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Objective: Myelin oligodendrocyte glycoprotein-associated disorders (MOGADs) are a rare new neurological autoimmune disease with unclear pathogenesis. Since a linkage of the disease to the human leucocyte antigen (HLA) has not been shown, we here investigated whether MOGAD is associated with the HLA locus., Methods: HLA genotypes of 95 patients with MOGADs, assessed between 2016 and 2018 from three academic centres, were compared with 481 healthy Chinese Han individuals. Patients with MOGADs included 51 paediatric-onset and 44 adult-onset cases. All patients were seropositive for IgG targeting the myelin oligodendrocyte glycoprotein (MOG)., Results: Paediatric-onset MOGAD was associated with the DQB1*05:02-DRB1*16:02 alleles (OR=2.43; OR=3.28) or haplotype (OR=2.84) of HLA class II genes. The prevalence of these genotypes in patients with paediatric-onset MOGAD was significantly higher than healthy controls (p adj =0.0154; p adj =0.0221; p adj =0.0331). By contrast, adult-onset MOGAD was not associated with any HLA genotype. Clinically, patients with the DQB1*05:02-DRB1*16:02 haplotype exhibited significantly higher expanded disability status scale scores at onset (p=0.004) and were more likely to undergo a disease relapse (p=0.030). HLA-peptide binding prediction algorithms and computational docking analysis provided supporting evidence for the close relationship between the MOG peptide subunit and DQB1*05:02 allele. In vitro results indicated that site-specific mutations of the predicted target sequence reduced the antigen-antibody binding, especially in the paediatric-onset group with DQB1*05:02 allele., Conclusions: This study demonstrates a possible association between specific HLA class II alleles and paediatric-onset MOGAD, providing evidence for the conjecture that different aetiology and pathogenesis likely underlie paediatric-onset and adult-onset cases of MOGAD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Anti‐N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis is an autoimmune disease of the central nervous system. Gasdermin D (GSDMD) is associated with autoimmune disorders and neuroinflammatory disorders, but its role in anti‐NMDAR encephalitis is unclear. In this study, we measured serum levels of GSDMD in 42 patients with anti‐NMDAR encephalitis and 25 healthy controls. Of the 42 patients, 17 had follow‐up evaluation of GSDMD levels and modified Rankin scale (mRS) scores at 3 months. Association of GSDMD with anti‐NMDAR encephalitis and its clinical parameters were evaluated. Serum GSDMD levels were significantly higher in patients with anti‐NMDAR encephalitis than in healthy controls (p = 0.002, padjusted = 0.009), especially in males (p = 0.001, padjusted = 0.022). This was also evident in patients with severe impairment (mRS >3 vs mRS ≤3; p < 0.001). Serum GSDMD was associated with mRS before and after adjustment for age and gender (r = 0.440 and 0.430, p = 0.004 and 0.006, respectively) as well as serum CH50 (r = −0.419 and −0.426, p = 0.011 and 0.012, respectively). Furthermore, 3‐month follow‐up evaluation revealed that after treatment, anti‐NMDAR encephalitis patients had significantly decreased serum GSDMD levels (p = 0.007) and significantly decreased mRS scores (p = 0.002) compared with before treatment. Furthermore, the changes in mRS scores were negatively associated with changes in GSDMD levels, although the associations were not significant (r = −0.222, p = 0.393). Our findings show that serum GSDMD levels are elevated in anti‐NMDAR encephalitis and are associated with disease prognosis. [ABSTRACT FROM AUTHOR]

Recent clinical data have led to the consideration of sexual steroids as new potential therapeutic tools for multiple sclerosis. Selective estrogen receptor modulators can exhibit neuroprotective effects like estrogen, with fewer systemic estrogen side effects than estrogen, offering a more promising therapeutic modality for multiple sclerosis. The important role of astrocytes in a proinflammatory effect mediated by CCL20 signaling on inflammatory cells has been documented. Their potential contribution to selective estrogen receptor modulator-mediated protection is still unknown. Using a mouse model of chronic neuroinflammation, we report that raloxifene, a selective estrogen receptor modulator, alleviated experimental autoimmune encephalomyelitis–an animal model of multiple sclerosis–and decreased astrocytic production of CCL20. Enzyme-linked immunosorbent assay, immunohistochemistry imaging and transwell migration assays revealed that reactive astrocytes express CCL20, which promotes Th17 cell migration. In cultured rodent astrocytes, raloxifene inhibited IL-1β-induced CCL20 expression and chemotaxis ability for Th17 migration, whereas the estrogen receptor antagonist ICI 182,780 blocked this effect. Western blotting further indicated that raloxifene suppresses IL-1β-induced NF-κB activation (phosphorylation of p65) and translocation but does not affect phosphorylation of IκB. In conclusion, these data demonstrate that raloxifene provides robust neuroprotection against experimental autoimmune encephalomyelitis, partially via an inhibitory action on CCL20 expression and NF-κB pathways in reactive astrocytes. Our results contribute to a better understanding of the critical roles of raloxifene in treating experimental autoimmune encephalomyelitis and uncover reactive astrocytes as a new target for the inhibitory action of estrogen receptors on chemokine CCL20 expression. [ABSTRACT FROM AUTHOR]

Background: BAFF (B-cell activating factor of the tumor necrosis factor family) and APRIL (a proliferation-inducing ligand) are two of the major survival factors for B cells. Many studies have shown that BAFF levels were elevated in MS patients. However, whether the levels of CSF BAFF/APRIL increased in NMO patients was still unclear. Objective: To measure the CSF BAFF and APRIL concentration of in NMO patients, and explore their relationship with disease activity in NMO. Methods: CSF BAFF and APRIL was measured by an enzyme-linked immunosorbent assay (ELISA) in NMO ( n = 22), MS ( n = 18) patients and controls ( n = 14). Results: Concentration of BAFF and APRIL in NMO patients were significantly higher than MS and controls. CSF BAFF and APRIL levels in controls were also lower than MS. Both NMO and MS revealed an increased disease disability with increased CSF BAFF. CSF APRIL was associated with EDSS scores in NMO, but not found in MS. Conclusions: BAFF/APRIL system considered important for aggressive B cells and T-cell responses, and may stimulates B cells and T cell activation in acute relapse of NMO and MS. In NMO patients, CSF BAFF and APRIL may be key factors of B cell immune response and reflect disease severity. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2012) 122, 19-23. Abstract The concept that the immune system plays a central role in the pathogenesis of multiple sclerosis (MS) and neuromyelitis optica (NMO) was indisputable. However, neurodegenerative pathological features including loss of axons and neurons were also found in the lesions of these diseases. α-Synuclein is one of the most abundant proteins in pre-synaptic terminals. Recently, many research show α-synuclein level in CSF may reflect the progression of synaptic dysfunction and neuronal apoptosis. Whether the levels of CSF α-synuclein are changed in MS and NMO patients remain unknown. In this study, CSF α-synuclein was measured by an enzyme-linked immunosorbent assay (ELISA) in MS ( n = 18) patients, NMO ( n = 22) patients, Parkinson's disease patients ( n = 9), and the controls ( n = 11). We found concentration of α-synuclein in MS and NMO patients were significantly higher than Parkinson's disease subgroup and the controls. Both MS and NMO revealed an increased disease disability with increased CSF α-synuclein. Thus, CSF α-synuclein may be reflect injure axons and neurons in inflammatory demyelinating diseases. [ABSTRACT FROM AUTHOR]

Ulinastatin has previously been used as a drug for patients with acute inflammatory disorders. The goal of the present study was to investigate the protective effects of ulinastatin on myelin sheaths and oligodendrocytes in experimental autoimmune encephalomyelitis (EAE), and to explore the possible underlying mechanism. Mice were divided into an ulinastatin treatment group, a normal saline treatment group, and a normal control group. EAE was induced in the mice with and without ulinastatin treatment. Demyelination was evaluated, as was the number of oligodendrocytes. The ulinastatin treatment group had a significantly lower clinical score, demyelinating score, and large numbers of oligodendrocytes compared with the group without ulinastatin treatment. Furthermore, ulinastatin treatment increased the expression of nerve growth factor and brain-derived neurotrophic factor, and protected against oligodendrocyte apoptosis. Thus, ulinastatin is shown to have a protective effect against EAE. [ABSTRACT FROM AUTHOR]

Recent studies have implicated Chlamydia pneumoniae (C. pneumoniae) is present in a subset of patients with multiple sclerosis (MS) in which C. pneumoniae could act as a cofactor in the development of the disease. Macrolide antibiotics are most widely used anti-chlamydial agents and have immunomodulatory effect independently of their anti-bacterial activity. To investigate their effects on experimental autoimmune encephalomyelitis (EAE), EAE was induced by immunization with MBP68-86 peptide emulsified in complete Freund's adjuvant (CFA). Clarithromycin (CM) or azithromycin (AM, 50 mg/100 g body weight) was administrated daily from day 2 before immunization. All rats developed and survived EAE, but the groups administrated CM or AM had more severe symptoms. On day 11 post-immunization, mononuclear cells (MNCs) were prepared from the spleen of control group and cultured with or without macrolide antibiotics (10μg/ml). We evaluated nitric oxide (NO) production in the serum and culture supernatant. Inducible nitric oxide synthase (iNOS) mRNA and protein expression in the spinal cords and cultured MNCs were measured. The results showed that CM and AM similarly inhibited NO production and iNOS mRNA and protein expression in vivo and in vitro. Macrolide antibiotics may aggravate EAE by inhibiting iNOS mRNA and protein expression. Further studies are needed to investigate the effect of macrolide antibiotics on MS and to compare the effect of different anti-chlamydial antibiotics on MS. [ABSTRACT FROM AUTHOR]

Abstract: There has been enormous progress in the treatment of multiple sclerosis (MS) in recent years, but further improvement in therapy is still required because not all patients respond optimally to existing treatments. Increasing evidence has demonstrated that combination therapies produce a more favorable clinical outcome than monotherapy in MS treatment. Minocycline is effective in experimental autoimmune encephalomyelitis (EAE), and is a promising candidate for future MS medication. Glucocorticosteroids (GCS) belong to the most potent immunosuppressive drugs and are the mainstay for treatment of acute relapses in MS. In this study, we tested whether the combination of minocycline and prednisone (a synthetic GCS) at suboptimal doses could produce synergistic effects in EAE. Our findings showed that the combination of these two drugs functioned better than when they were individually administered in EAE mice, as evidenced by decreased clinical scores, reduced inflammation and demyelination, and improved magnetic resonance imaging outcomes. Further studies revealed that the combined treatment prevented the reduction of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) mRNA expression in cerebral cortex of EAE mice. In conclusion, our findings indicated that this combination therapy suppressed disease severity of EAE partially through blocking the downregulation of neurotrophic factor expression, suggesting that the combination of minocycline and prednisone could be a novel treatment in MS. [Copyright &y& Elsevier]

Abstract: Human Mesenchymal Stem Cells (MSCs) were previously reported to ameliorate neuronal functional deficits in the MOG35-55-induced experimental autoimmune encephalomyelitis (EAE) mice by inducing T cell anergy. Human Ciliary neurotrophic factor (CNTF) recently was found to promote myelogenesis and reduce inflammation in CNTF-deficient EAE mice. We ectopically overexpressed CNTF in human MSCs to investigate its potential role in promoting remyelination and improving functional recovery in EAE mice. MSCs transfected by Ad-CNTF–IRES–EGFP (MSC–CNTF) were injected intravenously into EAE mice 10 days after the immunization. Neurological functional tests were scored daily by grading clinical signs (score 0–6). Immunofluorescence microscopy was used to detect MSC–CNTF in spinal cord. Expression of NG2, CNTF, and cleaved caspase-3 was measured by immunohistochemistry. CNTF expression was also analyzed by Western blot. Myelin was detected by Solochrome Cyanin staining. Our results found that CNTF concentration in MSC–CNTF cells was 20-fold higher than that in either MSC or Ad-EGFP-transfected MSCs (MSC–EGFP) in vitro. Mice receiving MSC–CNTF cells showed remarkable neuronal functional recovery: the cumulative clinical scores were significantly decreased, and the disease onset was statistically delayed. Mice receiving MSC–CNTF cells showed reduced TNF-α, IFN-γ and increased the level of cytokine IL-10 in peripheral blood and a large number of MSC–CNTF cells were detected in the spleen, but were not detected in other organs such as lung, liver and kidney. In the lesions of these mice, 1) the number of cleaved caspase3-positive cells was significantly reduced; 2) MSC–CNTF- and NG2-positive cells were significantly increased; and 3) the expression of CNTF was dramatically increased. In addition, demyelination was significantly reduced in MSC–CNTF mice. These data indicated that MSC–CNTF may improve functional recovery in EAE mice, possibly by exerting their immunoregulatory activity, inhibiting inflammation, homing MSC–CNTF cells to the lesions, elevating CNTF expression, reducing demyelination, and stimulating oligodendrogenesis. [Copyright &y& Elsevier]

CCL20 is a potentially important component in the pathogenesis of multiple sclerosis (MS). SIRT1 exhibits a negative regulatory effect on a variety of inflammatory cytokines and can relieve experimental autoimmune encephalomyelitis. The association between the level of CCL20 and SIRT1 activity in MS patients has not been investigated. In the present study, blood samples were collected from 38 RRMS patients and 40 healthy controls. The serum CCL20 levels were measured by ELISA. SIRT1 activity was evaluated by fluorometric assay. We revealed elevated serum CCL20 concentrations in MS, and discovered an inverse correlation between CCL20 and SIRT1 activity in MS patients. [ABSTRACT FROM AUTHOR]

Background Uric acid (UA) levels are associated with autoimmune and neurodegenerative disorders, but their relationship with anti- N -methyl- d -aspartate receptor (anti-NMDAR) encephalitis is unknown. Methods UA levels were evaluated in 58 patients with anti-NMDAR encephalitis, and 58 age- and sex-matched healthy controls (CTLs). Follow-up evaluations of 30 out of the 58 patients with anti-NMDAR encephalitis were conducted 3 months after admission. Modified Rankin scale (mRS) scores and clinical and cerebrospinal fluid parameters were evaluated in all anti-NMDAR encephalitis patients. Results Serum UA levels were significantly lower in patients with anti-NMDAR encephalitis than those in CTLs (p < 0.001), and this was especially evident in patients with severe impairments (mRS ≥ 4 vs. <4, p = 0.004) or with limited response to treatment (vs. favourable outcome, p = 0.002). Follow-up evaluations revealed that serum UA levels normalized after treatment, with significantly increased serum UA levels (p < 0.001), and that mRS scores were significantly lower (p < 0.001) than those before treatment. In addition, serum UA levels were significantly associated with mRS scores (r = −0.463, p < 0.001). Conclusion Our results showed that serum UA levels in patients with anti-NMDAR encephalitis are reduced during attacks compared with those in CTLs, are normalized after treatment, and are associated with disease severity. [ABSTRACT FROM AUTHOR]

Highlights: [•] UTI protected against EAE by suppressing inflammatory responses. [•] UTI reduced CD11b+ cells in spinal cord lesions. [•] UTI decreased serum MMP-9, IL-1β, and IL-6 concentrations. [•] UTI reduced the expressions of TNF-α, NF-κB, iNOS proteins. [ABSTRACT FROM AUTHOR]

Anti– N -methyl- d -aspartate receptor encephalitis (anti-NMDARE) is a B cell- and antibody-mediated autoimmune disease which may be regulated by CD40/CD40L signaling pathway. we enrolled anti-NMDARE patients and measured the serum CD40 and CD40L concentrations. The serum concentration of CD40 was decreased, while CD40L was increased in anti-NMDARE patients compared with that of healthy controls. The concentrations of CD40 and CD40L were both elevated in the acute stage of anti-NMDARE and were reduced during remission. Serum CD40L levels were positively correlated with serum CD40 levels. These results revealed that the CD40/CD40L signaling pathway might contribute to the pathogenesis of anti-NMDARE. [Display omitted] • Serum levels of CD40 and CD40L were dysregulated in anti-NMDARE patients. • Serum CD40L was increased in acute stage while reduced in remission. • Serum CD40 levels were positively correlated with serum CD40L levels. • CD40/CD40L signaling pathway might participate the pathogenesis of anti-NMDARE. [ABSTRACT FROM AUTHOR]

Abstract: Background: Soluble forms of CD28 (sCD28) and CTLA-4 (sCTLA-4) were associated with many autoimmune diseases like Sjögren''s syndrome, systemic lupus erythematosus, asthma, and autoimmune myasthenia gravis. However, sCD28 and sCTLA-4 in neuromyelitis optica (NMO) and multiple sclerosis (MS) patients were less studied. Objective: To measure the plasma sCD28, sCTLA-4 in NMO and MS patients, and investigate whether sCD28 and sCTLA-4 possible use as sensitive biomarkers for diseases activity. Methods: Plasma concentrations of sCD28, sCTLA-4 were measured by an enzyme-linked immunosorbent assay (ELISA) in NMO (n=22), MS (n=21) patients and controls (n=18). Results: The concentration of sCD28 levels were higher in the inflammatory demyelinating diseases cohort compared with the controls (NMO, p =0.034; MS, p =0.026) and the levels of sCD28 were slightly higher in NMO compared with MS. The sCTLA-4 levels were lower in the MS subgroup compared with the controls (p =0.032). Both sCD28 and sCTLA-4 did not show any correlation with EDSS score in NMO and MS patients. Conclusions: Our study revealed for the first time that the levels of increased plasma sCD28 and decreased plasma sCTLA-4 in NMO and MS patients, but had little correlation with clinical presentations. [Copyright &y& Elsevier]

Abstract: Background: B cells are believed to play an important role in the pathogenesis of NMO. Chemokine (C-X-C motif) ligand 13 (CXCL13), the most potent B-cell chemoattractant, is a chemokine which is critical for secondary lymphoid tissue development and for B-cell migration. Concentration of CXCL13 in cerebral spinal fluid (CSF) is elevated in patients with multiple sclerosis (MS). However, whether levels of CSF CXCL13 are elevated in NMO patients still remain unknown. Objective: To measure the CSF concentration of CXCL13 in NMO patients, and to determine its relationship with NMO disease activity. Methods: CSF CXCL13 was measured by an enzyme-linked immunosorbent assay (ELISA) in NMO (n=22), MS (n=18) patients and controls (CTLs) (n=12). Results: CSF CXCL13 levels in NMO were notable higher than MS (p =0.015) and CTLs (p <0.001), and were related to the NMO disease activity indicated by relapse rate and Expanded Disability Status Scale (EDSS) scores. NMO Patients with the higher relapse rates exhibited the higher CXCL13 concentrations in their CSF; and a trend of increased disease disability with increased CSF CXCL13 level was revealed. The CSF CXCL13 concentrations seemed to associate with CSF white blood cell counting, total protein concentration in NMO subgroup, thought did not quite reach statistical significance (WBC, p =0.473; TP, p =0.276). Conclusions: The concentration of CSF CXCL13 was elevated in NMO patients, and correlated with NMO activity. [Copyright &y& Elsevier]