myelin-basic-protein and Inflammation

myelin-basic-protein has been researched along with Inflammation* in 106 studies

Reviews

4 review(s) available for myelin-basic-protein and Inflammation

ArticleYear
Back to the future for multiple sclerosis therapy: focus on current and emerging disease-modifying therapeutic strategies.
    Immunotherapy, 2009, Volume: 1, Issue:3

    The last decade has seen numerous advances in the treatment of multiple sclerosis with six immunotherapeutic agents licensed for use. Although these therapeutic agents have powerful effects upon the inflammatory phase of disease, they have limitations in treating the progression of disability and in their safety profile. This review focuses on our current understanding of first- and second-line treatments for multiple sclerosis, including combination therapies, and also discusses the most promising novel therapeutic strategies on the horizon. Such agents include orally administered immunosuppressive drugs, monoclonal antibodies, antigen-specific tolerance, and neural protection and repair strategies. The challenge ahead lies in the delivery of potent drugs to inhibit inflammation and neurodegeneration while limiting side effects. Further elucidation of the pathophysiology of disease may provide new clinical targets and disease-relevant biomarkers that, in combination with proteomics, may help personalize treatment to individual patients.

    Topics: Animals; Antibodies, Monoclonal; Clinical Trials as Topic; Cytokines; Drug Combinations; Humans; Immunosuppressive Agents; Immunotherapy; Inflammation; Multiple Sclerosis; Myelin Basic Protein; Peptide Fragments

2009
Biomarkers of primary and evolving damage in traumatic and ischemic brain injury: diagnosis, prognosis, probing mechanisms, and therapeutic decision making.
    Current opinion in critical care, 2008, Volume: 14, Issue:2

    Emerging data suggest that biomarkers of brain injury have potential utility as diagnostic, prognostic, and therapeutic adjuncts in the setting of traumatic and ischemic brain injury. Two approaches are being used, namely, assessing markers of structural damage and quantifying mediators of the cellular, biochemical, or molecular cascades in secondary injury or repair. Novel proteomic, multiplex, and lipidomic methods are also being applied.. Biochemical markers of neuronal, glial, and axonal damage such as neuron-specific enolase, S100B, and myelin basic protein, respectively, are readily detectable in biological samples such as serum or cerebrospinal fluid and are being studied in patients with ischemic and traumatic brain injury. In addition, a number of studies have demonstrated that novel tools to assess simultaneously multiple biomarkers can provide unique insight such as details on specific molecular participants in cell death cascades, inflammation, or oxidative stress.. Multifaceted cellular, biochemical, and molecular monitoring of proteins and lipids is logical as an adjunct to guiding therapies and improving outcomes in traumatic and ischemic brain injury and we appear to be on the verge of a breakthrough with the use of these markers as diagnostic, prognostic, and monitoring adjuncts, in neurointensive care.

    Topics: Biomarkers; Brain Injuries; Brain Ischemia; Decision Making; Humans; Inflammation; Myelin Basic Protein; Nerve Growth Factors; Oxidative Stress; Phosphopyruvate Hydratase; Prognosis; Proteomics; S100 Calcium Binding Protein beta Subunit; S100 Proteins

2008
Multiple sclerosis cerebrospinal fluid biomarkers.
    Disease markers, 2006, Volume: 22, Issue:4

    Cerebrospinal fluid (CSF) is the body fluid closest to the pathology of multiple sclerosis (MS). For many candidate biomarkers CSF is the only fluid that can be investigated. Several factors need to be standardized when sampling CSF for biomarker research: time/volume of CSF collection, sample processing/storage, and the temporal relationship of sampling to clinical or MRI markers of disease activity. Assays used for biomarker detection must be validated so as to optimize the power of the studies. A formal method for establishing whether or not a particular biomarker can be used as a surrogate end-point needs to be adopted. This process is similar to that used in clinical trials, where the reporting of studies has to be done in a standardized way with sufficient detail to permit a critical review of the study and to enable others to reproduce the study design. A commitment must be made to report negative studies so as to prevent publication bias. Pre-defined consensus criteria need to be developed for MS-related prognostic biomarkers. Currently no candidate biomarker is suitable as a surrogate end-point. Bulk biomarkers of the neurodegenerative process such as glial fibrillary acidic protein (GFAP) and neurofilaments (NF) have advantages over intermittent inflammatory markers.

    Topics: Biomarkers; Follow-Up Studies; Glial Fibrillary Acidic Protein; Humans; Inflammation; Multiple Sclerosis; Myelin Basic Protein; Nerve Growth Factors; Neurofilament Proteins; S100 Calcium Binding Protein beta Subunit; S100 Proteins

2006
Role of the clotting system in the pathogenesis of neuroimmunologic disease.
    Federation proceedings, 1987, Volume: 46, Issue:1

    Experimental allergic encephalomyelitis (EAE) is a prototypic neuroautoimmune disease involving sensitization to central nervous system myelin basic protein (MBP). Our studies of the clotting system and ensuing fibrinolysis implicate coagulation and cleavage of fibrin within or on the luminal surface of the cerebrovasculature as events initiating the inflammation characterizing EAE. Among recipient rats injected with MPB-primed, cultured-activated lymph node cells, opening of the blood-brain barrier (BBB) and deposition of perivascular fibrin within the spinal cord occur in parallel 1 day before onset of clinical signs of EAE. Daily treatment of recipient rats with trans-4-(aminomethyl)cyclohexanecarboxylic acid, a synthetic product that specifically inhibits plasminogen activator derived from endothelial cells, results in marked reduction of increased permeability of the BBB and suppression of clinical signs of EAE. We postulate that the critical event precipitating EAE is binding of circulating MBP-reactive immune effector cells to MBP immunodeterminants on the surface of cerebrovascular endothelial cells. Coagulation and ensuing fibrinolysis occur at sites of binding of effector cells to cerebrovascular endothelium. Release of biologically active peptides cleaved from fibrin open the BBB, thereby setting the stage for the cascade of inflammatory events culminating in clinical manifestations of EAE.

    Topics: Animals; Blood Coagulation; Blood-Brain Barrier; Cerebrovascular Circulation; Encephalomyelitis, Autoimmune, Experimental; Fibrinolysis; Inflammation; Multiple Sclerosis; Myelin Basic Protein; Rats; Rats, Inbred Lew; T-Lymphocytes; Tranexamic Acid

1987

Other Studies

102 other study(ies) available for myelin-basic-protein and Inflammation

ArticleYear
Involvement of Degenerating 21.5 kDa Isoform of Myelin Basic Protein in the Pathogenesis of the Relapse in Murine Relapsing-Remitting Experimental Autoimmune Encephalomyelitis and MS Autopsied Brain.
    International journal of molecular sciences, 2023, May-02, Volume: 24, Issue:9

    Multiple sclerosis (MS) is the chronic inflammatory demyelinating disease of the CNS. Relapsing-remitting MS (RRMS) is the most common type of MS. However, the mechanisms of relapse and remission in MS have not been fully understood. While SJL mice immunized with proteolipid protein (PLP) develop relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE), we have recently observed that some of these mice were resistant to the active induction of relapsing EAE after initial clinical and histological symptoms of EAE with a severity similar to the relapsing EAE mice. To clarify the mechanism of relapsing, we examined myelin morphology during PLP

    Topics: Animals; Brain; Chronic Disease; Encephalomyelitis, Autoimmune, Experimental; Inflammation; Mice; Mice, Inbred Strains; Multiple Sclerosis; Myelin Basic Protein; Myelin Proteolipid Protein; Neoplasm Recurrence, Local; Protein Isoforms; Spinal Cord

2023
Toll-like receptor 4-mediated microglial inflammation exacerbates early white matter injury following experimental subarachnoid hemorrhage.
    Journal of neurochemistry, 2023, Volume: 166, Issue:2

    Neuroinflammation has been reported to be associated with white matter injury (WMI) after subarachnoid hemorrhage (SAH). As the main resident immune cells of the brain, microglia can be activated into proinflammatory and anti-inflammatory phenotypes. Toll-like receptor 4 (TLR4), expressed on the surface of the microglia, plays a key role in microglial inflammation. However, the relationship between TLR4, microglial polarization, and WMI following SAH remains unclear. In this study, a total of 121 male adult C57BL/6 wild-type (WT) mice, 20 WT mice at postnatal day 1 (P1), and 41 male adult TLR4 gene knockout (TLR4-/-) mice were used to investigate the potential role of TLR4-induced microglial polarization in early WMI after SAH by radiological, histological, microstructural, transcriptional, and cytological evidence. The results indicated that microglial inflammation was associated with myelin loss and axon damage, shown as a decrease in myelin basic protein (MBP), as well as increase in degraded myelin basic protein (dMBP) and amyloid precursor protein (APP). Gene knockout of TLR4 revised microglial polarization toward the anti-inflammatory phenotype and protected the white matter at an early phase after SAH (24 h), as shown through reduction of toxic metabolites, preservation of myelin, reductions in APP accumulation, reductions in white matter T

    Topics: Animals; Anti-Inflammatory Agents; Brain Injuries; Inflammation; Male; Mice; Mice, Inbred C57BL; Microglia; Myelin Basic Protein; Neuroinflammatory Diseases; Subarachnoid Hemorrhage; Toll-Like Receptor 4; White Matter

2023
Antipsychotic drugs counteract autophagy and mitophagy in multiple sclerosis.
    Proceedings of the National Academy of Sciences of the United States of America, 2021, 06-15, Volume: 118, Issue:24

    Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease characterized by myelin damage followed by axonal and ultimately neuronal loss. The etiology and physiopathology of MS are still elusive, and no fully effective therapy is yet available. We investigated the role in MS of autophagy (physiologically, a controlled intracellular pathway regulating the degradation of cellular components) and of mitophagy (a specific form of autophagy that removes dysfunctional mitochondria). We found that the levels of autophagy and mitophagy markers are significantly increased in the biofluids of MS patients during the active phase of the disease, indicating activation of these processes. In keeping with this idea, in vitro and in vivo MS models (induced by proinflammatory cytokines, lysolecithin, and cuprizone) are associated with strongly impaired mitochondrial activity, inducing a lactic acid metabolism and prompting an increase in the autophagic flux and in mitophagy. Multiple structurally and mechanistically unrelated inhibitors of autophagy improved myelin production and normalized axonal myelination, and two such inhibitors, the widely used antipsychotic drugs haloperidol and clozapine, also significantly improved cuprizone-induced motor impairment. These data suggest that autophagy has a causal role in MS; its inhibition strongly attenuates behavioral signs in an experimental model of the disease. Therefore, haloperidol and clozapine may represent additional therapeutic tools against MS.

    Topics: Animals; Antipsychotic Agents; Autophagy; Autophagy-Related Proteins; Axons; Biomarkers; Clozapine; Cytokines; Demyelinating Diseases; Disease Models, Animal; Glucose; Haloperidol; Inflammation; Interleukin-1beta; Mitochondria; Mitophagy; Models, Biological; Motor Activity; Multiple Sclerosis; Myelin Basic Protein; Myelin Sheath; Stress, Physiological; Tumor Necrosis Factor-alpha

2021
Phloroglucinol derivative compound 21 attenuates cuprizone-induced multiple sclerosis mice through promoting remyelination and inhibiting neuroinflammation.
    Science China. Life sciences, 2020, Volume: 63, Issue:6

    Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease in the central nervous system. The myelin loss is mainly caused by dysfunction of oligodendrocytes and inflammatory responses of microglia and astrocytes further aggravate the demyelination. Current therapies for MS focus on suppressing the overactivated immune response but cannot halt the disease progress, so effective drugs are urgently needed. Compound 21 is a phloroglucinol derivative that has been proved to have an outstanding anti-inflammatory effect. The purpose of the present study is to investigate whether this novel compound is effective in MS. The cuprizone-induced model was used in this study to mimic the pathological progress of MS. The results showed that Compound 21 significantly improved the neurological dysfunction and motor coordination impairment. Luxol Fast Blue staining and myelin basic protein immunostaining demonstrated that Compound 21 remarkably promoted remyelination. In addition, Compound 21 significantly promoted oligodendrocytes differentiation. Furthermore, we found that Compound 21 decreased microglia and astrocytes activities and the subsequent neuroinflammatory response, indicating that the anti-inflammatory effect of Compound 21 was also involved in its neuro-protection. All the data prove that Compound 21 exerts protective effect on MS through promoting remyelination and suppressing neuroinflammation, indicating that Compound 21 might be a potential drug candidate for MS treatment.

    Topics: Animals; Astrocytes; Brain; Cuprizone; Cytokines; Disease Models, Animal; Drug Discovery; Inflammation; Male; Mice; Mice, Inbred C57BL; Microglia; Multiple Sclerosis; Myelin Basic Protein; Oligodendroglia; Phloroglucinol; Remyelination; Treatment Outcome

2020
Neuroprotective effect of l-serine against white matter demyelination by harnessing and modulating inflammation in mice.
    Neuropharmacology, 2019, 03-01, Volume: 146

    Demyelination in white matter is the end product of numerous pathological processes. This study was designed to evaluate the neuroprotective effect of l-serine and the underlying mechanisms against the demyelinating injury of white matter. A model of focal demyelinating lesions (FDL) was established using the two-point stereotactic injection of 0.25% lysophosphatidylcholine (LPC, 10 μg per point) into the corpus callosum of mice. Mice were then intraperitoneally injected with one of three doses of l-serine (114, 342, or 1026 mg/kg) 2 h after FDL, and then twice daily for the next five days. Behavior tests and histological analysis were assessed for up to twenty-eight days post-FDL induction. Electron microscopy was used for ultrastructural investigation. In vitro, we applied primary co-cultures of microglia and oligodendrocytes for oxygen glucose deprivation (OGD). After establishing FDL, l-serine treatment: 1) improved spatial learning, memory and cognitive ability in mice, and relieved anxiety for 4 weeks post-FDL induction; 2) reduced abnormally dephosphorylated neurofilament proteins, increased myelin basic protein, and preserved anatomic myelinated axons; 3) inhibited microglia activation and reduced the release of inflammatory factors; 4) promoted recruitment and proliferation of oligodendrocyte progenitor cells, and the efficiency of subsequent remyelination on day twenty-eight post-FDL induction. In vitro experiments, showed that l-serine not only directly protected against oligodendrocytes from OGD damage, but also provided an indirect protective effect by regulating microglia. In our study, l-serine offered long-lasting behavioral and oligodendrocyte protection and promoted remyelination. Therefore, l-serine may be an effective clinical treatment aganist white matter injury.

    Topics: Animals; Anxiety; Axons; Calcium-Binding Proteins; Corpus Callosum; Demyelinating Diseases; Exploratory Behavior; Inflammation; L-Lactate Dehydrogenase (Cytochrome); Lysophosphatidylcholines; Male; Mice; Mice, Inbred C57BL; Microfilament Proteins; Microglia; Myelin Basic Protein; Myelin Sheath; Oligodendroglia; Serine; Spatial Learning; Spatial Memory

2019
Manual therapy prevents onset of nociceptor activity, sensorimotor dysfunction, and neural fibrosis induced by a volitional repetitive task.
    Pain, 2019, Volume: 160, Issue:3

    Painful and disabling musculoskeletal disorders remain prevalent. In rats trained to perform repetitive tasks leading to signs and dysfunction similar to those in humans, we tested whether manual therapy would prevent the development of the pathologies and symptoms. We collected behavioral, electrophysiological, and histological data from control rats, rats that trained for 5 weeks before performing a high-repetition high-force (HRHF) task for 3 weeks untreated, and trained rats that performed the task for 3 weeks while being treated 3x/week using modeled manual therapy (MMT) to the forearm (HRHF + MMT). The MMT included bilateral mobilization, skin rolling, and long axis stretching of the entire upper limb. High-repetition high-force rats showed decreased performance of the operant HRHF task and increased discomfort-related behaviors, starting after training. HRHF + MMT rats showed improved task performance and decreased discomfort-related behaviors compared with untreated HRHF rats. Subsets of rats were assayed for presence or absence of ongoing activity in C neurons and slow Aδ neurons in their median nerves. Neurons from HRHF rats had a heightened proportion of ongoing activity and altered conduction velocities compared with control and MMT-treated rats. Median nerve branches in HRHF rats contained increased numbers of CD68 macrophages and degraded myelin basic protein, and showed increased extraneural collagen deposition, compared with the other groups. We conclude that the performance of the task for 3 weeks leads to increased ongoing activity in nociceptors, in parallel with behavioral and histological signs of neuritis and nerve injury, and that these pathophysiologies are largely prevented by MMT.

    Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Case-Control Studies; Cumulative Trauma Disorders; Disease Models, Animal; Electrophysiology; Fasting; Female; Gait Disorders, Neurologic; Inflammation; Median Nerve; Musculoskeletal Manipulations; Myelin Basic Protein; Nociceptors; Pain; Rats; Rats, Sprague-Dawley; Statistics, Nonparametric

2019
Treatment of Surgical Brain Injury by Immune Tolerance Induced by Peripheral Intravenous Injection of Biotargeting Nanoparticles Loaded With Brain Antigens.
    Frontiers in immunology, 2019, Volume: 10

    Once excessive, neurological disorders associated with inflammatory conditions will inevitably cause secondary inflammatory damage to brain tissue. Immunosuppressive therapy can reduce the inflammatory state, but resulting infections can expose the patient to greater risk. Using specific immune tolerance organs or tissues from the body, brain antigen immune tolerance treatment can create a minimal immune response to the brain antigens that does not excessively affect the body's immunity. However, commonly used immune tolerance treatment approaches, such as those involving the nasal, gastrointestinal mucosa, thymus or liver portal vein injections, affect the clinical conversion of the therapy due to uncertain drug absorption, or inconvenient routes of administration. If hepatic portal intravenous injections of brain antigens could be replaced by normal peripheral venous infusion, the convenience of immune tolerance treatment could certainly be greatly increased. We attempted to encapsulate brain antigens with minimally immunogenic nanomaterials, to control the sizes of nanoparticles within the range of liver Kupffer cell phagocytosis and to coat the antigens with a coating material that had an affinity for liver cells. We injected these liver drug-loaded nanomaterials via peripheral intravenous injection. With the use of microparticles with liver characteristics, the brain antigens were transported into the liver out of the detection of immune armies in the blood. This approach has been demonstrated in rat models of surgical brain injury. It has been proven that the immune tolerance of brain antigens can be accomplished by peripheral intravenous infusion to achieve the effect of treating brain trauma after operations, which simplifies the clinical operation and could elicit substantial improvements in the future.

    Topics: Animals; Brain Injuries; Cells, Cultured; Cytophagocytosis; Disease Models, Animal; Humans; Immune Tolerance; Inflammation; Injections, Intravenous; Kupffer Cells; Liver; Mice; Mice, Nude; Myelin Basic Protein; Nanoparticles; Neurodegenerative Diseases; Particle Size; T-Lymphocytes

2019
The therapeutic effect of platelet-rich plasma on the experimental autoimmune encephalomyelitis mice.
    Journal of neuroimmunology, 2019, 08-15, Volume: 333

    The use of growth factors is considered to be one of the promising therapeutic strategies for multiple sclerosis (MS). Various studies have shown that platelet-rich plasma (PRP), a bioproduct of concentrated platelets, contains a variety of growth factors such as insulin-like growth factor 1 (IGF-1), platelet-derived growth factor (PDGF), epithelial growth factor (EGF), and transforming growth factor β (TGF-β). The therapeutic roles of PRP, with regard to a wide range of growth factors, on the nervous system have been shown in a limited number of studies. This study aimed to investigate the therapeutic effect of PRP in experimental autoimmune encephalomyelitis (EAE) mouse model of MS. PRP was prepared and intrathecally injected into the EAE mice. The EAE scoring test, the modified neurological severity score (mNSS) test, luxol fast blue and hematoxylin and eosin staining, real-time PCR, and western blotting were used for studying the effect of PRP on the motosensory function, remyelination, inflammatory cell infiltration, gliosis, and inflammatory cytokines expression. PRP administration in treated animals improved the functional abilities, remyelination, and oligodendrogenesis compared to the EAE mice. Furthermore, high numbers of microglia, astrocytes and infiltrating inflammatory cells and also the expression of proinflammatory cytokines were reversed after PRP therapy. In conclusion, these data suggest the PRP as a potential candidate for MS treatment.

    Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Female; Gliosis; Inflammation; Injections, Spinal; Interleukin-1beta; Interleukin-6; Mice; Mice, Inbred C57BL; Myelin Basic Protein; Platelet-Rich Plasma; Spinal Cord; Up-Regulation

2019
Effect of NIR laser therapy by MLS-MiS source against neuropathic pain in rats: in vivo and ex vivo analysis.
    Scientific reports, 2019, 06-26, Volume: 9, Issue:1

    Neuropathic pain is characterized by an uncertain etiology and by a poor response to common therapies. The ineffectiveness and the frequent side effects of the drugs used to counteract neuropathic pain call for the discovery of new therapeutic strategies. Laser therapy proved to be effective for reducing pain sensitivity thus improving the quality of life. However, its application parameters and efficacy in chronic pain must be further analyzed. We investigated the pain relieving and protective effect of Photobiomodulation Therapy in a rat model of compressive mononeuropathy induced by Chronic Constriction Injury of the sciatic nerve (CCI). Laser (MLS-MiS) applications started 7 days after surgery and were performed ten times over a three week period showing a reduction in mechanical hypersensitivity and spontaneous pain that started from the first laser treatment until the end of the experiment. The ex vivo analysis highlighted the protective role of laser through the myelin sheath recovery in the sciatic nerve, inhibition of iNOS expression and enhancement of EAAT-2 levels in the spinal cord. In conclusion, this study supports laser treatment as a future therapeutic strategy in patients suffering from neuropathic pain induced by trauma.

    Topics: Animals; Behavior, Animal; Excitatory Amino Acid Transporter 2; Hyperalgesia; Inflammation; Lasers; Low-Level Light Therapy; Male; Myelin Basic Protein; Myelin Sheath; Neuralgia; Nitric Oxide Synthase Type II; Pain Threshold; Pressure; Quality of Life; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Spinal Cord

2019
Olfactory Dysfunction in Autoimmune Central Nervous System Neuroinflammation.
    Molecular neurobiology, 2018, Volume: 55, Issue:11

    Olfactory dysfunction is an early sign of neuroinflammation of the central nervous system (CNS). Microgliosis and astrogliosis are representative pathological changes that develop during neuroinflammation of CNS tissues. Autoimmune CNS inflammation, including human multiple sclerosis, is an occasional cause of olfactory disorders. We evaluated whether gliosis and olfactory dysfunction developed in animals with experimental autoimmune encephalomyelitis (EAE), a model of human multiple sclerosis. Neuroinflammatory lesions characterized by infiltration of inflammatory cells and microglial cell activation were occasionally found in the olfactory bulbs of EAE-affected rats. Microglial activation, visualized by immunohistochemical staining of ionized calcium binding protein (Iba)-1, and astrogliosis in the olfactory bulb were also evident in the olfactory bulb of EAE rats. Inflammatory cells were found along the olfactory nerves and in the olfactory submucosa. Western blot analysis of olfactory marker protein (OMP) levels showed that OMP expression was significantly downregulated in the olfactory mucosa of EAE rats. On the buried food test, EAE-affected mice required significantly more time to find a bait pellet. Collectively, the results suggest that the olfactory dysfunction of EAE is closely linked to downregulation of OMP and the development of inflammatory foci in the olfactory system in an animal model of human multiple sclerosis.

    Topics: Animals; Behavior, Animal; Biomarkers; Calcium-Binding Proteins; Central Nervous System; Encephalomyelitis, Autoimmune, Experimental; Female; Glial Fibrillary Acidic Protein; Guinea Pigs; Immunization; Inflammation; Mice, Inbred C57BL; Microfilament Proteins; Models, Biological; Myelin Basic Protein; Olfactory Bulb; Olfactory Mucosa; Rats, Sprague-Dawley; Spinal Cord

2018
CXCR6
    Proceedings of the National Academy of Sciences of the United States of America, 2018, 10-16, Volume: 115, Issue:42

    Memory T helper (mTh) cells play important roles in the reinfection of pathogens and drive the pathogenesis of diseases. While recent studies have characterized the pathogenic mTh2 cell subpopulations driving allergic inflammation, those that induce immune responses against helminth infection remain unknown. We found that IL-5-producing CXCR6

    Topics: Animals; Eosinophils; Fertility; Immunologic Memory; Inflammation; Interleukin-1 Receptor-Like 1 Protein; Lung; Mice; Mice, Inbred BALB C; Myelin Basic Protein; Nippostrongylus; Receptors, CXCR6; Receptors, Interleukin; Strongylida Infections; T-Lymphocytes, Regulatory; Th1 Cells; Th2 Cells

2018
Effect of CXCR2 Inhibition on Behavioral Outcomes and Pathology in Rat Model of Neuromyelitis Optica.
    Journal of immunology research, 2018, Volume: 2018

    To reduce immune-mediated damage in a rat model of neuromyelitis optica (NMO) by blocking neutrophil migration using SCH527123, a drug that inhibits CXCR2.. Neuromyelitis optica is a relapsing autoimmune disease that preferentially targets the optic nerves and spinal cord leading to blindness and paralysis. Part of the immunopathogenesis of this disease is thought to involve neutrophils, which are present within NMO lesions. We tested the effect of blocking neutrophil migration in an NMO rat model.. The Lewis rat model of NMO uses a myelin-reactive experimental autoimmune encephalomyelitis (EAE) background with passive transfer of pooled human antibody from patients with aquaporin-4 (AQP4) seropositive NMO at onset of EAE symptoms. We treated rats early in the course of EAE with CXCR2 inhibitor and assessed the extent of neutrophil infiltration into the spinal cord and the extent of AQP4 depletion.. CXCR2 inhibitor decreased neutrophil migration into the spinal cord of AQP4 IgG-treated EAE rats. However, there was no difference in the acute behavioral signs of EAE or the extent and distribution of AQP4 lesions. This suggests that neutrophils are not centrally involved in the immunopathogenesis of the Lewis rat NMO disease model.. CXCR2 inhibitor blocks neutrophil migration into the spinal cord during EAE but does not significantly reduce inflammation or AQP4 lesions in the Lewis rat model of NMO.

    Topics: Animals; Antibodies; Aquaporin 4; Behavior, Animal; Benzamides; Cell Movement; Cyclobutanes; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Inflammation; Myelin Basic Protein; Neuromyelitis Optica; Neutrophils; Rats; Rats, Inbred Lew; Receptors, Interleukin-8B; Swine

2018
LPS-matured CD11c+ bone marrow-derived dendritic cells can initiate autoimmune pathology with minimal injection site inflammation.
    Laboratory animals, 2017, Volume: 51, Issue:3

    The pathogenesis of human autoimmune disorders is incompletely understood. This has led to the development of numerous murine models in which the pathogenesis of autoimmunity can be probed and the efficacy of novel therapies can be tested. One of the most widely-used murine models of autoimmunity is experimental autoimmune encephalomyelitis (EAE). To induce autoimmune pathology, mice are often immunized with an autoantigen alongside an adjuvant, typically complete Freund's adjuvant (CFA). Unfortunately, CFA causes significant inflammation at the site of administration. Despite the well-recognized complication of injection site inflammation, CFA with autoantigen immunization is widely used to induce central nervous system autoimmunity. We performed a literature review which allowed us to estimate that over 10,000 mice were immunized with CFA in published EAE studies in 2013. In this study, we demonstrated that subcutaneously administered myelin basic protein (MBP)-pulsed CD11c+ bone marrow-derived dendritic cells (BMDC) were as effective at inducing EAE as subcutaneously administered MBP plus CFA. Importantly, we also discovered that the CD11c+ BMDC caused significantly less injection site inflammation than MBP plus CFA immunization. This study demonstrated that the use of CD11c+ BMDC can enable the development of autopathogenic T-cells to be studied in vivo without the unwanted side-effects of long-lasting injection site inflammation. This model represents a significant refinement to existing EAE models and may lead to the improvement of the welfare of experimental mice used to study the development of autoimmunity in vivo.

    Topics: Animals; Antigen Presentation; Autoantigens; Bone Marrow Cells; Dendritic Cells; Encephalomyelitis, Autoimmune, Experimental; Humans; Inflammation; Mice; Myelin Basic Protein

2017
Demyelination-Induced Inflammation Attracts Newly Born Neurons to the White Matter.
    Molecular neurobiology, 2017, Volume: 54, Issue:8

    There is compelling evidence that microglial activation negatively impacts neurogenesis. However, microglia have also been shown to promote recruitment of newly born neurons to injured areas of the gray matter. In the present study, we explored whether demyelination-triggered inflammation alters the process of neurogenesis in the white matter. A 2-μl solution of 0.04 % ethidium bromide was stereotaxically injected into the corpus callosum of adult male rats. Brain inflammation was dampened by daily injections of progesterone (5 mg/kg, s.c.) for 14 days. Control rats received oil (s.c.). Newly born neurons (DCX and Tbr2), microglia (Iba-1), astrocytes (vimentin or GFAP), oligodendrocyte progenitor cells (OPCs; NG2), and mature oligodendrocytes (CC-1) were monitored in the vicinity of demyelination site using immunofluorescent staining. Western blot was used to explore microglial polarization using M1 (iNOS) and M2 (arginase-1) markers. Focal demyelination elicited strong microglial and astroglial activation and reduced the number of OPCs at the site of demyelination. This inflammatory response was associated with enhanced number of newly born neurons in the white matter and the subventricular zone (SVZ). A proportion of newly born neurons within the white matter showed features of OPCs. Interestingly, blunting brain inflammation led to reduced neurogenesis around the demyelination area and in the SVZ. These data suggest that the white matter inflammation creates a conducive environment for the recruitment of newly born neurons. The fact that a sizable fraction of these newly born neurons adopt OPC features suggests that they could contribute to the remyelination process.

    Topics: Animals; Astrocytes; Cell Differentiation; Corpus Callosum; Demyelinating Diseases; Doublecortin Protein; Inflammation; Male; Microglia; Myelin Basic Protein; Myelin Sheath; Neurons; Oligodendroglia; Progesterone; Rats, Sprague-Dawley; White Matter

2017
Mice lacking BCAS1, a novel myelin-associated protein, display hypomyelination, schizophrenia-like abnormal behaviors, and upregulation of inflammatory genes in the brain.
    Glia, 2017, Volume: 65, Issue:5

    The abnormal expression and function of myelin-related proteins contribute to nervous system dysfunction associated with neuropsychiatric disorders; however, the underlying mechanism of this remains unclear. We found here that breast carcinoma amplified sequence 1 (BCAS1), a basic protein abundant in the brain, was expressed specifically in oligodendrocytes and Schwann cells, and that its expression level was decreased by demyelination. This suggests that BCAS1 is a novel myelin-associated protein. BCAS1 knockout mice displayed schizophrenia-like behavioral abnormalities and a tendency toward reduced anxiety-like behaviors. Moreover, we found that the loss of BCAS1 specifically induced hypomyelination and the expression of inflammation-related genes in the brain. These observations provide a novel insight into the functional link between oligodendrocytes and inflammation and/or abnormal behaviors.

    Topics: Animals; Brain; Demyelinating Diseases; Inflammation; Mice, Knockout; Myelin Basic Protein; Myelin Sheath; Neoplasm Proteins; Oligodendroglia; Schizophrenia; Transcriptional Activation; Up-Regulation

2017
Perinatal chronic hypoxia induces cortical inflammation, hypomyelination, and peripheral myelin-specific T cell autoreactivity.
    Journal of leukocyte biology, 2016, Volume: 99, Issue:1

    pCH is an important risk factor for brain injury and long-term morbidity in children, occurring during the developmental stages of neurogenesis, neuronal migration, and myelination. We show that a rodent model of pCH results in an early decrease in mature myelin. Although pCH does increase progenitor oligodendrocytes in the developing brain, BrdU labeling revealed a loss in dividing progenitor oligodendrocytes, indicating a defect in mature cell replacement and myelinogenesis. Mice continued to exhibited hypomyelination, concomitant with long-term impairment of motor function, weeks after cessation of pCH. The implication of a novel neuroimmunologic interplay, pCH also induced a significant egress of infiltrating CD4 T cells into the developing brain. This pCH-mediated neuroinflammation included oligodendrocyte-directed autoimmunity, with an increase in peripheral myelin-specific CD4 T cells. Thus, both the loss of available, mature, myelin-producing glial cells and an active increase in autoreactive, myelin-specific CD4 T cell infiltration into pCH brains may contribute to early pCH-induced hypomyelination in the developing CNS. The elucidation of potential mechanisms of hypoxia-driven autoimmunity will expand our understanding of the neuroimmune axis during perinatal CNS disease states that may contribute to long-term functional disability.

    Topics: Animals; Autoimmunity; Behavior, Animal; CD4-Positive T-Lymphocytes; Cerebral Cortex; Disease Models, Animal; Female; Hypoxia; Inflammation; Mice; Motor Activity; Myelin Basic Protein; Myelin Sheath; Neuroglia; Pregnancy; T-Cell Antigen Receptor Specificity; T-Lymphocyte Subsets

2016
Characterization of White Matter Injury in a Rat Model of Chronic Cerebral Hypoperfusion.
    Stroke, 2016, Volume: 47, Issue:2

    Chronic cerebral hypoperfusion can lead to ischemic white matter injury resulting in vascular dementia. To characterize white matter injury in vascular dementia, we investigated disintegration of diverse white matter components using a rat model of chronic cerebral hypoperfusion.. Chronic cerebral hypoperfusion was modeled in Wistar rats by permanent occlusion of the bilateral common carotid arteries. We performed cognitive behavioral tests, including the water maze task, odor discrimination task, and novel object test; histological investigation of neuroinflammation, oligodendrocytes, myelin basic protein, and nodal or paranodal proteins at the nodes of Ranvier; and serial diffusion tensor imaging. Cilostazol was administered to protect against white matter injury.. Diverse cognitive impairments were induced by chronic cerebral hypoperfusion. Disintegration of white matter was characterized by neuroinflammation, loss of oligodendrocytes, attenuation of myelin density, structural derangement at the nodes of Ranvier, and disintegration of white matter tracts. Cilostazol protected against cognitive impairments and white matter disintegration.. White matter injury induced by chronic cerebral hypoperfusion can be characterized by disintegration of diverse white matter components. Cilostazol might be a therapeutic strategy against white matter disintegration in patients with vascular dementia.

    Topics: Animals; Behavior, Animal; Brain Ischemia; Carotid Stenosis; Chronic Disease; Cilostazol; Cognition; Dementia, Vascular; Diffusion Tensor Imaging; Disease Models, Animal; Hippocampus; Inflammation; Leukoencephalopathies; Myelin Basic Protein; Neuroprotective Agents; Neuropsychological Tests; Oligodendroglia; Ranvier's Nodes; Rats; Rats, Wistar; Tetrazoles; White Matter

2016
Myelin Basic Protein-Induced Production of Tumor Necrosis Factor-α and Interleukin-6, and Presentation of the Immunodominant Peptide MBP85-99 by B Cells from Patients with Relapsing-Remitting Multiple Sclerosis.
    PloS one, 2016, Volume: 11, Issue:1

    B cells are involved in driving relapsing-remitting multiple sclerosis (RRMS), as demonstrated by the positive effect of therapeutic B-cell depletion. Aside from producing antibodies, B cells are efficient antigen-presenting and cytokine-secreting cells. Diverse polyclonal stimuli have been used to study cytokine production by B cells, but here we used the physiologically relevant self-antigen myelin basic protein (MBP) to stimulate B cells from untreated patients with RRMS and healthy donors. Moreover, we took advantage of the unique ability of the monoclonal antibody MK16 to recognize the immunodominant peptide MBP85-99 presented on HLA-DR15, and used it as a probe to directly study B-cell presentation of self-antigenic peptide. The proportions of B cells producing TNF-α or IL-6 after stimulation with MBP were higher in RRMS patients than in healthy donors, indicating a pro-inflammatory profile for self-reactive patient B cells. In contrast, polyclonal stimulation with PMA + ionomycin and MBP revealed no difference in cytokine profile between B cells from RRMS patients and healthy donors. Expanded disability status scale (EDSS) as well as multiple sclerosis severity score (MSSS) correlated with reduced ability of B cells to produce IL-10 after stimulation with MBP, indicative of diminished B-cell immune regulatory function in patients with the most severe disease. Moreover, EDSS correlated positively with the frequencies of TNF-α, IL-6 and IL-10 producing B cells after polyclonal stimulation. Patient-derived, IL-10-producing B cells presented MBP85-99 poorly, as did IL-6-producing B cells, particulary in the healthy donor group. B cells from MS patients thus present antigen to T cells in a pro-inflammatory context. These findings contribute to understanding the therapeutic effects of B-cell depletion in human autoimmune diseases, including MS.

    Topics: Adult; Autoantigens; B-Lymphocytes; Cytokines; Female; HLA-DR Serological Subtypes; Humans; Inflammation; Interleukin-10; Interleukin-6; Leukocytes, Mononuclear; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein; Peptide Fragments; Severity of Illness Index; Tumor Necrosis Factor-alpha

2016
Environmental Enrichment Stimulates Immune Cell Secretion of Exosomes that Promote CNS Myelination and May Regulate Inflammation.
    Cellular and molecular neurobiology, 2016, Volume: 36, Issue:3

    Environmental enrichment (EE) consists of increased physical, intellectual, and social activity, and has wide-ranging effects, including enhancing cognition, learning and memory, and motor coordination. Animal studies have demonstrated that EE improves outcome of brain trauma and neurodegenerative disorders, including demyelinating diseases like multiple sclerosis, making it a promising therapeutic option. However, the complexity of applying a robust EE paradigm makes clinical use difficult. A better understanding of the signaling involved in EE-based neuroprotection may allow for development of effective mimetics as an alternative. In prior work, we found that exosomes isolated from the serum of rats exposed to EE impact CNS myelination. Exosomes are naturally occurring nanovesicles containing mRNA, miRNA, and protein, which play important roles in cell function, disease, and immunomodulation. When applied to hippocampal slice cultures or nasally administered to naïve rats, EE-serum exosomes significantly increase myelin content, oligodendrocyte precursor (OPC) and neural stem cell levels, and reduce oxidative stress (OS). We found that rat EE exosomes were enriched in miR-219, which is necessary and sufficient for OPC differentiation into myelinating cells. Thus, peripherally produced exosomes may be a useful therapy for remyelination. Here, we aim to better characterize the impact of EE on CNS health and to determine the cellular source of nutritive exosomes found in serum. We found that exosomes isolated from various circulating immune cell types all increased slice culture myelin content, contained miR-219, and reduced OS, suggesting that EE globally alters immune function in a way that supports brain health.

    Topics: Animals; Axons; B-Lymphocytes; Brain; Cells, Cultured; Central Nervous System; Dendritic Cells; Environment; Exosomes; Gene Expression Profiling; Gene Expression Regulation; Gliosis; Inflammation; Leukocytes; Lipopolysaccharides; Lymph Nodes; Male; MicroRNAs; Myelin Basic Protein; Myelin Sheath; Oxidative Stress; Rats, Wistar; Spleen; T-Lymphocytes

2016
Adenosine A1-Receptors Modulate mTOR Signaling to Regulate White Matter Inflammatory Lesions Induced by Chronic Cerebral Hypoperfusion.
    Neurochemical research, 2016, Volume: 41, Issue:12

    We sought to investigate the role of the adenosine A1 receptors (A1ARs) in white matter lesions under chronic cerebral hypoperfusion (CCH) and explore the potential repair mechanisms by activation of the receptors. A right unilateral common carotid artery occlusion (rUCCAO) method was used to construct a CCH model. 2-chloro-N6-cyclopentyladenosine (CCPA), a specific agonist of A1ARs, was used to explore the biological mechanisms of repair in white matter lesions under CCH. The expression of mammalian target of rapamycin (mTOR), phosphorylation of mTOR (P-mTOR), myelin basic protein (MBP, a marker of white matter myelination) were detected by Western-blot. Pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and anti-inflammatory cytokine interleukin-10 (IL-10) levels were determined by ELISA. Compared with the control groups on week 2, 4 and 6, in CCPA-treated groups, the ratio of P-mTOR/mTOR, expression of MBP and IL-10 increased markedly, while the expression of TNF-α reduced at week 6. In conclusion, A1ARs appears to reduce inflammation in white matter via the mTOR signaling pathway in the rUCCAO mice. Therefore, A1ARs may serve as a therapeutic target during the repair of white matter lesions under CCH.

    Topics: Animals; Brain; Carotid Artery, Common; Carotid Stenosis; Inflammation; Interleukin-10; Leukoencephalopathies; Ligation; Male; Mice, Inbred C57BL; Myelin Basic Protein; Phosphorylation; Receptor, Adenosine A1; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha

2016
Inflammation Combined with Ischemia Produces Myelin Injury and Plaque-Like Aggregates of Myelin, Amyloid-β and AβPP in Adult Rat Brain.
    Journal of Alzheimer's disease : JAD, 2015, Volume: 46, Issue:2

    Ischemia, white matter injury, and Alzheimer's disease (AD) pathologies often co-exist in aging brain. How one condition predisposes to, interacts with, or perhaps causes the others remains unclear.. To better understand the link between ischemia, white matter injury, and AD, adult rats were administered lipopolysaccharide (LPS) to serve as an inflammatory stimulus, and 24 h later subjected to 20-min focal cerebral ischemia (IS) followed by 30-min hypoxia (H).. Myelin and axonal damage, as well as amyloid-β (Aβ) and amyloid-β protein precursor (AβPP) deposition were examined by Western blot and immunocytochemistry following LPS/IS/H. Findings were compared to the 5XFAD mouse AD brain.. Myelin/axonal injury was observed bilaterally in cortex following LPS/IS/H, along with an increase in IL-1, granzyme B, and LPS. AβPP deposition was present in ischemic striatum in regions of myelin loss. Aβ(1-42) and AβPP were deposited in small foci in ischemic cortex that co-localized with myelin aggregates. In the 5XFAD mouse AD model, cortical amyloid plaques also co-localized with myelin aggregates.. LPS/IS/H produce myelin injury and plaque-like aggregates of myelin. AβPP and Aβ co-localize with these myelin aggregates.

    Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Brain Ischemia; Disease Models, Animal; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Transgenic; Myelin Basic Protein; Myelin Sheath; Peptide Fragments; Plaque, Amyloid; Rats; Rats, Sprague-Dawley

2015
Fructus mume alleviates chronic cerebral hypoperfusion-induced white matter and hippocampal damage via inhibition of inflammation and downregulation of TLR4 and p38 MAPK signaling.
    BMC complementary and alternative medicine, 2015, Apr-22, Volume: 15

    Fructus mume (F. mume) has been used as a traditional medicine for many years in Asian countries. The present study was designed to determine the effect of a 70% ethanol extract of F. mume on white matter and hippocampal damage induced by chronic cerebral hypoperfusion.. Permanent bilateral common carotid artery occlusion (BCCAo) was performed on male Wistar rats to induce chronic cerebral hypoperfusion. Daily oral administration of F. mume (200 mg/kg) was initiated 21 days after BCCAo and continued for 42 days. The experimental groups in this study were divided into three groups: a sham-operated group, a BCCAo group, and a BCCAo group that was administered with the F. mume extract. The activation of glial cells, including microglia and astrocytes, and the levels of myelin basic protein (MBP), inflammatory mediators, Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and p38 mitogen-activated protein kinase (MAPK) phosphorylation were measured in brains from rats subjected to chronic BCCAo.. Our results revealed that F. mume alleviates the reduction in MBP expression caused by chronic BCCAo in the white matter and the hippocampus and significantly attenuates microglial and astrocytic activation induced by chronic BCCAo in the optic tract of white matter. In addition, F. mume treatment reduced the increased expression of cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β) and interleukin-6 (IL-6), as well as the activation of TLR4/MyD88 and p38 MAPK signaling, in the hippocampus of rats subjected to chronic BCCAo.. Taken together, our findings demonstrate that brain injury induced by chronic BCCAo is ameliorated by the anti-inflammatory effects of F. mume via inhibition of MBP degradation, microglial and astrocytic activation, increased inflammatory mediator expression, and activated intracellular signalings, including TLR4 and p38 MAPK, implying that F. mume is potentially an effective therapeutics for the treatment of vascular dementia.

    Topics: Animals; Anti-Inflammatory Agents; Brain; Brain Ischemia; Cytokines; Dementia, Vascular; Down-Regulation; Drugs, Chinese Herbal; Hippocampus; Inflammation; Inflammation Mediators; Male; Myelin Basic Protein; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Phytotherapy; Prunus; Rats, Wistar; Signal Transduction; Toll-Like Receptor 4; White Matter

2015
Systemic inflammation in early neonatal mice induces transient and lasting neurodegenerative effects.
    Journal of neuroinflammation, 2015, Apr-29, Volume: 12

    The inflammatory mediator lipopolysaccharide (LPS) has been shown to induce acute gliosis in neonatal mice. However, the progressive effects on the murine neurodevelopmental program over the week that follows systemic inflammation are not known. Thus, we investigated the effects of repeated LPS administration in the first postnatal week in mice, a condition mimicking sepsis in late preterm infants, on the developing central nervous system (CNS).. Systemic inflammation was induced by daily intraperitoneal administration (i.p.) of LPS (6 mg/kg) in newborn mice from postnatal day (PND) 4 to PND6. The effects on neurodevelopment were examined by staining the white matter and neurons with Luxol Fast Blue and Cresyl Violet, respectively. The inflammatory response was assessed by quantifying the expression/activity of matrix metalloproteinases (MMP), toll-like receptor (TLR)-4, high mobility group box (HMGB)-1, and autotaxin (ATX). In addition, B6 CX3CR1(gfp/+) mice combined with cryo-immunofluorescence were used to determine the acute, delayed, and lasting effects on myelination, microglia, and astrocytes.. LPS administration led to acute body and brain weight loss as well as overt structural changes in the brain such as cerebellar hypoplasia, neuronal loss/shrinkage, and delayed myelination. The impaired myelination was associated with alterations in the proliferation and differentiation of NG2 progenitor cells early after LPS administration, rather than with excessive phagocytosis by CNS myeloid cells. In addition to disruptions in brain architecture, a robust inflammatory response to LPS was observed. Quantification of inflammatory biomarkers revealed decreased expression of ATX with concurrent increases in HMGB1, TLR-4, and MMP-9 expression levels. Acute astrogliosis (GFAP(+) cells) in the brain parenchyma and at the microvasculature interface together with parenchymal microgliosis (CX3CR1(+) cells) were also observed. These changes preceded the migration/proliferation of CX3CR1(+) cells around the vessels at later time points and the subsequent loss of GFAP(+) astrocytes.. Collectively, our study has uncovered a complex innate inflammatory reaction and associated structural changes in the brains of neonatal mice challenged peripherally with LPS. These findings may explain some of the neurobehavioral abnormalities that develop following neonatal sepsis.

    Topics: Age Factors; Anethole Trithione; Animals; Animals, Newborn; Body Weight; Cerebellum; CX3C Chemokine Receptor 1; Demyelinating Diseases; Developmental Disabilities; Gene Expression Regulation; Green Fluorescent Proteins; HMGB1 Protein; Inflammation; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Myelin Basic Protein; Nervous System Malformations; Neurodegenerative Diseases; Receptors, Chemokine; Time Factors; Toll-Like Receptor 4

2015
MOG-induced experimental autoimmune encephalomyelitis in the rat species triggers anti-neurofascin antibody response that is genetically regulated.
    Journal of neuroinflammation, 2015, Oct-29, Volume: 12

    Ιn multiple sclerosis (MS), axonal damage leads to permanent neurological disabilities and the spreading of the autoimmune response to axonal antigens is implicated in disease progression. Experimental autoimmune encephalomyelitis (EAE) provides an animal model that mimics MS. Using different EAE models, we investigated the pathophysiological basis of epitope spreading to neurofascin, a protein localized at the node of Ranvier and its regulation by non-MHC genes.. We used two different EAE models in DA rat; one which is induced with myelin oligodendrocyte glycoprotein (MOG) which leads to disease characterized by profound demyelination, and the second which is induced with myelin basic protein (MBP) peptide 63-88 which results in severe central nervous system (CNS) inflammation but little or no demyelination. We determined anti-neurofascin antibody levels during the course of disease. Furthermore, the anti-neurofascin IgG response was correlated with clinical parameters in 333 (DAxPVG.1AV1) x DA rats on which we performed linkage analysis to determine if epitope spreading to neurofascin was affected by non-MHC genes.. Spreading of the antibody response to neurofascin occurred in demyelinating MOG-induced EAE but not in EAE induced with MBP peptide 63-88. Anti-neurofascin IgG levels correlated with disease severity in (DAxPVG.1AV1) x DA rats, and a genomic region on chromosome 3 was found to influence this response.. Inter-molecular epitope spreading to neurofascin correlates with disease severity in MOG-EAE is dependent on extensive demyelination and is influenced by non-MHC genes. The findings presented here may shed light on factors involved in the severity of MS and its genetics.

    Topics: Animals; Cell Adhesion Molecules; Demyelinating Diseases; Encephalomyelitis, Autoimmune, Experimental; Epitopes; Female; Immunoglobulin G; Inflammation; Male; Myelin Basic Protein; Myelin-Oligodendrocyte Glycoprotein; Nerve Growth Factors; Peptides; Rats

2015
Neurotrophin 3 transduction augments remyelinating and immunomodulatory capacity of neural stem cells.
    Molecular therapy : the journal of the American Society of Gene Therapy, 2014, Volume: 22, Issue:2

    Neural stem cells (NSCs) have therapeutic potential in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS); however, to date, their use has resulted in only limited clinical and pathological improvement. To enhance their therapeutic capacity, in the present study, we transduced bone marrow-derived NSCs (BM-NSCs) with neurotrophin 3 (NT-3), a potent neurotrophic factor that is both neuroprotective and immunomodulatory. We found that BM-NSCs transduced with NT-3 reduced central nervous system (CNS) inflammation and neurological deficits in ongoing EAE significantly more than conventional NSC therapy, and, in addition, had the following advantages: (i) enhanced BM-NSC proliferation and differentiation into oligodendrocytes and neurons, as well as inhibited differentiation into astrocytes, thus promoting remyelination and neuronal repopulation, and reducing astrogliosis; (ii) enhanced anti-inflammatory capacity of BM-NSCs, thus more effectively suppressing CNS inflammation and accelerating remyelination; (iii) the easy accessibility of BM-NSCs provides another advantage over brain-derived NSCs for MS therapy; and (iv) a novel Tet-on system we used enables efficient control of NT-3 expression. Thus, our study provides a novel approach to break the vicious inflammation-demyelination cycle, and could pave the way to an easily accessible and highly effective therapy for CNS inflammatory demyelination.

    Topics: Animals; Astrocytes; Bone Marrow Cells; Cell Movement; Cell Proliferation; Encephalomyelitis, Autoimmune, Experimental; Gene Expression; Genes, Reporter; Glial Cell Line-Derived Neurotrophic Factor; Immunomodulation; Inflammation; Interleukin-10; Mice; Mucolipidoses; Myelin Basic Protein; Myelin Sheath; Neural Stem Cells; Neurons; Neurotrophin 3; Oligodendroglia; Transduction, Genetic

2014
Ulinastatin attenuates experimental autoimmune encephalomyelitis by enhancing anti-inflammatory responses.
    Neurochemistry international, 2014, Volume: 64

    Multiple sclerosis (MS) is a common inflammatory and demyelinating neurological disease. Experimental autoimmune encephalomyelitis (EAE), an animal model of MS, has been widely used to test MS treatment methods. Ulinastatin (UTI), a drug used to treat acute inflammatory disorders, has been tested in animal models of autoimmune inflammatory diseases, such as ulcerative colitis and crescentic glomerulonephritis. We recently found that UTI has a neuroprotective effect on EAE by reducing oligodendrocyte apoptosis and demyelination. The anti-inflammatory effects of UTI on EAE/MS, however, have never been investigated. We have therefore evaluated the anti-inflammatory effects of UTI in EAE and explored the mechanisms underlying this effect. EAE was induced in mice with and without UTI treatment. Inflammation and demyelination of spinal cords were evaluated by staining with hematoxylin and eosin and with Luxol fast blue, respectively. Inflammatory markers in serum were analyzed by the Luminex method, and spinal cords were evaluated by immunofluorescence and Western blotting. UTI significantly lowered the clinical and pathological scores and the serum concentrations of the inflammatory cytokines interleukin (IL)-1β, IL-6, and matrix metal protease-9 (MMP-9). UTI also reduced the expression of tumor necrosis factor-alpha (TNF-α)/nuclear factor kappaB (NF-κB)/inducible nitric oxide synthase (iNOS) proteins and decreased CD11b(+) cells in spinal cord lesions. UTI may protect against EAE in mice by suppressing inflammatory responses. We think that UTI might be a potential therapeutic agent for MS.

    Topics: Animals; Cytokines; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Glycoproteins; Inflammation; Interleukin-6; Mice; Mice, Inbred C57BL; Myelin Basic Protein; Spinal Cord; Tumor Necrosis Factor-alpha

2014
Diffusion basis spectrum imaging detects and distinguishes coexisting subclinical inflammation, demyelination and axonal injury in experimental autoimmune encephalomyelitis mice.
    NMR in biomedicine, 2014, Volume: 27, Issue:7

    Clinicopathological paradox has hampered significantly the effective assessment of the efficacy of therapeutic intervention for multiple sclerosis. Neuroimaging biomarkers of tissue injury could guide more effective treatment by accurately reflecting the underlying subclinical pathologies. Diffusion tensor imaging-derived directional diffusivity and anisotropy indices have been applied to characterize white matter disorders. However, these biomarkers are sometimes confounded by the complex pathologies seen in multiple sclerosis and its animal models. Recently, a novel technique of diffusion basis spectrum imaging has been developed to quantitatively assess axonal injury, demyelination and inflammation in a mouse model of inflammatory demyelination. Lenaldekar, which inhibits T-cell expansion in a non-cytolytic manner, has been shown to suppress relapses and preserve white matter integrity in mice with experimental autoimmune encephalomyelitis. In this study, relapsing-remitting experimental autoimmune encephalomyelitis was induced through active immunization of SJL/J mice with a myelin proteolipid protein peptide. The therapeutic efficacy of Lenaldekar treatment was evaluated via daily clinical score, cross-sectional ex vivo diffusion basis spectrum imaging examination and histological analysis. Lenaldekar greatly reduced relapse severity and protected white matter integrity in these experimental autoimmune encephalomyelitis mice. Diffusion basis spectrum imaging-derived axial diffusivity, radial diffusivity and restricted diffusion tensor fraction accurately reflected axonal injury, myelin integrity and inflammation-associated cellularity change, respectively. These results support the potential use of diffusion basis spectrum imaging as an effective outcome measure for preclinical drug evaluation.

    Topics: Animals; Axons; Biomarkers; Demyelinating Diseases; Diffusion Tensor Imaging; Encephalomyelitis, Autoimmune, Experimental; Female; Hydrazones; Indoles; Inflammation; Mice; Myelin Basic Protein; Quinolines; Recurrence

2014
Thymosin β4 up-regulation of microRNA-146a promotes oligodendrocyte differentiation and suppression of the Toll-like proinflammatory pathway.
    The Journal of biological chemistry, 2014, Jul-11, Volume: 289, Issue:28

    Thymosin β4 (Tβ4), a G-actin-sequestering peptide, improves neurological outcome in rat models of neurological injury. Tissue inflammation results from neurological injury, and regulation of the inflammatory response is vital for neurological recovery. The innate immune response system, which includes the Toll-like receptor (TLR) proinflammatory signaling pathway, regulates tissue injury. We hypothesized that Tβ4 regulates the TLR proinflammatory signaling pathway. Because oligodendrogenesis plays an important role in neurological recovery, we employed an in vitro primary rat embryonic cell model of oligodendrocyte progenitor cells (OPCs) and a mouse N20.1 OPC cell line to measure the effects of Tβ4 on the TLR pathway. Cells were grown in the presence of Tβ4, ranging from 25 to 100 ng/ml (RegeneRx Biopharmaceuticals Inc., Rockville, MD), for 4 days. Quantitative real-time PCR data demonstrated that Tβ4 treatment increased expression of microRNA-146a (miR-146a), a negative regulator the TLR signaling pathway, in these two cell models. Western blot analysis showed that Tβ4 treatment suppressed expression of IL-1 receptor-associated kinase 1 (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6), two proinflammatory cytokines of the TLR signaling pathway. Transfection of miR-146a into both primary rat embryonic OPCs and mouse N20.1 OPCs treated with Tβ4 demonstrated an amplification of myelin basic protein (MBP) expression and differentiation of OPC into mature MBP-expressing oligodendrocytes. Transfection of anti-miR-146a nucleotides reversed the inhibitory effect of Tβ4 on IRAK1 and TRAF6 and decreased expression of MBP. These data suggest that Tβ4 suppresses the TLR proinflammatory pathway by up-regulating miR-146a.

    Topics: Animals; Cell Differentiation; Cytokines; Hep G2 Cells; Humans; Inflammation; Interleukin-1 Receptor-Associated Kinases; Mice; MicroRNAs; Myelin Basic Protein; Oligodendroglia; Rats; Rats, Wistar; Signal Transduction; Thymosin; TNF Receptor-Associated Factor 6; Toll-Like Receptors; Up-Regulation

2014
Complex pattern of interaction between in utero hypoxia-ischemia and intra-amniotic inflammation disrupts brain development and motor function.
    Journal of neuroinflammation, 2014, Aug-01, Volume: 11

    Infants born preterm commonly suffer from a combination of hypoxia-ischemia (HI) and infectious perinatal inflammatory insults that lead to cerebral palsy, cognitive delay, behavioral issues and epilepsy. Using a novel rat model of combined late gestation HI and lipopolysaccharide (LPS)-induced inflammation, we tested our hypothesis that inflammation from HI and LPS differentially affects gliosis, white matter development and motor impairment during the first postnatal month.. Pregnant rats underwent laparotomy on embryonic day 18 and transient systemic HI (TSHI) and/or intra-amniotic LPS injection. Shams received laparotomy and anesthesia only. Pups were born at term. Immunohistochemistry with stereological estimates was performed to assess regional glial loads, and western blots were performed for protein expression. Erythropoietin ligand and receptor levels were quantified using quantitative PCR. Digigait analysis detected gait deficits. Statistical analysis was performed with one-way analysis of variance and post-hoc Bonferonni correction.. Microglial and astroglial immunolabeling are elevated in TSHI + LPS fimbria at postnatal day 2 compared to sham (both P < 0.03). At postnatal day 15, myelin basic protein expression is reduced by 31% in TSHI + LPS pups compared to shams (P < 0.05). By postnatal day 28, white matter injury shifts from the acute injury pattern to a chronic injury pattern in TSHI pups only. Both myelin basic protein expression (P < 0.01) and the phosphoneurofilament/neurofilament ratio, a marker of axonal dysfunction, are reduced in postnatal day 28 TSHI pups (P < 0.001). Erythropoietin ligand to receptor ratios differ between brains exposed to TSHI and LPS. Gait analyses reveal that all groups (TSHI, LPS and TSHI + LPS) are ataxic with deficits in stride, paw placement, gait consistency and coordination (all P < 0.001).. Prenatal TSHI and TSHI + LPS lead to different patterns of injury with respect to myelination, axon integrity and gait deficits. Dual injury leads to acute alterations in glial response and cellular inflammation, while TSHI alone causes more prominent chronic white matter and axonal injury. Both injuries cause significant gait deficits. Further study will contribute to stratification of injury mechanisms in preterm infants, and guide the use of promising therapeutic interventions.

    Topics: Animals; Animals, Newborn; Axons; Brain; Calcium-Binding Proteins; Disease Models, Animal; Embryo, Mammalian; Erythropoietin; Female; Gene Expression Regulation, Developmental; Glial Fibrillary Acidic Protein; Hypoxia-Ischemia, Brain; Inflammation; Leukoencephalopathies; Lipopolysaccharides; Microfilament Proteins; Myelin Basic Protein; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin

2014
Lentivirus-mediated estrogen receptor α overexpression in the central nervous system ameliorates experimental autoimmune encephalomyelitis in mice.
    International journal of molecular medicine, 2013, Volume: 31, Issue:5

    Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory cell infiltration of the central nervous system (CNS) and multifocal demyelination. Clinical data and clinical indicators demonstrate that estrogen improves the relapse-remittance of MS patients. This study aimed to investigate the anti-inflammatory effects and the underlying mechanism(s) of action of estrogen and estrogen receptor α (ERα) in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. An ERα recombinant lentivirus was constructed. Mouse neurons were cultured in serum-free culture medium, and ERα recombinant lentivirus with a multiplicity of infection (MOI) of 5 was used to infect the neurons. Furthermore, neuronal ERα mRNA and protein expression were detected using real-time quantitative PCR and western blot analysis. We sterotaxically injected ERα recombinant lentivirus into the lateral ventricle of mouse brains, and successfully identified infected neurons using Flag immunofluorescence staining to determine the optimal dose. A total of 75 C57BL/6 mice were ovariectomized. After 2 weeks, EAE was induced with myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide. The EAE mice were divided into 5 groups: the estrogen group (treatment with estradiol), the ERα agonist group (treatment with raloxifene), the ERα recombinant lentivirus group (ERα group, treatment with ERα recombinant lentivirus), the empty virus group and the normal saline (NS) group; clinical symptoms and body weight were compared among the groups. We assessed EAE-related parameters, detected pathological changes with immunohistochemistry and quantified the expression of myelin basic protein (MBP), matrix metalloproteinase-9 (MMP-9), and a subset of EAE-related cytokines using enzyme-linked immunosorbent assay (ELISA). We successfully constructed an ERα recombinant lentivirus. C57BL/6 mouse neurons can survive in culture for at least 8 weeks. During that period, the recombinant lentivirus was able to infect the neurons, while sustaining green fluorescence protein (GFP) expression. ERα recombinant lentivirus also infected the neurons at a MOI of 5. The ERα mRNA and protein expression levels were higher in the infected neurons compared to the uninfected ones. We successfully infected the CNS of C57BL/6 mice by stereotaxically injecting ERα recombinant lentivirus into the lateral ventricle of the mouse brains and induced EAE. The lentivirus-mediated overexpression of ERα reduced the inciden

    Topics: Animals; Body Weight; Brain; Central Nervous System; Cytokines; Demyelinating Diseases; Encephalomyelitis, Autoimmune, Experimental; Estrogen Receptor alpha; Green Fluorescent Proteins; HEK293 Cells; Humans; Immunohistochemistry; Inflammation; Lentivirus; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Myelin Basic Protein; Nerve Fibers; Recombination, Genetic; RNA, Messenger; Spinal Cord; Transfection

2013
An ex-vivo multiple sclerosis model of inflammatory demyelination using hyperbranched polymer.
    Biomaterials, 2013, Volume: 34, Issue:23

    Multiple sclerosis (MS) is characterized by the presence of inflammatory demyelinating foci throughout the brain and spinal cord, accompanied by axonal and neuronal damage. Although inflammatory processes are thought to underlie the pathological changes, the individual mediators of this damage are unclear. In order to study the role of pro-inflammatory cytokines in demyelination in the central nervous system, we have utilized a hyperbranched poly(2-dimethyl-aminoethylmethacrylate) based non-viral gene transfection system to establish an inflammatory demyelinating model of MS in an ex-vivo environment. The synthesized non-viral gene transfection system was optimized for efficient transfection with minimal cytotoxicity. Organotypic brain slices were then successfully transfected with the TNF or IFNγ genes. TNF and IFNγ expression and release in cerebellar slices via non-viral gene delivery approach resulted in inflammation mediated myelin loss, thus making it a promising ex-vivo approach for studying the underlying mechanisms of demyelination in myelin-related diseases such as MS.

    Topics: Animals; Cerebral Cortex; Demyelinating Diseases; Humans; Inflammation; Interferon-gamma; Methacrylates; Models, Biological; Multiple Sclerosis; Myelin Basic Protein; Myelin Sheath; Neurofilament Proteins; Polymers; Rats; Rats, Sprague-Dawley; Transfection; Tumor Necrosis Factor-alpha

2013
The absence of myelin basic protein promotes neuroinflammation and reduces amyloid β-protein accumulation in Tg-5xFAD mice.
    Journal of neuroinflammation, 2013, Nov-05, Volume: 10

    Abnormal accumulation of amyloid β-protein (Aβ) in the brain plays an important role in the pathogenesis \\of Alzheimer's disease (AD). Aβ monomers assemble into oligomers and fibrils that promote neuronal dysfunction. This assembly pathway is influenced by naturally occurring brain molecules, the Aβ chaperone proteins, which bind to Aβ and modulate its aggregation. Myelin basic protein (MBP) was previously identified as a novel Aβ chaperone protein and a potent inhibitor for Aβ fibril assembly in vitro.. In this study, we determined whether the absence of MBP would influence Aβ pathology in vivo by breeding MBP knockout mice (MBP-/-) with Tg-5xFAD mice, a model of AD-like parenchymal Aβ pathology.. Through biochemical and immunohistochemical experiments, we found that bigenic Tg-5xFAD/MBP-/- mice had a significant decrease of insoluble Aβ and parenchymal plaque deposition at an early age. The expression of transgene encoded human AβPP, the levels of C-terminal fragments generated during Aβ production and the intracellular Aβ were unaffected in the absence of MBP. Likewise, we did not find a significant difference in plasma Aβ or cerebrospinal fluid Aβ, suggesting these clearance routes were unaltered in bigenic Tg-5xFAD/MBP-/- mice. However, MBP-/- mice and bigenic Tg-5xFAD/MBP-/- mice exhibited elevated reactive astrocytes and activated microglia compared with Tg-5xFAD mice. The Aβ degrading enzyme matrix metalloproteinase 9 (MMP-9), which is expressed by activated glial cells, was significantly increased in the Tg-5xFAD/MBP-/- mice.. These findings indicate that the absence of MBP decreases Aβ deposition in transgenic mice and that this consequence may result from increased glial activation and expression of MMP-9, an Aβ degrading enzyme.

    Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Humans; Immunoblotting; Immunohistochemistry; Inflammation; Mice; Mice, Knockout; Mice, Transgenic; Myelin Basic Protein

2013
Myelin loss associated with neuroinflammation in hypertensive rats.
    Stroke, 2012, Volume: 43, Issue:4

    Small vessel disease is the major cause of white matter injury in patients with vascular cognitive impairment. Matrix metalloproteinase (MMP)-mediated inflammation may be involved in the white matter damage with oligodendrocyte (Ol) death. Therefore, we used spontaneously hypertensive stroke-prone rats to study the role of neuroinflammation in white matter damage.. Permanent unilateral carotid artery occlusion was performed at 12 weeks of age in spontaneously hypertensive stroke-prone rats. Following surgery, rats were placed on a Japanese permissive diet and received 1% NaCl in drinking water. MRI, histology, biochemistry, and ELISA characterized white matter lesions, and cognitive impairment was tested by Morris water maze.. White matter damage was observed 4 to 5 weeks following permanent unilateral carotid artery occlusion/Japanese permissive diet. Immunoblotting showed marked reduction in myelin basic protein and upregulation of immature Ols. Mature Ols underwent caspase-3-mediated apoptosis. Morris water maze showed cognitive impairment. Abnormally appearing vessels were observed and surrounded by inflammatory-like cells. IgG extravasation and hemorrhage, indicating blood-brain barrier (BBB) disruption, was closely associated with MMP-9 expression. Lesions in white matter showed reactive astrocytosis and activated microglia that expressed tumor necrosis factor-α. MMP-3 and MMP-9 were significantly increased, and MMP-2 was reduced in both astrocytes and Ol.. We found apoptosis of mature Ols with an increase in immature Ols. Increased MMP-3, MMP-9, and tumor necrosis factor-α were associated with myelin breakdown and BBB disruption. Neuroinflammation is an important factor in white matter damage and Ol death, and studies using this new model can be performed to assess agents to block inflammation.

    Topics: Animals; Apoptosis; Astrocytes; Blood-Brain Barrier; Caspase 3; Cerebral Cortex; Humans; Inflammation; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Microglia; Myelin Basic Protein; Myelin Sheath; Rats; Rats, Inbred SHR; Tumor Necrosis Factor-alpha

2012
Adhesive properties and inflammatory potential of citrullinated myelin basic protein peptide 45-89.
    Neurochemical research, 2012, Volume: 37, Issue:9

    Deimination of arginyl residue of myelin basic protein (MBP) reduces cationicity of MBP and impedes the normal myelin membrane assembly. Less ordered structure of MBP is more susceptible to proteolytic attack that may lead to the release of highly immunogenic deiminated peptides into extracellular milieu. We have studied the association of peptides 45-89 derived from citrullinated MBP (C8 isomer) and phosphorylated MBP (C3 isomer) with the myelin lipids in a model membrane system using optical waveguide lightmode spectrometry. The analysis of association/dissociation kinetics to planar lipids under controlled hydrodynamic conditions has shown that MBP 45-89 peptide from citrullinated C8 isomer is less effectively adsorbed on the lipid membrane, than peptide from phosphorylated C3 isomer and packing densities for phosphorylated 45-89 MBP peptide is higher than for citrullinated forms. On the other hand, our results shown that continuous (24 h) exposure of mixed oligodendrocyte/microglial cells to peptides 45-89 from MBP-C8 induces apoptosis via mitochondrial pathway. In addition, peptides 45-89 stimulated the secretion of nitric oxide from microglial cells via induction of iNOS and decreased the level of the inhibitory protein IkB, indicating involvement of the transcription factor NF-kB in these processes. Our results suggest that some citrullinated peptides, initially released from oligodendrocytes, might activate microglia, which produces reactive nitrogen species and generates in turn fatal feedbacks that kill oligodendrocytes.

    Topics: Animals; Biotransformation; Blotting, Western; Cell Adhesion; Cell Death; Cell Survival; Cells, Cultured; Chromatography, High Pressure Liquid; Citrulline; Inflammation; Lipids; Microglia; Myelin Basic Protein; NF-kappa B; Nitric Oxide; Oligodendroglia; Peptide Fragments; Rats; Rats, Wistar; Spectrum Analysis

2012
Both MHC and non-MHC genes regulate inflammation and T-cell response after traumatic brain injury.
    Brain, behavior, and immunity, 2011, Volume: 25, Issue:5

    Genetic regulation of autoimmune neuroinflammation is a well known phenomenon, but genetic influences on inflammation following traumatic nerve injuries have received little attention. In this study we examined the inflammatory response in a rat traumatic brain injury (TBI) model, with a particular focus on major histocompatibility class II (MHC II) presentation, in two inbred rat strains that have been extensively characterized in experimental autoimmune encephalomyelitis (EAE); DA and PVG. In addition, MHC and Vra4 congenic strains on these backgrounds were studied to give information on MHC and non-MHC gene contribution. Thus, allelic differences in Vra4, harboring the Ciita gene, was found to regulate expression of the invariant chain at the mRNA level, with a much smaller effect exerted by the MHC locus itself. Notably, however, at the protein level the MHC congenic PVG-RT1(av1) strain displayed much stronger MHCII(+) presentation, as shown both by immunolabeling and flow cytometry, than the PVG strain, dwarfing the effect of Ciita. The PVG-RT1(av1) strain had significantly more T-cell influx than both DA and PVG, suggesting regulation both by MHC and non-MHC genes. Finally, in terms of outcome, the EAE susceptible DA strain displayed a significantly smaller resulting lesion volume than the resistant PVG-RT1(av1) strain. These results provide additional support for a role of adaptive immune response after neurotrauma and demonstrate that outcome is significantly affected by host genetic factors.

    Topics: Animals; Brain; Brain Injuries; Flow Cytometry; Genes, MHC Class II; Inflammation; Major Histocompatibility Complex; Male; Myelin Basic Protein; Peptide Fragments; Rats; Rats, Inbred Strains; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes

2011
Hydrogen-rich saline reduces delayed neurologic sequelae in experimental carbon monoxide toxicity.
    Critical care medicine, 2011, Volume: 39, Issue:4

    We investigated the feasibility and efficacy of hydrogen-rich saline therapy on delayed neurologic sequelae in a rat model of severe acute carbon monoxide (CO) poisoning.. Controlled animal study.. University research laboratory for Diving Medicine.. Sprague-Dawley rats weighing 250 ± 20 g.. The rats were exposed to 1000 ppm CO in air for 40 min and then to 3000 ppm for another 20 min until they lost consciousness. Rats were intraperitoneal injected with hydrogen-rich saline or normal saline (10 mL/kg) for six times after resuscitation at 0, 12, 24, 36, 48, and 60 hrs, respectively. The rats without CO poisoning were used as normal controls.. Brain tissue inflammation, cell death, and cognitive dysfunction were observed at one week after CO poisoning. Hydrogen-rich saline treatment significantly reduced the level of degraded myelin basic protein, decreased the expression of ionized calcium-binding adapter molecule 1, Iba1, a microglial marker, reduced DNA oxidation, and suppressed proinflammatory cytokine interleukin-1β, interleukin-6, and tumor necrosis factor-α in the cortex and hippocampal tissues when compared with those in normal saline-treated rats. These histologic and biological improvements were accompanied with an improvement in the Morris water maze test.. This observation demonstrated that hydrogen-rich saline peritoneal injection improves histologic and functional assessment in a rat model of CO encephalopathy. Hydrogen saline has potentials as a novel and alternative therapy for severely CO-poisoned patients with delayed neurologic sequelae. The therapeutic effects of hydrogen-rich saline may be related to antioxidant and anti-inflammatory actions.

    Topics: Animals; Brain; Brain Chemistry; Calcium-Binding Proteins; Carbon Monoxide Poisoning; Cerebral Cortex; Hippocampus; Hydrogen; Inflammation; Interleukin-1beta; Interleukin-6; Male; Maze Learning; Microfilament Proteins; Myelin Basic Protein; Rats; Rats, Sprague-Dawley; Sodium Chloride; Tumor Necrosis Factor-alpha

2011
Mucosal tolerance to brain antigens preserves endogenous TGFβ-1 and improves neurological outcomes following experimental craniotomy.
    Acta neurochirurgica. Supplement, 2011, Volume: 111

    Intracranial surgery causes brain damage from cortical incisions, intraoperative hemorrhage, retraction, and electrocautery; collectively these injuries have recently been coined surgical brain injury (SBI). Inflammation following SBI contributes to neuronal damage. This study develops T-cells that are immunologically tolerant to brain antigen via the exposure of myelin basic protein (MBP) to airway mucosa. We hypothesize that these T-cells will migrate to the site of corticotomy, secrete immunosuppressive cytokines, such as TGFβ1, reduce inflammation, and improve neurological outcomes following SBI. A standard model for SBI was used for this experiment. C57 mice were divided into six groups: SHAM+Vehicle, SHAM+Ovalbumin, SHAM+MBP, SBI+Vehicle, SBI+OVA, and SBI+MBP. Induction of mucosal tolerance to vehicle, ovalbumin, or MBP was performed prior to SBI. Neurological scores and TBFβ1 cytokine levels were measured 48 h postoperatively. Mice receiving craniotomy demonstrated a reduction in neurological score. Animals tolerized to MBP (SBI+MBP) had better postoperative neurological scores than SBI+Vehicle and SBI+OVA. SBI inhibited the cerebral expression TGFβ1 in PBS and OVA treated groups, whereas MBP treated-animals preserved preoperative levels. Mucosal tolerance to MBP leads to significant improvement in neurological outcome that is associated with the preservation of endogenous levels of brain TGFβ1.

    Topics: Analysis of Variance; Animals; Brain; Brain Injuries; Craniotomy; Disease Models, Animal; Drug Tolerance; Inflammation; Mice; Mice, Inbred C57BL; Mucous Membrane; Myelin Basic Protein; Neurologic Examination; Ovalbumin; Transforming Growth Factor beta1; Treatment Outcome

2011
Evolution of inflammation and white matter injury in a model of transient focal ischemia.
    Journal of neuropathology and experimental neurology, 2010, Volume: 69, Issue:1

    After an ischemic stroke, there is a prolonged inflammatory response and secondary phase of injury that is more amenable to treatment than acute neurotoxicity. Surprisingly, little is known about temporal and spatial relationships between inflammation and white matter injury. Here, we quantified development of white matter damage, inflammation, and a glial limitans at 1, 3, and 7 days after transient ischemia in the rat striatum using immunohistochemistry. Quantitative analysis showed that decreased staining for myelin basic protein and increased staining for damaged myelin basic protein began in the core, coincided with neutrophil infiltration, and progressed outward over time. Axon damage (i.e. accumulation of amyloid precursor protein) began at the edge of the lesion, coinciding with substantial microglia/macrophage activation, and progressed into the core. During the 7 days, activated microglia/macrophages dramatically increased only in the core and edge of the lesion. Detailed spatial analyses revealed that activated microglia/macrophages that surrounded undamaged axon bundles did not express ED1, a marker of phagocytic cells, whereas those inside damaged bundles expressed ED1. These results imply different contributions of neutrophils and microglia/macrophages to white matter injury after ischemic stroke. The distinct localizations of activated microglia/macrophages imply complex signals that regulate their migration toward and infiltration of damaged white matter.

    Topics: Amyloid beta-Protein Precursor; Animals; Astrocytes; Brain Infarction; Calcium-Binding Proteins; Corpus Striatum; Disease Models, Animal; Disease Progression; DNA-Binding Proteins; Ectodysplasins; Functional Laterality; Glial Fibrillary Acidic Protein; Inflammation; Ischemic Attack, Transient; Male; Microfilament Proteins; Myelin Basic Protein; Nerve Fibers, Myelinated; Neuroglia; Protease Nexins; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Tetrazolium Salts; Time Factors

2010
Prolyl oligopeptidase is inhibited in relapsing-remitting multiple sclerosis.
    Journal of neuroinflammation, 2010, Apr-06, Volume: 7

    Multiple sclerosis (MS) is a complex, inflammatory and neurodegenerative disease of the central nervous system leading to long-term disability. Recent studies indicate a close association between inflammation and neurodegeneration in all lesions and disease stages of MS. Prolyl oligopeptidase (POP) is a proline-specific serine protease that cleaves several neuroactive peptides. This peptidase has been implicated in neurodegeneration, as well as in the modulation of the inflammatory response.. We examined plasma POP and the levels of an endogenous POP inhibitor from relapsing remitting MS patients and compared these with healthy controls, by monitoring the fluorescent changes due to standard fluorescently labelled substrate cleavage. We analysed the data in relationship to patient age and disease disability status.. We observed a significant decrease in POP activity in plasma of relapsing remitting MS patients relative to healthy controls, coupled with an increase of POP endogenous inhibitor. The POP activity was also correlated with patient age and disability status. The lowered POP activity from plasma of MS patients could be rescued by reductants. The decrease in circulating POP activity measured in MS is reverted by reductants. This suggests that POP inactivation in MS might be a result of the oxidative conditions prevailing in the plasma of the diseased patients. Plasma levels of POP activity as well as those of their endogenous inhibitor are suggested as biomarkers of inflammation and oxidative stress in MS.

    Topics: Adult; Aging; Axonal Transport; Biomarkers; Disability Evaluation; Extracellular Matrix; Female; Humans; Inflammation; Male; Microglia; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein; Oxidation-Reduction; Prolyl Oligopeptidases; Serine Endopeptidases; Serine Proteinase Inhibitors; T-Lymphocytes

2010
Impact of acute inflammation on spinal motoneuron synaptic plasticity following ventral root avulsion.
    Journal of neuroinflammation, 2010, May-04, Volume: 7

    Ventral root avulsion is a proximal nerve root lesion in which ventral motor nerve rootlets are torn from surface of the spinal cord, resulting in extensive death of motoneurons. It has been previously shown that if such lesioning is performed in an animal with experimental autoimmune encephalomyelitis (EAE), a significant number of motoneurons can be rescued despite an intense inflammatory reaction. This rescue effect has been attributed to production of a number of neurotrophic factors by invading T cells. Synaptological changes may be involved in neuronal degeneration, and a better understanding of the role of these changes may be of importance for developing new strategies to promote neuronal survival. The objective of the present work was to evaluate neuronal survival, astroglial reaction and synaptic input changes in spinal cord anterior horn motor nuclei after ventral root avulsion in animals with EAE, both during peak disease and after remission.. Lewis rats were subjected to unilateral avulsion of lumbar ventral roots (VRA) and divided into three groups: VRA control, VRA at peak of EAE, and VRA during EAE remission. The animals were sacrificed and their lumbar spinal cords processed for immunohistochemistry, transmission electron microscopy, and motoneuron counting.. The results indicate a reduction in astroglial reaction, a maintenance of microglial reactivity, and increases in synaptic covering of, and survival of, motoneurons in the VRA+EAE group as compared to VRA alone.. The present findings indicate that CNS inflammation may directly influence synaptic plasticity as well as the stability of neuronal networks, positively influencing the survival of lesioned neurons.

    Topics: Animals; Cell Count; Cell Survival; Encephalomyelitis, Autoimmune, Experimental; Female; Freund's Adjuvant; Guinea Pigs; Immunohistochemistry; Inflammation; Microscopy, Electron, Transmission; Motor Neurons; Myelin Basic Protein; Neuronal Plasticity; Radiculopathy; Rats; Rats, Inbred Lew; Spinal Cord; Synapses; T-Lymphocytes

2010
Involvement of brain-derived neurotrophic factor (BDNF) in MP4-induced autoimmune encephalomyelitis.
    Clinical immunology (Orlando, Fla.), 2010, Volume: 137, Issue:2

    The role of brain-derived neurotrophic factor (BDNF) in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) is still unclear. Here we investigate the clinical course, CNS histopathology and peripheral antigen-specific immunity in MP4-induced EAE of BDNF (-/+) mice. We demonstrate that these mice displayed less severe disease compared to BDNF (+/+) mice, reflected by decreased inflammation and demyelination. In correspondence to diminished frequencies of T and B cells in CNS infiltrates, the peripheral MP4-specific T(H)1/T(H)17 response was attenuated in BDNF (-/+), but not in wild-type animals. In contrast, immunization with ovalbumin triggered similar frequencies of IFN-γ- and IL-17-secreting T cells in both groups. The cytokine secretion and proliferative activity upon mitogen stimulation did not reveal any global defect of T cell function in BDNF (-/+) mice. By influencing the antigen-specific immune response in autoimmune encephalomyelitis, BDNF may support and maintain the disease in ways that go beyond its alleged neuroprotective role.

    Topics: Animals; Brain-Derived Neurotrophic Factor; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Proliferation; Cerebellum; Encephalomyelitis, Autoimmune, Experimental; Heterozygote; Inflammation; Interferon-gamma; Interleukin-17; Interleukin-2; Lymph Nodes; Lymphocyte Activation; Lymphocytes; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myelin Basic Protein; Myelin Proteolipid Protein; Recombinant Fusion Proteins; Severity of Illness Index; Spinal Cord; Spleen; Vaccination

2010
Demyelination, inflammation, and neurodegeneration in multiple sclerosis deep gray matter.
    Journal of neuropathology and experimental neurology, 2009, Volume: 68, Issue:5

    Gray matter (GM) lesions are recognized as important components of the pathology of multiple sclerosis (MS), and involvement of the deep gray matter (DGM) is suggested by magnetic resonance imaging. The aims of this study were to determine the frequency and distribution of lesions and characterize the inflammatory and neurodegenerative changes in DGM of MS patients. Histochemistry, immunohistochemistry, and morphometry were performed on whole coronal sections of 14 MS and 12 control (6 normal, 6 from amyotrophic lateral sclerosis patients) brains. Demyelinating lesions were frequent in MS DGM; most often in the thalamus and caudate, but they were also seen in the putamen, pallidum, claustrum, amygdala, hypothalamus, and substantia nigra. Most DGM lesions involved both GM and white matter. Inflammation in active DGM lesions was similar to that in lesions only in white matter but was less intense, and there was a preponderance of activated microglia, scarce myelin-laden macrophages, and a lesser extent of axonal damage. Neuronal loss was observed both in DGM lesions and nondemyelinated DGM with neuron atrophy in nondemyelinated DGM. In conclusion, demyelination and neurodegenerative changes are common in MS DGM and may contribute to clinical impairment. Inflammation in DGM lesions is intermediate between the destructive inflammation of white matter lesions and the minimal inflammation of cortical lesions. We hypothesize that alterations of glutamate reuptake mechanisms may contribute to these differences.

    Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Antigens, CD; Brain; Demyelinating Diseases; Female; Fibrinogen; HLA-DR Antigens; Humans; Inflammation; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Nerve Tissue Proteins; Neurodegenerative Diseases; Neuroglia; Neurons; Staining and Labeling

2009
Mild cerebral hypoxia-ischemia produces a sub-acute transient inflammatory response that is less selective and prolonged after a substantial insult.
    International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, 2009, Volume: 27, Issue:7

    Cerebral ischemia initiates various injurious processes including neuroinflammatory responses such as activation of microglia and increases in cytokine and nitric oxide release. Evidence primarily from in vitro studies, indicates that neuroinflammatory effects can be either beneficial or harmful, possibly related to stimulus strength. We investigated using in vivo models, the effect of a mild or substantial cerebral hypoxia-ischemia on: cerebral microglial/macrophage activation (ED1), pro-inflammatory cytokines (tumor necrosis factor-alpha), nitrosative stress (nitrotyrosine) and permanent brain damage. A mild insult produced a transient (1-2 days post) increase in activated microglia/macrophages within subcortical white and not gray matter but transiently increased cytokine or nitrotyrosine expression in cortex and not white matter. There was also prolonged scattered cell death in cortex and white matter over weeks along with loss of myelin/axons and cortical atrophy at 4 weeks post-insult. In contrast, a substantial insult produced white and gray matter necrosis, cyst formation and atrophy, along with increases in tumor necrosis factor and nitrotyrosine staining within both white and gray matter starting at 1-2 days post-insult. Microglial/macrophage staining was increased starting at 1-week post a substantial insult and remained elevated for weeks thereafter. Thus, a transient neuroinflammatory response occurs following a mild insult whereas prolonged scattered cell death occurs for weeks, particularly in white matter. Insult severity also affects the progression of the neuroinflammatory response, which is prolonged after a substantial insult. Effective therapy will need to be customized for insult severity and timing; and, monitoring the injury processes with imaging or biomarkers may help guide treatment.

    Topics: Animals; Brain; Cell Death; Glial Fibrillary Acidic Protein; Hypoxia-Ischemia, Brain; Inflammation; Myelin Basic Protein; Random Allocation; Rats; Tumor Necrosis Factor-alpha; Tyrosine

2009
Inflammatory proprotein convertase-matrix metalloproteinase proteolytic pathway in antigen-presenting cells as a step to autoimmune multiple sclerosis.
    The Journal of biological chemistry, 2009, Oct-30, Volume: 284, Issue:44

    Multiple sclerosis (MS) is a disease of the central nervous system with autoimmune etiology. Susceptibility to MS is linked to viral and bacterial infections. Matrix metalloproteinases (MMPs) play a significant role in the fragmentation of myelin basic protein (MBP) and demyelination. The splice variants of the single MBP gene are expressed in the oligodendrocytes of the central nervous system (classic MBP) and in the immune cells (Golli-MBPs). Our data suggest that persistent inflammation caused by environmental risk factors is a step to MS. We have discovered biochemical evidence suggesting the presence of the inflammatory proteolytic pathway leading to MS. The pathway involves the self-activated furin and PC2 proprotein convertases and membrane type-6 MMP (MT6-MMP/MMP-25) that is activated by furin/PC2. These events are followed by MMP-25 proteolysis of the Golli-MBP isoforms in the immune system cells and stimulation of the specific autoimmune T cell clones. It is likely that the passage of these autoimmune T cell clones through the disrupted blood-brain barrier to the brain and the recognition of neuronal, classic MBP causes inflammation leading to the further up-regulation of the activity of the multiple individual MMPs, the massive cleavage of MBP in the brain, demyelination, and MS. In addition to the cleavage of Golli-MBPs, MMP-25 proteolysis readily inactivates crystallin alphaB that is a suppressor of MS. These data suggest that MMP-25 plays an important role in MS pathology and that MMP-25, especially because of its restricted cell/tissue expression pattern and cell surface/lipid raft localization, is a promising drug target in MS.

    Topics: Antigen-Presenting Cells; Brain; GPI-Linked Proteins; Humans; Inflammation; Matrix Metalloproteinases, Membrane-Associated; Membrane Microdomains; Multiple Sclerosis; Myelin Basic Protein; Proprotein Convertases; Signal Transduction; Tissue Distribution; Up-Regulation

2009
White matter damage after chronic subclinical inflammation in newborn mice.
    Journal of child neurology, 2009, Volume: 24, Issue:9

    Preterm infants exposed to inflammation are at increased risk of white matter injury and/or cerebral palsy. To investigate the effect of chronic inflammation on the developing white matter, we administered low-dose lipopolysaccharide once a day from postnatal days 3 to 11, examined white matter changes at postnatal day 12, and monitored serum levels of insulin-like growth factor 1 and insulin-like factor binding protein-3. A single injection of lipopolysaccharide decreased the serum insulin-like growth factor 1 level but not the insulin-like factor binding protein-3 level. At postnatal day 12, quantification of immunohistochemical staining for axonal, myelin, and oligodendrocyte markers revealed impaired myelination in subcortical white matter. In addition, brain gray matter volume decreased and spleen and liver weight increased at postnatal day 12. These data suggest chronic subclinical inflammation hampers development of white and gray matter in early life, which may be associated with insulin-like growth factor 1 deficiency.

    Topics: Animals; Animals, Newborn; Brain Injuries; Central Nervous System; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Inflammation; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor I; Interleukin-6; Liver; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Myelin Basic Protein; Neurofilament Proteins; Organ Size; Polysaccharides; Pregnancy; Spleen

2009
Regulatory and pro-inflammatory phenotypes of myelin basic protein-autoreactive T cells in multiple sclerosis.
    International immunology, 2009, Volume: 21, Issue:12

    MBP-specific autoreactive T cells are considered pro-inflammatory T cells and thought to play an important role in the pathogenesis of multiple sclerosis (MS). Here, we report that MBP(83-99)-specific T cells generated from MS patients (n = 7) were comprised of pro-inflammatory and regulatory subsets of distinct phenotypes. The pro-inflammatory phenotype was characterized by high production of IFN-gamma, IL-6, IL-21 and IL-17 and low expression of FOXP3, whereas the regulatory subset expressed high levels of FOXP3 and exhibited potent regulatory functions. The regulatory subset of MBP-specific T cells appeared to expand from the CD4(+)CD25(-) T-cell pool. Their FOXP3 expression was stable, independent of the activation state and it correlated with suppressive function and inversely with the production of IFN-gamma, IL-6, IL-21 and IL-17. In contrast, the phenotype and function of FOXP3(low) MBP-specific T cells were adaptive and dependent on IL-6. The higher frequency of FOXP3(high) MBP-specific T cells was observed when IL-6 was neutralized in the culture of PBMC with MBP. The study provides new evidence that MBP-specific T cells are susceptible to pro-inflammatory cytokine milieu and act as either pro-inflammatory or regulatory T cells.

    Topics: Cell Differentiation; Forkhead Transcription Factors; Humans; Inflammation; Interleukin-6; Lymphocyte Activation; Multiple Sclerosis; Myelin Basic Protein; T-Lymphocytes; T-Lymphocytes, Regulatory

2009
Effects of autoimmunity on recovery of function in adult rats following spinal cord injury.
    Brain, behavior, and immunity, 2008, Volume: 22, Issue:8

    The central nervous system (CNS) is considered to be an immune-privileged site. For a long time, autoimmunity-induced inflammation has been viewed as an important mediator of secondary damage in the CNS following injury. However, other studies also suggest that autoimmunity is protective and beneficial. To investigate whether protective autoimmunity is present following spinal cord injury (SCI), we employed neonatally thymectomized (Tx) rats which contain few T lymphocytes in their peripheral blood, and passively immunized them with T lymphocytes activated by myelin basic protein (MBP) or spinal cord homogenate (SCH). Here we report that, among Tx, sham-Tx (sTx) and normal rats that received a contusive SCI, no significant histological and behavioral differences were found, suggesting that the endogenous T lymphocytes had no significant influence on the pathogenesis of secondary SCI. In rats passively immunized with MBP- or SCH-activated T cells (MBP-T or SCH-T, respectively), similar numbers of CD4(+) T cells were found to infiltrate into the injured spinal cords. However, only the MBP-T immunization showed neuroprotection, evidenced by the reduction of post-traumatic neuronal losses and improvement of functional recovery. These results collectively suggest that not all T lymphocytes against CNS antigens are neuroprotective and that a subpopulation of them, such as those of MBP-T cells, could be beneficial for SCI repair.

    Topics: Analysis of Variance; Animals; Autoimmunity; Cell Survival; Cytoprotection; Flow Cytometry; Fluorescent Antibody Technique; Immunization, Passive; Inflammation; Lymphocyte Activation; Microscopy, Electron; Motor Activity; Motor Neurons; Myelin Basic Protein; Rats; Rats, Sprague-Dawley; Recovery of Function; Reverse Transcriptase Polymerase Chain Reaction; Spinal Cord; Spinal Cord Injuries; Staining and Labeling; T-Lymphocytes; Thoracic Vertebrae; Thymectomy; Time Factors

2008
Heme oxygenase-1 stabilizes the blood-spinal cord barrier and limits oxidative stress and white matter damage in the acutely injured murine spinal cord.
    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2007, Volume: 27, Issue:5

    We hypothesized that heme oxygenase (HO)-1, the inducible form of HO, represents an important defense against early oxidative injury in the traumatized spinal cord by stabilizing the blood-spinal cord barrier and limiting the infiltration of leukocytes. To test this hypothesis, we first examined the immunoexpression of HO-1 and compared barrier permeability and leukocyte infiltration in spinal cord-injured HO-1-deficient (+/-) and wild-type (WT, +/+) mice. Heme oxygenase was expressed in both endothelial cells and glia of the injured cord. Barrier disruption to luciferase and infiltration of neutrophils were significantly greater in the HO-1+/- than WT mice at 24 h postinjury (P

    Topics: Aldehydes; Animals; Blood Vessels; Blotting, Western; Brain; Enzyme Induction; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Immunohistochemistry; Inflammation; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin Basic Protein; Neutrophil Infiltration; Oxidative Stress; Spinal Cord; Spinal Cord Injuries

2007
Localisation and modulation of prostanoid receptors EP1 and EP4 in the rat chronic constriction injury model of neuropathic pain.
    European journal of pain (London, England), 2007, Volume: 11, Issue:6

    Immunohistochemistry was used to examine the expression of prostaglandin E(2) receptors EP1 and EP4 in sciatic nerves from the rat chronic constriction injury (CCI) model of neuropathic pain. At 21 days post-surgery the CCI rats had developed mechanical hyperalgesia on the operated side, and quantitative image analysis showed a highly significant doubling of the area occupied by EP1- and EP4-positive pixels in sections from CCI nerves when compared to sham-operated controls. Co-localisation studies with the marker ED1 revealed that 73% of the EP1-positive cells and 54% of the EP4-positive cells in the injured nerves represented infiltrating macrophages. Cells negative for ED1 and positive for either EP1 or EP4 were characterised as Schwann cells from their morphology and expression of myelin basic protein and S100 antigens. Similar EP1- and EP4-positive Schwann cell profiles were observed in sections of uninjured control nerves. Low levels of EP receptor expression were found in neurofilament-immunostained axons, but no consistent differences were observed in the levels of axonal EP staining between CCI and control tissue. These data provide further evidence of the importance of prostaglandins in the pathogenesis of neuropathic pain, and suggest that not only infiltrating macrophages but also Schwann cells may be involved in the modulation of these mediators in response to nerve injury.

    Topics: Animals; Axons; Chemotaxis, Leukocyte; Chronic Disease; Disease Models, Animal; Immunohistochemistry; Inflammation; Ligation; Macrophages; Male; Myelin Basic Protein; Neuralgia; Peripheral Nervous System Diseases; Prostaglandins; Rats; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Prostaglandin E, EP4 Subtype; S100 Proteins; Schwann Cells; Sciatic Neuropathy; Up-Regulation

2007
Effects of intrauterine inflammation on the developing mouse brain.
    Brain research, 2007, May-04, Volume: 1144

    Clinical and experimental evidence indicate that the presence of intrauterine inflammation in pregnancy is not only a cause of preterm birth but is also associated with perinatal brain damage and long-term neurological handicap. In the present study, the neuropathological outcome was investigated in surviving pups in a model of inflammation-induced preterm delivery. C57BL/6 mice were subjected to intrauterine injection of lipopolysaccharide (LPS) or saline, at a time corresponding to 79% of average gestation (gestational day 15). Fetuses that survived after LPS administration were sacrificed on postnatal day 14 (PND 14). At PND 14, the brain weight of LPS-exposed pups was significantly lower than that of saline-exposed. A high proportion of LPS-exposed brains were found affected and exhibited hypomyelination, enlarged ventricles, and in some cortical gray matter lesions were evident. None of these pathologies were detected in sham-treated animals.. Intrauterine inflammation impaired brain development and various brain lesions were produced in both the white and gray matter after intrauterine LPS administration in mice.

    Topics: Animals; Animals, Newborn; Body Weight; Brain; Female; Inflammation; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Myelin Basic Protein; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects

2007
Antimyelin antibodies in clinically isolated syndromes correlate with inflammation in MRI and CSF.
    Journal of neurology, 2007, Volume: 254, Issue:2

    We investigated the correlation of antimyelin oligodendrocyte glycoprotein-(anti-MOG) and anti-myelin basic protein antibodies (anti-MBP) in serum of CIS patients with inflammatory signs in MRI and in CSF and, as previously suggested,the incidence of more frequent and rapid progression to clinically definite MS (CDMS).. 133CIS patients were analysed for anti-MOG and anti-MBP (Western blot). Routine CSF and cranial MRI (quantitatively and qualitatively) measures were analyzed. 55 patients had a follow-up of at least 12 months or until conversion to CDMS.. Patients with anti-MOG and anti-MBP had an increased intrathecal IgG production and CSF white blood cell count(p = 0.048 and p = 0.036). When anti-MBP alone, or both antibodies were present the cranial MRI showed significantly more T2 lesions (p = 0.007 and p = 0.01,respectively). There was a trend for more lesion dissemination in anti-MBP positive patients (p = 0.076).Conversely, anti-MOG- and/or anti-MBP failed to predict conversion to CDMS in our follow-up group (n = 55). Only in female patients with at least one MRI lesion (n = 34) did the presence of anti-MOG correlate with more frequent (p = 0.028) and more rapid (p = 0.0209) transition to CDMS.. Presence of anti-MOG or anti-MBP or both was not significantly associated with conversion to CDMS in our CIS cohort. However, patients with anti-MOG and anti-MBP had higher lesion load and more disseminated lesions in cranial MRI as well as higher values for CSF leucocytes and intrathecal IgG production. Our data support a correlation of anti-MOG and anti-MBP to inflammatory signs in MRI and CSF. The prognostic value of these antibodies for CDMS, however, seems to be less pronounced than previously reported.

    Topics: Adult; Antibodies; Chi-Square Distribution; Female; Follow-Up Studies; Humans; Inflammation; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Retrospective Studies; Statistics, Nonparametric

2007
Epicutaneous (EC) immunization with myelin basic protein (MBP) induces TCRalphabeta+ CD4+ CD8+ double positive suppressor cells that protect from experimental autoimmune encephalomyelitis (EAE).
    Journal of autoimmunity, 2007, Volume: 28, Issue:4

    Multiple sclerosis (MS) is a central nervous system (CNS) chronic inflammatory autoimmune disease with limited treatment modalities. Oral tolerance is one of the experimental methods that protects from autoimmune diseases. However, this method failed to be therapeutic in clinical trials. In our previous work we found that epicutaneous (EC) immunization with protein antigen induced a state of profound immunosuppression that inhibited inflammatory response in contact sensitivity, in experimental autoimmune encephalomyelitis (EAE) and in allogeneic skin graft rejection. In our current work, we precisely determined the phenotype of EC induced T suppressor (Ts) cells that reduce the progress of EAE. Employing TCRdelta-/-, CD1d-/- mice, we showed that EC induced Ts cells do not belong either to the population of TCRgammadelta cells or CD1d restricted NKT cells. Moreover, we noticed that a lack of CD1d-/- restricted NKT lymphocytes resulted in the induction of much stronger suppression of EAE than in wild type mice. This might suggest that NKT cells could interfere with the induction of Ts cells. Using beta2m-/- mice, negative selection and positive selection of EC induced Ts cells, we showed that Ts cells protecting from EAE belong to the population of TCRalphabeta+ CD4+ CD8+ double positive lymphocytes.

    Topics: Animals; Antigens, CD1; Antigens, CD1d; beta 2-Microglobulin; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Encephalomyelitis, Autoimmune, Experimental; Female; Guinea Pigs; Immunization; Inflammation; Killer Cells, Natural; Mice; Mice, Knockout; Multiple Sclerosis; Myelin Basic Protein; Receptors, Antigen, T-Cell, alpha-beta; Receptors, Antigen, T-Cell, gamma-delta; Skin Transplantation; Transplantation, Homologous

2007
Differential patterns of inflammatory response, axonal damage and myelin impairment following excitotoxic or ischemic damage to the trigeminal spinal nucleus of adult rats.
    Brain research, 2007, Oct-03, Volume: 1172

    Inflammatory response, axonal damage and demyelination are important components of the pathophysiology of acute neurodegenerative diseases. We have investigated the outcome of these pathological events following an excitotoxic or an ischemic damage to the spinal nucleus of adult rats at 1 and 7 days postinjury. Microinjections of 80 nmol of NMDA or 40 pmol of endothelin-1 into the rat spinal nucleus induced differential histopathological events. NMDA injection induced intense tissue loss in the gray matter (GM) without significant tissue loss in the white matter (WM). There was a mild inflammatory response, with recruitment of a few neutrophils and macrophages. Axonal damage was present in the GM following NMDA injection, with negligible axonal damage in the WM. Myelin impairment was apparent at 7 days. Microinjections of endothelin-1 into the same region induced lesser tissue loss than NMDA injections, concomitant with an intense inflammatory response characterized by recruitment of macrophages, but not of neutrophils. There were more axonal damage and early myelin impairment after endothelin-1 injection. These results were confirmed by quantitative analysis. Microcysts were present in the WM of the trigeminothalamic tract at 7 days following injection of endothelin-1. These results show that an ischemic damage to the spinal nucleus affects both GM and WM with more bystander inflammation, axonal damage and myelin impairment, while excitotoxic damage induces effects more restricted to the GM. These pathological events may occur following acute damage to the human brain stem and can be an important contributing factor to the underlying functional deficits.

    Topics: Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Axons; Brain Ischemia; Cell Count; Demyelinating Diseases; Ectodysplasins; Endothelin-1; Inflammation; Male; Myelin Basic Protein; N-Methylaspartate; Neurotoxins; Rats; Rats, Wistar; Time Factors; Trigeminal Nucleus, Spinal

2007
Induction of Golli-MBP expression in CNS macrophages during acute LPS-induced CNS inflammation and experimental autoimmune encephalomyelitis (EAE).
    TheScientificWorldJournal, 2007, Nov-02, Volume: 7

    Microglia are the tissue macrophages of the CNS. Microglial activation coupled with macrophage infiltration is a common feature of many classic neurodegenerative disorders. The absence of cell-type specific markers has confounded and complicated the analysis of cell-type specific contributions toward the onset, progression, and remission of neurodegeneration. Molecular screens comparing gene expression in cultured microglia and macrophages identified Golli-myelin basic protein (MBP) as a candidate molecule enriched in peripheral macrophages. In situ hybridization analysis of LPS/IFNg and experimental autoimmune encephalomyelitis (EAE)-induced CNS inflammation revealed that only a subset of CNS macrophages express Golli-MBP. Interestingly, the location and morphology of Golli-MBP+ CNS macrophages differs between these two models of CNS inflammation. These data demonstrate the difficulties of extending in vitro observations to in vivo biology and concretely illustrate the complex heterogeneity of macrophage activation states present in region- and stage-specific phases of CNS inflammation. Taken altogether, these are consistent with the emerging picture that the phenotype of CNS macrophages is actively defined by their molecular interactions with the CNS microenvironment.

    Topics: Acute Disease; Animals; Cells, Cultured; Central Nervous System; Encephalomyelitis, Autoimmune, Experimental; Gene Expression Regulation; Inflammation; Interferon-gamma; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred C57BL; Microglia; Myelin Basic Protein; Nerve Tissue Proteins; RNA, Messenger; Transcription Factors

2007
Myelin basic protein-primed T cells of female but not male mice induce nitric-oxide synthase and proinflammatory cytokines in microglia: implications for gender bias in multiple sclerosis.
    The Journal of biological chemistry, 2005, Sep-23, Volume: 280, Issue:38

    Females are more susceptible than males to multiple sclerosis (MS). However, the underlying mechanism behind this gender difference is poorly understood. Because the presence of neuroantigen-primed T cells within the CNS is necessary for the development of MS, the present study was undertaken to investigate the activation of microglia by myelin basic protein (MBP)-primed T cells of male, female, and castrated male mice. Interestingly, MBP-primed T cells isolated from female and castrated male but not from male mice induced the expression of inducible nitric-oxide synthase (iNOS) and proinflammatory cytokines (interleukin-1beta (IL-1beta), IL-1alpha, IL-6, and tumor necrosis factor-alpha) in microglia by cell-cell contact. Again there was no apparent defect in male microglia, because MBP-primed T cells isolated from female and castrated male but not male mice were capable of inducing the production of NO in male primary microglia. Inhibition of female T cell contact-mediated microglial expression of proinflammatory molecules by dominant-negative mutants of p65 and C/EBPbeta suggest that female MBP-primed T cells induce microglial expression of proinflammatory molecules through the activation of NF-kappaB and C/EBPbeta. Interestingly, MBP-primed T cells of male, female, and castrated male mice were able to induce microglial activation of NF-kappaB. However, MBP-primed T cells of female and castrated male but not male mice induced microglial activation of C/EBPbeta. These studies suggest that microglial activation of C/EBPbeta but not NF-kappaB by T cell:microglial contact is a gender-specific event and that male MBP-primed T cells are not capable of inducing microglial expression of proinflammatory molecules due to their inability to induce the activation of C/EBPbeta in microglia. This novel gender-sensitive activation of microglia by neuroantigen-primed T cell contact could be one of the mechanisms behind the female-loving nature of MS.

    Topics: Animals; Castration; CCAAT-Enhancer-Binding Protein-beta; Cell Membrane; Cell Nucleus; Central Nervous System; Cytokines; Female; Genes, Dominant; Immunoblotting; Inflammation; Interleukin-1; Interleukin-6; Male; Mice; Microglia; Multiple Sclerosis; Mutation; Myelin Basic Protein; NF-kappa B; Nitric Oxide; Oligonucleotide Array Sequence Analysis; RNA; Sex Factors; T-Lymphocytes; Transcription, Genetic; Tumor Necrosis Factor-alpha

2005
Redox regulation of cytokine-mediated inhibition of myelin gene expression in human primary oligodendrocytes.
    Free radical biology & medicine, 2005, Sep-15, Volume: 39, Issue:6

    Multiple sclerosis (MS) is a chronic autoimmune demyelinating disorder of the central nervous system (CNS) of unknown etiology. Several studies have shown that demyelination in MS is caused by proinflammatory mediators which are released by perivascular infiltrates and/or activated glial cells. To understand if proinflammatory mediators such as IL (interleukin)-1beta and TNF (tumor necrosis factor)-alpha are capable of modulating the expression of myelin-specific genes, we investigated the effect of these cytokines on the expression of myelin basic protein (MBP), 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), myelin oligodendrocyte glycoprotein (MOG), and proteolipid protein (PLP) in human primary oligodendrocytes. Interestingly, both IL-1beta and TNF-alpha markedly inhibited the expression of MOG, CNPase, and PLP but not MBP, the effect that was blocked by antioxidants such as N-acetylcysteine (NAC) and pyrrolidine dithiocarbamate (PDTC). Consistently, oxidants and prooxidants like H(2)O(2) and diamide also markedly inhibited the expression of MOG, CNPase, and PLP. Furthermore, both IL-1beta and TNF-alpha induced the production of H(2)O(2). Taken together, these studies suggest that proinflammatory cytokines inhibit the expression of myelin genes in human primary oligodendrocytes through the alteration of cellular redox.

    Topics: Acetylcysteine; Animals; Antioxidants; Cells, Cultured; Cytokines; DNA Primers; Dose-Response Relationship, Drug; Down-Regulation; Encephalomyelitis, Autoimmune, Experimental; Female; Gene Expression Regulation; Humans; Hydrogen Peroxide; Inflammation; Interleukin-1; Mice; Multiple Sclerosis; Myelin Basic Protein; Myelin Proteins; Myelin Proteolipid Protein; Myelin Sheath; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Neuroglia; Oligodendroglia; Oxidants; Oxidation-Reduction; Phosphoric Diester Hydrolases; Proline; Pyrrolidines; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; Sulfhydryl Compounds; Thiocarbamates; Time Factors; Tumor Necrosis Factor-alpha

2005
Autoantigen specific T cells inhibit glutamate uptake in astrocytes by decreasing expression of astrocytic glutamate transporter GLAST: a mechanism mediated by tumor necrosis factor-alpha.
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2005, Volume: 19, Issue:13

    Glutamate excitotoxicity is increasingly being recognized as a pathogenic mechanism in autoimmune inflammatory disorders of the central nervous system (CNS). Astrocytes are the predominant players in clearing the extracellular space from glutamate and normally have extensive spare capacities in terms of glutamate uptake. We asked what might be the basis of glutamate accumulation in T cell triggered autoimmune inflammation. In vitro, coculture of primary rat astrocytes with activated myelin basic protein (MBP)-specific T cells resulted in a decrease of astrocytic glutamate uptake rates (Vmax). In parallel, the amount of the Na+-dependent glutamate transporter GLAST was reduced within 48-60 h. Significant decreases of GLAST protein were observed in astrocytes harvested after incubation with T cells activated by MBP during coculture or after incubation with T cell blasts preactivated in the presence of splenocytes beforehand. Since exposure of astrocytes to cell-free supernatant of MBP-activated T cells also resulted in reduced expression of GLAST, a humoral factor appeared to be the driving agent. In blocking experiments using neutralizing antibodies and by incubation of astrocytes with recombinant cytokines, tumor necrosis factor-alpha (TNF-alpha) was identified as being responsible for the down-modulation of GLAST. GLAST was also down-regulated in the CNS of autoimmune encephalomyelitic rats but not in animals suffering from systemic inflammation. Since the loss of GLAST was not confined to inflammatory infiltrates, here too, a humoral factor seemed to be causative. In conclusion, T cell derived TNF-alpha impairs glutamate clearance capacity of astrocytes in vitro and probably also in vivo providing a pathogenic link to glutamate excitotoxicity that may contribute to early axonal dysfunction remote from active autoimmune inflammatory demyelination.

    Topics: Amino Acid Transport System X-AG; Animals; Astrocytes; Autoantigens; Binding Sites; Central Nervous System; Coculture Techniques; Cytokines; Demyelinating Diseases; Dose-Response Relationship, Drug; Down-Regulation; Encephalomyelitis, Autoimmune, Experimental; Flow Cytometry; Glutamates; Immunoblotting; Inflammation; Kinetics; Models, Biological; Myelin Basic Protein; Rats; Sodium; T-Lymphocytes; Time Factors; Tumor Necrosis Factor-alpha

2005
Interaction between microglia and oligodendrocyte cell progenitors involves Golli proteins.
    Annals of the New York Academy of Sciences, 2005, Volume: 1048

    Multiple sclerosis (MS) is an autoimmune and chronic inflammatory disease characterized by plaques, areas of destroyed myelin sheaths in the CNS, which results in multiple disabilities for patients. In addition to demyelinated plaques, pathophysiological studies have shown "shadow plaques" that represent areas of partial remyelination. New myelin can be made by oligodendrocytes (OLs) generated from oligodendrocyte progenitor cells (OPCs) that pre-exist in the demyelinated area or recruited from surrounding areas. To successfully repopulate the demyelinated area, OPCs have to proliferate, migrate, and differentiate into mature OLs capable of forming myelin. Identifying factors that influence remyelination is a current topic in developmental neurobiology. Previously, we showed that Golli proteins, which have a broad distribution in the nervous and immune systems, are present both in OPCs and activated microglia around MS lesions. We hypothesized that in response to inflammation, Golli proteins may promote proliferation of OPCs through microglial cells. To test this, we established neonatal mouse brain slice and cell cultures and used lipopolysaccharide (LPS) to induce inflammation. In LPS-treated brain slices, Golli proteins displayed increased expression in the cortical subventricular zone. Furthermore, Golli proteins were demonstrated only in the conditioned medium from LPS-treated microglial cell cultures (LPS-MCM), and were absent in either conditioned medium from LPS-treated astrocytes or control media. Finally, proliferation of purified OPCs was promoted with LPS-MCM or Golli proteins, but not with LPS alone. In summary, these results demonstrate that activated microglia are beneficial for proliferation of OPCs and suggest possible involvement of Golli proteins as one of mediators in this process.

    Topics: Animals; Cell Proliferation; Cells, Cultured; Humans; Inflammation; Lipopolysaccharides; Mice; Microglia; Multiple Sclerosis; Myelin Basic Protein; Nerve Tissue Proteins; Oligodendroglia; Stem Cells; Transcription Factors

2005
Ligands for the peroxisome proliferator-activated receptor-gamma and the retinoid X receptor exert additive anti-inflammatory effects on experimental autoimmune encephalomyelitis.
    Journal of neuroimmunology, 2004, Volume: 148, Issue:1-2

    Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear-receptor superfamily that binds to DNA with retinoid X receptors (RXRs) as PPAR-RXR heterodimers. In experimental autoimmune encephalomyelitis (EAE), the gene expression of PPAR-gamma was demonstrated in spinal cord during the course of EAE. Administration of 15-deoxy-(12,14)-prostaglandin J2 (15d-PGJ2) or 9-cis-retinoic acid (RA) alone at the onset of clinical signs of EAE reduced the severity of disease, however, their combination resulted in enhanced amelioration of disease. These results suggest that use of RXR specific ligands may be highly effective when combined with PPAR-gamma agonists in the treatment of autoimmune demyelinating diseases such as multiple sclerosis (MS).

    Topics: Alitretinoin; Analysis of Variance; Animals; Cells, Cultured; Cytokines; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Immunization; Immunohistochemistry; Inflammation; Ligands; Lymph Nodes; Mice; Mice, Transgenic; Microglia; Myelin Basic Protein; Nitric Oxide; Peptide Fragments; Prostaglandin D2; Receptors, Antigen, T-Cell, alpha-beta; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoid X Receptors; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spleen; Time Factors; Transcription Factors; Tretinoin

2004
Inflammatory cell expression of cyclooxygenase-2 in the multiple sclerosis lesion.
    Journal of neuroimmunology, 2004, Volume: 149, Issue:1-2

    Multiple sclerosis (MS) is a progressive immune-mediated disease characterized by the loss of the oligodendrocytes that constitute the myelin sheath. Recent reports show that glutamate-mediated excitotoxic death of oligodendrocytes contributes to pathogenesis in demyelinating disease. A link between the immune-mediated inflammatory response and glutamate-mediated excitotoxicity of oligodendrocytes could involve the interaction of inducible isoforms of nitric oxide synthase (iNOS) and cyclooxygenase (COX-2). Both enzymes are tightly coupled to neuronal excitotoxic death. We examined tissue from two controls and seven MS patients with chronic active lesions to determine the extent of COX-2 and iNOS expression. In contrast to the lack of expression in controls, there was a marked induction of COX-2 in all these MS lesions. COX-2 was frequently expressed in association with iNOS. COX-2 was found in areas that contained catabolites of myelin basic protein, indicating recent demyelination. COX-2 expression was found near damaged oligodendrocytes in cells that expressed the macrophage/microglia marker CD64, indicating that a substantial portion of the COX-2 in the lesions was expressed in immune-derived cells. We discuss these findings in the context of how COX-2 could be coupled with iNOS to contribute to excitotoxic death and damage of oligodendrocytes.

    Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Adult; Brain; Cell Count; Cyclooxygenase 2; Demyelinating Diseases; Female; Fluorescent Antibody Technique; Humans; Inflammation; Isoenzymes; Male; Membrane Proteins; Microscopy, Confocal; Middle Aged; Models, Neurological; Multiple Sclerosis; Myelin Basic Protein; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oligodendroglia; Prostaglandin-Endoperoxide Synthases; Protein Isoforms; Receptors, IgG; Staining and Labeling

2004
Brain injury induced by intracerebral injection of interleukin-1beta and tumor necrosis factor-alpha in the neonatal rat.
    Pediatric research, 2004, Volume: 56, Issue:3

    To examine the possible role of inflammatory cytokines in mediating neonatal brain injury, we investigated effects of intracerebral injection of IL-1beta (IL-1beta) or tumor necrosis factor-alpha (TNFalpha) on brain injury in the neonatal rat. A stereotaxic intracerebral injection of IL-1beta or TNFalpha (10 ng per pup) was performed in postnatal day 5 (P5) SD rats. Although no necrosis of neurons was found, increased astrogliosis, as indicated by GFAP positive staining was observed 24 and 72 h following the injection of IL-1beta or TNFalpha. IL-1beta induced apoptotic cell death in the rat brain 24 h after the injection, as indicated by increases in positive TUNEL staining and caspase-3 activity, and apoptotic cell death was partially blocked by systemic administration of NBQX, an antagonist of the AMPA glutamate receptor. IL-1beta also significantly reduced the number of developing oligodendrocytes (OLs) 24 h after the injection and this impairment was not prevented by NBQX. On the contrary, TNFalpha induced a much smaller increase in the number of TUNEL positive cells and did not reduce the number of developing OLs. By P8, myelin basic protein (MBP) was clearly detected in the control rat brain, while MBP positive staining was very weak, if any, in the IL-1beta treated rat brain. MBP expression in the TNFalpha treated rat brain was less affected. The overall results indicate that IL-1beta may directly cause injuries to developing OLs and impair myelination in the neonatal rat brain and TNFalpha may have different roles in mediating brain injury.

    Topics: Animals; Animals, Newborn; Apoptosis; Brain Injuries; Caspase 3; Caspases; Cerebral Cortex; Excitatory Amino Acid Antagonists; Humans; In Situ Nick-End Labeling; Infant; Inflammation; Interleukin-1; Myelin Basic Protein; Oligodendroglia; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Tumor Necrosis Factor-alpha

2004
T-cell properties determine disease site, clinical presentation, and cellular pathology of experimental autoimmune encephalomyelitis.
    The American journal of pathology, 2004, Volume: 165, Issue:5

    Two distinct clinical phenotypes of experimental autoimmune encephalomyelitis are observed in BALB interferon-gamma knockout mice immunized with encephalitogenic peptides of myelin basic protein. Conventional disease, characterized by ascending weakness and paralysis, occurs with greater frequency after immunizing with a peptide comprising residues 59 to 76. Axial-rotatory disease, characterized by uncontrolled axial rotation, occurs with greater frequency in mice immunized with a peptide corresponding to exon 2 of the full length 21.5-kd protein. The two clinical phenotypes are histologically distinguishable. Conventional disease is characterized by inflammation and demyelination primarily in spinal cord, whereas axial-rotatory disease involves inflammation and demyelination of lateral medullary areas of brain. Both types have infiltrates in which neutrophils are a predominating component. By isolating T cells and transferring disease to naive recipients, we show here that the type of disease is determined entirely by the inducing T cell. Furthermore, studies using CXCR2 knockout recipients, unable to recruit neutrophils to inflammatory sites, show that although neutrophils are critical for some of these T cells to effect disease, there are also interferon-gamma-deficient T cells that induce disease in the absence of both interferon-gamma and neutrophils. These results highlight the multiplicity of T-cell-initiated effector pathways available for inflammation and demyelination.

    Topics: Animals; Antigen Presentation; Cell Proliferation; Central Nervous System; Cloning, Molecular; Cytokines; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Exons; Flow Cytometry; Heterozygote; Homozygote; Inflammation; Interferon-gamma; Mice; Mice, Inbred BALB C; Mice, Knockout; Myelin Basic Protein; Neutrophils; Peptides; Phenotype; Protein Structure, Tertiary; Ribonucleases; T-Lymphocytes; Time Factors

2004
IFN-beta gene deletion leads to augmented and chronic demyelinating experimental autoimmune encephalomyelitis.
    Journal of immunology (Baltimore, Md. : 1950), 2003, May-01, Volume: 170, Issue:9

    Since the basic mechanisms behind the beneficial effects of IFN-beta in multiple sclerosis (MS) patients are still obscure, here we have investigated the effects of IFN-beta gene disruption on the commonly used animal model for MS, experimental autoimmune encephalomyelitis (EAE). We show that IFN-beta knockout (KO) mice are more susceptible to EAE than their wild-type (wt) littermates; they develop more severe and chronic neurological symptoms with more extensive CNS inflammation and demyelination. However, there was no discrepancy observed between wt and KO mice regarding the capacity of T cells to proliferate or produce IFN-gamma in response to recall Ag. Consequently, we addressed the effect of IFN-beta on encephalitogenic T cell development and the disease initiation phase by passive transfer of autoreactive T cells from KO or wt littermates to both groups of mice. Interestingly, IFN-beta KO mice acquired a higher incidence and augmented EAE regardless of the source of T cells. This shows that the anti-inflammatory effect of endogenous IFN-beta is predominantly exerted on the effector phase of the disease. Histopathological investigations of CNS in the effector phase revealed an extensive microglia activation and TNF-alpha production in IFN-beta KO mice; this was virtually absent in wt littermates. This coincided with an increase in effector functions of T cells in IFN-beta KO mice, as measured by IFN-gamma and IL-4 production. We suggest that lack of endogenous IFN-beta in CNS leads to augmented microglia activation, resulting in a sustained inflammation, cytokine production, and tissue damage with consequent chronic neurological deficits.

    Topics: Adjuvants, Immunologic; Adoptive Transfer; Animals; Autoantibodies; Autoantigens; Cells, Cultured; Chronic Disease; Encephalomyelitis, Autoimmune, Experimental; Gene Deletion; Genetic Predisposition to Disease; Immunophenotyping; Incidence; Inflammation; Interferon-beta; Macrophage Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin Basic Protein; Myelin Sheath; Peptide Fragments; Severity of Illness Index; T-Lymphocyte Subsets; Th1 Cells; Th2 Cells

2003
Adoptive transfer of myelin basic protein-tolerized splenocytes to naive animals reduces infarct size: a role for lymphocytes in ischemic brain injury?
    Stroke, 2003, Volume: 34, Issue:7

    Breakdown of the blood-brain barrier during stroke allows central nervous system antigens to leak into the systemic circulation and allows circulating leukocytes access to the brain. Encounter of central nervous system antigens by the peripheral immune system can be capitalized on to modulate the postischemic inflammatory response and potentially improve outcome from stroke.. Male Lewis rats were tolerized to myelin basic protein (MBP) or ovalbumin (OVA) and subjected to 3 hours of middle cerebral artery occlusion (MCAO) or used as splenocyte donors for immunologically naive animals undergoing MCAO. Infarct size was determined at 24 hours by 2,3,5-triphenyltetrazolium chloride staining. In separate studies, mononuclear cells were removed from the brains of animals after MCAO for enzyme-linked immunospot (ELISPOT) assay and flow cytometry.. Median infarct volume in animals tolerized to MBP and those receiving splenocytes from MBP-tolerized donors was less than in animals tolerized to OVA and those receiving splenocytes from OVA-tolerized donors (87.7+/-54.9 versus 148+/-61.6 mm3 [P=0.01] and 89.2+/-77.5 versus 153+/-77.1 mm3 [P=0.05], respectively). There was an increase in the number of transforming growth factor-beta1-secreting mononuclear cells in MBP-tolerized animals undergoing sham surgery (P=0.001) as well as in ischemic animals 48 hours (P=0.02) and 336 hours (P=0.04) after stroke. A distinct subset of gammadelta T cells was present in the brains of MBP-tolerized but not control animals after stroke.. Immunologic tolerance and its neuroprotective effects can be transferred to naive animals and appear to be related to antigen-specific induction of transforming growth factor-beta1.

    Topics: Administration, Intranasal; Adoptive Transfer; Animals; Brain Ischemia; Cell Count; Cerebral Infarction; Cytoprotection; Disease Progression; Immune Tolerance; Inflammation; Lymphocytes; Male; Myelin Basic Protein; Nasal Mucosa; Rats; Rats, Inbred Lew; Spleen

2003
The role of CTLA-4 in induction and maintenance of peripheral T cell tolerance.
    European journal of immunology, 2002, Volume: 32, Issue:4

    T cell receptor engagement and the B7-CD28 / CTLA-4 signaling pathways play critical roles in T cell activation and regulation. CD28 engagement results in T cell activation, differentiation and survival while CTLA-4 signals block IL-2 production, cell cycle progression and T cell differentiation. We explored the role of CTLA-4 in peripheral tolerance induced by intravenous administration of ethylene carbodiimide-fixed, antigen-coupled splenocytes in the PLP139 - 151-induced relapsing experimental autoimmune encephalomyelitis system. Tolerance induction with PLP139 - 151-coupled splenocytes correlates with low B7 expression on the fixed antigen-presenting cells, conditions that would favor CTLA-4-mediated inhibition. Administration of CTLA-4Ig or anti-CTLA-4 concomitant with the 'tolerogenic' stimulus, however, failed to reverse tolerance induction. In contrast, blocking CTLA-4 at the time of secondary 'immunogenic' encounter with antigen reversed the tolerant state. These findings indicate that CTLA-4 is required to maintain the unresponsive state of the tolerized T cells upon antigenic stimulation under inflammatory conditions and, therefore, have important implications for therapeutic regulation of autoimmune disease.

    Topics: Abatacept; Amino Acid Sequence; Animals; Antigens, CD; Antigens, Differentiation; Autoantigens; Autoimmune Diseases; B7-1 Antigen; B7-2 Antigen; Capsid; Capsid Proteins; Cells, Cultured; Clonal Anergy; CTLA-4 Antigen; Encephalomyelitis, Autoimmune, Experimental; Female; Hypersensitivity, Delayed; Immune Tolerance; Immunization; Immunoconjugates; Inflammation; Lymphocyte Activation; Membrane Glycoproteins; Mice; Mice, Mutant Strains; Molecular Sequence Data; Myelin Basic Protein; Myelin Proteolipid Protein; Ovalbumin; Peptide Fragments; Receptors, Antigen, T-Cell; Specific Pathogen-Free Organisms; T-Lymphocyte Subsets; Thymectomy

2002
Distinct inflammatory stimuli induce different patterns of myelin phagocytosis and degradation in recruited macrophages.
    Experimental neurology, 2001, Volume: 167, Issue:2

    Injury and demyelinating diseases result in the disruption of the myelin sheath that surrounds axons in the nervous system. The removal of degenerating myelin by macrophages and microglia is central to repair mechanisms that follow. The efficiency of myelin removal depends on magnitudes and rates of myelin phagocytosis and degradation. In the present study we test whether environmental conditions within a tissue can control patterns of myelin removal. We document that macrophages that are recruited to the same tissue but by distinct inflammatory stimuli differ in their ability to phagocytose and degrade myelin. These observations may apply to the nervous system where different pathological conditions that involve distinct inflammatory stimuli may induce different functional states in microglia and macrophages.

    Topics: Animals; Cell Adhesion; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Immunohistochemistry; Inflammation; Macrophage-1 Antigen; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Myelin Basic Protein; Myelin Sheath; Phagocytosis

2001
Elevated interferon-gamma in CNS inflammatory disease: a potential complication for bone marrow reconstitution in MS.
    Journal of neuroimmunology, 2000, Aug-01, Volume: 108, Issue:1-2

    Bone marrow transplantation (BMT) is increasingly used to treat Multiple Sclerosis (MS) a CNS inflammatory disease with elevated CNS and systemic IFNgamma levels. We wished to determine the effect of IFNgamma on BM graft survival in a transgenic mouse model for chronic MS. BM transplantation into transgenic mice which express elevated levels of IFNgamma in the CNS was unsuccessful. By contrast, there was 100% survival of even fully allogeneic, T-depleted transplants to transgenics that over express TNFalpha in the CNS, using the same MBP promoter. IFNgamma was detectable in spleen of irradiated mice but levels were higher in IFNgamma transgenics. BM transplantation into IFNgamma-deficient recipients also had a high failure rate. Transplants of BM from mice lacking expression of IFNgamma-receptor failed, whereas IFNgamma-deficient grafts survived, suggesting that IFNgamma response status of the graft can also positively influence survival. IFNgamma therefore has a dual role in BM transplantation and the outcome will depend on relative levels of cytokine expression.

    Topics: Animals; Bone Marrow Transplantation; Central Nervous System; Central Nervous System Diseases; Female; Gene Expression; Graft Rejection; Graft Survival; Inflammation; Interferon gamma Receptor; Interferon-gamma; Mice; Mice, Inbred Strains; Mice, Transgenic; Multiple Sclerosis; Myelin Basic Protein; Promoter Regions, Genetic; Receptors, Interferon; Specific Pathogen-Free Organisms; Spleen; Survival Rate; Transgenes; Transplants; Tumor Necrosis Factor-alpha

2000
Inhibition of experimental allergic encephalomyelitis in the Lewis rat by paclitaxel.
    Journal of neuroimmunology, 2000, Aug-01, Volume: 108, Issue:1-2

    Experimental allergic encephalomyelitis (EAE), an animal model for multiple sclerosis (MS), is useful for preclinical testing for agents to be considered for treatment for this human demyelinating disease. Microtubules in lymphocytes play an important role in the cascade of human T cell activation, and paclitaxel (PTX), a microtubule stabilizer, can inhibit T cell function. A new formulation of micellar PTX, free of Cremophor and ethanol, was tested for its effect on the induction of EAE in Lewis rats. Adoptive EAE was induced with an encephalitogenic T cell line activated with guinea pig myelin basic protein (GP MBP) peptide 68-88. PTX (10 mg/kg) was administered 24 and 72 h after cell transfer. The clinical signs, fulminating in controls, were completely blocked by PTX, but mild CNS inflammation remained unaltered. A similar dose of PTX, given on days 6 and 8 to animals developing active EAE after immunization with GP MBP peptide 68-88 in complete Freund's adjuvant, greatly reduced the severity of paralysis and delayed the onset of disease by 8-9 days. Marked weight loss and severe toxicity were noted with higher and more prolonged administration. In vitro micellar PTX inhibited activation of encephalitogenic T cells by both specific antigen and mitogen. Lower doses and longer treatment programs may provide effective treatment with acceptable adverse effects with this agent in the treatment of inflammatory demyelinating disease.

    Topics: Amino Acid Sequence; Animals; Antigens; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Encephalomyelitis, Autoimmune, Experimental; Female; Freund's Adjuvant; Guinea Pigs; Immunization, Passive; Inflammation; Lymphocyte Activation; Micelles; Molecular Sequence Data; Multiple Sclerosis; Myelin Basic Protein; Paclitaxel; Paralysis; Peptide Fragments; Rats; Rats, Inbred Lew; T-Lymphocytes; Weight Loss

2000
Characterization of acute versus chronic relapsing autoimmune encephalomyelitis in DA rats.
    Journal of neuroimmunology, 2000, Aug-01, Volume: 108, Issue:1-2

    This study was undertaken to better understand the role of cytokines in the pathogenesis, especially in the mechanisms of relapse, of experimental autoimmune encephalomyelitis (EAE). For this purpose, we induced acute and chronic relapsing (CR) EAE in DA rats and determined several immunological parameters in rats at various stages of two types of EAE. Histopathological analysis revealed that there was no significant difference in the severity of inflammation in the spinal cord lesions between the two groups. However, demyelination was observed only in rats with CR EAE. Cytokine analysis by competitive PCR demonstrated that levels of TNF-alpha, IL-6 and IL-12 p40 mRNA in the spinal cord at the first attack of CR EAE were significantly higher than those at the peak stage of acute EAE. The mRNA expression of anti-inflammatory cytokines, IL-10 and TGF-beta1, was generally low in both acute EAE and the first attack of CR EAE and upregulated at later stages of CR EAE. These findings suggest that persistent high-level expression of pro-inflammatory cytokines is closely associated with demyelination and relapse of EAE. In contrast, anti-inflammatory cytokines play only a minor role in the relapse.

    Topics: Acute Disease; Amino Acid Sequence; Animals; Chronic Disease; Cytokines; Encephalomyelitis, Autoimmune, Experimental; Inflammation; Interferon-gamma; Interleukins; Molecular Sequence Data; Myelin Basic Protein; Peptide Fragments; Rats; Rats, Inbred Strains; Recurrence; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spinal Cord; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

2000
Intrathecal administration of neutralizing antibody against Fas ligand suppresses the progression of experimental autoimmune encephalomyelitis.
    Biochemical and biophysical research communications, 2000, Aug-18, Volume: 275, Issue:1

    A therapy aimed at blocking the Fas/Fas ligand (FasL) system was investigated using a relapsing form of experimental autoimmune encephalomyelitis (EAE) in mice, an animal model of multiple sclerosis (MS). Intracisternal administration of neutralizing antibody against FasL during the progression phase of EAE significantly reduced the severity of the disease with milder inflammation and myelin breakdown in the central nervous system (CNS). These results raised the possibility that the Fas/FasL system might contribute to tissue destruction in the CNS in the acute phase of EAE and that the intrathecal administration of neutralizing antibody against FasL may be beneficial for suppression of the acute phase of MS.

    Topics: Acute Disease; Animals; Antibodies; Central Nervous System; Disease Models, Animal; Disease Progression; DNA Fragmentation; Encephalomyelitis, Autoimmune, Experimental; Fas Ligand Protein; Female; Histocytochemistry; In Situ Nick-End Labeling; Inflammation; Injections, Spinal; Membrane Glycoproteins; Mice; Mice, Inbred Strains; Multiple Sclerosis; Myelin Basic Protein; Myelin Sheath

2000
Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation?
    The Journal of experimental medicine, 1999, Mar-01, Volume: 189, Issue:5

    Brain-derived neurotrophic factor (BDNF) has potent effects on neuronal survival and plasticity during development and after injury. In the nervous system, neurons are considered the major cellular source of BDNF. We demonstrate here that in addition, activated human T cells, B cells, and monocytes secrete bioactive BDNF in vitro. Notably, in T helper (Th)1- and Th2-type CD4(+) T cell lines specific for myelin autoantigens such as myelin basic protein or myelin oligodendrocyte glycoprotein, BDNF production is increased upon antigen stimulation. The BDNF secreted by immune cells is bioactive, as it supports neuronal survival in vitro. Using anti-BDNF monoclonal antibody and polyclonal antiserum, BDNF immunoreactivity is demonstrable in inflammatory infiltrates in the brain of patients with acute disseminated encephalitis and multiple sclerosis. The results raise the possibility that in the nervous system, inflammatory infiltrates have a neuroprotective effect, which may limit the success of nonselective immunotherapies.

    Topics: Autoantigens; B-Lymphocytes; Brain Diseases; Brain-Derived Neurotrophic Factor; Encephalitis; Glycoproteins; Humans; Inflammation; Lymphocyte Activation; Monocytes; Multiple Sclerosis; Myelin Basic Protein; Neurodegenerative Diseases; Oligodendroglia; RNA, Messenger; T-Lymphocytes; Transcription, Genetic

1999
Gender differences in protection from EAE induced by oral tolerance with a peptide analogue of MBP-Ac1-11.
    Journal of neuroscience research, 1999, Feb-15, Volume: 55, Issue:4

    Mechanisms that contribute to increased female susceptibility to multiple sclerosis can be studied in the murine model of experimental autoimmune encephalomyelitis (EAE). In this report, we compared oral tolerance induction in male and female B10.PL mice using fed myelin basic protein (MBP) Ac1-11 peptide or a high-affinity analogue, Ac1-11[4Y]. We found that fed Ac1-11[4Y] peptide, but not native Ac1-11, could limit cellular infiltration into the central nervous system (CNS) and protect male mice from EAE, an effect that was completely obviated by castration. In contrast, female mice could not be orally tolerized or protected from EAE with either peptide. Tolerance induction in males was reflected by the appearance of Ac1-11[4Y]-reactive splenocytes that produced a sharply increased ratio of transforming growth factor (TGF)-beta:interleukin (IL)-2 and induced bystander suppression. These data directly demonstrate gender differences in regulatory T cells, and support the concept that androgens are involved in governing oral tolerance to EAE.

    Topics: Administration, Oral; Animals; Castration; Disease Susceptibility; Encephalomyelitis, Autoimmune, Experimental; Female; Immune Tolerance; Inflammation; Interleukin-2; Male; Mice; Myelin Basic Protein; Peptide Fragments; Sex Factors; Spinal Cord; Spleen; T-Lymphocytes; Transforming Growth Factor beta

1999
Soluble ICAM-1, demyelination, and inflammation in multiple sclerosis and acute optic neuritis.
    Journal of neuroimmunology, 1998, Aug-01, Volume: 88, Issue:1-2

    We measured sICAM-1 in paired samples of serum and cerebrospinal fluid (CSF) from patients with an attack of multiple sclerosis (MS) (n = 50) and patients with acute monosymptomatic optic neuritis (ON) as a possible first attack of MS were also included (n = 25). Based on calculations of extended indices we found evidence of intrathecal synthesis of sICAM-1 both in patients with clinically definite MS and in patients with idiopathic ON compared to neurological control subjects. The amount of intrathecally synthesized sICAM-1 correlated significantly to the CSF leukocyte count and to the concentration of myelin basic protein in the CSF. The serum concentrations of sICAM-1 were not increased in patients with demyelinating disease compared to the neurological control subjects.

    Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Female; Humans; Inflammation; Intercellular Adhesion Molecule-1; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Myelin Sheath; Optic Neuritis; Osmolar Concentration; Regression Analysis; Serum Albumin; Solubility; Spinal Cord

1998
Cultured human monocytes release proinflammatory cytokines in response to myelin basic protein.
    Neuroscience letters, 1998, Aug-21, Volume: 252, Issue:3

    In human cultured monocytes we examined the ability of myelin basic protein (MBP) to induce the production of proinflammatory cytokines potentially involved in inflammatory demyelination. Northern blots and specific immunoassays demonstrated that monocytes incubated with optimal doses of MBP showed increased mRNA expression and release of tumor necrosis factor (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interleukin-8 (IL-8) but not of interleukin-12/p40 (IL-12/p40). We also showed that cytokine production by MBP-stimulated monocytes was abrogated by incubation with Dexamethasone. These data suggest that interaction of mononuclear phagocytes with MBP may participate in the regulatory process of cytokine production during inflammatory demyelination and support the beneficial role of corticosteroids therapy in aberrant immune responses to the myelin sheath.

    Topics: Animals; Blotting, Northern; Cells, Cultured; Guinea Pigs; Humans; Immunoassay; Inflammation; Interleukins; Monocytes; Myelin Basic Protein; Tumor Necrosis Factor-alpha

1998
Antibodies against IL-12 prevent superantigen-induced and spontaneous relapses of experimental autoimmune encephalomyelitis.
    Journal of immunology (Baltimore, Md. : 1950), 1998, Nov-01, Volume: 161, Issue:9

    Immunization of (PL/J x SJL/J)F1 mice with myelin basic protein (MBP) induces relapsing experimental autoimmune encephalomyelitis (EAE). Relapses occur 7 to 10 days after recovery from the initial paralysis. Staphylococcal enterotoxins (SE) A or B, administered after recovery from the initial paralysis, induce immediate relapses. IL-12 is involved in the induction of EAE. Here, we show that SEA and SEB induce IL-12 in splenocytes from (PL/J x SJL/J)F1 mice in vitro and increase the level of IL-12 in the sera of mice treated with these superantigens. IL-12 administration mimics SE in inducing spontaneous relapses and in enhancing the severity and frequency of spontaneous relapses. IL-12 neutralization blocks SE-induced and subsequent relapses of EAE, and, when instituted after recovery from the initial attack, prevents spontaneous relapse. This is the first report of prevention of relapses of EAE with anti-IL-12 Ab, an approach which may prove useful in the prevention of exacerbations in multiple sclerosis.

    Topics: Animals; Antibodies, Monoclonal; Antigens, Bacterial; Autoimmune Diseases; Brain; Cytokines; Demyelinating Diseases; Encephalomyelitis, Autoimmune, Experimental; Enterotoxins; Female; Guinea Pigs; Immunization; Inflammation; Interleukin-12; Male; Mice; Molecular Mimicry; Myelin Basic Protein; Rats; Recurrence; Severity of Illness Index; Spinal Cord; Staphylococcus aureus; Superantigens; Th1 Cells

1998
Antigen therapy eliminates T cell inflammation by apoptosis: effective treatment of experimental autoimmune neuritis with recombinant myelin protein P2.
    Proceedings of the National Academy of Sciences of the United States of America, 1997, Feb-18, Volume: 94, Issue:4

    Exposure of T cells to their specific antigen normally results in proliferation, but in the presence of high and repeatedly administered doses of antigen, T cells may undergo apoptosis. Here we demonstrate that i.v. administration of as little as 100 microg of recombinant P2 protein twice daily completely prevents experimental autoimmune neuritis induced by adoptive transfer of neuritogenic P2-specific T cells or by immunization with the neuritogenic P2-peptide-spanning amino acids 53-78. Antigen treatment started after disease onset markedly ameliorated experimental autoimmune neuritis. The mechanism of action may be through programmed T cell death; a profound increase of the rate of apoptosis was seen in inflammatory foci of peripheral nerves and in the spleen. There was no cytokine switch by our Th1 cells after exposure to their specific antigen, but increased secretion of interferon gamma and tumor necrosis factor alpha was demonstrated. High antigen dose therapy using recombinant, pathogen-free protein may prove useful for the treatment of autoimmune inflammatory disorders of the nervous system.

    Topics: Adoptive Transfer; Animals; Apoptosis; Cells, Cultured; Dose-Response Relationship, Drug; Female; Humans; Immunization; Inflammation; Lymphocyte Activation; Myelin Basic Protein; Myelin P2 Protein; Neuritis, Autoimmune, Experimental; Peptide Fragments; Rats; Rats, Inbred Lew; Recombinant Proteins; T-Lymphocytes

1997
Experimental autoimmune encephalomyelitis: the antigen specificity of T lymphocytes determines the topography of lesions in the central and peripheral nervous system.
    Laboratory investigation; a journal of technical methods and pathology, 1997, Volume: 76, Issue:3

    Recent studies on autoimmune encephalomyelitis and neuritis reveal that many different antigens of the central (CNS) and peripheral nervous system may become targets of an encephalitogenic T-cell response. The aim of this study was to determine the influence of T-cell specificity on the pathology of autoimmune-mediated inflammation in the nervous system. Autoimmune encephalomyelitis was induced by the adoptive transfer of CD4+ T-line cells specific for either myelin basic protein, myelin oligodendrocyte glycoprotein (MOG), myelin-associated glycoprotein, S100 beta, or glial fibrillary acidic protein. The severity of the inflammatory response was antigen- and dose-dependent. With the exception of MOG-specific T-line cells, all autoreactive T-cell lines induced inflammation in the CNS and peripheral nervous system. In the myelin-basic-protein-mediated model, the spinal cord was most severely affected with only minor inflammation in the forebrain. In contrast, both MOG- and myelin-associated-glycoprotein-specific T cells induced a far higher density of lesions in the periventricular and cerebellar white matter. S100 beta- and glial-fibrillary-acidic-protein-specific T cells mediated particularly severe inflammation in the gray matter. In addition to these topographic differences, antigen specificity also influenced the extent of both parenchymal inflammation and macrophage activation in the CNS. However, irrespective of the specificity or number of T cells transferred, the major neuropathologic correlate with disease severity was the absolute number of activated macrophages recruited into the CNS parenchyma (r = 0.9; p < 0.0001). This study suggests that differences in lesion distribution in multiple sclerosis patients may reflect differences in the antigen specificity of an encephalitogenic T-cell response.

    Topics: Amino Acid Sequence; Animals; Brain; Cell Line; Encephalomyelitis, Autoimmune, Experimental; Epitopes; Glial Fibrillary Acidic Protein; Guinea Pigs; Inflammation; Molecular Sequence Data; Myelin Basic Protein; Peripheral Nerves; Rats; Rats, Inbred Lew; Spinal Cord; T-Lymphocytes

1997
Binding of complement component Clq to myelin oligodendrocyte glycoprotein: a novel mechanism for regulating CNS inflammation.
    Molecular immunology, 1997, Volume: 34, Issue:1

    Myelin oligodendrocyte glycoprotein (MOG) is a myelin-specific protein restricted to the central nervous system (CNS). While MOG is considered a putative autoantigen in MS, its function(s) in myelin is unknown. As CNS myelin is able to activate the classical complement pathway, it must contain a Clq-binding/activating protein but the identity of this protein has not been reported. The data in this paper clearly demonstrate that MOG specifically binds Clq in a dose-dependent and saturating manner. This calcium-dependent interaction is mediated by the extracellular immunoglobulin-like domain of MOG. This MOG domain contains an amino acid motif similar to the core Clq-binding sequence previously identified in IgG antibodies. Purified MOG also inhibited the antibody-dependent lysis of RBC by complement. Taken together, these results demonstrate that MOG binds Clq near the IgG binding site and may be the protein responsible for complement activation in myelin. This direct interaction between a myelin-specific protein and Clq has significant implications for CNS inflammation and could be particularly important in demyelinating diseases such as multiple sclerosis.

    Topics: Animals; Calcium; Central Nervous System Diseases; Complement C1q; Complement Hemolytic Activity Assay; Dose-Response Relationship, Immunologic; Enzyme-Linked Immunosorbent Assay; Extracellular Space; Humans; Inflammation; Myelin Basic Protein; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Oligodendroglia; Protein Binding; Protein Structure, Tertiary; Rats

1997
Cytosolic domain of the type I interleukin-1 receptor spontaneously recruits signaling molecules to activate a proinflammatory gene.
    The Journal of clinical investigation, 1997, Jul-15, Volume: 100, Issue:2

    Immediate postreceptor events activated by IL-1-IL-1R interaction remain undefined. We have initiated studies to identify candidate signal transducers that associate with the cytosolic domain (cd) of the IL-1R. Immunocomplex kinase assays demonstrated an IL-1-activated myelin basic protein kinase activity that coprecipitated with the IL-1R from rat mesangial, mouse EL-4, and HeLa cells. Using glutathione-S-transferase (GST) fusion proteins, HeLa cell lysates next were assayed for kinases that associated with IL-1R cytoplasmic sequences. A GST-IL-1R fusion protein containing the entire cd (amino acids 369-569; GST-IL-1Rcd) recruited a kinase activity in the absence and presence of IL-1 stimulation. In contrast, a GST-IL-1R membrane-proximal region mutant (amino acids 369-501; GST-IL-1RcdDelta), which lacks COOH-terminal amino acid residues required for nuclear factor-kappaB activation, poorly phosphorylated MBP. In gel, kinase assays demonstrated 63-, 83-, and 100-kD kinases that specifically coprecipitated with the HeLa IL-1R and the GST-IL-1Rcd, but not GST-IL-1RcdDelta. 35S-labeled proteins, with Mrs identical to the kinase activities, stably associated with GST-IL-1Rcd. Transient transfection assays of 293 cells were used to evaluate the functional significance of these findings. Simply increasing IL-1cd expression in 293 cells stimulated 5'-IL-6 flanking region-regulated CAT activity threefold above control, an effect blocked by the kinase inhibitors staurosporine and calphostin C. In summary, we have identified two previously unrecognized 63- and 83-kD kinases as well as a protein with an Mr similar to the recently cloned IL-1R-associated kinase, all of which associate spontaneously with the IL-1Rcd. Ectopic IL-1Rcd expression was sufficient to trigger cellular activation, suggesting that the extracellular domain of the intact receptor represses signal transduction until IL-1 is bound. Given that the IL-1Rcd signaling domain has been conserved in a functionally diverse group of transmembrane receptors, further characterization of this signaling process may define novel molecular mechanisms controlling cellular function and differentiation.

    Topics: Calcium-Calmodulin-Dependent Protein Kinases; Cell Line; Chloramphenicol O-Acetyltransferase; Enzyme Inhibitors; Gene Expression Regulation; Glutathione Transferase; Glycogen Synthase Kinase 3; HeLa Cells; Humans; Inflammation; Interleukin-1; Interleukin-1 Receptor-Associated Kinases; Molecular Weight; Myelin Basic Protein; Phosphorylation; Protein Binding; Protein Kinases; Proteins; Receptors, Interleukin-1; Recombinant Fusion Proteins; Signal Transduction

1997
Inflammation promotes survival and migration of the CG4 oligodendrocyte progenitors transplanted in the spinal cord of both inflammatory and demyelinated EAE rats.
    Journal of neuroscience research, 1997, Dec-01, Volume: 50, Issue:5

    Oligodendrocyte progenitor CG4 cells were labeled with bisbenzimide and transplanted in the lumbar spinal cord of rats 15 to 17 days prior to the induction of experimental autoimmune encephalomyelitis (EAE). EAE was induced by immunization with the encephalitogenic peptide of myelin basic protein (amino acids 68-88; C1) in adjuvant, either alone or in combination with a single injection of an anti-myelin oligodendrocyte glycoprotein (MOG) antibody to enhance central nervous system (CNS) demyelination. In control animals without EAE, the survival and migration capacity of CG4 cells was minimal. In striking contrast, both the survival and migration of this oligodendrocyte progenitor cell line were greatly enhanced in animals with EAE. In both disease models, large number of CG4 cells were still found in the spinal cord 50 days after transplantation, by which time they had migrated up to 6 cm from the transplantation site. Migrating CG4 cells were found in the subpial space, around the ependyma and blood vessels, and as well as in the grey and white matter of the CNS parenchyma. In all these locations, the CG4 cells were often associated with reactive astrocytes. These data strongly support the concept that inflammatory responses within the CNS promote, rather than inhibit, the survival and migration of transplanted oligodendrocyte progenitors in the adult CNS.

    Topics: Animals; Antibodies; Cell Line; Cell Movement; Encephalomyelitis, Autoimmune, Experimental; Graft Survival; Inflammation; Male; Myelin Basic Protein; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Oligodendroglia; Rats; Rats, Inbred Lew; Spinal Cord; Stem Cells; Time Factors

1997
HLA-DR4-IE chimeric class II transgenic, murine class II-deficient mice are susceptible to experimental allergic encephalomyelitis.
    The Journal of experimental medicine, 1996, Jun-01, Volume: 183, Issue:6

    To investigate the development of HLA-DR-associated autoimmune diseases, we generated transgenic (Tg) mice with HLA-DRA-IE alpha and HLA-DRB1*0401-IE beta chimeric genes. The transgene-encoded proteins consisted of antigen-binding domains from HLA-DRA and HLA-DRB1*0401 molecules and the remaining domains from the IE(d)-alpha and IE(d)-beta chains. The chimeric molecules showed the same antigen-binding specificity as HLA-DRB1*0401 molecules, and were functional in presenting antigens to T cells. The Tg mice were backcrossed to MHC class II-deficient (IA beta-, IE alpha-) mice to eliminate any effect of endogenous MHC class II genes on the development of autoimmune diseases. As expected, IA alpha beta or IE alpha beta molecules were not expressed in Tg mice. Moreover, cell-surface expression of endogenous IE beta associated with HLA-DRA-IE alpha was not detectable in several Tg mouse lines by flow cytometric analysis. The HLA-DRA-IE alpha/HLA-DRB1*0401-IE beta molecules rescued the development of CD4+ T cells in MHC class II-deficient mice, but T cells expressing V beta 5, V beta 11, and V beta 12 were specifically deleted. Tg mice were immunized with peptides, myelin basic protein (MBP) 87-106 and proteolipid protein (PLP) 175-192, that are considered to be immunodominant epitopes in HLA-DR4 individuals. PLP175-192 provoked a strong proliferative response of lymph node T cells from Tg mice, and caused inflammatory lesions in white matter of the CNS and symptoms of experimental allergic encephalomyelitis (EAE). Immunization with MBP87-106 elicited a very weak proliferative T cell response and caused mild EAE. Non-Tg mice immunized with either PLP175-192 or MBP87-106 did not develop EAE. These results demonstrated that a human MHC class II binding site alone can confer susceptibility to an experimentally induced murine autoimmune disease.

    Topics: Amino Acid Sequence; Animals; Antigens; Autoimmune Diseases; Base Sequence; Binding Sites; Brain; CD4-Positive T-Lymphocytes; Disease Susceptibility; DNA Primers; Encephalomyelitis, Autoimmune, Experimental; Flow Cytometry; Genes, MHC Class II; HLA-DR alpha-Chains; HLA-DR Antigens; HLA-DR4 Antigen; HLA-DRB1 Chains; Humans; Inflammation; Lymph Nodes; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Sequence Data; Myelin Basic Protein; Myelin Proteins; Polymerase Chain Reaction; Recombinant Fusion Proteins; Spinal Cord; T-Lymphocytes

1996
Transforming growth factor-beta 1 suppresses autoantigen-induced expression of pro-inflammatory cytokines but not of interleukin-10 in multiple sclerosis and myasthenia gravis.
    Journal of neuroimmunology, 1995, Volume: 58, Issue:1

    Multiple sclerosis (MS) is associated with high levels of circulating T lymphocytes that respond to the myelin antigens myelin basic protein (MBP) and proteolipid protein (PLP) by producing various cytokines including interferon-gamma (IFN-gamma) that makes MS worse and transforming growth factor-beta (TGF-beta), an endogenously produced immunosuppressant that might act beneficially. To further define the role of TGF-beta in MS, we examined the effects of recombinant TGF-beta 1 (rTGF-beta 1) on autoantigen-mediated regulation of cytokines in MS and myasthenia gravis (MG). Blood mononuclear cells (MNC) were cultivated with or without rTGF-beta 1, and with or without autoantigen or the recall antigen PPD. MNC expressing cytokine mRNA were detected after in situ hybridization with radiolabeled cDNA oligonucleotide probes. Femtogram concentrations of rTGF-beta 1 suppressed MBP-, PLP- and PPD-induced upregulation of IFN-gamma, IL-4, IL-6, tumor necrosis factor-alpha (TNF-alpha), TNF-beta and perforin in MS, and acetylcholine receptor (AChR)-induced augmentation of these pro-inflammatory cytokines in MG, but had no effects on autoantigen- or PPD-induced expression of IL-10 or TGF-beta itself. rTGF-beta 1 also suppressed numbers of myelin antigen-reactive IFN-gamma- and IL-4-secreting cells in MS and AChR-reactive IFN-gamma and IL-4 secreting cells in MG. The selective suppressive effects of TGF-beta 1 on autoantigen-induced upregulation of pro-inflammatory cytokines makes TGF-beta 1 attractive as a treatment alternative in MS and MG.

    Topics: Adult; Aged; Autoantigens; Cells, Cultured; Cytokines; Female; Gene Expression; Humans; In Situ Hybridization; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-4; Leukocytes, Mononuclear; Male; Middle Aged; Multiple Sclerosis; Myasthenia Gravis; Myelin Basic Protein; Oligonucleotide Probes; Recombinant Proteins; RNA, Messenger; Transforming Growth Factor beta

1995
Antibody facilitation of multiple sclerosis-like lesions in a nonhuman primate.
    The Journal of clinical investigation, 1995, Volume: 96, Issue:6

    In the human disease multiple sclerosis (MS), the immune mechanisms responsible for selective destruction of central nervous system myelin are unknown. In the common marmoset Callithrix jacchus, a unique demyelinating form of experimental allergic encephalomyelitis resembling MS can be induced by immunization with whole myelin. Here we show that the MS-like lesion can be reproduced by immunization against the extracellular domain of a single myelin protein, myelin/oligodendrocyte glycoprotein (MOG). By contrast, immunization against the quantitatively major myelin proteins myelin basic protein or proteolipid protein results in inflammation but little or no demyelination. Furthermore, in the presence of encephalitogenic (e.g., disease-inducing) T cells, the fully demyelinated lesion is reconstructed by systemic administration of IgG purified from whole myelin-, or MOG-immunized animals, and equally by a monoclonal antibody against MOG, but not by control IgG. Encephalitogenic T cells may contribute to the MS-like lesion through disruption of the blood-brain barrier that permits access of demyelinating antibody into the nervous system. The identification of MOG as a major target antigen for autoimmune demyelination in a nonhuman primate should facilitate development of specific immunotherapies for human MS.

    Topics: Animals; Autoantibodies; Brain; Callithrix; Chromatography, Affinity; Encephalomyelitis, Autoimmune, Experimental; Humans; Immunotherapy, Adoptive; Inflammation; Multiple Sclerosis; Myelin Basic Protein; Myelin Proteins; Myelin Sheath; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Proteolipids; Recombinant Proteins

1995
Clinical and histological findings in proteolipid protein-induced experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. Distribution of demyelination differs from that in EAE induced by other antigens.
    Journal of the neurological sciences, 1994, Volume: 123, Issue:1-2

    Proteolipid protein (PLP) is the major protein of central nervous system (CNS) myelin. In some species, intradermal inoculation with PLP and adjuvants causes experimental autoimmune encephalomyelitis (PLP-EAE) characterized by neurological signs of tail and limb weakness and by inflammation and demyelination in the CNS. A previous study found that inoculation of Lewis rats with 100 micrograms of PLP causes PLP-EAE with a low incidence of neurological signs and a highly variable clinical course. In the present study we assessed PLP-EAE produced by inoculation with 1000 micrograms of PLP per rat. Fifty-one of 59 (86%) Lewis rats developed neurological signs 8 to 20 days (mean = 12.0 +/- 2.0) after inoculation with 1000 micrograms of PLP. In such rats, mononuclear cell infiltrates were present in the brain and spinal cord while primary demyelination occurred mainly in the subpial regions of the spinal cord, especially in the dorsal root entry and ventral root exit zones. The histological findings were compared with those in acute EAE induced in the Lewis rat by inoculation with whole CNS tissue or with myelin basic protein: in PLP-EAE, in contrast to these other models, the disease was essentially restricted to the CNS. This form of EAE should be useful in future studies of the consequences of autoimmunity to PLP.

    Topics: Animals; Antigens; Brain; Encephalomyelitis, Autoimmune, Experimental; Ganglia, Spinal; Inflammation; Myelin Basic Protein; Myelin Proteins; Myelin Proteolipid Protein; Myelin Sheath; Peripheral Nerves; Rats; Rats, Inbred Lew; Spinal Cord; Spinal Nerve Roots; Time Factors

1994
Adhesion and cytotoxicity of myelin basic protein-specific encephalitogenic T cells to normal and inflamed cerebral endothelial cells.
    Autoimmunity, 1994, Volume: 17, Issue:3

    To study the mechanisms involved in the pathogenesis of the blood-brain barrier (BBB) breakdown in autoimmune demyelinating diseases, such as experimental allergic encephalomyelitis (EAE), we investigated the cell interaction in vitro between myelin basic protein (MBP)-specific encephalitogenic T cells and normal and inflamed cerebral endothelial cells, and the cytotoxic effect of antigen specific T cell lines on normal and inflamed cerebral endothelial cells. The importance of relationship between cell surface adhesion and cytotoxic T lymphocyte (CTL) was examined by monoclonal antibodies (mAb) against adhesion receptors. The adhesion of encephalitogenic T cells to inflamed endothelial cells was significantly increased as compared with normal endothelial cells (P < 0.001). The percentage lysis of inflamed endothelial target cells was significantly increased by incubation with MBP-encephalitogenic T cell lines in the presence of MBP as compared with those of normal endothelial targets (P < 0.0001). Intercellular adhesion molecule-1 (ICAM-1) is not involved in T cell adhesion to endothelial cells or cytotoxic endothelial cell lysis. Antibodies against human alpha 4 integrin (HP 2/1) and beta 1 (A11B2) inhibited T cell adhesion, but did not block cytotoxic endothelial cell lysis. These results indicate that T cell adhesion to inflamed cerebral endothelial cells and cytotoxicity of T cells for cerebral endothelial cells may play a central role in the breakdown of the BBB and development of inflammatory lesions in the central nervous system(CNS).

    Topics: Animals; Antibodies, Monoclonal; Brain; Cell Adhesion; Cytotoxicity Tests, Immunologic; Encephalomyelitis, Autoimmune, Experimental; Endothelium, Vascular; Fluorescent Antibody Technique; Inflammation; Myelin Basic Protein; Rats; Rats, Inbred Lew; T-Lymphocytes, Cytotoxic

1994
The distribution of inflammatory demyelinated lesions in the central nervous system of rats with antibody-augmented demyelinating experimental allergic encephalomyelitis.
    Experimental neurology, 1994, Volume: 129, Issue:2

    Experimental allergic encephalomyelitis (EAE) has long been studied as an animal model of the human demyelinating disease Multiple Sclerosis. However, EAE induced in the Lewis rat by injection of myelin basic protein (MBP), or MBP-specific T-lymphocytes, is primarily an inflammatory condition of the central nervous system (CNS) with little or no demyelination. In EAE models in which demyelination does result, it is either not very widespread or is unpredictable in its degree and location. In this study we have produced antibody-augmented demyelinating EAE (ADEAE) in the Lewis rat by injection of activated MBP-specific T-lymphoblasts, followed by injection 4 days later of a monoclonal antibody against myelin/oligodendrocyte glycoprotein, an extrinsic protein of myelin. We have documented the extent and location of inflammatory cell infiltrates and demyelination throughout the CNS using histochemistry, immunofluorescence, and image analysis. Perivascular inflammatory infiltrates were seen in the deep cerebellar white matter and in the folia. Perivascular, periventricular, and subpial inflammation was widespread throughout the pons/medulla and at all levels of the spinal cord. Very little inflammation was apparent in the forebrain. MBP immunofluorescence demonstrated extensive areas of periventricular demyelination in the forebrain around the third ventricle. Both periventricular and perivascular lesions were commonly observed in the cerebellum and pons/medulla. The extent of demyelination in the spinal cord increased caudally with large confluent areas of subpial demyelination seen throughout the lumbar cord. The extensive and reproducible distribution of inflammatory demyelinating lesions in ADEAE provide the possibility to select areas of the CNS for more detailed analysis of the cellular changes that accompany demyelination and remyelination.

    Topics: Animals; Antibodies; Brain; Brain Stem; Cell Line; Concanavalin A; Encephalomyelitis, Autoimmune, Experimental; Female; Immunization, Passive; Immunoglobulins; Immunohistochemistry; Inflammation; Lymphocyte Activation; Lymphocytes; Mice; Mice, Inbred BALB C; Myelin Basic Protein; Myelin Sheath; Neurofilament Proteins; Rats; Rats, Inbred Lew; Spinal Cord; Spleen; T-Lymphocytes

1994
Adoptive transfer of experimental allergic neuritis in the immune suppressed host.
    Acta neuropathologica, 1993, Volume: 86, Issue:6

    Experimental allergic neuritis (EAN) was induced in normal and irradiated Lewis rats by passively transferring T cells sensitized to SP-26, a peptide fragment of P2 myelin protein. The recipients became sick 4-8 days post transfer and the degree of disability correlated directly with the dose of T cells. Smaller doses caused demyelination of nerve roots and sciatic nerves and larger doses produced more severe demyelination and significant axonal degeneration. Irradiated recipients developed similar clinical EAN and showed macrophage-mediated demyelination despite severe suppression of the host inflammatory response.

    Topics: Animals; Axons; Edema; Female; Immunization; Immunotherapy, Adoptive; Inflammation; Myelin Basic Protein; Myelin P2 Protein; Myelin Sheath; Nerve Degeneration; Neuritis, Autoimmune, Experimental; Peptide Fragments; Rats; Rats, Inbred Lew; Sciatic Nerve; Spinal Nerve Roots; T-Lymphocytes; Time Factors; Whole-Body Irradiation

1993
Chronologic localization of myelin-reactive cells in the lesions of relapsing EAE: implications for the study of multiple sclerosis.
    Neurology, 1993, Volume: 43, Issue:5

    Although T cells play a pathogenetic role in MS, specific disease-inducing T cells have not been identified. T cells can be labeled and traced in adoptively transferred experimental autoimmune encephalomyelitis (EAE), a T-cell-mediated animal model for MS. We have followed the appearance and topographic localization of radio-labeled myelin basic protein-reactive (MBP+) T cells in evolving lesions as EAE extended to other regions of the CNS. By high-resolution autoradiography, we confirmed that MBP+ cells initially homed to perivascular regions in the lower spinal cord. With increasing time after cell transfer, labeled cells appeared in more recent lesions in rostral locations (upper spinal cord, cerebellum, and forebrain) and constituted a progressively smaller percentage of cells in lower spinal cord lesions. The presence of unlabeled inflammatory cells in the CNS parenchyma coincided temporally with clinical signs. In agreement with previous studies, we have shown that MBP+ cells constituted a minority (mean, < 1.5%) of the total infiltrating cells and were most numerous in fresh lesions. We suggest that the perivascular regions of recent lesions would be the most likely areas to detect putative antigen-specific cells in MS lesions.

    Topics: Animals; Autoradiography; Brain; Carbon Radioisotopes; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Immunotherapy, Adoptive; Inflammation; Mice; Mice, Inbred Strains; Multiple Sclerosis; Myelin Basic Protein; Spinal Cord; T-Lymphocytes; Thymidine; Time Factors

1993
Neurological signs in inflammatory demyelination.
    Annals of neurology, 1993, Volume: 33, Issue:5

    Topics: Animals; Ataxia; Encephalomyelitis, Autoimmune, Experimental; Ganglia, Spinal; Inflammation; Myelin Basic Protein; Myelin Sheath; Rabbits; Rats; Rats, Inbred Lew; Spinal Cord; Spinal Nerve Roots

1993
Inflammatory leukocytes and cytokines in the peptide-induced disease of experimental allergic encephalomyelitis in SJL and B10.PL mice.
    Proceedings of the National Academy of Sciences of the United States of America, 1992, Jan-15, Volume: 89, Issue:2

    Experimental allergic encephalomyelitis (EAE) was generated in SJL and B10.PL mice by using the synthetic myelin basic protein peptides. Inflammation in brain and spinal cord preceded clinical signs of disease. Infiltrating lymphocytes were predominantly Lyt1+ (CD5+), L3T4+ (CD4+) T cells, until day 18. After that, F4/80+ monocyte/macrophages outnumbered T cells. Ia+ cells were microglia, macrophages, and endothelial cells, but Ia was not detectable on astrocytes in this EAE model. Ia+ endothelial cells appeared later in the disease than Ia+ microglia and macrophages, suggesting that antigen presentation at the blood-brain barrier is not initially responsible for inflammation. Cells staining for interferon gamma, interleukin 2 (IL-2), and IL-2 receptors were more prominent than IL-4, IL-5, lymphotoxin (LT), and tumor necrosis factor alpha (TNF-alpha), which occurred transiently in the second week and were associated with fewer cells. TNF-alpha and LT were never seen in spinal cord, suggesting that these cytokines are not responsible for initiation of clinical disease. Few or no cells stained for IL-6, IL-1, or transforming growth factor beta. Control animals injected with complete Freund's adjuvant in saline or control antigen demonstrated no inflammatory cell infiltration or cytokine production. Thus, our findings suggest a peptide-induced EAE model in which Th1 T-cell-macrophage interactions result in the disease process.

    Topics: Animals; Antigens, Differentiation; Encephalomyelitis, Autoimmune, Experimental; Female; Histocompatibility Antigens Class II; Inflammation; Interferon-gamma; Interleukin-2; Lymphocyte Activation; Mice; Mice, Inbred Strains; Monocytes; Myelin Basic Protein; Peptides; T-Lymphocyte Subsets; T-Lymphocytes, Helper-Inducer; Time Factors

1992
Evolution of the cellular response in P2-induced experimental allergic neuritis.
    Pathobiology : journal of immunopathology, molecular and cellular biology, 1992, Volume: 60, Issue:2

    We examined the development of the inflammatory cellular response and demyelination in P2 protein-induced experimental allergic neuritis (EAN). Collections of inflammatory cells were first identified in nerve roots 14 days after immunization. Ia+ cells predominated in the evolving lesions and T-helper cells were the dominant T-cell type with T-suppressor/cytotoxic cells appearing later in the course of the disease. Vesiculation, the earliest change seen in the myelin sheath, appeared before the wave of cellular infiltration. These results indicate that myelin injury precedes inflammation in P2 protein-induced EAN, and provide further evidence that this disorder is indistinguishable from EAN induced with whole peripheral nerve myelin.

    Topics: Animals; Demyelinating Diseases; Inflammation; Male; Myelin Basic Protein; Myelin P2 Protein; Myelin Sheath; Neuritis, Autoimmune, Experimental; Rats; Rats, Inbred Lew; Spinal Nerve Roots

1992
Apoptosis in the nervous system in experimental allergic encephalomyelitis.
    Journal of the neurological sciences, 1991, Volume: 104, Issue:1

    We report here for the first time the occurrence of apoptosis of cells in the spinal cord in experimental allergic encephalomyelitis (EAE), an autoimmune, T-cell-mediated demyelinating disease. Four different forms of EAE were studied in the Lewis rat: (i) acute EAE induced by inoculation with whole spinal cord and adjuvants; (ii) acute EAE induced by inoculation with myelin basic protein (MBP) and adjuvants; (iii) acute EAE induced by the passive transfer of MBP-sensitized spleen cells; (iv) chronic relapsing EAE induced by inoculation with whole spinal cord and adjuvants followed by treatment with low-dose cyclosporin A. Cells undergoing apoptosis were recognized at light and electron microscopy by the presence of either crescentic masses of condensed chromatin lying against the nuclear envelope or rounded masses of uniformly dense chromatin. They were found in both the white and grey matter of the spinal cord in all 4 forms of this disease. Although it was not possible to identify definitively the types of cells undergoing apoptosis, the size and location of some of the affected cells suggested that they were oligodendrocytes. As there is now a large body of evidence that T-cell-induced target cell death takes the form of apoptosis, it is attractive to hypothesize that oligodendrocyte apoptosis is occurring in EAE as a result of oligodendrocyte-directed T-cell cytotoxicity. However, other apoptotic cells were located within the myelin sheath, meninges and perivascular spaces and were clearly not oligodendrocytes but were most likely blood-derived mononuclear cells. The sparsity of their cytoplasm and the absence of phagocytosed material suggested that they were mainly lymphocytes rather than macrophages. Apoptosis has been shown to be involved in deleting autoreactive T-cells during the normal development of tolerance. Thus apoptotic deletion of myelin/oligodendrocyte-specific lymphocytes in the central nervous system in EAE might explain both the subsidence of inflammation and the acquisition of tolerance in this autoimmune disease.

    Topics: Animals; Cyclosporine; Demyelinating Diseases; Encephalomyelitis, Autoimmune, Experimental; Ganglia, Spinal; Immunization, Passive; Inflammation; Meninges; Microscopy, Electron; Myelin Basic Protein; Nerve Degeneration; Rats; Rats, Inbred Strains; Spinal Cord; Spleen

1991
Damage to bulbospinal serotonin-, tyrosine hydroxylase-, and TRH-containing axons occurs early in the development of experimental allergic encephalomyelitis in rats.
    Journal of neuroscience research, 1990, Volume: 27, Issue:1

    Spinal cord monoaminergic and peptidergic axonal damage occurring during the development of experimental allergic encephalomyelitis (EAE) was assessed using immunohistochemistry. Spinal cord axons immunoreactive for serotonin, catecholamines, or a thyrotropin-releasing hormone marker peptide were found to be markedly swollen and distorted by the earliest stage of detectable paralysis during EAE development (the flaccid tail stage). As clinical signs progressed to complete hindlimb paralysis, axonal damage became increasingly extensive. Axonal damage was equally pronounced whether EAE was induced by inoculation with purified myelin basic protein or with whole spinal cord homogenate, suggesting that the damage did not result from an immune attack directed against specific monoaminergic and/or peptidergic antigens present in the inoculant. However, two observations suggested that mechanical or chemical factors associated with the inflammatory foci contribute to the axonal damage: first, distorted axons were nearly always located adjacent to blood vessels or the pial surface, sites at which inflammation occurs during EAE. Second, the severity of axonal damage correlated with the severity of the inflammation. The early onset of axonal damage during development of EAE and the close correlation that was found between the severity of axonal damage and the severity of clinical signs suggested that the axonal damage may contribute to the clinical signs of the disease.

    Topics: Animals; Axons; Encephalomyelitis, Autoimmune, Experimental; Inflammation; Male; Myelin Basic Protein; Rats; Rats, Inbred Lew; Serotonin; Spinal Cord; Thyrotropin-Releasing Hormone; Tyrosine 3-Monooxygenase

1990
Rat T-cell lines specific to a nonimmunodominant determinant of a retinal protein (IRBP) produce uveoretinitis and pinealitis.
    Cellular immunology, 1989, Volume: 122, Issue:1

    Rat lymphocyte lines were established, with specificity toward two synthetic peptides derived from the interphotoreceptor retinoid-binding protein (IRBP), which specifically localizes in the retina and pineal gland. One of the peptides, R4, is immunopathogenic, producing experimental autoimmune uveoretinitis (EAU) and pinealitis (EAP) in immunized rats, while the other peptide, R3, exhibits no detectable immunopathogenicity in rats. The cell lines carry surface markers specific for the helper/inducer subset of T-lymphocytes. When tested by the proliferation assay, the line cells demonstrated major histocompatibility-restricted vigorous responses against the immunizing (homologous) peptide, but failed to recognize the intact IRBP molecule. This finding is in line with other data indicating that peptides R3 and R4 are nonimmunodominant determinants of IRBP for the Lewis rat. Yet, the cell lines specific for R4 were highly immunopathogenic, producing EAU and EAP in naive rats at numbers as low as 0.25 x 10(6), with histopathological changes similar to those induced by active immunization with this peptide. The immunological capacity of the cell lines was further demonstrated by the finding that spleen cells from recipient rats of these lines responded well against the homologous peptides. The uniqueness of this system, in which lymphocytes specific toward a nondominant determinant are immunopathogenic, is underscored and the possible mechanisms of disease induction are discussed.

    Topics: Animals; Autoimmune Diseases; Brain Diseases; Cell Line; Eye Proteins; Inflammation; Lymphocyte Activation; Male; Myelin Basic Protein; Pineal Gland; Rats; Rats, Inbred Lew; Retinitis; Retinol-Binding Proteins; T-Lymphocytes; Uveitis

1989
Chronic relapsing necrotizing encephalomyelitis produced by myelin basic protein in mice.
    Laboratory investigation; a journal of technical methods and pathology, 1987, Volume: 57, Issue:2

    Chronic relapsing experimental autoimmune encephalomyelitis is commonly seen in a number of species after a single injection of whole white matter in adjuvant but not after inoculation with myelin basic protein, the major encephalitogen of central myelin. In the present report on large groups of SJL mice, we describe a form of chronic relapsing experimental autoimmune encephalomyelitis with destructive lesions after a single inoculation of myelin basic protein in complete Freund's adjuvant. This condition was studied for up to 19 months postinoculation and was characterized by a relapsing-remitting or a chronic progressive course, usually with a prolonged latent period. Higher doses of 400 and 800 micrograms of myelin basic protein were more effective in inducing this condition than were lower doses of 100 and 200 micrograms. Large lesions were apparent in the white matter. These comprised widespread destruction and Wallerian degeneration with some demyelination towards the margins. Demyelination was an initial, albeit transient, event which was subsequently masked by nerve fiber destruction. Polymorphonuclear leukocytes were early and prominent components of the inflammatory infiltrate and together with macrophages appeared to be involved in the lysis of myelin and axons. Thus, despite the clinical similarities, these features contrast the model with the more purely demyelinative lesions of chronic relapsing experimental autoimmune encephalomyelitis in other species and multiple sclerosis in man.

    Topics: Adjuvants, Immunologic; Animals; Demyelinating Diseases; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Inflammation; Macrophages; Mice; Mice, Inbred Strains; Multiple Sclerosis; Myelin Basic Protein; Neutrophils; Wallerian Degeneration

1987
Humoral immune response in experimental allergic encephalomyelitis in inbred chicken lines.
    Folia biologica, 1987, Volume: 33, Issue:6

    Chickens of the inbred IA line develop clinical signs of experimental allergic encephalomyelitis (EAE) after immunization with myelin basic protein (MP) or spinal cord tissue (SCT). The disease is accompanied by convulsions and paralysis of wings and legs. EAE leads to a 100% mortality in IA line chickens. On the other hand, no clinical signs appear in WA line and (CB x IA) F1 chickens following immunization with either antigen. The IA line and (CB x IA)F1 chickens develop severe inflammatory changes in brain and spinal cord tissues after immunization with SCT, whereas no such alterations occur in WA line chickens. Immunization with MP does not lead to histopathological changes in any chicken line investigated. MP, however, induces high production of specific IgM antibodies in all lines. IgG antibody levels are elevated only in IA line chickens after immunization with either antigen.

    Topics: Animals; Autoantibodies; Autoantigens; Chickens; Encephalomyelitis, Autoimmune, Experimental; Immunoglobulin M; Inbreeding; Inflammation; Kidney Glomerulus; Liver; Myelin Basic Protein; Nervous System; Spinal Cord; Spleen

1987
Dose-dependency of MBP-induced demyelination in the guinea pig.
    Journal of the neurological sciences, 1985, Volume: 70, Issue:2

    The pathology of experimental allergic encephalomyelitis (EAE) induced by bovine myelin basic protein (MBP) has been examined in the guinea pig with a series of doses ranging from 37.5 micrograms to 600 micrograms. This was to investigate whether the previously demonstrated lack of demyelinative effect by MBP was dose-related. At all doses tested, MBP induced clinical disease. Inflammation was the major feature of lesions in all animals. However, no demyelination was seen when 75 micrograms MBP or less was given. At higher doses (150 micrograms upwards), MBP always induced intense inflammation but demyelination was encountered inconsistently. These observations support the contention that in addition to an immune response to MBP, other factors contribute to autoimmune demyelination.

    Topics: Animals; Autoantibodies; Dose-Response Relationship, Immunologic; Encephalomyelitis, Autoimmune, Experimental; Female; Galactosylceramides; Guinea Pigs; Inflammation; Myelin Basic Protein; Myelin Sheath

1985
Suppression of experimental allergic encephalomyelitis by transfer of lymph node cells from Lewis rats pretreated with complete Freund's adjuvant.
    International archives of allergy and applied immunology, 1981, Volume: 66, Issue:3

    Experimental allergic encephalomyelitis (EAE) in Lewis rats was suppressed by pretreatment with complete Freund's adjuvant (CFA) 14-16 days before immunization with basic protein (BP) in CFA. Suppression of active EAE was also accomplished clinically and even histologically if lymph node cells from CFA-treated donors were passively transferred. Obviously this depends first on a certain amount of transferred lymph node cells (about 3 X 108) and secondly on the interval between CFA application and cell harvest (more than 14 days). No suppression was obtained by transfer of serum from CFA-treated donors. This indicates that there is a suppressor cell population which can be raised or stimulated by CFA and which is capable of suppressing the immune response EAE.

    Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Female; Freund's Adjuvant; Guinea Pigs; Immunization, Passive; Immunosuppression Therapy; Inflammation; Lymph Nodes; Myelin Basic Protein; Rats; Rats, Inbred Lew

1981
Neutral proteinases secreted by macrophages degrade basic protein: a possible mechanism of inflammatory demyelination.
    Advances in experimental medicine and biology, 1978, Volume: 100

    In the inflammatory demyelinating diseases, such as multiple sclerosis, Landry-Guillain-Barré syndrome and experimental allergic encephalomyelitis, demyelination occurs in the vicinity of infiltrating mononuclear cells. Although the histopathology is characteristic of each disease, the general observation that myelin destruction in inflammatory lesions begins prior to phagocytosis suggests a common mechanism for myelinolysis in these diseases. Recent studies show that stimulated macrophages secrete several neutral proteinases, including plasminogen (Plg) activator. We have tested the possibility that these proteinases could, directly or indirectly, initiate myelin destruction. Isolated brain myelin was incubated with supernatant media from cultures of stimulated mouse peritoneal macrophages in the presence and absence of Plg. Cell supernatants alone caused some degradation of basic protein (BP) in myelin. The amount degraded was considerably enhanced in the presence of Plg. The other myelin proteins remained essentially intact. While the Plg-independent proteolytic activity in the supernatants was abolished by EDTA, known to inhibit the neutral proteinases, the Plg-dependent hydrolysis was inhibited by p-nitrophenylguanidinobenzoate, an inhibitor of Plg activator and plasmin. These results suggested that the Plg activator secreted by the macrophages generated plasmin, which selectively degraded BP. This interpretation was confirmed by the observation that urokinase, a Plg activator, plus Plg was effective in degrading BP in myelin. We propose that the action of neutral proteinases released by stimulated macrophages, and its amplification by the Plg-plasmin system, may play a significant role in several inflammatory demyelinating diseases; and that the relative specificity of these reactions for myelin lies in the extreme susceptibility of BP to proteolysis.

    Topics: Animals; Brain; Cats; Cattle; Demyelinating Diseases; Fibrinolysin; Inflammation; Macrophages; Molecular Weight; Myelin Basic Protein; Myelin Sheath; Peptide Hydrolases; Plasminogen; Plasminogen Activators

1978
Experimental allergic encephalomyelitis: role of fibrin deposition in immunopathogenesis of inflammation in rats.
    Federation proceedings, 1976, Volume: 35, Issue:13

    The immunopathogenesis of experimental allergic encephalomyelitis (EAE) is reviewed with special focus on the role of central nervous system fibrin deposition in the inflammatory cascade characterizing this autoimmune disease. Among rats sensitized to whole spinal cord or myelin basic protein of either guinea pig or bovine origin, there is a striking degree of concordance of perivascular fibrin deposits and occurrence of clinical paralytic signs. Neither paralytic signs nor fibrin deposition are temporally related to development of perivascular cellular infiltrates. Rats sensitized to neuroantigen and treated with ancrod, a polypeptide derived from the venom of Agkistrodon rhodostoma, develop profound hypofibrinogenemia, have a marked inhibition of fibrin deposition, and often exhibit no paralytic signs whatsoever. In contrast, cellular infiltrates are not demonstrably influenced by ancrod treatment. Activation of the clotting cascade at loci of developing immune injury of nervous tissue appears to result from and lead to increasing neurovascular permeability and accumulation of edema fluid. Distention of the extracellular space in central and peripheral nervous system tissues by edema fluid appears to be directly responsible for clinical abnormalities characterizing EAE in rats. Cellular infiltrates, on the other hand, appear to be an independent immune response to neuroantigenic sensitization.

    Topics: Animals; Cattle; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Fibrin; Guinea Pigs; Inflammation; Myelin Basic Protein; Rats; Rats, Inbred Lew; Spinal Cord

1976
Allergic encephalomyelitis: modification of the response by synthetic membrane structures containing bovine myelin basic protein and cerebroside.
    Brain research, 1975, Jul-25, Volume: 93, Issue:1

    Topics: Animals; Antigens; Cattle; Central Nervous System; Cerebrosides; Demyelinating Diseases; Encephalomyelitis, Autoimmune, Experimental; Guinea Pigs; Inflammation; Membranes, Artificial; Myelin Basic Protein; Myelin Sheath; Time Factors

1975
Three localized forms of experimental allergic encephalomyelitis: an ultrastructural comparison.
    Journal of neuropathology and experimental neurology, 1974, Volume: 33, Issue:2

    Topics: Animals; Basophils; Brain Edema; Cerebral Cortex; Cyclophosphamide; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Endothelium; Extracellular Space; Fibrin; Freund's Adjuvant; Immunization, Passive; Inflammation; Intercellular Junctions; Lymphocytes; Macrophages; Microscopy, Electron; Myelin Basic Protein; Neutrophils; Pertussis Vaccine; Rats

1974
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