Encephalomyelitis Research Articles

Effect of matrine on Calpain/MAP-2 of experimental autoimmune encephalomyelitic rats

Objective To study the effect of matrine on Calpain and MAP-2 in rats with experimental autoimmune encephalomyelitis(EAE). Methods In accordance with the random number table, 60 Wistar rats were divided into 6 groups randomly: normal group, model group, dexamethasone(DEX)-treated group(1mg/kg), high-dose matrine(MAT)-treated group(250mg/kg), middle-dose MAT-treated group(200mg/kg) and low-dose MAT-treated group(150mg/kg). The EAE models were induced by immunized spinal cord extracts of guinea pig with complete Freunds' adjuvant.Rats of three MAT-treated groups and DEX-treated group were injected intraperitoneally with MAT and DEX daily for 16 days respectively, whereas rats of normal group and model group were injected intraperitoneally with normal saline.Clinical signs of rats in six groups were observed daily.Hematoxylin-eosin(HE) was used to analyze histopathological evaluation of spinal cord.μ-Calpain, m-Calpain and MAP-2 in spinal cord were determined using RT-PCR and immunohistochemistry respectively. Results Compared with the model group[(2.85±0.78)points], the clinical scores were significantly decreased in high-dose-MAT group[(1.28±0.59)points], middle-dose-MAT group[(1.45±0.64)points] and low-dose-MAT group[(2.09±0.71)points](t=5.345, 4.314, 2.869, all P<0.05). The HE score of rats in model group[(2.49±0.29)points] was significantly higher than that in high-dose-MAT group[(1.04±0.26)points], middle-dose-MAT group[(1.29±0.20)points] and low-dose-MAT group[(1.77±0.24)points](t=5.185, 4.274, 3.629, all P<0.01). The levels of μ-Calpain mRNA and m-Calpain mRNA in the three MAT-treated groups were significantly lower than those in model group(t=10.656, 9.418, 7.044, all P<0.01; t=6.332, 5.416, 3.978, all P<0.01). In addition, the expression of MAP-2 in the spinal cord of EAE rats showed a marked elevation after MAT treatment(t=12.841, 9.924, 7.038, all P<0.01). Conclusion Matrine may be an effective therapeutic approach for EAE by inhibiting Calpain and increase MAP-2 expression. Key words: Matrine; Encephalomyelitis, autoimmune, experimental; Calpain; Microtubule associated protein-2; Rats

18F]FSPG-PET reveals increased cystine/glutamate antiporter (xc-) activity in a mouse model of multiple sclerosis

BackgroundThe cystine/glutamate antiporter (xc-) has been implicated in several neurological disorders and, specifically, in multiple sclerosis (MS) as a mediator of glutamate excitotoxicity and proinflammatory immune responses. We aimed to evaluate an xc-specific positron emission tomography (PET) radiotracer, (4S)-4-(3-[18F]fluoropropyl)-l-glutamate ([18F]FSPG), for its ability to allow non-invasive monitoring of xc- activity in a mouse model of MS.MethodsExperimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice by subcutaneous injection of myelin oligodendrocyte glycoprotein (MOG35–55) peptide in complete Freund’s adjuvant (CFA) followed by pertussis toxin. Control mice received CFA emulsion and pertussis toxin without MOG peptide, while a separate cohort of naïve mice received no treatment. PET studies were performed to investigate the kinetics and distribution of [18F]FSPG in naïve, control, pre-symptomatic, and symptomatic EAE mice, compared to 18F-fluorodeoxyglucose ([18F]FDG). After final PET scans, each mouse was perfused and radioactivity in dissected tissues was measured using a gamma counter. Central nervous system (CNS) tissues were further analyzed using ex vivo autoradiography or western blot. [18F]FSPG uptake in human monocytes, and T cells pre- and post-activation was investigated in vitro.Results[18F]FSPG was found to be more sensitive than [18F]FDG at detecting pathological changes in the spinal cord and brain of EAE mice. Even before clinical signs of disease, a small but significant increase in [18F]FSPG signal was observed in the spinal cord of EAE mice compared to controls. This increase in PET signal became more pronounced in symptomatic EAE mice and was confirmed by ex vivo biodistribution and autoradiography. Likewise, in the brain of symptomatic EAE mice, [18F]FSPG uptake was significantly higher than controls, with the largest changes observed in the cerebellum. Western blot analyses of CNS tissues revealed a significant correlation between light chain of xc- (xCT) protein levels, the subunit of xc- credited with its transporter activity, and [18F]FSPG-PET signal. In vitro [18F]FSPG uptake studies suggest that both activated monocytes and T cells contribute to the observed in vivo PET signal.ConclusionThese data highlight the promise of [18F]FSPG-PET as a technique to provide insights into neuroimmune interactions in MS and the in vivo role of xc- in the development and progression of this disease, thus warranting further investigation.

Therapeutic effects of pegylated-interferon-α2a in a mouse model of multiple sclerosis.

IntroductionExperimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS). EAE is mainly mediated by adaptive and innate immune responses that lead to an inflammatory demyelination and axonal damage. The aim of the present research was to examine the therapeutic efficacy of Peg interferon alpha 2a (Peg-IFN α-2a) as a serine protease inhibitor on EAE model.Material and methodsEAE induction was performed in female C57BL/6 mice by myelin oligodendrocyte glycoprotein (35-55) (MOG35-55) in Complete Freund’s Adjuvant (CFA) emulsion, and Peg-IFN α-2a was used for the treatment of EAE. During the course of the study, clinical evaluation was assessed, and on day 21 post-immunisation blood samples were taken from the heart of mice for evaluation of IL-6, and enzymatic and non-enzymatic antioxidants. The mice were sacrificed and the brains and cerebellums were removed for histological analysis.ResultsOur findings indicated that Peg-IFN α-2a had beneficial effects on EAE by attenuation of the severity and a delay in the onset of disease. Histological analysis showed that treatment with Peg-IFN α-2a can reduce inflammation criteria. Moreover, in Peg-IFN α-2a-treated mice the serum level of IL-6 was significantly less than in controls, and total antioxidant capacity was significantly more than in the control animals.ConclusionsThese data indicate that Peg-IFN α-2a as an anti-serine protease with immunomodulatory properties may be useful for the treatment of MS.

Treatment with relaxin reduces disease symptoms and enhances neuroprotection and remyelination in murine experimental autoimmune encephalomyelitis

The use of glucocorticoid agonists in treating acute attacks of multiple sclerosis is well established. Relaxin, a member of the insulin super family is a pleiotropic hormone capable of influencing multiple pathways which include the glucocorticoid receptor and relaxin family peptide receptors 1 and 2. In addition to the action of relaxin on the glucocorticoid receptor, activation of the relaxin receptors have additional anti-inflammatory and immuno-modulating effects. In the present study we investigated the effectiveness of relaxin in treating a murine model of MS, experimental allergic encephalomyelitis. Disease was induced and the mice were scored daily for clinical signs of disease (0=normal, 3=hind limb paralysis, 5=found dead). When a clinical score of 3 or higher was reached, relaxin was continuously infused for 8 days. Plasma for RT-PCR and spinal cords for histology were collected. The levels of CCR2, CCR5, CCR7, interleukins-6 and 17 were analyzed using quantitect primers and SYBR green based RT-PCR kits. Spinal cords were formalin fixed, paraffin embedded, sectioned and scored for myelin content, macrophage infiltration, neurofilaments, gliosis and markers of remyelination. The results of the study show that continuous infusion of relaxin significantly reduced the clinical signs of disease, decreased mRNA expression of pro-inflammatory cytokines and chemokine receptors. Histological staining and immune-histochemistry of the spinal cords showed that relaxin treatment lead to a decrease in lesion load and size and macrophage infiltration, preserved myelin and neurofilaments, reduced gliosis and promoted remyelination.

Nicotine Augments the Beneficial Effects of Mesenchymal Stem Cell-based Therapy in Rat Model of Multiple Sclerosis

ABSTRACTExperimental autoimmune encephalomyelitis (EAE) in rats through immunization with guinea pig spinal cord homogenate (GPSCH) produces a chronic disease with a relapsing pattern such as multiple sclerosis (MS) in humans. In previous studies, the immunomodulatory benefits of mesenchymal stem cells (MSCs) and nicotine have already been determined. Thus, this research was conducted to assess the additional benefits of the combination therapy of MSCs and nicotine in a rat model of MS. EAE was induced by GPSCH and complete Freund’s adjuvant (CFA) in female Wistar rats. The therapies were initiated at day 12 post-immunization (p.i.), when the rats developed a neurological disability score. The symptoms were recorded daily until day 33, when the rats were sacrificed. Finally, the splenocytes were evaluated by Enzyme-linked immunosorbent assay (ELISA) for cytokine production. The therapeutic treatment in the EAE rats with a combination of MSCs and nicotine exhibited a more desirable outcome, causing the regression of the average mean clinical score and neuropathological features to be more favorable than the treatment with either therapy alone. The combination therapy led to a significant reduction in the cumulative disease disability from day 21. For the EAE rats treated with nicotine and MSCs, this period was started from day 22 and 28 p.i., respectively. Besides the increase in the levels of IL-10, the combined therapy significantly reduced the splenocytes production of pro-inflammatory IL-17 as well as TNF-α more profoundly than either of the medications alone. In conclusion, the combination of MSCs and nicotine can be suggested as a promising strategy for further MS therapeutics improvement.

The Effects of Intestinal Nematode L4 Stage on Mouse Experimental Autoimmune Encephalomyelitis

Helminths use various immunomodulatory and anti-inflammatory strategies to evade immune attack by the host. During pathological conditions, these strategies alter the course of disease by reducing immune-mediated pathology. The study examines the therapeutic effect of the nematode L4 stage based on an in vivo model of multiple sclerosis, monophasic encephalomyelitis (EAE), induced by sensitization with MOG35–55 peptide in C57BL/6 female mice infected with the intestinal nematode Heligmosomoides polygyrus. The EAE remission was correlated with altered leukocyte number identified in the central nervous system (CNS), and temporary permeability of the blood–brain barrier at the histotrophic phase of infection. At 6 days post-infection, when the L4 stage had almost completely attenuated the clinical severity and pathological signs of EAE, CD25+ cell numbers expanded significantly, with parallel growth of CD8+ and CD4+, both CD25+Foxp3+ and CD25+Foxp3− subsets and alternatively activated macrophages. The phenotypic changes in distinct subsets of cerebrospinal fluid cells were correlated with an inhibited proliferative response of encephalitogenic T cells and elevated levels of nerve growth factor and TGF-β. These results enhance our understanding of mechanisms involved in the inhibition of immune responses in the CNS during nematode infection.

Innate immunity and neuroinflammation

Innate-like lymphocytes emerged as an important plyaers to brigde innate and acquired immunity in a variety of immune reactions as they rapidly exert effector functions in the absence of clonal expansion. They participate the immune-regulation through rapid production of divers cytokines. Invariant natural killer (iNKT) cells and mucosal associated invariant T (MAIT) cells are members of innate-like cells which express invariant T cell receptor a chain paired with a limited set of Vb chanis. These cells are restricted by a nonpolymorphic MHC class 1b molecule, CD1and the MHC-related molecule-1 (MR1), and recognize glycolipid antigens and vitamine metabolites generated by microbiota, respectively. We previously found the regulatory role of MAIT cells in autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS) using MR1 knockout mouse and MAIT-TCR transgenic mouse. We also reported that stimulation of iNKT cells with a synthetic glycolipid prevent disease severity of EAE. We further investigated that MAIT cells and iNKT cells reduced in patients with MS, suggesting the involvement of these cells in the pathogenesis of MS.

Acute Disseminated Encephalomyelitis and Myelin Oligodendrocyte Glycoprotein Antibodies in Children

Investigators from a multicenter consortium collected serum from 210 children with acute demyelinating syndromes. At presentation, 60 were diagnosed

Expression and significance of estrogen receptor in bladder of experimental autoimmune encephalomyelitis mouse model

Objective To study the changes of estrogen receptor (ER) expression in neurogenic bladder caused by multiple sclerosis (MS) and its significance by establishing an experimental autoimmune encephalomyelitis (EAE) model in mice. Methods The EAE models were induced by an antigen emulsion mixture that was well mixed with mog35-55 and complete Freund’s adjuvant. Twenty female C57Bl/6 mice were randomly divided into experimental group and control group. The clinical symptoms of mice were observed and recorded after immunization. Twenty-third days after immunization, micturition frequency and mean void weight were observed within 4 h. The spinal cord as well as the bladder was collected and the bladder was weighed. The pathological changes were observed by hematoxylin-eosin (HE) staining and Luxol fast blue (LFB) staining. The expression of ER in bladder of EAE mice was detected by Western blotting. Results The clinical score of neurological function in EAE mice increased, and typical MS symptoms appeared. The weight of the control group and experimental group was (23.0±1.1) g and (16.5±1.5) g respectively. As compared with the control group, the weight of the mice in the model group was obviously reduced. The average number of 4H urination in model group (8.7±1.4) was significantly greter than in the control group (4.2±1.1, P=0.001). The urine volume in the model group [(0.22±0.11) mg] was significantly less than that in the control group [(0.34±0.07) mg, P=0.008]. In the model group, the bladder weight ratio [(0.26±0.09)‰] was significantly higher than that in the model group [(0.11±0.03)‰, P=0.001]. HE-LFB staining showed obvious inflammatory cell infiltration and demyelination in the spinal cord of EAE model mice, and Western blotting showed that the relative expression of ER in the bladder of model group (0.38±0.08) was significantly lower than that in the control group (0.71±0.19, P=0.001). Conclusion Mog35-55 can successfully induce the EAE mice model. The EAE mice model can well simulate the MS neurogenic bladder symptoms. ER and estrogen may be the important factors in bladder dysfunction caused by multiple sclerosis. Key words: Estrogen receptor; Experimental autoimmune encephalomyelitis; Neurogenic bladder

Natural Docosahexaenoic Acid in the Triglyceride Form Attenuates In Vitro Microglial Activation and Ameliorates Autoimmune Encephalomyelitis in Mice.

Many neurodegenerative diseases are associated, at least in part, to an inflammatory process in which microglia plays a major role. The effect of the triglyceride form of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (TG-DHA) was assayed in vitro and in vivo to assess the protective and anti-inflammatory activity of this compound. In the in vitro study, BV-2 microglia cells were previously treated with TG-DHA and then activated with Lipopolysaccharide (LPS) and Interferon-gamma (IFN-γ). TG-DHA treatment protected BV-2 microglia cells from oxidative stress toxicity attenuating NO production and suppressing the induction of inflammatory cytokines. When compared with DHA in the ethyl-ester form, a significant difference in the ability to inhibit NO production in favor of TG-DHA was observed. TG-DHA inhibited significantly splenocyte proliferation but isolated CD4+ lymphocyte proliferation was unaffected. In a mice model of autoimmune encephalomyelitis (EAE), 250 mg/kg/day oral TG-DHA treatment was associated with a significant amelioration of the course and severity of the disease as compared to untreated animals. TG-DHA-treated EAE mice showed a better weight profile, which is a symptom related to a better course of encephalomyelitis. TG-DHA may be a promising therapeutic agent in neuroinflammatory processes and merit to be more extensively studied in human neurodegenerative disorders.

Stem cells from human-exfoliated deciduous teeth reduce tissue-infiltrating inflammatory cells improving clinical signs in experimental autoimmune encephalomyelitis

Stem cells from human exfoliated deciduous teeth (SHED) have great therapeutic potential and here, by the first time, we evaluated their immunomodulatory effect on experimental model of autoimmune encephalomyelitis (EAE). Specifically, we investigated the effect of SHED administration on clinical signs and cellular patterns in EAE model using Foxp3 GFP + transgenic mice (C57Bl/6-Foxp3GFP). The results showed that SHED infusion ameliorated EAE clinical score with reduced number of infiltrating IFN-γ+CD8+, IL-4+CD8+, IFN-γ+CD4+ and IL-4+CD4+ T cells into the central nervous system (CNS). In addition, we observed that SHED promoted a significant increase in CD4+FOXP3+ T cells population in the spleen of EAE-affected animals. Taken together, our results provide strong evidence that SHED can modulate peripherally the CD4+ T cell responses suggesting that SHED would be explored as part of cellular therapy in autoimmune diseases associated with CNS.

Elevated serum [Met5]-enkephalin levels correlate with improved clinical and behavioral outcomes in experimental autoimmune encephalomyelitis.

Methionine enkephalin ([Met5]-enkephalin, Opioid growth factor (OGF)) is a small neuropeptide with growth-related as well as immunomodulatory properties. OGF is distributed widely throughout the body, is both autocrine and paracrine produced, and has a very short half-life in serum. In addition to its neurotransmitter functions, OGF inhibits cell replication of a wide variety of cells involved in the autoimmune process. In this preclinical study, mice were immunized with myelin oligodendrocytic glycoprotein (MOG35-55) to establish a chronic progressive form of autoimmune encephalomyelitis (EAE), and serum enkephalin levels were assessed throughout the disease as well as in response to OGF therapy in order to determine whether OGF may be a biological marker for EAE and multiple sclerosis. Immunized mice were randomly assigned to groups receiving daily 10mg/kg OGF (n=24) or saline (n=25) beginning at the time of established disease and clinical behavior. Open field activity, rearing, forced swimming, and novel object tests were monitored. Serum levels of peptide were measured prior to immunization, before clinical symptoms were observed, and at the onset and peak period of disease. Spinal cord neuropathology was evaluated 40days after immunization. EAE disease onset occurred on day 9 post immunization when the mean clinical score was 1.5. Peak disease scores for saline-injected EAE mice reached a mean of 5.7 on day 18, whereas mice receiving OGF had a peak clinical score of 2.5. Behavioral tests conducted 5days post-immunization (and before clinical signs of EAE) revealed that EAE mice had reduced serum enkephalin levels related to elevated clinical disease scores. Serum levels of enkephalin collected at peak disease and after 40days correlated with clinical scores. Disease status was associated with activity in the open field, rearing, time associating with a novel object, and pain sensitivity. Clinical signs of EAE correlated with levels of enkephalins such that as behavioral scores increased, serum [Met5]-enkephalin levels decreased. Thus, [Met5]-enkephalin is a novel biomarker that is associated with disease onset and progression, as well as response to therapy in a mouse model of EAE, and may provide new insight into MS.

Estrogen protection against EAE modulates the microbiota and mucosal-associated regulatory cells

Sex hormones promote immunoregulatory effects on multiple sclerosis. In the current study we evaluated the composition of the gut microbiota and the mucosal-associated regulatory cells in estrogen or sham treated female mice before and after autoimmune encephalomyelitis (EAE) induction. Treatment with pregnancy levels of estrogen induces changes in the composition and diversity of gut microbiota. Additionally, estrogen prevents EAE-associated changes in the gut microbiota and might promote the enrichment of bacteria that are associated with immune regulation. Our results point to a possible cross-talk between the sex hormones and the gut microbiota, which could promote neuroprotection.

Clinical and imageology follow-up study of acute disseminated encephalomyelitis

Objective To explore the clinical manifestations and recovery from neuroimaging abnormalities of acute disseminated encephalomyelitis (ADEM), in order to improve the understanding of ADEM. Methods A total of 47 children with ADEM in Department of Neurology, Children′s Hospital of Soochow University were followed up for 1 year.The clinical manifestations, auxiliary examination (especially neuroimaging), treatment and prognosis were analyzed.The recovery conditions from clinical and neuroimaging abnormalities were summarized. Results Among 47 cases, 37 cases (78.72%) had prodromic infection history, and 5 cases (10.64%) had the history of vaccination.The clinical manifestations were varied, including 36 cases (76.60%) with somatic discomfort, 30 cases (63.83%) with fever, 30 cases (63.83%) with disturbance of consciousness, 28 cases (59.57%) with epileptic seizure, 24 cases (51.06%) with headache and dizziness, 22 cases (46.81%) with nausea and vomiting, 15 cases (31.91%) with dyskinesia, 15 cases (31.91%) with cranial nerve injury, 9 cases (19.14%) with incoordination, and 8 cases (17.02%) with mental and behavior disorders.Abnormal lesions presented multiple, asymmetric patchy and large patchy signal image showed by brain magnetic resonance imaging (MRI), and 7 cases (14.89%) involved the spinal cord.All patients received the treatment of Methylprednisolone [15-20 mg/(kg·d)] combined with intravenous gamma globulin (total 2 g/kg, 3 to 5 days). The dose of Methylprednisolone gradually decreased after it had been used for 3 days.In the end, it was replaced by an oral administration of Prednisone [1.0-2.0 mg/(kg·d)], and the total treatment period was for 2-3 months.The follow-ups of 47 children with ADEM showed that the MRI lesions of all the children were reduced and the MRI lesions in 4 (8.51%) of them disappeared completely after 0.5 month of follow-up; the lesions disappeared completely in 13 cases (27.66%) after 1 month of follow-up; the lesions disappeared completely in 23 cases (48.94%) after 3 months of follow-up; the lesions disappeared completely in 32 cases (68.09%) after 6 months of follow-up; the lesions disappeared completely in 43 cases (91.49%) after 1 year of follow-up; and finally there were 4 cases (8.51%) with residual lesions. Conclusion The clinical manifestations of children with ADEM are varied.Most children with ADEM have a favorable prognosis.Imaging lesions of 68.09% of the cases completely disappeared after the onset of 6 months.Imaging lesions in 91.49% of the cases completely disa-ppeared at the onset of 1 year.Only a small fraction of patients present permanent lesions. Key words: Acute disseminated encephalomyelitis; Clinical manifestation; Neuroimaging; Magnetic resonance imaging; Child

Failure of alemtuzumab therapy to control MOG encephalomyelitis

Myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG)–associated encephalomyelitis (EM) is a rare autoimmune disorder that displays substantial clinicoradiologic overlap with aquaporin-4 (AQP4)-IgG-seropositive neuromyelitis optica spectrum disorders (NMOSD) and classic multiple sclerosis (MS).1–3,e1 The long-term outcome is often poor.2,3,e1 Recent evidence suggests that many disease-modifying agents approved for the treatment of MS may be ineffective or even harmful in AQP4-IgG-positive and MOG-IgG-positive patients.2–4 Acknowledgment: The authors thank Anna Eschlbeck and Kathrin Schanda for technical assistance.

CpG type-A induction of an early protective environment in experimental multiple sclerosis

Abstract Experimental autoimmune encephalomyelitis (EAE) is an inflammatory, demyelinating disease of the CNS that mimics human multiple sclerosis (MS), and it is thought to be driven by Th1 and Th17 myelin-reactive cells. Although adaptive immununity is clearly pivotal in the pathogenesis of EAE – with an essential role of CD4+ T cells – little is known of early, innate responses in this experimental setting. CpG-rich oligodeoxynucleotides (ODNs), typically found in microbial genomes, are potent activators of TLR9 in plasmacytoid dendritic cells (pDCs). In this study, we compared the effects of two types of CpG, namely, type A and type B, on EAE. We found that treatment with CpG type-A ODN (CpG-A) – known to induce high amounts of IFN-α in pDCs – significantly reduced disease severity in EAE, relative to controls (12.63 ± 1.86 vs. 23.49 ± 1.46, respectively; p = 0.001). Treatment also delayed onset of neurological deficits and reduced spinal cord demyelination, while increasing the percentage of splenic regulatory (Foxp3+CD4+) T cells. CpG-A likewise reduced the levels of IL-17 and IFN-γ in the CNS. Mechanistic insight into those events showed that CpG-A promoted a regulatory phenotype in pDCs. Moreover, adoptive transfer of pDCs isolated from CpG-A–treated mice inhibited CNS inflammation and induced disease remission in acute-phase EAE. Our data thus identify a link between TLR9 activation by specific ligands and the induction of tolerance via innate immunity mechanisms.

The Extracellular Matrix Proteoglycan Decorin is Upregulated by Endothelial Cells During Inflammation and Contributes to Blood‐Brain Barrier Dysfunction

The blood‐brain barrier (BBB) selectively regulates solute flux and protects the brain from bloodborne neurotoxic substances. Endothelial cells (ECs) forming the BBB establish highly restrictive cell‐cell contacts known as tight junctions (TJs), which aid in sealing paracellular clefts. The TJ protein claudin‐5 (CLDN5) is the primary constitutive protein responsible for the restriction of paracellular permeability to small molecules and the level of CLDN5 expression has been positively correlated with endothelial barrier tightness. Situated below the ECs is the extracellular matrix (ECM) which not only helps anchor the ECs, but also participates in ECM‐EC regulatory signaling. Under normal conditions, certain ECM proteins, such as collagens, have been shown to enhance the barrier properties of the BBB, whereas during inflammation other ECM proteins can contribute to BBB dysfunction, although the particulars of these mechanisms are still yet to be fully understood. In certain neuroinflammatory diseases, such as multiple sclerosis (MS), the upregulation of the ECM small leucine‐rich repeat proteoglycan (SLRP) decorin has been identified within the perivascular space of vessels in the inflammatory lesions of MS patients. The cellular origin of this decorin release and its potential impact on the BBB, however, has yet to be determined. In this study, we used murine models of inflammation in vivo and in vitro to determine a spatial‐temporal relationship between BBB dysfunction, CLDN5 loss, and increased decorin accumulation in the ECM. Consistent with the MS lesions, we identified increased decorin expression in mouse cerebellar microvessels post‐experimental autoimmune encephalomyelitis (EAE) induction as well as in primary brain microvascular endothelial cells (BMVECs) treated in vitro with inflammatory cytokines. Additionally, we evaluated the effect of different ECM‐EC interactions on CLDN5 expression and BMVEC monolayer integrity in vitro. Primary BMVECs cultivated on collagen‐coated surfaces showed a decrease in baseline solute permeability and increased CLDN5 expression compared to those on non‐coated surfaces, with those on collagen type IV‐coated surfaces showing a greater decrease in baseline permeability and CLDN5 expression compared to those on type I‐coated surfaces. However, surfaces containing decorin resulted in increased monolayer permeability and decreased CLDN5 expression, while matrices containing both decorin and type IV collagen resulted in abrogation of the observed enhancement of monolayer permeability and CLDN5 expression by type IV collagen. Taken together, our data suggest that ECs themselves may be the source of decorin accumulation in perivascular inflammatory lesions and that inflammatory‐induced decorin upregulation may perpetuate BBB dysfunction.Support or Funding InformationSupported by NIH P20 GM109095, 2P20GM103408.

Mechanism of MOG i. p. for protecting mice from EAE

Objective To investigate mechanisms underlying the prevention of experimental autoimmune encephalomyelitis (EAE) in mice by intraperitoneal infusion of myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) (MOG i. p.). Methods C57BL/6 mice were immunized with MOG35-55 to establish the model of EAE and then were intraperitoneally injected daily with MOG35-55 or ovalbumin (OVA, served as control) from day 6 to day 16. EAE was evaluated daily using a general clinical scoring system and histological analysis. Numbers of lymphocytes in peripheral blood and central nervous system (CNS) were detected at different time points. Effects of MOG i. p. on the migration of MOG-T cells in vivo were analyzed by an adoptive transfer experiment. Maturation of splenic antigen-presenting cells (APCs) and migration of MOG-T cells in vitro were examined by fluorescence activated cell sorting (FACS) and a Transwell system, respectively. Results MOG i. p. protected the mice from development of EAE by blocking the lymphocyte recruitment to CNS. More effector T cells were trapped in the periphery of EAE and naive mice in adoptive transfer experiment after MOG i. p. treatment. MOG i. p. induced the maturation of splenic APCs and enhanced the expression of CD80, CD86 and major histocompatibility complex class Ⅱ (MHCⅡ) molecules. Mature APCs blocked the recruitment of effector T cells to CNS. Conclusion MOG i. p. protects mice from EAE by inducing the maturation of splenic APCs. Key words: Experimental autoimmune encephalomyelitis; Immune tolerance; Antigen-presenting cell; Cell migration

Differences in ME and CFS Symptomology in Patients with Normal and Abnormal Exercise Test Results.

Post-exertional malaise (PEM) is a cardinal symptom of myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS), which often distinguishes patients with this illness from healthy controls or individuals with exclusionary illnesses such as depression. However, occurrence rates for PEM fluctuate from subject to how the symptom is operationalized. One commonly utilized method is exercise testing, maximal or submaximal. Many patients with ME and CFS experience PEM after participating in these tests, and often show abnormal results. However, some patients still exhibit normal results after participating in the exercise testing. This study examined the differences between two patient groups with ME and CFS, those with normal results and those with abnormal results, on several PEM-related symptoms and illness characteristics. The results suggest those that displayed abnormal results following testing have more frequent and severe PEM, worse overall functioning, and are more likely to be bedbound than those that displayed normal results.

An interpretation of consensus statements on diagnostic criteria for multiple sclerosis and demyelinating diseases of the central nervous system in children (2012 version)

The International Pediatric Multiple Sclerosis Study Group (IPMSSG) put forward the 2007 version of the diagnostic criteria for multiple sclerosis and other immune-mediated demyelinating diseases of the central nervous system in children in 2007 ("2007 version" for short). In 2012, IPMSSG proposed the new diagnostic criteria with reference to the latest research achievements of 150 members ("2012 version" for short). The 2012 version of the consensus statements covers the diagnostic criteria for acute disseminated encephalomyelitis, clinically isolated syndrome, neuromyelitis optica, and multiple sclerosis in children. As the two IPMSSG members in China, the authors give an interpretation of the 2012 version of the consensus statements with reference to related literature and clinical and scientific experience. The authors focus on how the 2012 version comprehensively and thoroughly elaborates on the clinical features, diagnostic criteria, influencing factors, and new ideas of acute demyelinating diseases of the central nervous system in children. These become more operable in clinical diagnosis and treatment of multiple sclerosis and other immune-mediated demyelinating diseases of the central nervous system in children.