myelin-basic-protein and Encephalitis

In experimental models of stroke, inflammation appears to contribute to cerebral ischemic injury. Clinical trials that are aimed at limiting the postischemic inflammatory response, however, have thus far had disappointing results. These clinical failures probably reflect the fact that there has been insufficient preclinical data and inadequate trial design, rather than provide evidence against a role for inflammation in ischemic brain injury.

Topics: Animals; Autoantigens; Blood-Brain Barrier; Cerebral Infarction; Cytokines; Encephalitis; Humans; Leukocytes; Myelin Basic Protein

This review article summarises the initial preclinical studies as well as the different stages of clinical trials in multiple sclerosis (MS) with Copolymer 1 (Cop 1), recently denoted glatiramer acetate. Experimental studies on autoimmune encephalomyelitis (EAE), the animal model of MS, as well as studies on the mechanism of action in both animals and humans are discussed. The review describes the early clinical trials which were followed by Phase II and III trials, culminating in FDA approval in 1996 for the treatment of relapsing-remitting MS. The accumulated experience with glatiramer acetate indicates that its efficacy is apparently increased as a function of usage time while the favourable side effect profile is sustained. MRI studies revealed that treatment with glatiramer acetate resulted in a significant reduction of gadolinium (Gd)-enhancing lesions. Ongoing clinical trials which might extend its usage or change its mode of delivery are also described. Glatiramer acetate appears to be a treatment of choice for the relapsing-remitting type of MS.

Topics: Animals; Antibody Formation; Clinical Trials as Topic; Cross Reactions; Drug Approval; Encephalitis; Glatiramer Acetate; Guidelines as Topic; Histocompatibility Antigens Class II; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Multicenter Studies as Topic; Multiple Sclerosis; Myelin Basic Protein; Patient Dropouts; Peptides; T-Lymphocytes; T-Lymphocytes, Regulatory; Th1 Cells

The pathophysiology of unilateral cortical fluid-attenuated inversion recovery (FLAIR)-hyperintense lesions in anti-myelin oligodendrocyte glycoprotein (MOG)-associated encephalitis with seizures (FLAMES) is unclear. A 26-year-old man was referred because of a seizure. FLAIR showed an increased signal intensity and swelling of the right frontal cortex. His symptoms and imaging abnormalities were improved after intravenous methylprednisolone therapy. MOG antibody was detected both in serum and cerebrospinal fluid (CSF). Therefore, the patient was diagnosed with FLAMES. Myelin basic protein (MBP) was elevated in CSF. The high MBP value in the CSF in the present case suggested that demyelination as well as inflammation can occur in some FLAMES patients.

Topics: Autoantibodies; Encephalitis; Humans; Magnetic Resonance Imaging; Myelin Basic Protein; Myelin-Oligodendrocyte Glycoprotein; Myelitis; Seizures

The obstacle to successful remyelination in demyelinating diseases, such as multiple sclerosis, mainly lies in the inability of oligodendrocyte precursor cells (OPCs) to differentiate, since OPCs and oligodendrocyte-lineage cells that are unable to fully differentiate are found in the areas of demyelination. Thus, promoting the differentiation of OPCs is vital for the treatment of demyelinating diseases. Shikimic acid (SA) is mainly derived from star anise, and is reported to have anti-influenza, anti-oxidation, and anti-tumor effects. In the present study, we found that SA significantly promoted the differentiation of cultured rat OPCs without affecting their proliferation and apoptosis. In mice, SA exerted therapeutic effects on experimental autoimmune encephalomyelitis (EAE), such as alleviating clinical EAE scores, inhibiting inflammation, and reducing demyelination in the CNS. SA also promoted the differentiation of OPCs as well as their remyelination after lysolecithin-induced demyelination. Furthermore, we showed that the promotion effect of SA on OPC differentiation was associated with the up-regulation of phosphorylated mTOR. Taken together, our results demonstrated that SA could act as a potential drug candidate for the treatment of demyelinating diseases.

Topics: Animals; Apoptosis; Cell Differentiation; Cell Proliferation; Cells, Cultured; Demyelinating Diseases; Encephalitis; Encephalomyelitis, Autoimmune, Experimental; Female; Mice, Inbred C57BL; Myelin Basic Protein; Neuroprotective Agents; Oligodendrocyte Precursor Cells; Rats; Remyelination; Shikimic Acid; TOR Serine-Threonine Kinases

Intra-amniotic Candida albicans (C. Albicans) infection is associated with preterm birth and high morbidity and mortality rates. Survivors are prone to adverse neurodevelopmental outcomes. The mechanisms leading to these adverse neonatal brain outcomes remain largely unknown. To better understand the mechanisms underlying C. albicans-induced fetal brain injury, we studied immunological responses and structural changes of the fetal brain in a well-established translational ovine model of intra-amniotic C. albicans infection. In addition, we tested whether these potential adverse outcomes of the fetal brain were improved in utero by antifungal treatment with fluconazole.. Pregnant ewes received an intra-amniotic injection of 10(7) colony-forming units C. albicans or saline (controls) at 3 or 5 days before preterm delivery at 0.8 of gestation (term ~ 150 days). Fetal intra-amniotic/intra-peritoneal injections of fluconazole or saline (controls) were administered 2 days after C. albicans exposure. Post mortem analyses for fungal burden, peripheral immune activation, neuroinflammation, and white matter/neuronal injury were performed to determine the effects of intra-amniotic C. albicans and fluconazole treatment.. Intra-amniotic exposure to C. albicans caused a severe systemic inflammatory response, illustrated by a robust increase of plasma interleukin-6 concentrations. Cerebrospinal fluid cultures were positive for C. albicans in the majority of the 3-day C. albicans-exposed animals whereas no positive cultures were present in the 5-day C. albicans-exposed and fluconazole-treated animals. Although C. albicans was not detected in the brain parenchyma, a neuroinflammatory response in the hippocampus and white matter was seen which was characterized by increased microglial and astrocyte activation. These neuroinflammatory changes were accompanied by structural white matter injury. Intra-amniotic fluconazole reduced fetal mortality but did not attenuate neuroinflammation and white matter injury.. Intra-amniotic C. albicans exposure provoked acute systemic and neuroinflammatory responses with concomitant white matter injury. Fluconazole treatment prevented systemic inflammation without attenuating cerebral inflammation and injury.

Topics: Animals; Brain Injuries; Calcium-Binding Proteins; Candida albicans; Candidiasis; Caspase 3; Disease Models, Animal; DNA-Binding Proteins; Encephalitis; Enzyme-Linked Immunosorbent Assay; Female; Fluoresceins; Granulocyte Colony-Stimulating Factor; Interleukin-3; Interleukin-6; Ki-67 Antigen; Male; Microfilament Proteins; Myelin Basic Protein; Nerve Tissue Proteins; Pregnancy; Prenatal Exposure Delayed Effects; Recombinant Fusion Proteins; Sheep

Evidence have been accumulated that continuous oligodendrogenesis occurs in the adult mammalian brain. The fornix, projection and commissure pathway of hippocampal neurons, carries signals from the hippocampus to other parts of the brain and has critical role in memory and learning. However, basic characterization of adult oligodendrogenesis in this brain region is not well understood. In the present study, therefore, we aimed to examine the proliferation and differentiation of oligodendrocyte progenitor cells (OPCs) and the effect of acute inflammatory stimulation on oligodendrogenesis in the fornix of adult mouse. We demonstrated the proliferation of OPCs and a new generation of mature oligodendrocytes by using bromodeoxyuridine and Ki67 immunohistochemistry. Oligodendrogenesis of adult fornix was also demonstrated by using oligodendrocyte transcription factor 2 transgenic mouse. A single systemic administration of lipopolysaccharide (LPS) attenuated proliferation of OPCs in the fornix together with reduced proliferation of hippocampal neural stem/progenitor cells. Time course analysis showed that a single administration of LPS attenuated the proliferation of OPCs during 24-48 h. On the other hand, consecutive administration of LPS did not suppress proliferation of OPCs. The treatment of LPS did not affect differentiation of OPCs into mature oligodendrocytes. Treatment of a microglia inhibitor minocycline significantly attenuated basal proliferation of OPCs under normal condition. In conclusion, the present study indicates that continuous oligodendrogenesis occurs and a single administration of LPS transiently attenuates proliferation of OPCs without changing differentiation in the fornix of the adult mouse brains.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Calcium-Binding Proteins; Cell Differentiation; Disease Models, Animal; Encephalitis; Fornix, Brain; GAP-43 Protein; Glial Fibrillary Acidic Protein; Ki-67 Antigen; Lipopolysaccharides; Male; Mice; Mice, Inbred ICR; Mice, Transgenic; Microfilament Proteins; Myelin Basic Protein; Nerve Tissue Proteins; Neurofilament Proteins; Oligodendrocyte Transcription Factor 2; Oligodendroglia; Receptor, Platelet-Derived Growth Factor alpha; Stem Cells

We provide evidence of cortical neuronopathy in myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis, an established model of chronic multiple sclerosis. To investigate phenotypic perturbations in neurons in this model, we used apoptotic markers and immunohistochemistry with antibodies to NeuN and other surrogate markers known to be expressed by adult pyramidal Layer V somas, including annexin V, encephalopsin, and Emx1. We found no consistent evidence of chronic loss of Layer V neurons but detected both reversible and chronic decreases in the expression of these markers in conjunction with evidence of cortical demyelination and presynaptic loss. These phenotypic perturbations were present in, but not restricted to, the neocortical Layer V. We also investigated inflammatory responses in the cortex and subcortical white matter of the corpus callosum and spinal dorsal funiculus and found that those in the cortex and corpus callosum were delayed compared with those in the spinal cord. Inflammatory infiltrates initially included T cells, neutrophils, and Iba1-positive microglia/macrophages in the corpus callosum, whereas only Iba1-positive cells were present in the cortex. These data indicate that we have identified a new temporal pattern of subtle phenotypic perturbations in neocortical neurons in this chronic multiple sclerosis model.

Topics: Animals; Caspase 3; Cell Death; Disease Models, Animal; Encephalitis; Freund's Adjuvant; Humans; In Situ Nick-End Labeling; Male; Mice; Mice, Inbred C57BL; Motor Neurons; Multiple Sclerosis; Myelin Basic Protein; Myelin-Oligodendrocyte Glycoprotein; Neocortex; Peptide Fragments; Phosphopyruvate Hydratase; Synaptophysin; Time Factors

Administration of antigens into the anterior chamber (AC) of the eye induces a form of antigen-specific immune tolerance termed anterior chamber-associated immune deviation (ACAID). This immune tolerance effectively impairs host delayed-type hypersensitivity (DTH) responses. We hypothesized that ACAID could be generated in BALB/c mice following AC inoculation of the encephalitogenic antigens myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP).. We used DTH assays and local adoptive transfer (LAT) assays to test whether MOG/MBP-induced ACAID following their administration into the AC, whether they elicited this immune tolerance via CD8(+) T cells, and whether their AC coadministration (MOG/MBP) induced specific immune tolerance to one or both antigens.. We showed that MOG/MBP-induced AC-mediated specific immune tolerance, as evident from impaired DTH responses. This antigen-driven DTH suppression was solely mediated via splenic CD8(+) T cells as confirmed by LAT assays. Finally, a single AC injection with both antigens was sufficient to induce specific immune tolerance to these antigens, as evident from DTH and LAT assays.. ACAID T-cell regulation could be used as a therapeutic tool in the treatment of complicated autoimmune diseases that involve multiple antigens such as multiple sclerosis.

Topics: Adoptive Transfer; Animals; Anterior Chamber; Antigens; CD8-Positive T-Lymphocytes; Encephalitis; Hypersensitivity, Delayed; Immune Tolerance; Immunization; Immunomagnetic Separation; Injections; Injections, Subcutaneous; Mice; Mice, Inbred BALB C; Myelin Basic Protein; Myelin-Oligodendrocyte Glycoprotein; Ocular Physiological Phenomena; Spleen

Although peroxisome biogenesis and β-oxidation disorders are well known for their neurodevelopmental defects, patients with these disorders are increasingly diagnosed with neurodegenerative pathologies. In order to investigate the cellular mechanisms of neurodegeneration in these patients, we developed a mouse model lacking multifunctional protein 2 (MFP2, also called D-bifunctional protein), a central enzyme of peroxisomal β-oxidation, in all neural cells (Nestin-Mfp2(-/-)) or in oligodendrocytes (Cnp-Mfp2(-/-)) and compared these models with an already established general Mfp2 knockout. Nestin-Mfp2 but not Cnp-Mfp2 knockout mice develop motor disabilities and ataxia, similar to the general mutant. Deterioration of motor performance correlates with the demise of Purkinje cell axons in the cerebellum, which precedes loss of Purkinje cells and cerebellar atrophy. This closely mimics spinocerebellar ataxias of patients affected with mild peroxisome β-oxidation disorders. However, general knockouts have a much shorter life span than Nestin-Mfp2 knockouts which is paralleled by a disparity in activation of the innate immune system. Whereas in general mutants a strong and chronic proinflammatory reaction proceeds throughout the brain, elimination of MFP2 from neural cells results in minor neuroinflammation. Neither the extent of the inflammatory reaction nor the cerebellar degeneration could be correlated with levels of very long chain fatty acids, substrates of peroxisomal β-oxidation. In conclusion, MFP2 has multiple tasks in the adult brain, including the maintenance of Purkinje cells and the prevention of neuroinflammation but this is not mediated by its activity in oligodendrocytes nor by its role in very long chain fatty acid degradation.

Topics: 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; Age Factors; Animals; Antigens, Differentiation; Brain; Calcium-Binding Proteins; Cytokines; Deficiency Diseases; Encephalitis; Fatty Acids; Gas Chromatography-Mass Spectrometry; Gene Expression Regulation; Locomotion; Mice; Mice, Transgenic; Microfilament Proteins; Myelin Basic Protein; Nerve Degeneration; Nestin; Peroxisomal Multifunctional Protein-2; Purkinje Cells

The objective of this study was to determine whether the presence of maternal tooth periapical lesions was associated with foetal brain inflammation in a pregnant rat model.. Sprague-Dawley rats were divided into two groups: pregnant rats with induced periapical abscesses (E, n=8) and sham-operated control pregnant rats (S, n=8). The pulps of the first and second maxillary right molars had been exposed and the tooth left open to the oral environment for two weeks prior to initiation of the pregnancy. Following delivery of the pups (E, n=99; S, n=101), each pup was decapitated and the brain was removed and immediately frozen in liquid nitrogen. The tissues were solubilized in PBS containing a protease inhibitor, and norepinephrine (NE), IL-6, IL-1-β, TNF-α, and myelin basic protein (MBP) were determined by ELISA. Group means were compared by factorial analysis of variance, a post hoc Tukey test, and Pearson's correlation test. p<0.05 was used to reject the null hypothesis.. E pups were significantly heavier than S pups. Brain tissue concentrations of IL-6, IL-1-β, and TNF-α were significantly higher and MBP and norepinephrine concentrations significantly lower in E pups than S pups. Concentrations of IL-6, TNF-α and IL-1-β were significantly correlated between E serum, pup birthweight, and E pup brain tissue. MBP, NE and IL-6 were significantly correlated within the brain tissues of E pups.. The data suggest that brain inflammation may be associated with maternal periapical inflammation. This association identifies a modifiable risk factor for adverse pregnancy outcomes.

Topics: Animals; Biomarkers; Birth Weight; Blood Glucose; Brain; Brain Chemistry; Encephalitis; Female; Interleukin-1beta; Interleukin-6; Myelin Basic Protein; Norepinephrine; Periapical Abscess; Pregnancy; Pregnancy Complications, Infectious; Rats; Rats, Sprague-Dawley; Spectrophotometry; Tumor Necrosis Factor-alpha

Intracranial surgery causes cortical injury from incisions, hemorrhage, retraction, and electrocautery. The term "surgical brain injury" (SBI) has been developed to categorize this injury inherent to the procedure. Neuroinflammation plays a significant role in SBI. Traditional antiinflammatory therapies are often limited by their immunosuppressive side effects and poor CNS penetration. This study uses mucosal tolerance to develop an immune system that is tolerant to brain myelin basic protein (MBP) so that inflammation can be suppressed in a timely and site-specific manner following surgical disruption of the blood-brain barrier.. A standard SBI model using CD57 mice was used. Nasopharyngeal mucosa was exposed to vehicle, ovalbumin, or MBP to develop mucosal tolerance to these antigens. Immunological tolerance to MBP was confirmed in vivo through hypersensitivity testing. Neurological scores, cerebral edema, and interleukin (IL)-1β and transforming growth factor (TGF)-β1 cytokine levels were measured 48 hours postoperatively.. Hypersensitivity testing confirmed the development of immune tolerance to MBP. Myelin basic protein-tolerant mice demonstrated reduced neurological injury, less cerebral edema, decreased levels of IL-1β, and increased levels of TGFβ1 following SBI.. Developing preoperative immunological tolerance to brain antigens through mucosal tolerance provides neuroprotection, reduces brain edema, and modulates neuroinflammation following SBI.

Topics: Animals; Brain; Brain Edema; Brain Injuries; Cytokines; Encephalitis; Immune Tolerance; Immunity, Mucosal; Mice; Myelin Basic Protein

Opticospinal demyelinating diseases in humans are mostly characterized by the opticospinal form of multiple sclerosis (MS) and neuromyelitis optica (NMO). Increasing attention has recently focused on astrocyte markers, aquaporin-4 (AQP4) and glial fibrillary acidic protein (GFAP) in these diseases. We induced opticospinal demyelination in Brown Norway rats with soluble recombinant rat myelin oligodendrocyte glycoprotein (1-116) and incomplete Freund's adjuvant. Clinical, MRI, neuropathological and immunological evaluations were performed, with a focus on AQP4 and GFAP. We confirmed the opticospinal phenotype, including extensive myelitis, but also showed the MRI-characterized involvement of the periventricular area. Expression levels of myelin, AQP4 and GFAP showed the early involvement of astrocytes before demyelination in the optic nerve. The overexpression of AQP4 was particularly pronounced in the spinal cord and was concomitant with demyelination and astrocyte apoptosis. The disability scores were correlated with demyelination and inflammation but not with AQP4/GFAP expression. No antibodies against the linear and conformational epitopes of AQP4 were detected. Whereas a NMO-like phenotype was observed in this model, the AQP4/GFAP expression during the disease process was more closely related to opticospinal MS than NMO. However, this model raises the question of a continuum between opticospinal MS and the seronegative NMO subtype.

Topics: Animals; Aquaporin 4; Disease Models, Animal; Encephalitis; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Magnetic Resonance Imaging; Multiple Sclerosis; Myelin Basic Protein; Myelin-Oligodendrocyte Glycoprotein; Neuromyelitis Optica; Optic Nerve; Peptide Fragments; Rats; Spinal Cord; Statistics, Nonparametric; Time Factors

Encephalitis/encephalopathy is a rare, but severe, complication of pertussis. Here, we report a case of an unimmunized 7-year-old boy with confirmed pertussis complicated by acute encephalitis/encephalopathy. Eighteen days after the onset of pertussis, generalized seizures began. Magnetic resonance imaging (MRI) indicated that marked demyelination without cytotoxic edema may have occurred to the patient. Notably, this is the first report to show precise MRI findings of pertussis-associated encephalitis/encephalopathy. Markedly increased myelin basic protein levels in the cerebrospinal fluid were consistent with the MRI findings. There was no evidence of direct invasion of the causative bacterium or its products into the central nervous system. The levels of interleukin-6 and -10 in the cerebrospinal fluid were higher than those in serum. Taken together, we conclude that indirect immune-mediated mechanisms may have contributed to the pathogenesis of the encephalitis/encephalopathy.

Topics: Child; Demyelinating Diseases; Encephalitis; Humans; Immunization; Interleukin-10; Interleukin-6; Magnetic Resonance Imaging; Male; Myelin Basic Protein; Neuroimaging; Whooping Cough

Pathological changes occur in areas of CNS tissue remote from inflammatory lesions in multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE). To determine if oxidative stress is a significant contributor to this non-inflammatory pathology, cortex tissues from mice with clinical signs of EAE were examined for evidence of inflammation and oxidative stress. Histology and gene expression analysis showed little evidence of immune/inflammatory cell invasion but reductions in natural antioxidant levels and increased protein oxidation that paralleled disease severity. Two-dimensional oxyblots and mass-spectrometry-based protein fingerprinting identified glutamine synthetase (GS) as a particular target of oxidation. Oxidation of GS was associated with reductions in enzyme activity and increased glutamate/glutamine levels. The possibility that this may cause neurodegeneration through glutamate excitotoxicity is supported by evidence of increasing cortical Ca(2+) levels in cortex extracts from animals with greater disease severity. These findings indicate that oxidative stress occurs in brain areas that are not actively undergoing inflammation in EAE and that this can lead to a neurodegenerative process due to the susceptibility of GS to oxidative inactivation.

Topics: Analysis of Variance; Animals; Calcium; Cerebral Cortex; Chromatography, High Pressure Liquid; Disease Models, Animal; Electrophoresis, Gel, Two-Dimensional; Encephalitis; Encephalomyelitis, Autoimmune, Experimental; Female; Glutamate-Ammonia Ligase; Glutamic Acid; Glutamine; Glutathione; Glutathione Disulfide; Guinea Pigs; Mice; Myelin Basic Protein; NAD; NADP; Nitric Oxide Synthase Type II; Oxidative Stress; Tandem Mass Spectrometry

SLC25A12, a susceptibility gene for autism spectrum disorders that is mutated in a neurodevelopmental syndrome, encodes a mitochondrial aspartate-glutamate carrier (aspartate-glutamate carrier isoform 1 [AGC1]). AGC1 is an important component of the malate/aspartate shuttle, a crucial system supporting oxidative phosphorylation and adenosine triphosphate production.. We characterized mice with a disruption of the Slc25a12 gene, followed by confirmatory in vitro studies.. Slc25a12-knockout mice, which showed no AGC1 by immunoblotting, were born normally but displayed delayed development and died around 3 weeks after birth. In postnatal day 13 to 14 knockout brains, the brains were smaller with no obvious alteration in gross structure. However, we found a reduction in myelin basic protein (MBP)-positive fibers, consistent with a previous report. Furthermore, the neocortex of knockout mice contained abnormal neurofilamentous accumulations in neurons, suggesting defective axonal transport and/or neurodegeneration. Slice cultures prepared from knockout mice also showed a myelination defect, and reduction of Slc25a12 in rat primary oligodendrocytes led to a cell-autonomous reduction in MBP expression. Myelin deficits in slice cultures from knockout mice could be reversed by administration of pyruvate, indicating that reduction in AGC1 activity leads to reduced production of aspartate/N-acetylaspartate and/or alterations in the dihydronicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide(+) ratio, resulting in myelin defects.. Our data implicate AGC1 activity in myelination and in neuronal structure and indicate that while loss of AGC1 leads to hypomyelination and neuronal changes, subtle alterations in AGC1 expression could affect brain development, contributing to increased autism susceptibility.

Topics: Aggrecans; Animals; Animals, Newborn; Brain; Calbindins; Cells, Cultured; Cerebellum; Developmental Disabilities; Disease Models, Animal; Embryo, Mammalian; Encephalitis; Gene Expression Regulation, Developmental; Green Fluorescent Proteins; Male; Membrane Transport Proteins; Mice; Mice, Knockout; Mitochondrial Membrane Transport Proteins; Mitochondrial Proteins; Myelin Basic Protein; Myelin-Associated Glycoprotein; Neurons; Oligodendroglia; Organ Culture Techniques; Pyruvic Acid; Receptors, Cell Surface; S100 Calcium Binding Protein G; Stem Cells

Brain inflammation plays a central role in numerous brain pathologies, including multiple sclerosis (MS). Microglial cells and astrocytes are the effector cells of neuroinflammation. They can be activated also by agents such as interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS). Peroxisome proliferator-associated receptor (PPAR) pathways are involved in the control of the inflammatory processes, and PPAR-beta seems to play an important role in the regulation of central inflammation. In addition, PPAR-beta agonists were shown to have trophic effects on oligodendrocytes in vitro, and to confer partial protection in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In the present work, a three-dimensional brain cell culture system was used as in vitro model to study antibody-induced demyelination and inflammatory responses. GW 501516, a specific PPAR-beta agonist, was examined for its capacity to protect from antibody-mediated demyelination and to prevent inflammatory responses induced by IFN-gamma and LPS.. Aggregating brain cells cultures were prepared from embryonal rat brain, and used to study the inflammatory responses triggered by IFN-gamma and LPS and by antibody-mediated demyelination induced by antibodies directed against myelin-oligodendrocyte glycoprotein (MOG). The effects of GW 501516 on cellular responses were characterized by the quantification of the mRNA expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), inducible NO synthase (i-NOS), PPAR-beta, PPAR-gamma, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and high molecular weight neurofilament protein (NF-H). GFAP expression was also examined by immunocytochemistry, and microglial cells were visualized by isolectin B4 (IB4) and ED1 labeling.. GW 501516 decreased the IFN-gamma-induced up-regulation of TNF-alpha and iNOS in accord with the proposed anti-inflammatory effects of this PPAR-beta agonist. However, it increased IL-6 m-RNA expression. In demyelinating cultures, reactivity of both microglial cells and astrocytes was observed, while the expression of the inflammatory cytokines and iNOS remained unaffected. Furthermore, GW 501516 did not protect against the demyelination-induced changes in gene expression.. Although GW 501516 showed anti-inflammatory activity, it did not protect against antibody-mediated demyelination. This suggests that the protective effects of PPAR-beta agonists observed in vivo can be attributed to their anti-inflammatory properties rather than to a direct protective or trophic effect on oligodendrocytes.

Topics: Animals; Anti-Inflammatory Agents; Antibodies; Astrocytes; Brain; Cells, Cultured; Demyelinating Diseases; Encephalitis; Encephalomyelitis, Autoimmune, Experimental; Glial Fibrillary Acidic Protein; Interferon-gamma; Interleukin-6; Lipopolysaccharides; Microglia; Myelin Basic Protein; Neurofilament Proteins; Nitric Oxide Synthase Type II; PPAR gamma; PPAR-beta; Rats; Thiazoles; Tumor Necrosis Factor-alpha

Following acute and chronic neurodegenerative disorders, a cascade of pathological events including inflammatory response, excitotoxicity and oxidative stress induces secondary tissue loss in both gray and white matter. Axonal damage and demyelination are important components of the white matter demise during these diseases. In spite of this, a few studies have addressed the patterns of inflammatory response, axonal damage and demyelination following focal ischemic damage to the central nervous system (CNS). In the present study, we describe the patterns of inflammatory response, axonal damage and myelin impairment following microinjections of 10 pmol of endothelin-1 into the rat striatum. Animals were perfused at 1 day, 3 days and 7 days after injection. 20 mum sections were stained by hematoxylin and immunolabeled for neutrophils (anti-MBS-1), activated macrophages/microglia (anti-ED1), damaged axons (anti-betaAPP) and myelin (anti-MBP). The evolution of acute inflammation was quantitatively assessed by cell counts in different survival times. There was recruitment of both neutrophils and macrophages to the damaged striatal parenchyma with maximum recruitment at 1 day and 7 days, respectively. Progressive myelin impairment in the striatal white matter tracts has been observed mainly at later survival times. beta-APP+ endbulbs were not present in all evaluated time points. These results suggest that progress myelin impairment in the absence of damage to axonal cylinder is a feature of white matter pathology following endothelin-1-induced focal striatal ischemia.

Topics: Amyloid beta-Peptides; Animals; Axons; Biomarkers; Brain Ischemia; Cerebral Arteries; Chemotaxis, Leukocyte; Corpus Striatum; Demyelinating Diseases; Disease Progression; Encephalitis; Endothelin-1; Male; Microcirculation; Microglia; Microinjections; Myelin Basic Protein; Nerve Fibers, Myelinated; Neutrophils; Rats; Rats, Wistar

Animals subjected to an inflammatory insult at the time of stroke are predisposed to the development of an inflammatory autoimmune response to brain. This response is associated with worse neurological outcome. Because induction of immunologic tolerance to brain antigens before stroke onset is associated with improved outcome, we sought to determine whether this paradigm could prevent the deleterious autoimmune response to brain provoked by an inflammatory stimulus at the time of ischemia.. Male Lewis rats were tolerized to myelin basic protein (MBP) or ovalbumin by intranasal administration before middle cerebral artery occlusion. At the time of reperfusion, all animals received lipopolysaccharide (1 mg/kg intraperitoneal). Behavioral tests were performed at set time intervals.. One month after middle cerebral artery occlusion, lymphocytes from the spleens of MBP-tolerized animals were less likely to evidence an autoimmune response and more likely to evidence a regulatory response (Treg) toward MBP than those from ovalbumin-tolerized animals. Animals that had an inflammatory response toward MBP (a Th1 response) performed worse on behavioral tests than those that did not. Fractalkine, a surrogate marker of inflammation, was elevated in animals with a Th1 response to MBP.. These data extend our previous findings and suggest that deleterious autoimmunity to brain antigens can be prevented by prophylactically inducing regulatory T-cell responses to those antigens.

Topics: Administration, Intranasal; Animals; Autoimmune Diseases of the Nervous System; Autoimmunity; Biomarkers; Chemokine CX3CL1; Encephalitis; Immune Tolerance; Immunity, Cellular; Immunotherapy; Infarction, Middle Cerebral Artery; Male; Myelin Basic Protein; Ovalbumin; Rats; Rats, Inbred Lew; Stroke; T-Lymphocytes, Regulatory; Treatment Outcome

Inhibition of matrix metalloproteinase-9 (MMP-9) protects the adult brain after cerebral ischemia. However, the role of MMP-9 in the immature brain after hypoxia-ischemia (HI) is unknown. We exposed MMP-9(-/-) [MMP-9 knock-out (KO)] and wild-type (WT) mice to HI on postnatal day 9. HI was induced by unilateral ligation of the left carotid artery followed by hypoxia (10% O2; 36 degrees C). Gelatin zymography showed that MMP-9 activity was transiently increased at 24 h after HI in the ipsilateral hemisphere and MMP-9-positive cells were colocalized with activated microglia. Seven days after 50 min of HI, cerebral tissue volume loss was reduced in MMP-9 KO (21.8 +/- 1.7 mm3; n = 22) compared with WT (32.3 +/- 2.1 mm3; n = 22; p < 0.001) pups, and loss of white-matter components was reduced in MMP-9 KO compared with WT pups (neurofilament: WT, 50.9 +/- 5.4%; KO, 18.4 +/- 3.1%; p < 0.0001; myelin basic protein: WT, 57.5 +/- 5.8%; KO, 23.2 +/- 3.5%; p = 0.0001). The neuropathological changes were associated with a delayed and diminished leakage of the blood-brain barrier (BBB) and a decrease in inflammation in MMP-9-deficient animals. In contrast, the neuroprotective effects after HI in MMP-9-deficient animals were not linked to either caspase-dependent (caspase-3 and cytochrome c) or caspase-independent (apoptosis-inducing factor) processes. This study demonstrates that excessive activation of MMP-9 is deleterious to the immature brain, which is associated with the degree of BBB leakage and inflammation. In contrast, apoptosis does not appear to be a major contributing factor.

Topics: Animals; Animals, Newborn; Apoptosis Inducing Factor; Blood-Brain Barrier; Brain; Brain Infarction; Caspase 3; Cell Death; Cytochromes c; Encephalitis; Gene Expression Regulation, Developmental; Hypoxia-Ischemia, Brain; Immunohistochemistry; Indoles; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin Basic Protein; Neurofilament Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Statistics, Nonparametric; Time Factors

Periventricular leukomalacia (PVL), the dominant form of brain injury in premature infants, is characterized by white matter injury (WMI) and is associated with cerebral palsy. The pathogenesis of PVL is complex and likely involves ischemia/reperfusion, free radical formation, excitotoxicity, impaired regulation of cerebral blood flow, a procoagulant state, and inflammatory mechanisms associated with maternal and/or fetal infection. Using an established animal model of human PVL, we investigated whether activated protein C (APC), an anti-coagulant factor with anti-inflammatory, anti-apoptotic, anti-oxidant, and cytoprotective activities, could reduce endotoxin-induced WMI in the developing rat brain. Intraperitoneal injections of lipopolysaccharide (LPS) (0.5 mg/kg body weight) were given at embryonic days 18 (E18) and 19 (E19) to pregnant Sprague-Dawley rats; control rats were injected with sterile saline. A single intravenous injection of recombinant human (rh) APC (0.2 mg /kg body weight) was given to pregnant rats following the second LPS dose on embryonic day 19 (E19). Reduced cell death in white matter and hypomyelination were shown on TUNEL and myelin basic protein (MBP) staining, respectively, on late postnatal days (P7) in APC-treated groups. There were significantly fewer TUNEL+nuclei in the periventricular WM in the APC+LPS group than in the untreated LPS group. Compared to the APC+LPS and control group, MBP expression was weak in the LPS group on P7, indicating endotoxin-induced hypomyelination in the developing rat brain. APC attenuated the LPS-induced protein expression of inflammatory cytokines, tumor necrosis factor-alpha, and interleukin-6, as evaluated by ELISA in neonatal rat brains. A single intraperitoneal injection of rhAPC (0.2 mg/kg body weight) to neonatal rats on P1 also had similar protective and anti-inflammatory effects against maternally administered LPS. Collectively, these data support the hypothesis that APC may provide protection against an endotoxin-evoked inflammatory response and WMI in the developing rat brain. Moreover, our results suggest that the possible use of APC in treatment of preterm infants and pregnant women with maternal or placental infection may minimize the risk of PVL and cerebral palsy.

Topics: Animals; Animals, Newborn; Anticoagulants; Apoptosis; Brain; Central Nervous System Bacterial Infections; Cerebral Palsy; Disease Models, Animal; Encephalitis; Endotoxins; Female; Humans; Infant, Newborn; Inflammation Mediators; Injections, Intravenous; Leukomalacia, Periventricular; Lipopolysaccharides; Myelin Basic Protein; Nerve Fibers, Myelinated; Neuroprotective Agents; Pregnancy; Protein C; Rats; Rats, Sprague-Dawley; Recombinant Proteins

Proliferation of oligodendrocyte progenitor cells (OPCs) is important for initial myelination as well as for remyelination in demyelinating diseases. Previously, we showed that numerous OPCs and activated microglia, are present around multiple sclerosis lesions, and that they accumulate Golli proteins. Golli proteins, present in both neuronal and immune cells, might have a role in the immune processes, as well as in development of neurons and oligodendrocytes. We hypothesize that Golli proteins, generated by microglia in response to inflammation, promote proliferation of OPCs. To test this hypothesis, we induced inflammation in neonatal mouse brain slice culture with bacterial endotoxin lipopolysaccharide (LPS). Treated slices showed an increase in the number of OPCs. Several results support the notion that this effect of LPS is conveyed through activation of microglia and upregulation of Golli proteins. First, LPS-treated brain slices have increased expression of Golli proteins observed by immunofluorescence and Western blot analysis. Second, Golli proteins were demonstrated only in the conditioned medium from LPS-treated microglial cell cultures (LPS-MCM), and were absent in either the conditioned media from LPS-treated astrocytes or the control media. Third, proliferation of purified OPCs was promoted with LPS-MCM or Golli proteins, but not with LPS alone. Taken together, these results demonstrate that microglia and/or microglia secreted factors, are necessary for the LPS-promoted proliferation of OPCs and suggest possible involvement of Golli proteins as one of mediators in this process.

Topics: Animals; Cell Communication; Cell Differentiation; Cell Proliferation; Cells, Cultured; Culture Media, Conditioned; Demyelinating Diseases; Encephalitis; Fluorescent Antibody Technique; Lipopolysaccharides; Mice; Mice, Inbred ICR; Microglia; Myelin Basic Protein; Nerve Regeneration; Nerve Tissue Proteins; Oligodendroglia; Organ Culture Techniques; Stem Cells; Transcription Factors; Up-Regulation

Small-molecular compounds with hydrogen bond (H-bond) donor function are able to trigger exchange reactions of MHC class II ligands. Here, we show that their effect is not limited to short peptides. Also encephalitogenic myelin basic protein (MBP) is transferred with great efficiency onto HLA-DR molecules when H-bond donor molecules such as parachlorphenol (pCP) are present. The effect was observed not only with soluble MHC class II but also with HLA-DR1 and HLA-DR2 molecules on the cell surface. The improved loading of APC translates directly into improved T cell activation. In the presence of pCP T cells reacted at significantly lower antigen concentrations, an effect observed with purified MBP protein as well as with crude spinal cord homogenate. The 'accidental' transfer of autoantigens such as MBP onto activated APC might trigger fatal autoimmune reactions and small molecules as catalysts of this process could represent risk factors, which had not been accounted for as yet.

Topics: Antigen-Presenting Cells; Encephalitis; Histocompatibility Antigens Class II; HLA-DR2 Antigen; Humans; Hydrogen Bonding; Myelin Basic Protein; T-Lymphocytes

Increasing data provide support for the hypothesis that inflammatory cytokines mediate inflammation-induced injury to developing white matter. In the present study, roles of tumor necrosis factor-alpha (TNFalpha) and interleukin-1 beta (IL-1beta) in mediating lipopolysaccharide (LPS)-induced brain injury were investigated by co-administration of LPS with IL-1 receptor antagonist (IL-1ra) or TNFalpha antibody in the 5-day-old rat brain. Intracerebral injection of LPS and other agents was performed in a stereotaxic apparatus at the location of 1.0 mm posterior and 1.0 mm lateral to the bregma, and 2.0 mm deep to the skull surface at the left hemisphere. Brain injury was examined in brain sections 3 and 11 days after LPS injection. LPS-induced inflammatory responses were evidenced by great increases in TNFalpha and IL-1beta concentrations in the neonatal rat brain 6 h after LPS injection. White matter rarefaction was observed in 71% (five out of seven) of the rat brains 3 days after LPS injection and bilateral ventricle dilation was found in 71% (five out of seven) of the P8 rat brains and in 100% of the P16 rat brains (four out of four). These alterations were not found in the control rat brains. No apparent histological changes in gray matter were observed in the LPS-injected rat brains. LPS injection also resulted in injuries to oligodendrocytes (OLs) and hypomyelination, as indicated by reduced immunostaining for O4 and myelin basic protein (MBP). Increased astrogliosis, as indicated by increased glial fibrillary acidic protein (GFAP) immunostaining, was also observed in the LPS-injected, but not the control rat brain. Co-administration of LPS with IL-1ra, but not with TNFalpha antibody, significantly attenuated LPS-induced white matter injury, as indicated by decreases in ventricle dilation, white matter rarefaction, GFAP positive staining and by improved O4 and MBP immunostaining. Co-administration of LPS with IL-1ra significantly reduced LPS-induced elevation of caspase-3 activity in the rat brain. While TNFalpha antibody had no effect on LPS-induced elevation of caspase-3 activity, co-administration of LPS with TNFalpha antibody partially, but significantly, decreased LPS-stimulated increase in IL-1beta in the neonatal rat brain. These data suggest that IL-1beta may play an important role in mediating LPS-induced brain injury and TNFalpha may have complicated, probably dual, effects in LPS-induced brain injury.

Topics: Animals; Animals, Newborn; Astrocytes; Caspase 3; Caspases; Encephalitis; Female; Glial Fibrillary Acidic Protein; Immunohistochemistry; Injections, Intraventricular; Interleukin-1; Lipopolysaccharides; Male; Myelin Basic Protein; Myelin Sheath; Oligodendroglia; Rats; Rats, Sprague-Dawley; Stereotaxic Techniques; Tumor Necrosis Factor-alpha

Apoptosis of autoaggressive T-cells in the CNS is an effective, noninflammatory mechanism for the resolution of T-cell infiltrates, contributing to clinical recovery in T-cell-mediated neuroinflammatory diseases. The clearance of apoptotic leukocytes by tissue-specific phagocytes is critical in the resolution of the inflammatory infiltrate and leads to a profound downregulation of phagocyte immune functions. Adult human microglia from surgically removed normal brain tissue was used in a standardized, light-microscopic in vitro phagocytosis assay of apoptotic autologous peripheral blood-derived mononuclear cells (MNCs). Microglia from five different patients had a high capacity for the uptake of apoptotic MNCs in contrast to nonapoptotic target cells with the phagocytosis rate for nonapoptotic MNCs amounting to only 61.6% of the apoptotic MNCs. A newly described phosphatidylserine receptor, critical in the phagocytosis of apoptotic cells by macrophages, is also expressed at similar levels on human microglia. The effects of the therapeutically used immunomodulatory agent interferon-beta (IFNbeta) were investigated using Lewis rat microglia and apoptotic, encephalitogenic, myelin basic protein-specific autologous T-cells. Also, rat microglia had a high capacity to phagocytose apoptotic T-cells specifically. IFNbeta increased the phagocytosis of apoptotic T-cells to 36.8% above the untreated controls. The enhanced phagocytic activity was selective for apoptotic T-cells and was not mediated by increased IL-10 secretion. Apoptotic inflammatory cells may be efficiently and rapidly removed by microglial cells in the autoimmune-inflamed human CNS. The in vitro increase of phagocytosis by IFNbeta merits further investigations whether this mechanism could also be therapeutically exploited.

Topics: Animals; Apoptosis; Autoimmune Diseases of the Nervous System; Cells, Cultured; Chemotaxis, Leukocyte; Cytokines; Encephalitis; Humans; Interferon-beta; Interleukin-10; Microglia; Myelin Basic Protein; Oligopeptides; Phagocytosis; Phosphoserine; Rats; Rats, Inbred Lew; T-Lymphocytes; Up-Regulation

We measured autoantibodies against nine different neuron-specific antigens and three cross-reactive peptides in the sera of autistic subjects and healthy controls by means of enzyme-linked immunosorbent assay (ELISA) testing. The antigens were myelin basic protein (MBP), myelin-associated glycoprotein (MAG), ganglioside (GM1), sulfatide (SULF), chondroitin sulfate (CONSO4), myelin oligodendrocyte glycoprotein (MOG), alpha,beta-crystallin (alpha,beta-CRYS), neurofilament proteins (NAFP), tubulin and three cross-reactive peptides, Chlamydia pneumoniae (CPP), streptococcal M protein (STM6P) and milk butyrophilin (BTN). Autistic children showed the highest levels of IgG, IgM and IgA antibodies against all neurologic antigens as well as the three cross-reactive peptides. These antibodies are specific because immune absorption demonstrated that only neuron-specific antigens or their cross-reactive epitopes could significantly reduce antibody levels. These antibodies may have been synthesized as a result of an alteration in the blood-brain barrier. This barrier promotes access of preexisting T-cells and central nervous system antigens to immunocompetent cells, which may start a vicious cycle. These results suggest a mechanism by which bacterial infections and milk antigens may modulate autoimmune responses in autism.

Topics: Antigens; Antigens, Bacterial; Autistic Disorder; Autoimmune Diseases of the Nervous System; Bacterial Infections; Bacterial Outer Membrane Proteins; Butyrophilins; Carrier Proteins; Child; Child, Preschool; Chlamydophila pneumoniae; Cross Reactions; Encephalitis; Female; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Male; Membrane Glycoproteins; Milk Hypersensitivity; Myelin Basic Protein; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Neurons; Neurotoxins; Streptococcus

Heme oxygenase-1 (HO-1), also known as heat-shock protein 32 (HSP-32), is induced in many cells by a large variety of stimuli. Its induction in nervous system cells following toxic and oxidative stress was suggested to play a protective role. Its presence was recently detected by immunohistochemical studies at the level of inflammatory lesions of rat experimental autoimmune encephalomyelitis. In the present study, we demonstrate that myelin basic protein (MBP) induces HO-1 in human astroglial cells, as shown by Western blots and RT-PCR. Proteolytic fragments derived from the whole MBP show a different behavior in the HO-1 induction: MBP152-167 was able to produce a light but still significant increase in HO-1 mRNA and protein levels, whereas MBP68-84 was not. The increase in HO-1 production seems to be mediated by a Ca(2+)-dependent mechanism, since MBP addition to astrocytoma cultures induced a strong and immediate increment of [Ca(2+)](i) increase; MBP152-167 elicited a delayed and less pronounced [Ca(2+)](i) increase; no [Ca(2+)](i) changes were induced following cell treatment with MBP68-84. NO pathway involvement in the induction of HO-1 by MBP was ruled out since the expression of the inducible isoform of nitric oxide synthase was not upregulated in treated cells, neither nitrite levels were modified, as demonstrated by Greiss reaction. The possible significance of HO-1 induction following MBP stimulation is discussed.

Topics: Astrocytes; Calcium; Encephalitis; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Humans; Immunohistochemistry; Membrane Proteins; Multiple Sclerosis; Myelin Basic Protein; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Peptide Fragments; RNA, Messenger; Tumor Cells, Cultured

Apoptosis of autoaggressive T cells in the central nervous system (CNS) is an effective, nonphlogistic mechanism for the termination of autoimmune inflammation in experimental autoimmune encephalomyelitis (EAE). The clearance of apoptotic leukocytes by tissue-specific phagocytes is a critical event in the resolution of the inflammatory attack. To investigate the role of microglia in the removal of apoptotic cells and potential regulatory mechanisms of microglial phagocytosis, an in vitro phagocytosis assay was established, using Lewis rat microglia. Microglia exhibited a high capacity for the uptake of apoptotic autologous thymocytes, as well as apoptotic encephalitogenic myelin basic protein (MBP)-specific T cells, in contrast to nonapoptotic target cells. Pretreatment of microglia with interferon-gamma (IFN-gamma) raised the proportion of microglia capable of phagocytosing apoptotic cells to 75% above the untreated controls. The increased phagocytic activity was selective for apoptotic target cells and was not dependent on phosphatidylserine-mediated recognition mechanisms. In contrast, preincubation of microglia with interleukin-4 (IL-4) inhibited the uptake of apoptotic cells, whereas tumor-necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) did not alter phagocytosis. Phagocytic clearance of apoptotic inflammatory cells by microglia may be an important mechanism for the termination of autoimmune inflammation in the CNS. Augmentation of microglial phagocytosis by the Th-1-type cytokine IFN-gamma suggests a feedback mechanism for the accelerated clearance of the inflammatory infiltrate in the CNS.

Topics: Animals; Animals, Newborn; Apoptosis; Cells, Cultured; Cytokines; Encephalitis; Interferon-gamma; Interleukin-4; Microglia; Myelin Basic Protein; Phagocytosis; Phosphatidylserines; Rats; Rats, Inbred Lew; T-Lymphocytes; Thymus Gland; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Theiler's murine encephalomyelitis virus (TMEV) infection produces a chronic inflammatory disease of the spinal cord white matter, with striking similarities to both experimental allergic encephalomyelitis (EAE) and human multiple sclerosis (MS). The first phase of demyelination in this model appears to be dependent on a delayed-type hypersensitivity (DTH) response to viral antigens, driven by CD4+, Th1 lymphocytes. Macrophages, recruited in the infected CNS, would be responsible for most of the myelin damage. Recently, new populations of CD4+ lymphocytes were demonstrated in infected mice, this time with specificity for myelin antigens, particularly PLP. This suggests that, in the chronic phase of the disease, an autoimmune mechanism of demyelination, similar to EAE, may participate in the process of myelin destruction. The present study represents a first step in exploring the functional activity of these anti-myelin lymphocytes that emerge during the chronic phase of the disease. Lymphocytes were removed from chronically infected animals, they were stimulated with the major PLP encephalitogenic epitope for SJL/J mice, and they were added to organotypic myelinated spinal cord cultures for different lengths of time. Results show that lymphocytes stimulated with the major PLP epitope have a powerful capacity for demyelinating these cultures, while MBP stimulated lymphocytes and lymphocytes from control animals do not. This study, suggests that the anti-myelin response that emerges during the chronic phase of the infection is functionally active. A similar phenomenon of epitope spreading from virus to organ specific antigens may take place in humans and be involved in a number of immune-mediated diseases, including MS.

Topics: Animals; Cardiovirus Infections; Cells, Cultured; Chronic Disease; Demyelinating Diseases; Encephalitis; Epitopes; Immunization; Lymphocytes; Mice; Mice, Inbred Strains; Myelin Basic Protein; Myelin Proteolipid Protein; Myelin Sheath; Organ Culture Techniques; Ovalbumin; Theilovirus

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

Topics: Animals; CD4 Antigens; Disease Models, Animal; DNA-Binding Proteins; Encephalitis; Genetic Predisposition to Disease; HLA-DR2 Antigen; Humans; Mice; Mice, Transgenic; Multiple Sclerosis; Myelin Basic Protein; Nuclear Proteins; Receptors, Antigen, T-Cell; T-Lymphocytes

Multiple sclerosis (MS) is a complex chronic neurologic disease with a suspected autoimmune pathogenesis. Although there is evidence that the development of MS is determined by both environmental influences and genes, these factors are largely undefined, except for major histocompatibility (MHC) genes. Linkage analyses and association studies have shown that susceptibility to MS is associated with genes in the human histocompatibility leukocyte antigens (HLA) class II region, but the contribution of these genes to MS disease development less compared with their contribution to disorders such as insulin-dependent diabetes mellitus. Due to the strong linkage disequilibrium in the MHC class II region, it has not been possible to determine which gene(s) is responsible for the genetic predisposition. In transgenic mice, we have expressed three human components involved in T-cell recognition of an MS-relevant autoantigen presented by the HLA-DR2 molecule: DRA*0101/DRB1*1501 (HLA-DR2), an MHC class II candidate MS susceptibility genes found in individuals of European descent; a T-cell receptor (TCR) from an MS-patient-derived T-cell clone specific for the HLA-DR2 bound immunodominant myelin basic protein (MBP) 4102 peptide; and the human CD4 coreceptor. The amino acid sequence of the MBP 84-102 peptide is the same in both human and mouse MBP. Following administration of the MBP peptide, together with adjuvant and pertussis toxin, transgenic mice developed focal CNS inflammation and demyelination that led to clinical manifestations and disease courses resembling those seen in MS. Spontaneous disease was observed in 4% of mice. When DR2 and TCR double-transgenic mice were backcrossed twice to Rag2 (for recombination-activating gene 2)-deficient mice, the incidence of spontaneous disease increased, demonstrating that T cells specific for the HLA-DR2 bound MBP peptide are sufficient and necessary for development of disease. Our study provides evidence that HLA-DR2 can mediate both induced and spontaneous disease resembling MS by presenting an MBP self-peptide to T cells.

Topics: Animals; Autoantigens; CD4 Antigens; Central Nervous System; Disease Models, Animal; DNA-Binding Proteins; Encephalitis; Freund's Adjuvant; Genes, Immunoglobulin; Genetic Predisposition to Disease; HLA-DR2 Antigen; Humans; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Multiple Sclerosis; Myelin Basic Protein; Nuclear Proteins; Peptide Fragments; Pertussis Toxin; Receptors, Antigen, T-Cell; T-Lymphocytes; Virulence Factors, Bordetella

We investigated T cell epitopes of guinea pig myelin basic protein (MBP) that induce experimental autoimmune encephalomyelitis (EAE) in DA rats, using synthetic peptides that correspond to regions of the guinea pig MBP molecule that are homologous to rat MBP. Four peptides were encephalitogenic when tested in DA rats. MBP63-81, which partially overlaps the dominant encephalitogenic MBP epitope for Lewis (LEW) rats, caused severe EAE in the DA strain but did not elicit EAE in LEW rats. MBP66-81 and MBP63-76 were also encephalitogenic for DA but not LEW rats. MBP79-99 also induced EAE in DA rats, although MBP87-99, the minor encephalitogenic LEW epitope, was inactive. This indicates that part of the 79-86 sequence is necessary for encephalitogenic activity in the DA strain. MBP101-120, and MBP142-167 were also encephalitogenic for DA rats. T cells from DA rats immunized with intact MBP proliferated in response to the whole protein and to MBP79-99, but were not stimulated to a significant extent by the other encephalitogenic peptides, suggesting that these may represent cryptic or subdominant epitopes. However, MBP63-81-specific T cell lines could be isolated by repeated restimulation with peptide, indicating that the peptide-specific T cells were present in DA rats at low frequency.

Topics: Animals; Encephalitis; Encephalomyelitis, Autoimmune, Experimental; Epitopes; Lymphocyte Activation; Myelin Basic Protein; Rats; Rats, Mutant Strains

Epitope mimicry is the theory that an infectious agent such as a virus causes pathological effects via mimicry of host proteins and thus elicits a cross-reactive immune response to host tissues. Weise and Carnegie (1988) found a region of sequence similarity between the pol gene of the Maedi Visna virus (MVV), which induces demyelinating encephalitis in sheep, and myelin basic protein (MBP), which is known to induce experimental allergic encephalitis (EAE) in laboratory animals. In this study, cross-reactions between sera raised in sheep against synthetic peptides of MVV (TGKIPWILLPGR) and 21.5 kDa MBP (SGKVPWLKPGR) were demonstrated using enzyme-linked immunosorbant assay (ELISA) and thin layer chromatography (TLC) immunoprobing. The antibody responses of MVV-infected sheep were investigated using ELISA against the peptides, and MBP protein, immunoprobing of the peptides on TLC plates and Western blotting against MBP. Slight significant reactions to the 21.5 kDa MBP peptide (P < 0.001) and to a lesser extent sheep MBP (P < 0.004) were detected in ELISA. The MBP peptide evoked stronger responses from more sera than the MVV peptide on immunoprobed TLC plates. On the Western blots, eight of the 23 sheep with Visna had serum reactivity to MBP. This slight reaction to MBP in MVV-infected sheep is of interest because of the immune responses to MBP evident in multiple sclerosis and EAE, but its relevance in Visna is limited since no correlation with disease severity was observed. The cell-mediated immune responses of MVV-infected sheep against similar peptides was assessed. The peptides did not stimulate proliferation of peripheral blood lymphocytes of MVV-infected sheep. Since the MVV peptide was not recognised by antibodies or T lymphocytes from MVV-infected and encephalic sheep, it was concluded that epitope mimicry of this 21.5 kDa MBP peptide by the similar MVV pol peptide was not contributing to the immunopathogensis of Visna. The slight antibody response to MBP and the MBP peptide can be attributed to by-stander effects of the immunopathology of MVV-induced encephalitis.

Topics: Animals; Antibodies, Viral; Chromatography, Thin Layer; Cross Reactions; Encephalitis; Enzyme-Linked Immunosorbent Assay; Epitopes; Gene Products, pol; Immunity, Cellular; Molecular Mimicry; Molecular Weight; Myelin Basic Protein; Peptides; Sheep; Visna-maedi virus

Subacute sclerosing panencephalitis (SSPE) patients carry persistent measles virus infection in the brain. Furthermore, the blood lymphocytes contain viral RNA. Lymphocytes derived from 6 SSPE patients were stimulated with Epstein-Barr virus (EBV). Production of antibodies against measles virus of the IgG isotype was detected in the supernatants of cell cultures of all patients, regardless of the disease's activity, duration or interferon therapy. In contrast, only some of these cell cultures also produced antibodies against myelin.

Topics: Adolescent; Adult; Antibodies, Viral; Antibody Specificity; B-Lymphocytes; Cell Line, Transformed; Cells, Cultured; Child; Encephalitis; Female; Galactosylceramides; Herpesvirus 4, Human; Humans; Immunoglobulin G; Lymphocyte Activation; Male; Measles virus; Multiple Sclerosis; Myelin Basic Protein; Pregnancy; Pregnancy Complications, Infectious; Subacute Sclerosing Panencephalitis

Infection of the central nervous (CNS) system by the human immunodeficiency virus (HIV) depends on the migration of infected hematogenous cells into the brain. We thus used quantitative light and electron microscopic immunocytochemistry to study the homing and turnover of bone marrow derived cells in the CNS in radiation bone marrow chimeras under normal conditions and in experimental autoimmune encephalomyelitis (EAE) as an experimental model of brain inflammation. Our studies suggest the following conclusions. First, the central nervous system is continuously patrolled by a small number of T-lymphocytes and monocytes. Meningeal and perivascular monocytes are slowly replaced by hematogenous cells under normal conditions, and this turnover is accelerated in the course of inflammation. In contrast, resident microglia represent a very stable cell pool, which in adult animals is only exceptionally replaced by hematogenous cells, even after recovery from severe brain inflammation. Second, although in bone-marrow-chimeric animals resident microglia, astrocytes, and ependymal cells are not able to present antigen to Lewis T-lymphocytes, the inflammatory reaction in EAE is qualitatively and quantitatively similar in these animals compared to fully histocompatible Lewis rats. Finally, resident microglia express the macrophage activation antigen ED1. Thus, microglia cells appear to function as effector cells in EAE lesions.

Topics: Animals; Autoimmune Diseases; Bone Marrow; Chimera; Encephalitis; Encephalomyelitis, Autoimmune, Experimental; Histocompatibility Antigens; Immunohistochemistry; Meninges; Microscopy, Electron; Myelin Basic Protein; Neuroglia; Rats; Rats, Inbred Lew

Studies on cerebrospinal fluid (CSF) concentrations of neuron-specific enolase (NSE), S-100 protein, and myelin basic protein (MBP) in patients with neurological lesions indicate a quantitative relation between the degree of cell damage in the central nervous system (CNS) and the concentration of these CNS-specific proteins in CSF. Thus NSE, S-100, and MBP could be of use as markers for destructive processes in the CNS. We collected 937 specimens of CSF from children and adults (from newborns to age 91 years) who were undergoing a diagnostic lumbar puncture for several clinical indications. Of these, 79 samples from subjects ranging in age from 0.7 to 66 years could be used retrospectively to construct a reference interval according to our criteria. In these 79 samples no sex dependency existed. The relative increase of NSE, S-100, and MBP with age was similar (1% per year), suggesting a common underlying mechanism. These results emphasize the necessity of using age-matched reference values when the CNS-specific proteins are to be evaluated in neurological diseases. We also present three case histories to discuss the possible clinical relevance of the measurement of NSE, S-100, and MBP in children and adults.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Child; Child, Preschool; Encephalitis; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Myelin Basic Protein; Nervous System Diseases; Phosphopyruvate Hydratase; Reference Values; Retrospective Studies; S100 Proteins

Topics: Antibodies; Cerebrovascular Disorders; Encephalitis; Humans; Multiple Sclerosis; Myelin Basic Protein

Highly purified synthetic peptides representing portions of the 68-86 sequence of guinea pig (GP) myelin basic protein (GPMBP) were used to define the N- and C-termini of encephalitogenic determinants that cause experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Each peptide was tested for: (a) induction of EAE, (b)in vitro potentiation of EAE transfer activity by GPMBP-sensitized lymph node cells (LNC), (c) in vitro proliferation of GPMBP-sensitized LNC, and (d) in vitro proliferation of a GPMBP-reactive line of EAE-inducing T cells. In these bioassays, the general rank order of potency was: GPMBP greater than or equal to GP68-86 greater than or equal to GP72-86 greater than [G84]GP68-86 greater than or equal to GP68-84 much greater than GP75-85 greater than or equal to GP75-84 = virtually no activity. These results demonstrate that the encephalitogenic region is bounded by the 72-74 and 84-86 sequences. Further evidence presented herein indicates that the 75-84 sequence contains the primary antigenic features required for specific T cell recognition of the encephalitogenic region.

Topics: Animals; Cell Division; Cell Line; Encephalitis; Epitopes; Immunization, Passive; Immunochemistry; Male; Myelin Basic Protein; Peptides; Rats; Rats, Inbred Lew; T-Lymphocytes

T cells from SJL mice reactive with myelin basic protein peptide 1-38 have been reported to be encephalitogenic when adoptively transferred into naive syngeneic recipients. To determine whether the encephalitogenic epitope recognized by peptide 1-38-specific SJL T cells was different from those recognized by H-2u-restricted MBP peptide 1-38-specific T cells, peptide 1-38-specific SJL T cell lines were developed following immunization with guinea pig MBP peptide 1-38. Following a period of in vitro selection in the presence of peptide 1-38 and syngeneic antigen-presenting cells, one of two T cell lines transferred severe clinical disease adoptively. The second line was not encephalitogenic. When the fine specificity for antigen of the two T cell lines was determined by the use of overlapping synthetic peptides, the encephalitogenic epitope recognized by the encephalitogenic line was localized to residues 17-27. This epitope is clearly distinct from that recognized by H-2u mice. The non-encephalitogenic line was found to react only with peptide 1-38, and did not react with mouse MBP.

Topics: Animals; Cell Line; Encephalitis; Epitopes; Female; Immunization, Passive; Immunochemistry; Lymph Nodes; Mice; Mice, Inbred Strains; Myelin Basic Protein; Peptide Fragments; T-Lymphocytes

The induction of experimental allergic encephalomyelitis (EAE) with purified myelin basic protein (MBP) has, heretofore, required its incorporation in a water-in-oil emulsion or adsorption on particulate adjuvants. In the present work, the absorption of a saline solution of MBP from the peritoneal cavity into the mediastinal lymph nodes was increased by giving repeated inoculations or by pretreating rats with a peritoneal irritant. Under these conditions, the only adjuvant needed for production of EAE was aqueous pertussis vaccine which was injected separately a few hours or one day after the MBP. Pertussis vaccine was also necessary for production of EAE with intradermal injection of aqueous MBP. By injecting the aqueous MBP directly into pre-enlarged popliteal lymph nodes, it was possible to produce EAE without the pertussis vaccine. Thus, EAE can be induced in rats using MBP without the addition of Freund's adjuvant or pertussis vaccine.

Topics: Animals; Dose-Response Relationship, Drug; Encephalitis; Guinea Pigs; Injections, Intradermal; Injections, Intraperitoneal; Injections, Intravenous; Lymph Nodes; Methods; Myelin Basic Protein; Pertussis Vaccine; Rats; Rats, Inbred Lew

T cell lines were selected from basic protein (BP)-immunized SJL/J mice using synthetic peptides encompassing the major SJL/J encephalitogenic determinant. Synthetic peptide-derived T cell lines proliferated in response to BP, the 89-169 peptidase fragment of BP and the synthetic peptides, pM87-99, pM90-99 and pM91-99. These lines transferred a demyelinating and chronic relapsing form of experimental autoimmune encephalomyelitis (EAE) into naive mice, and EAE induced by synthetic peptide-derived lines was more severe than that induced by whole BP-derived lines. This study demonstrates that T cell lines selected with synthetic peptides are encephalitogenic in SJL/J mice and offers an improved means for selecting SJL/J encephalitogenic T cell lines.

Topics: Animals; Cell Division; Cell Line; Encephalitis; Mice; Mice, Inbred Strains; Myelin Basic Protein; Peptide Fragments; Peptides; T-Lymphocytes

The major pathological abnormalities of HIV encephalopathy are infiltrates of macrophages, multinucleated giant cells, microglial nodules and demyelination. Elevated myelin basic protein (MBP) levels in the cerebrospinal fluid (CSF) provide a marker for central nervous system demyelination. The purpose of this study was to investigate the possible role of CSF MBP as a useful and early marker for HIV encephalopathy. The CSF of 40 consecutive patients with HIV infection of various clinical stages was investigated, including 13 patients with clinical signs of HIV encephalopathy. CSF MBP was elevated in 2 patients (5.0 and 5.3 ng/ml), both of whom had moderate to severe HIV encephalopathy. The course of the disease was rapid in both patients. In the remaining 38 patients, CSF MBP levels were marginally elevated (n = 12) or normal (n = 26). Our results suggest that CSF MBP is not a sensitive marker for the diagnosis and evaluation of HIV encephalopathy, but may be an indicator of prognosis for the course of the disease. There were only few findings of elevated CSF MBP levels in patients with HIV encephalopathy in the current study, and this may be because the disorder progressed slowly in most patients. It is possible that CSF MBP levels in HIV encephalopathy may only be elevated with acute clinical deterioration but are normal in slowly progressive forms of demyelination, as seen in multiple sclerosis.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Complex; Biomarkers; Encephalitis; HIV Antibodies; Humans; Myelin Basic Protein

Intracerebral inoculation of weanling Lewis rats with measles virus led to the development of subacute measles encephalomyelitis (SAME) 4-8 weeks after infection. The disease is characterized pathologically by an intense inflammatory infiltration within both the white and grey matter of the central nervous system (CNS) without apparent demyelination. Both during and after SAME splenic lymphocytes from these animals could be restimulated in vitro to proliferate in the presence of myelin base protein (MBP). MBP-specific class II MHC-restricted T cell lines were isolated from this cell population. They were shown to exhibit no cross-reactivity with measles virus and to induce experimental allergic encephalitis (EAE) in naive syngeneic recipients following adoptive transfer. The clinical and histopathological signs of this T cell-mediated disease were identical to that seen in classical T cell-mediated EAE. A humoral immune response to MBP was only detected in a limited number of those rats with SAME. These results indicate that autoimmune reactions to brain antigen can arise during measles virus infection which may contribute to the pathogenesis of measles virus-associated encephalomyelitis.

Topics: Animals; Antibodies, Viral; Autoantibodies; Autoimmune Diseases; Encephalitis; Encephalomyelitis, Autoimmune, Experimental; Immunization, Passive; Lymphocyte Activation; Measles; Myelin Basic Protein; Rats; Rats, Inbred Lew; T-Lymphocytes

Neurologic complications of brain tissue-derived rabies vaccine may be chronic or progressive. Lymphocytes and serum from three patients with this form of encephalitis were studied. Two patients had positive lymphoproliferation to purified myelin, two had antibody to white matter, and one had antibody to myelin basic protein. No patient had antibody to proteolipid protein, myelin-associated glycoprotein, or cerebroside.

Topics: Antibodies; Brain; Chronic Disease; Encephalitis; Enzyme-Linked Immunosorbent Assay; Humans; Myelin Basic Protein; Rabies Vaccines; Recurrence

Lymphocyte proliferation tests to rabies antigen and myelin basic protein were performed on peripheral blood lymphocytes from nine patients with the encephalitic form and on seven with the paralytic form of human rabies. Six of the nine patients with encephalitis had proliferative responses to rabies antigen, whereas all of the patients with paralysis had no response. Two patients in each group also had a proliferative response to myelin basic protein. The myelin basic protein-reactive patients had a more rapidly fatal disease than the non-reactive patients. This preliminary study suggests that host immune responses may influence the clinical manifestations and course in human rabies.

Topics: Adolescent; Adult; Aged; Antibodies, Viral; Child; Encephalitis; Female; Humans; Lymphocyte Activation; Male; Middle Aged; Myelin Basic Protein; Paralysis; Rabies; Rabies virus

Topics: Antibodies; Cerebrovascular Disorders; Encephalitis; Enzyme-Linked Immunosorbent Assay; Humans; Multiple Sclerosis; Myelin Basic Protein; Prognosis

Lines of rat T lymphocytes responsive to the basic protein of myelin (BP) or to the purified protein derivative of Mycobacterium tuberculosis (PPD) were inoculated i.v. into recipient rats. As reported previously, the anti-BP line cells, but not the anti-PPD line cells spontaneously accumulated in the central nervous system and caused encephalomyelitis. However, the anti-PPD line cells could be induced to enter the brain and cause bystander encephalitis by intracerebral inoculation of PPD. Anti-PPD or anti-BP line cells could mediate delayed-type hypersensitivity skin reactions or bystander arthritis elicited by specific antigen. The lines did not cause specific cytolysis in vitro. Susceptibility to delayed-type hypersensitivity or bystander disease was long lasting in rats inoculated with anti-PPD line cells, while rats inoculated with anti-BP line cells were susceptible for only a few days. Thus, lines of T lymphocytes can mediate a variety of pathological reactions directed by the presence of specific antigen, self or foreign.

Topics: Animals; Arthritis; Cell Line; Cytotoxicity, Immunologic; Dermatitis, Atopic; Encephalitis; Encephalomyelitis, Autoimmune, Experimental; Female; Hypersensitivity, Delayed; Injections, Intradermal; Macrophages; Male; Myelin Basic Protein; Rats; Rats, Inbred Lew; Skin Tests; T-Lymphocytes; Tuberculin

Topics: Adult; Animals; Autoantigens; Brain; Cell- and Tissue-Based Therapy; Encephalitis; Encephalomyelitis; Gangliosides; Humans; Immunoglobulin G; Lymphocyte Activation; Male; Myelin Basic Protein; Nerve Tissue; Polyradiculoneuropathy; Swine

Twelve-day-old cultures of dissociated newborn mouse brain were infected with neurotropic vaccinia virus strain WR. Using the indirect immuno-fluorescence staining technique the total destruction of galactocerebroside (GL) or myelin basic protein (MBP)-positive oligodendrocytes could be detected after 72 h of infection. The activity of the oligodendrocyte-specific enzymes, cerebroside sulfotransferase (CST) and 2'3'-cyclic nucleotide 3'-phosphohydrolase (CNP), was 27% and 17% respectively of the activity in noninfected controls. This reduction was not a result of viral-induced inhibition of host protein synthesis. In cultures treated with puromycin GC- and MBP- positive oligodendrocytes were detectable at a time at which no CST or CNP activity could detected.

Topics: 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; 2',3'-Cyclic-Nucleotide Phosphodiesterases; Animals; Animals, Newborn; Brain; Cells, Cultured; Encephalitis; Galactosylceramides; Mice; Myelin Basic Protein; Neuroglia; Oligodendroglia; Phosphoric Diester Hydrolases; Puromycin; Sulfotransferases; Sulfurtransferases; Vaccinia; Vaccinia virus

Topics: Animals; Autoantibodies; Distemper; Distemper Virus, Canine; Dogs; Encephalitis; Mice; Myelin Basic Protein; Myelin Sheath; Oligodendroglia; Vaccinia; Vaccinia virus

In measles encephalitis we: Confirmed the decrease in mitogen responses and have shown that it does not correlate with complications. Demonstrated that the 'immunosuppression' is not universal but may be an abnormality of immune regulation as shown by the response to measles virus and myelin basic protein and by an abnormality of suppressor cell activity in patients with measles. Have evidence that there is early demyelination, and a response to myelin basic protein in a large proportion of the patients, and a lack of evidence of direct virus invasion of the brain. These findings lead to our present hypothesis that measles virus infection, probably of lymphoid cells, leads to a breakdown of immune regulation. This lack of regulation may lead to dissemination and allow secondary infection. It may also lead to a break in tolerance leading to autoimmune demyelination, a regulation which as Patterson (1979) has said 'may effectively restrain our ever present capacity to react immunologically against our own nervous tissue'.

Topics: Adolescent; Antibodies, Viral; Brain; Child; Child, Preschool; Encephalitis; Humans; Infant; Lymphocyte Activation; Measles; Measles virus; Myelin Basic Protein

Nine dogs with canine distemper encephalitis (CDE) were examined with immunological techniques including demonstration of antibodies against canine distemper virus (CDV) in the serum and against myelin basic protein (MBP) in serum and in CSF. Mitogen stimulation tests of lymphocytes were also done. The brains were examined pathologically and immunoglobulin and C3 were demonstrated in lesions by means of immunohistological techniques. Six dogs with acute CDE had none or low antibody levels against CDV or MBP, and there was no immunoglobulin in demyelinating lesions. Some of these dogs had depressed lymphocyte mitogen responses. Two dogs with chronic CDE showed recovery of lymphocyte mitogen responses. One of these had a significant antibody response against CDV and MBP in the serum. Both dogs with chronic CDE had very high antibody titers against MBP in the CSF and demyelinating lesions contained immunoglobulin. These results suggest that acute demyelination in CDE is probably due to some direct viral activity and that the progression of demyelination in chronic CDE is associated with a local immune response.

Topics: Animals; Antibodies, Viral; Brain Chemistry; Complement C3; Demyelinating Diseases; Distemper; Distemper Virus, Canine; Dogs; Encephalitis; Female; Immunoglobulins; Lymphocyte Activation; Male; Myelin Basic Protein

Serum and CSF levels of myelin basic protein (MBP) were measured in 50 patients with encephalitis of various origins and severity. In nearly 50%, the CSF samples were found to display immunoreactivity of MBP. Positivity was found to be correlated with the severity of the clinical signs. More precisely, it corresponded to cases with suspected extensive brain destruction. No relationship could be observed with the cause of disease. Positive tests of sera were infrequent, even from patients whose CSF was rich in MBP. Longitudinal studies performed on 20 patients who were serially investigated during periods ranging from three weeks to 18 months demonstrated that after an attack, MBP liberation into the CSF persists for one to three weeks. The MBP assay should serve as an index for destruction of nervous tissue.

Topics: Encephalitis; Humans; Longitudinal Studies; Multiple Sclerosis; Myelin Basic Protein; Radioimmunoassay

Topics: Adult; Child; Encephalitis; Humans; Lymphocyte Activation; Meningitis; Multiple Sclerosis; Myelin Basic Protein; Neuritis; Peripheral Nerves; Tissue Extracts

Topics: Adolescent; Child; Child, Preschool; Encephalitis; Humans; Immunoglobulin G; Infant; Lymphocytes; Measles; Myelin Basic Protein

The macrophage migration inhibition factor (MIF) assay and a counterimmunodiffusion assay were utilized to measure immune responses to human myelin basic protein in 75 patients with multiple sclerosis (MS) and in 120 control subjects. Eight out of ten MS patients in acute exacerbation and one out of seventeen convalescent, but none of chronically ill MS patients gave positive results in the MIF test. Forty-six percent of the patients with negative MIF assays but only 22% of those with positive assays had positive antibody results. In the counterimmunodiffusion assay, myelin basic protein antibody was demonstrated in almost 2/3 of patients during convalescence but it was not present in those whose illness had been stable for 6 months or longer. While no correlation with the stage or duration of the illness was present in other disorders, in MS an inverse correlation with clinical activity and in vitro evidence of cellular sensitization to encephalitogenic basic protein was apparent.

Topics: Autoantibodies; Central Nervous System Diseases; Encephalitis; Humans; Immunity, Cellular; Macrophage Migration-Inhibitory Factors; Multiple Sclerosis; Myasthenia Gravis; Myelin Basic Protein; Peripheral Nervous System Diseases

Topics: Acute Disease; Adolescent; Adult; Aged; Antigens; Brain; Cell Migration Inhibition; Child; Child, Preschool; Encephalitis; Encephalomyelitis, Autoimmune, Experimental; Female; Freeze Drying; Humans; Infant; Leukocytes; Male; Meningitis; Middle Aged; Myelin Basic Protein; Polyradiculopathy