Elevated blood and cerebrospinal fluid biomarkers of microglial activation and blood‒brain barrier disruption in anti-NMDA receptor encephalitis.

BACKGROUND: Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disease characterized by complex neuropsychiatric syndrome and cerebrospinal fluid (CSF) NMDAR antibodies. Triggering receptor expressed on myeloid cells 2 (TREM2) has been reported to be associated with inflammation of the central nervous system (CNS). Matrix metalloproteinase-9 (MMP9) and cluster of differentiation (CD44) were measured to evaluate blood‒brain barrier (BBB) permeability in anti-NMDAR encephalitis. The roles of microglial activation and BBB disruption in anti-NMDAR encephalitis are not well known. FINDINGS: In this work, we detected increased expression levels of CSF sTREM2, CSF and serum CD44, and serum MMP9 in anti-NMDAR encephalitis patients compared with controls. CSF sTREM2 levels were positively related to both CSF CD44 levels (r = 0.702, p < 0.0001) and serum MMP9 levels (r = 0.428, p = 0.021). In addition, CSF sTREM2 levels were related to clinical parameters (modified Rankin Scale scores, r = 0.422, p = 0.023, and Glasgow Coma Scale scores, r = - 0.401, p = 0.031). CONCLUSION: Increased sTREM2 levels in CSF as well as increased CD44 and MMP9 in serum and CSF reflected activation of microglia and disruption of the BBB in anti-NMDAR encephalitis, expanding the understanding of neuroinflammation in this disease. The factors mentioned above may have potential as novel targets for intervention or novel diagnostic biomarkers.

Plasma Reference Ranges for Brain Injury Biomarkers (NfL, NfH, MCP-1, and MMP-9) in Healthy Chinese.

BACKGROUND: Brain injury triggers neuroaxonal injury and neural death, that leads to the development of secondary sequelae. Throughout this process, brain injury factors released into circulation via the injured neurovascular unit are important prognostic parameters. Plasma NfL, NfH, MCP-1, and MMP-9 have been identified as potential indicators in this regard. METHODS: Using a microfluidic ELISA platform, we measured plasma from 273 healthy subjects that underwent quantifications of NfL, NfH, MCP-1, and MMP-9 levels. We investigated the possible associations between biomarkers and basic demographics. RESULTS: The median concentration of plasma NfL was 10.40 (IQR = 6.73 - 16.60) pg/mL, NfH was 70.70 (IQR = 39.75 - 125.50) pg/mL, MCP-1 was 191.0 (IQR = 162.0 - 237.5) pg/mL, and MMP-9 was 169,255 (IQR = 107,657 - 231,276) pg/mL. Among all four biomarkers, plasma NfL and NfH levels were positively correlated with age (r = 0.557, p < 0.001, r = 0.364, p = 0.003). NfL was also correlated with NfH (r = 0.391, p = 0.002). CONCLUSIONS: These data provide a basis for the potential application of a brain-injury biomarker panel in routine clinical practice. It lays a significant foundation in supporting circulating CNS-biomarkers as noninvasive biomarkers for neurological disorders.

Glucocorticoid receptor mutations and clinical sensitivity to glucocorticoid in Chinese multiple sclerosis patients.

BACKGROUND: Glucocorticoid (GC) is the first-line therapy in acute attacks of multiple sclerosis (MS), but its efficacy is individually variable and may be associated with glucocorticoid receptor (GR) gene. OBJECTIVE: To establish the association between GR gene sequence and clinical GC sensitivity in Chinese MS patients. And to investigate the expression differences of serum GRα and FK506 binding protein 5 (FKBP5) in GC responders and non-responders. MATERIALS AND METHODS: Coding exons 2-9 of the GR gene from 97 MS patients were sequenced. We performed ELISA to detect serum GRα and FKBP5 before the GC impulse therapy in patients with different GC sensitivities (according to the EDSS changes before and after the GC medication). RESULTS: Seven new mutations were located in exon 2, but the presence or absence of mutations was not associated with the response to GC therapy (P = 0.416). The GC-sensitive patients had higher GRα (P = 0.011) but lower FKBP5 (P = 0.025) levels in the serum. CONCLUSIONS: The GR mutations detected in our study were not associated with the response to GC in Chinese MS patients. Higher GRα and lower FKBP5 levels in the serum might predict the response to GC, which may provide potential therapeutic target for GC-resistant patients with acute MS attack.

Cytokines and Tissue Damage Biomarkers in First-Onset Neuromyelitis Optica Spectrum Disorders: Significance of Interleukin-6.

OBJECTIVE: We investigated the contribution of several cytokines in the pathogenesis of first-onset neuromyelitis optica spectrum disorder (NMOSD) and determined the differences between aquaporin 4 immunoglobulin G (AQP4-IgG)-positive and AQP4-IgG-negative subtypes. METHODS: We enrolled 18 NMOSD (10 AQP4-IgG-positive and 8 AQP4-IgG-negative) and 8 multiple sclerosis (MS) patients, whose serum and cerebrospinal fluid (CSF) samples were collected during the acute phase of the first onset before immunotherapy. Fifteen patients with other noninflammatory neurological diseases (OND) were also included. The serum and CSF levels of interleukin (IL)-6, IL-10, IL-17, IL-21, IL-23, transforming growth factor (TGF)-ß1 and the CSF levels of 3 biomarkers of axonal loss and astrocytic damage were measured using the human cytokine multiplex assay or ELISA. RESULTS: Serum levels of IL-10 and TGF-ß1 and CSF levels of IL-6, IL-10, and TGF-ß1 were significantly increased in first-onset NMOSD compared to in OND patients. In a subgroup analysis, the CSF levels of IL-6, neurofilament light protein (NFL), S100B, and glial fibrillary acidic protein (GFAP) were significantly more elevated in the AQP4-IgG-positive patients than in the AQP4-IgG-negative NMOSD patients. Correlations were found between the CSF cytokines and tissue damage biomarkers and the clinical findings in NMOSD patients. Notably, the CSF IL-6 level had the strongest correlation with the tissue damage biomarkers and it also correlated with CSF white blood cell (WBC) count. CONCLUSIONS: IL-6 plays a role in the pathogenetic process of NMOSD, especially in the AQP4-IgG-positive subtype. Distinct pathogenesis exists between AQP4-IgG-positive and AQP4-IgG-negative NMOSD in the initial phase of the disease.

Unveiling the influence of circulating immune cells count on type 1 diabetes: Insight from bidirectional Mendelian randomization.

Observational studies have demonstrated an association between circulating immune cell and type 1 diabetes (T1D) risk. However, it is unknown whether this relationship is causal. Herein, we adopted a 2-sample bidirectional Mendelian randomization study to figure out whether circulating immune cell profiles causally impact T1D liability. Summary statistical data were obtained from genome-wide association study (GWAS) to investigate the causal relationship between white cell (WBC) count, 5 specific WBC count, and lymphocyte subtypes cell count and T1D risk. After false discovery rate (FDR) correction, the results indicated that lower lymphocyte cell count (odds ratio [OR] per 1 standard deviation [SD] decrease = 0.746, 95% confidence interval (CI): 0.673-0.828, PFDR = 0.036), and basophil cell count (OR per 1 SD decrease = 0.808, 95% CI: 0.700-0.932, PFDR = 0.010) were causally associated with T1D susceptibility. However, the absolute count of WBC, monocyte, neutrophil, eosinophil, and lymphocyte subtypes cell had no statistically significant effect on T1D risk. Taken together, this study indicates suggestive association between circulating immune cell count and T1D. Moreover, lower numbers of circulating lymphocyte and basophil cell were associated with the increased risk of T1D, which confirmed the immunity predisposition for T1D.

Decreased serum tryptophan levels in patients with MOGAD:a cross-sectional survey.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an inflammatory demyelinating disorder of central nervous system (CNS). Tryptophan indole catabolites have been reported to associate with the inflammatory diseases of the CNS. However, the roles of tryptophan indole catabolites have been rarely elucidated in MOGAD. METHODS: This cross-sectional study enrolled forty MOGAD patients, twenty patients with other non-inflammatory neurological diseases (OND) and thirty-five healthy participants. Serum and cerebrospinal fluid (CSF) samples of MOGAD and OND subjects during clinical attacks, serum samples of healthy participants were obtained. The concentrations of tryptophan, indoleacetic acid (IAA), indoleacrylic acid (IA) and indole-3-carboxylic acid (I-3-CA) were measured using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The correlations between tryptophan indole catabolites and maintenance immunotherapy, disease duration, overall numbers of attacks, short-term outcome in MOGAD patients were investigated. RESULTS: Levels of serum tryptophan, IAA, IA and CSF tryptophan in MOGAD patients were significantly decreased, while levels of serum I-3-CA and CSF IA were markedly increased compared with OND patients and healthy controls. Levels of serum tryptophan, CSF tryptophan and IA were significantly decreased in MOGAD patients who had received maintenance immunotherapy within 6 months before the attack. In MOGAD patients, serum and CSF tryptophan conversely correlated with disease duration and overall numbers of attacks, and serum IA negatively correlated with disease duration. Furthermore, serum tryptophan in MOGAD patients negatively correlated with the modified Rankin Scale (mRS) scores at 3 months. CONCLUSION: This study manifested decreased serum tryptophan levels and serum tryptophan may be the potential marker to predict the short-term outcome in MOGAD patients.

Extracellular vesicles bearing serum amyloid A1 exacerbate neuroinflammation after intracerebral haemorrhage.

INTRODUCTION: Intracerebral haemorrhage (ICH) elicits a robust inflammatory response, which significantly contributes to secondary brain damage. Extracellular vesicles (EVs) play a pivotal role in intercellular communication by transporting immune-regulatory proteins. However, the precise contribution of these EV-carried proteins to neuroinflammation following ICH remains elusive. Here, we identified proteins dysregulated in EVs and further studied the EVs-enriched Serum amyloid A 1 (SAA1) to understand its role in neuroinflammation and ICH injury. METHODS: We used mass spectrometry to analyse the EV protein cargo isolated from plasma samples of 30 ICH patients and 30 healthy controls. To validate the function of the dysregulated protein SAA1, an ICH mouse model was conducted to assess the effects of SAA1 neutralisation on brain oedema, neurological function and infiltration of peripheral leucocytes. RESULTS: 49 upregulated proteins and 12 downregulated proteins were observed in EVs from ICH patients compared with controls. Notably, SAA1 demonstrated a significant increase in EVs associated with ICH. We observed that exogenous SAA1 stimulation led to an augmentation in the population of microglia and astrocytes, exacerbating neuroinflammation. Neutralising SAA1 with an anti-SAA1 monoclonal antibody (mAb) diminished the prevalence of proinflammatory microglia and the infiltration of peripheral leucocytes, which ameliorates brain oedema and neurological function in ICH mice. CONCLUSION: Our findings provide compelling evidence implicating EVs and their cargo proteins in ICH pathogenesis. SAA1 emerges as a potential therapeutic target for mitigating neuroinjury and neuroinflammation following ICH.

Profile and potential role of novel metabolite biomarkers, especially indoleacrylic acid, in pathogenesis of neuromyelitis optica spectrum disorders.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune central nervous system (CNS) inflammatory and demyelinating disorder that can lead to serious disability and mortality. Humoral fluid biomarkers with specific, convenient, and efficient profiles that could characterize and monitor disease activity or severity are very useful. We aimed to develop a sensitive and high-throughput liquid chromatography-tandem mass spectrometry (LC-MS)/MS-based analytical method for novel biomarkers finding in NMOSD patients and verified its function tentatively. Methods: Serum samples were collected from 47 NMOSD patients, 18 patients with other neurological disorders (ONDs), and 35 healthy controls (HC). Cerebrospinal fluid (CSF) samples were collected from 18 NMOSD and 17 OND patients. Three aromatic amino acids (phenylalanine, tyrosine, and tryptophan) and nine important metabolites that included phenylacetylglutamine (PAGln), indoleacrylic acid (IA), 3-indole acetic acid (IAA), 5-hydroxyindoleacetic acid (HIAA), hippuric acid (HA), I-3-carboxylic acid (I-3-CA), kynurenine (KYN), kynurenic acid (KYNA), and quinine (QUIN) were analyzed by using the liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based method. The profile of IA was further analyzed, and its function was verified in an astrocyte injury model stimulated by NMO-IgG, which represents important events in NMOSD pathogenesis. Results: In the serum, tyrosine and some of the tryptophan metabolites IA and I-3-CA decreased, and HIAA increased significantly in NMOSD patients. The CSF levels of phenylalanine and tyrosine showed a significant increase exactly during the relapse stage, and IA in the CSF was also increased markedly during the relapse and remission phases. All conversion ratios had similar profiles with their level fluctuations. In addition, the serum IA levels negatively correlated with glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) levels in the serum of NMOSD patients were measured by using ultra-sensitive single-molecule arrays (Simoa). IA showed an anti-inflammatory effect in an in vitro astrocyte injury model. Conclusion: Our data suggest that essential aromatic amino acid tryptophan metabolites IA in the serum or CSF may serve as a novel promising biomarker to monitor and predict the activity and severity of NMOSD disease. Supplying or enhancing IA function can promote anti-inflammatory responses and may have therapeutic benefits.

Targeting chemoattractant chemokine (C-C motif) ligand 2 derived from astrocytes is a promising therapeutic approach in the treatment of neuromyelitis optica spectrum disorders.

Introduction: Aquaporin-4 immunoglobulin G (AQP4-IgG)-induced astrocytes injury is a key mechanism in the pathogenesis of neuromyelitis spectrum disorder (NMOSD), and although CCL2 is involved, its specific role has not been reported. We aimed to further investigate the role and potential mechanisms of CCL2 in AQP4-IgG-induced astrocyte injury. Methods: First, we evaluated CCL2 levels in paired samples of subject patients by automated microfluidic platform, Ella®. Second, we knock down astrocyte's CCL2 gene in vitro and in vivo to define the function of CCL2 in AQP4-IgG-induced astrocyte injury. Third, astrocyte injury and brain injury in live mice were assessed by immunofluorescence staining and 7.0T MRI, respectively. Western blotting and high-content screening were conducted to clarify the activation of inflammatory signaling pathways, and changes in CCL2 mRNA and cytokine/chemokines were measured by qPCR technique and flow cytometry, respectively. Results: There were greatly higher CSF-CCL2 levels in NMOSD patients than that in other non-inflammatory neurological diseases (OND) groups. Blocking astrocyte CCL2 gene expression can efficiently mitigate AQP4-IgG-induced damage in vitro and in vivo. Interestingly, prevention of CCL2 expression could decrease other inflammatory cytokines released, including IL-6 and IL-1ß. Our data suggest that CCL2 involves in the initiation and plays a pivotal role in AQP4-IgG-damaged astrocytes. Discussion: Our results indicate that CCL2 may serve as a promising candidate target for inflammatory disorder therapy, including NMOSD.

Pan-Cancer analysis shows that ACO2 is a potential prognostic and immunotherapeutic biomarker for multiple cancer types including hepatocellular carcinoma.

Background: Recent evidence increasingly suggests key roles for the tricarboxylic acid cycle and fatty acid metabolism in tumor progression and metastasis. Aconitase 2 (ACO2) is a component of the tricarboxylic acid cycle and represents a key cellular metabolic hub that promotes de novo fatty acid biosynthesis. However, there have been few reports on the role of ACO2 in tumorigenesis and cancer progression. Methods: Through the comprehensive use of datasets from The Cancer Genome Atlas, Genotype-Tissue Expression Project, cBioPortal, Human Protein Atlas, UALCAN, Gene Expression Profiling Interactive Analysis, DNA Methylation Interactive Visualization Database, and TIMER2, we adopted bioinformatics methods to uncover the potential carcinogenic roles of ACO2, including by analysing ACO2 expression and correlations between prognosis, genetic mutations, immune cell infiltration, DNA methylation, tumor mutational burden, and microsatellite instability in different tumors. Additionally, the expression level and tumor-promoting effect of ACO2 were verified in hepatocellular carcinoma (HCC) cells. To explore the underlying mechanisms of ACO2 in human cancer, ACO2-related gene enrichment analysis and lipid metabolomics were performed using LM3 cells with or without ACO2 knockdown. Results: The results indicated that ACO2 was highly expressed in most cancers, showing early diagnostic value in six tumor types, and was positively or negatively associated with prognosis in different tumors. Moreover, ACO2 expression was associated with immune cell infiltration, such as CD8+ T cells and tumor-associated neutrophils, in some cancers. For most cancer types, there was a significant association between immune checkpoint-associated genes and ACO2 expression. Compared with normal hepatocytes, ACO2 was upregulated in HCC cells, which promoted their proliferation and migration. Furthermore, to explore the underlying molecular mechanism, we performed KEGG pathway enrichment analysis of ACO2-associated genes and lipidomics using LM3 cells with or without ACO2 knockdown, which screened 19 significantly altered metabolites, including 17 with reduced levels and 2 with increased levels. Conclusion: Through pan-cancer analysis, we discovered for the first time and verified that ACO2 could be a useful diagnostic biomarker for cancer detection. Additionally, ACO2 could be used as an auxiliary prognostic marker or as a marker for immunotherapy in some tumor types.

High levels of cerebrospinal fluid soluble triggering receptor expressed on myeloid cells 2 might be a biomarker of activity in pediatric patients with MOG-AD.

Myelin oligodendrocyte glycoprotein antibody disease (MOG-AD) is characterized by its monophasic or relapsing course and inflammatory demyelinating condition which is unable to be classified in typical multiple sclerosis (MS) or other known neuroinflammatory conditions. In the condition of neuroinflammatory, activated microglia are essential for demyelination. The secreted ectodomain of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), expressed by microglial cells, is associated with abnormal biological pathways. It is known that the cerebrospinal fluid (CSF) sTREM2 concentration is much higher in neuroinflammatory and neurodegeneration diseases. However, the role of activated microglia has not been reported in MOG-AD pediatric patients. For the first time, the increased CSF and serum sTREM2 concentration in pediatric patients with MOG-AD is investigated in this work, showing evidence of microglia activation in MOG-AD. CSF sTREM2 levels significantly correlated with clinical inflammatory indexes and adapted modified Rankin Scale score, indicating the potential value of sTREM2 as a severity biomarker.

NMO-IgG Induce Interleukin-6 Release via Activation of the NF-κB Signaling Pathway in Astrocytes.

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disorder of the central nervous system (CNS) that frequently affects the optic nerve and spinal cord. Interleukin-6 (IL-6) is considered a key cytokine in the pathogenesis of NMOSD, and the level of IL-6 is significantly increased in the sera and cerebrospinal fluid (CSF) of patients with NMOSD. We have reported that the production of IL-6 depends on the JAK/STAT3 signaling pathway. However, it is not clear whether the NF-κB-dependent inflammatory response stimulated by neuromyelitis optica IgG (NMO-IgG) could also drive the production of IL-6 in astrocytes. In this study, we used an in vitro model of primary rat astrocytes stimulated by NMO-IgG to study the role of the NF-κB signaling pathway in mediating the release of IL-6. First, we confirmed that the level of IL-6 was significantly higher in the sera of NMOSD patients than that of healthy people by humoral fluid analysis and that NMO-IgG can significantly induce the release of IL-6 from astrocytes by enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Then, Western blotting and immunocytochemistry showed that NMO-IgG can activate the intracellular NF-κB signaling pathway. Finally, it was found that S3633, an inhibitor of the NF-κB signaling pathway, can effectively inhibit the increase in IL-6 levels. These results prove that the production of IL-6 is partly mediated by the NF-κB signaling pathway, providing a potential effective strategy for targeted treatment of NMOSD.

Ginsenoside Rg3 nanoparticles with permeation enhancing based chitosan derivatives were encapsulated with doxorubicin by thermosensitive hydrogel and anti-cancer evaluation of peritumoral hydrogel injection combined with PD-L1 antibody.

BACKGROUND: Combination of chemotherapy and immune checkpoint inhibitor therapy has greatly improved the anticancer effect on multiple malignancies. However, the efficiency on triple-negative breast cancer (TNBC) is limited, since most patients bear "cold" tumors with low tumor immunogenicity. Doxorubicin (DOX), one of the most effective chemotherapy agents, can induce immunogenic cell death (ICD) and thus initiating immune response. METHODS: In this study, to maximize the ICD effect induced by DOX, chitosan and cell-penetrating peptide (R6F3)-modified nanoparticles (PNPs) loaded with ginsenoside Rg3 (Rg3) were fabricated using the self-assembly technique, followed by co-encapsulation with DOX based on thermo-sensitive hydrogel. Orthotopic tumor model and contralateral tumor model were established to observe the antitumor efficacy of the thermo-sensitive hydrogel combined with anti-PD-L1 immunotherapy, besides, the biocompatibility was also evaluated by histopathological. RESULTS: Rg3-PNPs strengthened the immunogenic cell death (ICD) effect induced by DOX. Moreover, the hydrogel co-loading Rg3-PNPs and DOX provoked stronger immune response in originally nonimmunogenic 4T1 tumors than DOX monotherapy. Following combination with PD-L1 blocking, substantial antitumor effect was achieved due to the recruitment of memory T cells and the decline of adaptive PD-L1 enrichment. CONCLUSION: The hydrogel encapsulating DOX and highly permeable Rg3-PNPs provided an efficient strategy for remodeling immunosuppressive tumor microenvironment and converting immune "cold" 4T1 into "hot" tumors.

Soluble TREM2 is a potential biomarker for the severity of primary angiitis of the CNS.

Background: Primary angiitis of the central nervous system (PACNS) is a severe inflammatory disease, and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) has been reported to be associated with inflammation of the CNS. However, the role of sTREM2 in PACNS remains unknown. Methods: We obtained serum and cerebrospinal fluid (CSF) samples from 18 patients diagnosed with PACNS, as well as 14 patients diagnosed with other neurological disorders with no evidence of inflammation. sTREM2 concentrations in the samples were detected by enzyme-linked immunosorbent assay. And routine CSF measurements of PACNS patients were analysed, including number of White Blood Cells (WBC), protein, Immunoglobulin G (IgG) index and CSF/serum quotients. Levels of inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-6, IL-8, IL-1ß, and complement C4, also were tested. The modified Rankin scale (mRS), National Institutes of Health Stroke Scale (NIHSS), and activities of daily living (ADL) scores were obtained as indicators of disease severity. In PACNS patients, cerebral lesion volume was evaluated by magnetic resonance imaging. Results: sTREM2 levels in serum and CSF were significantly elevated in PACNS patients and significantly associated with the mRS, NIHSS and ADL scores as well as inflammatory cytokine levels. Additionally, positive correlations were observed between the cerebral lesion volume and the sTREM2 levels in both blood and CSF. Higher sTREM2 levels in either the blood or CSF seemed to predict a good prognosis in PACNS patients. Conclusion: Our results indicate an association between serum and CSF sTREM2 levels and the severity of neurological damage. Thus, sTREM2 represents a potential biomarker for monitoring disease and potentially predicting the prognosis of PACNS patients.

Efficacy of rituximab in the treatment of neuromyelitis optica spectrum disorders: An update systematic review and meta -analysis.

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) is an autoimmune astrocyte disease that mainly affects the optic nerve and spinal cord resulting in blindness or paralysis. Rituximab (RTX) is a chimeric monoclonal antibody directed against the surface antigen of CD20 on B lymphocytes and is an emerging treatment option in NMOSD. The present review aimed to conduct an update systematic review and meta-analysis for the efficacy of RTX in the treatment of NMOSD and analyze main factors affecting the efficacy of RTX. METHODS: The following Medical Subject Heading (MeSH) and related entry terms are used to search English literature in PubMed, MEDLINE and CENTRAL databases, respectively. MeSH include: Neuromyelitis optic and Rituximab; entry terms include: NMO Spectrum Disorder, NMO Spectrum Disorders, Neuromyelitis Optica (NMO) Spectrum Disorder, Neuromyelitis Optica Spectrum Disorders, Devic Neuromyelitis Optica, Neuromyelitis Optica, Devic, Devic's Disease, Devic Syndrome, Devic's Neuromyelitis Optica, Neuromyelitis Optica (NMO) Spectrum Disorders, CD20 Antibody, Rituximab CD20 Antibody, Mabthera, IDEC-C2B8 Antibody, GP2013, Rituxan; (note: literature retrieval operators "AND" "OR" "NOT" are used to link MeSH with Entry Terms.) 54 studies were included in this systematic review and 29 studies were included in meta-analysis. The main efficacy indicators were the difference of the expanded disability status scale (EDSS) and annualized relapse rate (ARR) between before and after rituximab treatments. RESULTS: In 29 studies involving 732 patients (643 women, 84 men, 5 with unknown gender), the EDSS and ARR were reduced by an average of -0.57 (95%CI, -0.69 to -0.44), -1.57 (95%CI, -1.78 to -1.35), respectively. CONCLUSION: Our systematic review and update meta-analysis provide new evidences that RTX can effectively improve disability and reduce ARR ratio.

Efficacy of mycophenolate mofetil in the treatment of neuromyelitis optica spectrum disorders: An update systematic review and meta -analysis.

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) is an autoimmune astrocyte disease that mainly affects the optic nerve and spinal cord resulting in blindness or paralysis. Mycophenolate mofetil (MMF) is one of the available immunotherapies with purported beneficial effects for patients with NMOSD. The present review aimed to conduct an update systematic review and meta-analysis for the efficacy of mycophenolate mofetil in the treatment of NMOSD and analyze main factors affecting the efficacy of mycophenolate mofetil. METHODS: The following Medical Subject Heading (MeSH) and related entry terms are used to search English literature in PubMed, MEDLINE and CENTRAL databases, respectively. MeSH include: Neuromyelitis optic and Mycophenolic Acid; entry terms include: NMO Spectrum Disorder, NMO Spectrum Disorders, Neuromyelitis Optica (NMO) Spectrum Disorder, Neuromyelitis Optica Spectrum Disorders, Devic Neuromyelitis Optica, Neuromyelitis Optica, Devic, Devic's Disease, Devic Syndrome, Devic's Neuromyelitis Optica, Neuromyelitis Optica (NMO) Spectrum Disorders, Mycophenolate Mofetil, Mofetil, Mycophenolate, Mycophenolic Acid Morpholinoethyl Ester, Cellcept, Mycophenolate Sodium, Myfortic, Mycophenolate Mofetil Hydrochloride, Mofetil Hydrochloride, Mycophenolate, RS 61,443, RS-61,443, RS61443; (note: literature retrieval operators "AND" "OR" "NOT" are used to link MeSH with Entry Terms.) 30 studies were included in this systematic review and 14 studies were included in meta-analysis. The main efficacy indicators were the difference of the annualized relapse rate (ARR) between before and after mycophenolate mofetil treatments. RESULTS: In 14 studies involving 930 patients (815 women, 115 men), the ARR were reduced by an average of -1.17 (95%CI, -1.28 to -1.07). CONCLUSION: Our systematic review and update meta-analysis provide new evidences that mycophenolate mofetil can substantially reduce ARR ratio.

Elevated chemokines and cytokines for eosinophils in neuromyelitis optica spectrum disorders.

BACKGROUND: Eosinophil infiltration is one of the distinctive features in neuromyelitis optica spectrum disorders (NMOSD) but not in other demyelinating diseases including multiple sclerosis (MS). Eosinophils express the chemokine receptor CCR3, which is activated by eotaxins (eotaxin-1, -2, and -3) and monocyte chemoattractant protein (MCP)-4. We aimed to investigate the role of MCPs (MCP-1, -2, -3, and -4) and eotaxins in the acute phase of NMOSD. METHODS: Levels of serum and cerebrospinal fluid (CSF) eotaxins, MCPs, interleukin (IL)-5, tumor necrosis factor (TNF)-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-6 were measured using the cytokine multiplex assay from 26 patients with NMOSD (13 with immunotherapy, 13 without immunotherapy), 9 patients with MS, and 9 patients with other noninflammatory neurological diseases (OND). Glial fibrillary acidic protein was assessed using ELISA. RESULTS: Serum MCP-1 and CSF MCP-2 levels were significantly higher in patients with NMOSD than in OND. Moreover, serum MCP-4 and CSF eotaxin-2 and -3 levels were significantly higher in NMOSD patients compared to MS and OND. Serum MCP-1, -4 and CSF eotaxin-2, -3 levels were significantly correlated with the Expanded Disability Status Scale in NMOSD. TNF-α and GM-CSF, which stimulate the above chemokines, were higher in patients with NMOSD than those in OND. Moreover, serum MCP-1 and -4 were significantly increased by IL-5 and GM-CSF stimulation, but not by TNF-α and IL-6. Only CSF eotaxin-2 was significantly increased by GM-CSF. There were no significant differences in serum MCP-1 and -4 levels between NMOSD patients with and without immunotherapy. CONCLUSION: These findings suggest that the elevated serum MCP-1, -4 and CSF eotaxin-2, -3 may be a key step in eosinophil recruitment in the acute phase of NMOSD.

Icariin ameliorates the cuprizone-induced acute brain demyelination and modulates the number of oligodendrocytes, microglia and astrocytes in the brain of C57BL/6J mice.

This study aimed at testing the hypothesis that treatment with icariin (ICA, a type of flavonoid) could mitigate the cuprizone (CPZ)-induced acute demyelination in the brain of mice and the potential mechanisms. Female C57BL/6J mice were fed continually with regular rodent chow or the chow supplemented with CPZ (0.2 % w/w) for six weeks to induce acute demyelination. The CPZ-fed mice were treated with vehicle or ICA at 12.5 or 25 mg/kg beginning at three weeks post CPZ feeding daily for three weeks. Their brain tissue sections were stained with oil red O, luxol-fast blue (LFB) and immunohistochemistry to characterize the levels of brain demyelination, myelin basic protein (MBP) and brain-derived neurotrophic factor (BDNF) and the numbers of oligodendrocytes (Ols), oligodendrocyte progenitor cells (OPCs), microglia and astrocytes in mice. Compared with the healthy controls, CPZ feeding caused the brain demyelination by increasing NG2+ OPCs, but decreased oil red O and LFB staining, MBP level and GST-pi+ Ols in the brain corpus callosum region of mice. Furthermore, CPZ feeding decreased the number of BDNF+ cells in the brain cortex and hippocampus regions, but increased microglia in the brain corpus callosum, cortex and caudate putamen, and astrocytes in the corpus callosum regions of mice. Treatment with ICA significantly mitigated or abrogated the toxic demyelination of CPZ by preserving MBP and BDNF proteins and modulating the numbers of Ols, OPCs, microglia and astrocytes in the brain of mice. ICA treatment significantly ameliorated the CPZ-mediated demyelination and modulated the number of Ols, microglia and astrocytes in the brain of mice.

Thymic Involution and Altered Naive CD4 T Cell Homeostasis in Neuromyelitis Optica Spectrum Disorder.

Circulating T helper cells with a type 17-polarized phenotype (TH17) and expansion of aquaporin-4 (AQP4)-specific T cells are frequently observed in patients with neuromyelitis optica spectrum disorder (NMOSD). However, naive T cell populations, which give rise to T helper cells, and the primary site of T cell maturation, namely the thymus, have not been studied in these patients. Here, we report the alterations of naive CD4 T cell homeostasis and the changes in thymic characteristics in NMOSD patients. Flow cytometry was performed to investigate the naive CD4+ T cell subpopulations in 44 NMOSD patients and 21 healthy controls (HC). On immunological evaluation, NMOSD patients exhibited increased counts of CD31+thymic naive CD4+ T cells and CD31-cental naive CD4+ T cells along with significantly higher fraction and absolute counts of peripheral blood CD45RA+ CD62L+ naive CD4+ T cells. Chest computed tomography (CT) images of 60 NMOSD patients and 65 HCs were retrospectively reviewed to characterize the thymus in NMOSD. Thymus gland of NMOSD patients exhibited unique morphological characteristics with respect to size, shape, and density. NMOSD patients showed exacerbated age-dependent thymus involution than HC, which showed a significant association with disease duration. These findings broaden our understanding of the immunological mechanisms that drive severe disease in NMOSD.

Different roles of soluble CD40 ligand in central nervous system damage.

Backgroud and purpose: Soluble CD40 ligand (sCD40L) plays an important role in inflammation and autoimmune disorders. There is still a controversy regarding sCD40L in neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS). Herein the aims of this study were to evaluate the levels of sCD40L in patients with NMOSD, MS, and other noninflammatory neurological diseases; to investigate its potential relationship with laboratory parameters, glial fibrillary acidic protein (GFAP), thrombopoietin (TPO) and IL-6; and to address whether serum sCD40L levels in acute attacks of NMOSD patients were decreased after treatment with immunoglobulins, plasma exchange, or methylprednisolone.Materials and methods: We enrolled 13 patients with NMOSD, 9 patients with MS, and 9 patients with other noninflammatory neurological diseases. The levels of sCD40L, IL-6 were measured by cytokine multiplex assay. GFAP levels were measured by ELISA.Results: Both serum and cerebrospinal fluid (CSF) sCD40L levels were increased in NMOSD and MS. No differences were found in serum and CSF sCD40L levels between NMOSD and MS. The CSF sCD40L levels were positively correlated with the CSF cell counts in NMOSD, whereas serum sCD40L levels were positively correlated with the albumin index in MS. Furthermore, the levels of CSF sCD40L were positively correlated with CSF GFAP levels in NMOSD. Serum sCD40L levels were correlated with serum TPO levels in MS. No correlation was found between levels of sCD40L and IL-6 in NMOSD and MS. No statistically meaningful difference between NMOSD patients with or without immunotherapy. Conclusions: Our study suggests that sCD40L can contribute to the destruction of the blood-brain barrier in MS, whereas it may contribute to CNS inflammation in NMOSD. The serum sCD40L concentrations were not changed after treatment with immunoglobulins, plasma exchange, or methylprednisolone in acute attacks of NMOSD.