and the control group (P &lt; 0.05), in the level of power in the upper body (P = 0.001), lower torso strength (P = 0.001), static balance (P = 0.001), dynamic balance (P = 0.001). the psychological and behavioral components. Conclusions: Present study suggests that aerobic exercise and HIFT in women with MS can improve and further enhance physical function plus psychological and behavioral factors.

Intravenous immunoglobulin preparations attenuate lysolecithin-induced peripheral demyelination in mice and comprise anti-large myelin protein zero antibody.

Intravenous immunoglobulin (IVIg) has been used to treat inflammatory demyelinating diseases such as chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, and multifocal motor neuropathy. Despite studies demonstrating the clinical effectiveness of IVIg, the mechanisms underlying its effects remain to be elucidated in detail. Herein, we examined the effects of IVIg on lysolecithin-induced demyelination of the sciatic nerve in a mouse model. Mice -administered with IVIg 1 and 3 days post-injection (dpi) of lysolecithin -exhibited a significantly decreased demyelination area at 7 dpi. Immunoblotting analysis using two different preparations revealed that IVIg reacted with a 36-kDa membrane glycoprotein in the sciatic nerve. Subsequent analyses of peptide absorption identified the protein as a myelin protein in the peripheral nervous system (PNS) known as large myelin protein zero (L-MPZ). Moreover, injected IVIg penetrated the demyelinating lesion, leading to deposition on L-MPZ in the myelin debris. These results indicate that IVIg may modulate PNS demyelination, possibly by binding to L-MPZ on myelin debris.

Transverse myelitis following bivalent COVID‐19 booster vaccine and quadrivalent seasonal influenza vaccine

Transverse myelitis following bivalent <scp>COVID</scp>‐19 booster vaccine and quadrivalent seasonal influenza vaccine

Diagnostic work-up, findings, and documentation of multiple sclerosis

Although multiple sclerosis is the most common chronic inflammatory demyelinating disease of the central nervous system, the rate of misdiagnosis in clinical practice is high. This is usually due to the inadequate application of the McDonald criteria and misinterpretation of images. This review focuses on typical clinical symptoms, choice of magnetic resonance imaging (MRI) sequences, correct application of the McDonald criteria, and finally interpretation of the images.

The repertoire of CSF antiviral antibodies in patients with neuroinflammatory diseases.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Although various viruses have been proposed to contribute to MS pathology, the etiology of MS remains unknown. Since intrathecal antibody synthesis is well documented in chronic viral infection and neuroinflammatory diseases, we hypothesized whether the patterns of antigen-specific antibody responses associated with various viral exposures may define patients with CNS chronic immune dysregulation. The pan-viral antibody profiling in cerebrospinal fluid (CSF) and serum of patients with MS showed significant differences from those in healthy volunteers and a pattern of antibody responses against multiple viruses, including the previously identified Epstein-Barr virus. These findings demonstrate that virus-specific antibody signatures might be able to reflect disease-associated inflammatory milieu in CSF of subjects with neuroinflammatory diseases.

Validation of elevated levels of interleukin-8 in the cerebrospinal fluid, and discovery of new biomarkers in patients with GBS and CIDP using a proximity extension assay.

Biomarkers for diagnosis of inflammatory neuropathies, assessment of prognosis, and treatment response are lacking. CSF and EDTA plasma from patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), healthy controls (HC) and disease controls were analyzed with Olink multiplex proximity extension assay (PEA) from two independent cohorts. Levels of interleukin-8 (IL8) were further analyzed with ELISA in patients with GBS, CIDP, paraproteinemia-related demyelinating polyneuropathy (PDN), multifocal motor neuropathy (MMN), HC and disease controls. ROC analysis was performed. Outcome was measured with the GBS-disability score (GBS-ds) or Inflammatory Neuropathy Cause and Treatment (INCAT) score. In CSF, multiplex PEA analysis revealed up-regulation of IL8 in GBS compared to CIDP and HC respectively, and CIDP compared to HC. In addition, levels of IL2RA were upregulated in GBS compared to both HC and CIDP, SELE in GBS compared to HC, and ITGAM, IL6, and NRP1 in GBS compared to CIDP. In plasma, levels of MMP3, THBD and ITGAM were upregulated in CIDP compared to HC. Validation of multiplex IL8 results using ELISA, revealed increased levels of IL8 in CSF in patients with GBS and CIDP versus HC and non-inflammatory polyneuropathies (NIP) respectively, as well as in PDN versus NIP and HC. Levels of IL8 in CSF correlated with impairment in the acute phase of GBS as well as outcome at 6-months follow up. IL8 in CSF is validated as a diagnostic biomarker in GBS and CIDP, and a prognostic biomarker in GBS. Multiplex PEA hereby identifies several potential biomarkers in GBS and CIDP.

Aquaporin 5 in Alzheimer's disease: a link between oral and brain pathology?

Aquaporin 5 in Alzheimer's disease: a link between oral and brain pathology?