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Scientific Reports Jun 2024Multiple sclerosis (MS) is a chronic neurological disease frequently associated with significant fatigue, anxiety, depression, and stress. These symptoms are difficult... (Observational Study)
Observational Study
Multiple sclerosis (MS) is a chronic neurological disease frequently associated with significant fatigue, anxiety, depression, and stress. These symptoms are difficult to treat, and prominently contribute to the decreases in quality of life observed with MS. The underlying mechanisms of these "silent" symptoms are not well understood and include not just the psychological responses to a chronic disease, but also biological contributions from bidirectional psycho-neuro-immune (dys)regulation of systemic inflammatory biology. To address these issues, we conducted a prospective, observational pilot study to investigate the psychological, biological, and neuroarchitecture changes associated with a mindfulness-based stress reduction (MBSR) program in MS. The overarching hypothesis was that MBSR modulates systemic and central nervous system inflammation via top-down neurocognitive control over forebrain limbic areas responsible for the neurobiological stress response. 23 patients were enrolled in MBSR and assessed pre/post-program with structural 3 T MRI, behavioral measures, hair cortisol, and blood measures of peripheral inflammation, as indexed by the Conserved Transcriptional Response to Adversity (CTRA) profile. MBSR was associated with improvements across a variety of behavioral outcomes, as well as on-study enlargement of the head of the right hippocampus. The CTRA analyses revealed that greater inflammatory gene expression was related to worse patient-reported anxiety, depression, stress, and loneliness, in addition to lower eudaimonic well-being. Hair cortisol did not significantly change from pre- to post-MBSR. These results support the use of MBSR in MS and elucidate inflammatory mechanisms related to key patient-reported outcomes in this population.
Topics: Humans; Female; Mindfulness; Pilot Projects; Male; Stress, Psychological; Middle Aged; Adult; Multiple Sclerosis; Magnetic Resonance Imaging; Neuroimaging; Inflammation; Prospective Studies; Hydrocortisone; Quality of Life
PubMed: 38890336
DOI: 10.1038/s41598-024-62960-w -
Neurology(R) Neuroimmunology &... Jul 2024Interleukin-6 receptor antibodies (IL-6R Abs), including satralizumab, are increasingly used to prevent relapse for neuromyelitis optica spectrum disorder (NMOSD)....
BACKGROUND AND OBJECTIVES
Interleukin-6 receptor antibodies (IL-6R Abs), including satralizumab, are increasingly used to prevent relapse for neuromyelitis optica spectrum disorder (NMOSD). However, the detailed mechanism of action of this treatment on the lymphocyte phenotype remains unclear. This study focused on B cells in patients with NMOSD, hypothesizing that IL-6R Ab enables B cells to acquire regulatory functions by producing the anti-inflammatory cytokine IL-10.
METHODS
Peripheral blood mononuclear cells were stimulated in vitro to induce the expansion of B-cell subsets, double-negative B cells (DNs; CD19 IgD, CD27) and plasmablasts (PBs; CD19, CD27, CD38). Whole B cells, DNs, or PBs were isolated after culture with IL-6R Ab, and IL-10 expression was quantified using quantitative PCR and a cytometric bead array. RNA sequencing was performed to identify the marker of regulatory PBs induced by IL-6R Ab.
RESULTS
DNs and PBs were observed to expand in patients with NMSOD during the acute attacks. In the in vitro model, IL-6R Ab increased IL-10 expression in B cells. Notably, IL-10 expression increased in PBs but not in DNs. Using RNA sequencing, CD200 was identified as a marker of regulatory PBs among the differentially expressed upregulated genes. CD200 PBs produced more IL-10 than CD200 PBs. Furthermore, patients with NMOSD who received satralizumab had a higher proportion of CD200 PBs than patients during the acute attacks.
DISCUSSION
Treatment with IL-6 signaling blockade elicited a regulatory phenotype in B cells and PBs. CD200 PBs may be a marker of treatment responsiveness in the context of NMOSD pathophysiology.
Topics: Humans; Neuromyelitis Optica; Female; Adult; Male; Middle Aged; Interleukin-6; Receptors, Interleukin-6; Plasma Cells; Interleukin-10; Signal Transduction
PubMed: 38889374
DOI: 10.1212/NXI.0000000000200266 -
Neurology Research International 2024Extracellular adenosine 5'-triphosphate (ATP) acts as a signaling molecule in the peripheral nerves, regulating myelination after nerve injury. The present study...
BACKGROUND
Extracellular adenosine 5'-triphosphate (ATP) acts as a signaling molecule in the peripheral nerves, regulating myelination after nerve injury. The present study examined whether the cerebrospinal fluid (CSF) ATP levels in patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are related to disease severity.
METHODS
CSF ATP levels in 13 patients with GBS and 18 patients with CIDP were compared with those in a control group of 16 patients with other neurological diseases (ONDs). In patients with CIDP, CSF ATP levels were compared before and after treatment. The correlations between CSF ATP levels and other factors, including clinical data and CSF protein levels, were also evaluated.
RESULTS
Median CSF ATP levels were significantly higher in patients with GBS and CIDP than in those with ONDs. When patients with CIDP were classified into two groups depending on their responsiveness to immunotherapy, median CSF ATP levels were significantly higher in good responders than in ONDs. CSF ATP levels tended to decrease after treatment in patients with CIDP. In patients with CIDP, there is a negative correlation between CSF ATP and CSF protein levels.
CONCLUSIONS
CSF ATP levels were increased in patients with GBS and CIDP. In particular, CSF ATP levels tended to decrease following treatment in patients with CIDP. CSF ATP levels may be useful biomarkers for the diagnosis or monitoring of therapeutic effects in patients with GBS and CIDP.
PubMed: 38887668
DOI: 10.1155/2024/7229216 -
Frontiers in Immunology 2024Aquaporin-4 antibodies (AQP4-Abs) are a diagnostic marker for patients with a demyelinating disease called neuromyelitis optica spectrum disorder (NMOSD). Anti-Argonaute...
Aquaporin-4 antibodies (AQP4-Abs) are a diagnostic marker for patients with a demyelinating disease called neuromyelitis optica spectrum disorder (NMOSD). Anti-Argonaute antibodies (AGO-Abs) present as potential biomarkers of the overlap syndrome between NMOSD and other autoimmune diseases. In this paper, we present the case of an adult woman with numbness, tingling, and burning sensations in her arms and subsequent bilateral internuclear ophthalmoplegia. Brain-cervical-thoracic magnetic resonance imaging (MRI) showed T2 hyperintensities in the dorsal brainstem and around the midbrain aqueduct and longitudinally transverse myelitis with homogeneous enhancement on gadolinium-enhanced MRI. The contemporaneous detection of AQP4- and AGO-Abs led to a definite diagnosis of overlap syndrome of NMOSD with AGO-Abs. The patient was treated with immunosuppressive agents, including corticosteroids and immunoglobulins, and achieved remission. This case highlights a novel phenotype of NMOSD with AGO-Abs overlap syndrome, which presents with relapsing brainstem syndrome and longitudinally extensive myelitis with acute severe neurological involvement. The promising prognosis of the disease could serve as a distinct clinical profile. Broad screening for antibodies against central nervous system autoimmune antigens is recommended in suspected patients with limited or atypical clinical manifestations.
Topics: Humans; Neuromyelitis Optica; Female; Autoantibodies; Aquaporin 4; Adult; Biomarkers; Magnetic Resonance Imaging; Middle Aged; Immunosuppressive Agents
PubMed: 38887290
DOI: 10.3389/fimmu.2024.1366531 -
Scientific Reports Jun 2024Demyelination is generated in several nervous system illnesses. Developing strategies for effective clinical treatments requires the discovery of promyelinating drugs....
Demyelination is generated in several nervous system illnesses. Developing strategies for effective clinical treatments requires the discovery of promyelinating drugs. Increased GABAergic signaling through γ-aminobutyric acid type A receptor (GABAR) activation in oligodendrocytes has been proposed as a promyelinating condition. GABAR expressed in oligodendroglia is strongly potentiated by n-butyl-β-carboline-3-carboxylate (β-CCB) compared to that in neurons. Here, mice were subjected to 0.3% cuprizone (CPZ) added in the food to induce central nervous system demyelination, a well-known model for multiple sclerosis. Then β-CCB (1 mg/Kg) was systemically administered to analyze the remyelination status in white and gray matter areas. Myelin content was evaluated using Black-Gold II (BGII) staining, immunofluorescence (IF), and magnetic resonance imaging (MRI). Evidence indicates that β-CCB treatment of CPZ-demyelinated animals promoted remyelination in several white matter structures, such as the fimbria, corpus callosum, internal capsule, and cerebellar peduncles. Moreover, using IF, it was observed that CPZ intake induced an increase in NG2 and a decrease in CC1 cell populations, alterations that were importantly retrieved by β-CCB treatment. Thus, the promyelinating character of β-CCB was confirmed in a generalized demyelination model, strengthening the idea that it has clinical potential as a therapeutic drug.
Topics: Animals; Cuprizone; Remyelination; Mice; Demyelinating Diseases; Disease Models, Animal; Carbolines; Myelin Sheath; Male; Mice, Inbred C57BL; Oligodendroglia; Multiple Sclerosis; White Matter; Magnetic Resonance Imaging
PubMed: 38886527
DOI: 10.1038/s41598-024-64501-x -
Neurology(R) Neuroimmunology &... Jul 2024AQP4 antibody-positive NMOSD (AQP4-NMOSD), MOG antibody-associated disease (MOGAD), and seronegative NMOSD (SN-NMOSD) are neuroautoimmune conditions that have...
BACKGROUND AND OBJECTIVES
AQP4 antibody-positive NMOSD (AQP4-NMOSD), MOG antibody-associated disease (MOGAD), and seronegative NMOSD (SN-NMOSD) are neuroautoimmune conditions that have overlapping clinical manifestations. Yet, important differences exist in these diseases, particularly in B-cell depletion (BCD) efficacy. Yet, the biology driving these differences remains unclear. Our study aims to clarify biological pathways distinguishing these diseases beyond autoantibodies and investigate variable BCD effects through proteomic comparisons.
METHODS
In a retrospective study, 1,463 serum proteins were measured in 53 AQP4-NMOSD, 25 MOGAD, 18 SN-NMOSD, and 49 healthy individuals. To identify disease subtype-associated signatures, we examined serum proteins in patients without anti-CD20 B-cell depletion (NoBCD). We then assessed the effect of BCD treatment within each subtype by comparing proteins between BCD-treated and NoBCD-treated patients.
RESULTS
In NoBCD-treated patients, serum profiles distinguished the 3 diseases. AQP4-NMOSD showed elevated type I interferon-induced chemokines (CXCL9 and CXCL10) and TFH chemokine (CXCL13). MOGAD exhibited increased cytotoxic T-cell proteases (granzyme B and granzyme H), while SN-NMOSD displayed elevated Wnt inhibitory factor 1, a marker for nerve injury. Across all subtypes, BCD-treated patients showed reduction of B-cell-associated proteins. In AQP4-NMOSD, BCD led to a decrease in several inflammatory pathways, including IL-17 signaling, cytokine storm, and macrophage activation. By contrast, BCD elevated these pathways in patients with MOGAD. BCD had no effect on these pathways in SN-NMOSD.
DISCUSSION
Proteomic profiles show unique biological pathways that distinguish AQP4-NMOSD, MOGAD, or SN-NMOSD. Furthermore, BCD uniquely affects inflammatory pathways in each disease type, providing an explanation for the disparate therapeutic response in AQP4-NMOSD and MOGAD.
Topics: Humans; Neuromyelitis Optica; Myelin-Oligodendrocyte Glycoprotein; Female; Middle Aged; Male; Adult; Retrospective Studies; Proteomics; B-Lymphocytes; Aquaporin 4; Autoantibodies; Aged
PubMed: 38885457
DOI: 10.1212/NXI.0000000000200268 -
SAGE Open Medical Case Reports 2024FLAMES, or fluid-attenuated inversion recovery-hyperintense lesions in anti-myelin oligodendrocyte glycoprotein (anti-myelin oligodendrocyte glycoprotein)-associated...
A burning encephalitis: Fluid-attenuated inversion recovery-hyperintense lesions in Anti-myelin oligodendrocyte glycoprotein-associated encephalitis with seizures in anti-myelin oligodendrocyte glycoprotein-associated encephalitis with seizures-A case report and review of the literature.
FLAMES, or fluid-attenuated inversion recovery-hyperintense lesions in anti-myelin oligodendrocyte glycoprotein (anti-myelin oligodendrocyte glycoprotein)-associated encephalitis with seizures, represents a rarely documented syndrome characterized by ambiguous features. Positioned within the spectrum of inflammatory demyelinating diseases of the central nervous system, it is regarded as a distinct subset of myelin oligodendrocyte glycoprotein antibody-associated disease, the latest classification in this domain. Myelin oligodendrocyte glycoprotein antibody-associated disease exhibits a diverse clinical spectrum, spanning from solitary optic neuritis or myelitis to multifocal central nervous system demyelination, manifesting as acute disseminated encephalomyelitis, or cortical encephalitis accompanied by seizures, delineating the fluid-attenuated inversion recovery-hyperintense lesions in anti-myelin oligodendrocyte glycoprotein-associated encephalitis with seizures syndrome. We present a compelling case study of a 30-year-old individual with a history of recurrent seizures initially diagnosed with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. However, the disease's progression more closely resembled self-resolving cerebral cortical encephalitis linked with myelin oligodendrocyte glycoprotein antibodies. In addition, we undertake a systematic review of literature cases to explore the diagnostic significance of magnetic resonance angiography, fluid-attenuated inversion recovery, and specialized markers such as diffusion-weighted imaging and perfusion in discerning fluid-attenuated inversion recovery-hyperintense lesions in anti-myelin oligodendrocyte glycoprotein-associated encephalitis with seizures syndrome and elucidating its distinctive characteristics.
PubMed: 38881971
DOI: 10.1177/2050313X241261021 -
ImmunoTargets and Therapy 2024Cytokines act a vital role in autoimmune neuroinflammatory diseases (ANDs) with undetermined causal relationships. Mendelian randomization (MR) analysis was performed to...
BACKGROUND
Cytokines act a vital role in autoimmune neuroinflammatory diseases (ANDs) with undetermined causal relationships. Mendelian randomization (MR) analysis was performed to estimate the causal effects of circulating levels of cytokines on the risk of ANDs.
METHODS
The causal relationship between 34 circulating cytokines and 4 kinds of ANDs, including multiple sclerosis (MS), neuromyelitis optica (NOM), chronic inflammatory demyelinating polyneuropathy (CIDP) and myasthenia gravis (MG) were explored using four methods of MR analysis. MR-PRESSO, MR-Egger regression methods and Cochran's Q statistic were utilized to identify the instrumental variables (IVs) with potential pleiotropy and heterogeneity. The Bonferroni correction was used for multiple group comparisons. -value less than 3.68E-04 (0.05/ (34*4)) was considered statistically significant.
RESULTS
Negative causal effects of circulating levels of interleukin (IL)-8 (OR = 0.648, 95% CI: 0.494-0.851, = 0.002) on risk of MS, chemokine (C-C Motif) ligand (CCL)-5 (OR = 0.295, 95% CI: 0.103-0.841, = 0.022) and stem cell growth factor-beta (SCGF-β) (OR = 0.745, 95% CI: 0.565-0.984, = 0.038) on risk of CIDP, as well as positive causal effects of circulating levels of IL-2 receptor α (IL-2Rα) (OR = 1.216, 95% CI: 1.120-1.320, = 3.20E-06) and chemokine C-X-C motif ligand (CXCL)-10 (OR = 1.404, 95% CI: 1.094-1.803, = 0.008) on MS were observed. Nevertheless, only IL-2Rα still had a causal effect on MS after Bonferroni correction.
CONCLUSION
The results identify a genetically predicted causal effect of IL-2Rα, IL-8 and CXCL-10 on MS, CCL-5 and SCGF-β on CIDP.
PubMed: 38881648
DOI: 10.2147/ITT.S456326 -
Biochemistry. Biokhimiia May 2024Multiple sclerosis (MS) is a complex autoimmune disease of central nervous system (CNS) characterized by the myelin sheath destruction and compromised nerve signal...
Multiple sclerosis (MS) is a complex autoimmune disease of central nervous system (CNS) characterized by the myelin sheath destruction and compromised nerve signal transmission. Understanding molecular mechanisms driving MS development is critical due to its early onset, chronic course, and therapeutic approaches based only on symptomatic treatment. Cytokines are known to play a pivotal role in the MS pathogenesis with interleukin-6 (IL-6) being one of the key mediators. This study investigates contribution of IL-6 produced by microglia and dendritic cells to the development of experimental autoimmune encephalomyelitis (EAE), a widely used mouse model of MS. Mice with conditional inactivation of IL-6 in the CXCR1 cells, including microglia, or CD11c dendritic cells, displayed less severe symptoms as compared to their wild-type counterparts. Mice with microglial IL-6 deletion exhibited an elevated proportion of regulatory T cells and reduced percentage of pathogenic IFNγ-producing CD4+ T cells, accompanied by the decrease in pro-inflammatory monocytes in the CNS at the peak of EAE. At the same time, deletion of IL-6 from microglia resulted in the increase of CCR6 T cells and GM-CSF-producing T cells. Conversely, mice with IL-6 deficiency in the dendritic cells showed not only the previously described increase in the proportion of regulatory T cells and decrease in the proportion of T17 cells, but also reduction in the production of GM-CSF and IFNγ in the secondary lymphoid organs. In summary, IL-6 functions during EAE depend on both the source and localization of immune response: the microglial IL-6 exerts both pathogenic and protective functions specifically in the CNS, whereas the dendritic cell-derived IL-6, in addition to being critically involved in the balance of regulatory T cells and T17 cells, may stimulate production of cytokines associated with pathogenic functions of T cells.
Topics: Animals; Dendritic Cells; Mice; Interleukin-6; Multiple Sclerosis; Microglia; Encephalomyelitis, Autoimmune, Experimental; Disease Models, Animal; Mice, Inbred C57BL; CX3C Chemokine Receptor 1; T-Lymphocytes, Regulatory; Receptors, CCR6; Female
PubMed: 38880650
DOI: 10.1134/S0006297924050109 -
EBioMedicine Jun 2024
Topics: Humans; Multiple Sclerosis; Neurofilament Proteins; Biomarkers
PubMed: 38880550
DOI: 10.1016/j.ebiom.2024.105214