myelin-basic-protein and Nervous-System-Diseases

In this study, data about protein S-100B, neuron-specific enolase, myelin basic protein and glial fibrillary acidic protein in cerebrospinal fluid and blood of patients with an acute or chronic progressive neurological disorder with brain damage are reviewed. Especially in disorders with acute brain damage, determination of these proteins in CSF and blood can be helpful to establish structural and/or functional brain damage to determine severity and prognosis of the disease process and to monitor treatment effects.

Topics: Adolescent; Adult; Age Factors; Aged; Child; Child, Preschool; Female; Glial Fibrillary Acidic Protein; Humans; Infant; Male; Middle Aged; Myelin Basic Protein; Nervous System Diseases; Phosphopyruvate Hydratase; Prognosis; Reference Values; S100 Proteins

Topics: Autoantibodies; Humans; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases

Cerebrospinal fluid (CSF) markers are a useful tool for determining disease progression or activity in some neurological disorders which need parameters both for evaluating treatments and investigating pathobiological evolution in research-oriented follow-up. A number of CSF proteins are reviewed with data on biological properties, analytical methods, clinical usefulness of: myelin basic protein, S-100 protein, glial fibrillary acidic protein, neural-cell adhesion molecule, neuron-specific enolase and others.

Topics: Biomarkers; Cell Adhesion Molecules, Neuronal; Glial Fibrillary Acidic Protein; Humans; Myelin Basic Protein; Nerve Tissue Proteins; Nervous System Diseases; Phosphopyruvate Hydratase; S100 Proteins

Topics: Humans; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Peptide Fragments

The major immune-mediated diseases affecting the nervous system are reviewed. The continued expansion of knowledge concerning the pathogenesis is leading to improved diagnosis and effective treatment regimens.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Cholinesterase Inhibitors; Humans; Hypergammaglobulinemia; Immune System Diseases; Immunoglobulins; Immunosuppression Therapy; Multiple Sclerosis; Myasthenia Gravis; Myelin Basic Protein; Nervous System Diseases; Plasma Exchange; Plasmapheresis; Polyradiculoneuropathy; Receptors, Cholinergic

In experimental animal models of multiple sclerosis demyelinating antibody responses are directed against the myelin oligodendrocyte glycoprotein (MOG). We have investigated whether a similar antibody response is also present in multiple sclerosis patients. Using the recombinant human extracellular immunoglobulin domain of MOG (MOG-Ig) we have screened the sera and CSFs of 130 multiple sclerosis patients, 32 patients with other inflammatory neurological diseases (OIND), 30 patients with other non-inflammatory neurological diseases (ONND) and 10 patients with rheumatoid arthritis. We report that 38% of multiple sclerosis patients are seropositive for IgG antibodies to MOG-Ig compared with 28% seropositive for anti-myelin basic protein (MBP). In contrast, OIND are characterized by similar frequencies of serum IgG antibody responses to MOG-Ig (53%) and MBP (47%), whereas serum IgG responses to MOG-Ig are rare in ONND (3%) and rheumatoid arthritis (10%). Anti-MBP IgG antibodies, however, are a frequent finding in ONND (23%) and rheumatoid arthritis (60%). Our results provide clear evidence that anti-MOG-Ig antibodies are common in CNS inflammation. However, in OIND these antibody responses are transient, whereas they persist in multiple sclerosis. We demonstrate that the serum anti-MOG-Ig response is already established in early multiple sclerosis (multiple sclerosis-R0; 36%). In later multiple sclerosis stages frequencies and titres are comparable with early multiple sclerosis. In contrast, the frequency of anti-MBP antibodies is low in multiple sclerosis-R0 (12%) and increases during disease progression in relapsing-remitting (32%) and chronic progressive multiple sclerosis (40%), thus suggesting that anti-MBP responses accumulate over time. Finally we provide evidence for intrathecal synthesis of IgG antibodies to MOG-Ig in multiple sclerosis.

Topics: Adult; Arthritis, Rheumatoid; Autoantibodies; Blotting, Western; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoglobulins; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Nervous System Diseases; Neuritis; Recombinant Proteins; Retrospective Studies

Immunoreactive material that appears to be a peptide encompassing all or a portion of residues 80 to 89 of myelin basic protein is present in normal unconcentrated urine and is increased in certain patients with multiple sclerosis (MS). Compared with normal controls, urines collected randomly from 158 MS patients or in a clinical research unit from 8 patients with MS had higher mean values of urinary MBP-like material (MBPLM). The level of MBPLM in urine showed no direct relationship to MBPLM in cerebrospinal fluid and did not correlate with clinical relapses of disease. In the other neurological disease control group (26 patients), some patients with other inflammatory diseases, but not stroke or early phase Guillain-Barré syndrome, also showed elevations. Among the subtypes of MS, those with secondary chronic progressive disease had the highest values. Urinary MBPLM showed no definite correlation with or effect of treatment with glucocorticoids and immunosuppressants except that a lower level of urinary MBPLM showed a weak relationship with improvement following treatment with methylprednisolone/prednisone. In a serial study of 8 patients with unenhanced cranial magnetic resonance imaging and 20 patients with gadolinium-enhanced cranial magnetic resonance imaging, urinary MBPLM did not show a direct correlation with new or enhancing lesions. Urinary MBPLM does not parallel acute myelin damage but appears to reflect an ongoing process, possibly linked to attempted efforts at remyelination.

Topics: Adult; Cyclosporine; Double-Blind Method; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Radioimmunoassay; Reference Values; Sensitivity and Specificity

Citrullination of arginine residues is a post-translational modification (PTM) found on myelin basic protein (MBP), which neutralizes MBPs positive charge, and is implicated in myelin damage and multiple sclerosis (MS). Here we identify lysine acetylation as another neutralizing PTM to MBP that may be involved in myelin damage. We quantify changes in lysine and arginine PTMs on MBP derived from mice induced with an experimental autoimmune encephalomyelitis (EAE) model of MS using liquid chromatography tandem mass spectrometry. The changes in PTMs are correlated to changes in neurological disability scoring (NDS), as a marker of myelin damage. We found that lysine acetylation increased by 2-fold on MBP during peak NDS post-EAE induction. We also found that mono- and dimethyl-lysine, as well as asymmetric dimethyl-arginine residues on MBP were elevated at peak EAE disability. These findings suggest that the acetylation and methylation of lysine on MBP are PTMs associated with the neurological disability produced by EAE. Since histone deacetylase (HDAC) inhibitors have been previously shown to improve neurological disability, we also show that treatment with trichostatin A (a HDAC inhibitor) improves the NDS of EAE mice but does not change MBP acetylation.

Topics: Acetylation; Animals; Encephalomyelitis, Autoimmune, Experimental; Histone Deacetylase Inhibitors; Hydroxamic Acids; Lysine; Methylation; Mice; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Protein Processing, Post-Translational

Multiple sclerosis (MS) is a neurological autoimmune disorder characterized by mistaken attacks of inflammatory cells against the central nervous system (CNS), resulting in demyelination and axonal damage. Kv1.3 channel blockers can inhibit T-cell activation and have been designed for MS therapy. However, little is known about the effects of Kv1.3 blockers on protecting myelin sheaths/axons in MS. This study aimed at investigating the neuroprotection efficacy of a selective Kv1.3 channel blocker ImKTx88 (ImK) in MS animal model.. Experimental autoimmune encephalomyelitis (EAE) rat model was established. The neuroprotective effect of ImK was assessed by immunohistochemistry and transmission electron microscopy (TEM). In addition, the antiinflammatory effect of ImK by suppressing T-cell activation was assessed by flow cytometry and ELISA in vitro.. Our results demonstrated that ImK administration ameliorated EAE clinical severity. Moreover, ImK increased oligodendrocytes survival, preserved axons, and myelin integrity and reduced the infiltration of activated T cells into the CNS. This protective effect of the peptide may be related to its suppression of autoantigen-specific T-cell activation via calcium influx inhibition.. ImK prevents neurological damage by suppressing T-cell activation, suggesting the applicability of this peptide in MS therapy.

Topics: Animals; Animals, Newborn; Cells, Cultured; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Kv1.3 Potassium Channel; Microscopy, Electron, Transmission; Mycobacterium tuberculosis; Myelin Basic Protein; Nerve Tissue Proteins; Nervous System Diseases; Neurons; Potassium Channel Blockers; Rats; Rats, Sprague-Dawley; T-Lymphocytes

Evidence continues to increase linking autoimmunity and other complex diseases to the chemicals commonly found in our environment. Bisphenol A (BPA) is a synthetic monomer used widely in many forms, from food containers to toys, medical products and many others. The potential for BPA to participate as a triggering agent for autoimmune diseases is likely due to its known immunological influences. The goal of this research was to determine if immune reactivity to BPA has any correlation with neurological antibodies. BPA binds to a target enzyme called protein disulfide isomerase (PDI). Myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) are neuronal antigens that are target sites for neuroinflammation and neuroautoimmunity. We determined the co-occurrence of anti-MBP and anti-MOG antibodies with antibodies made against BPA bound to human serum albumin in 100 healthy human subjects. Correlation between BPA to PDI, BPA to MOG, BPA to MBP, PDI to MBP and PDI to MOG were all highly statistically significant (P < 0.0001). The outcome of our study suggests that immune reactivity to BPA-human serum albumin and PDI has a high degree of statistical significance with substantial correlation with both MBP and MOG antibody levels. This suggests that BPA may be a trigger for the production of antibodies against PDI, MBP and MOG. Immune reactivity to BPA bound to human tissue proteins may be a contributing factor to neurological autoimmune disorders. Further research is needed to determine the exact relationship of these antibodies with neuroautoimmunities. Copyright © 2016 The Authors Journal of Applied Toxicology Published by John Wiley & Sons Ltd.

Topics: Adolescent; Adult; Aged; Antibodies; Antibodies, Blocking; Autoimmune Diseases; Autoimmunity; Benzhydryl Compounds; Humans; Middle Aged; Myelin Basic Protein; Myelin-Oligodendrocyte Glycoprotein; Nervous System Diseases; Neurons; Phenols; Protein Disulfide-Isomerases; Young Adult

Infections are common following stroke and associated with worse outcome. Using an animal model of pneumonia, we assessed the effect of infection and its treatment on the immune response and stroke outcome.. Lewis rats were subjected to transient cerebral ischemia and survived for 4weeks. One day after stroke animals were exposed to aerosolized Staphylococcus aureus, Pseudomonas aeruginosa or saline. Antibiotics (ceftiofur or enrofloxacin) were started immediately after exposure or delayed for 3days. Behavioral tests were performed weekly. ELISPOT assays were done on lymphocytes from spleen and brain to assess autoimmune responses to myelin basic protein (MBP).. Among animals that received immediate antibiotic therapy, infection was associated with worse outcome in ceftiofur but not enrofloxacin treated animals. (The outcome with immediate enrofloxacin therapy was so impaired that further worsening may have been difficult to detect.) A delay in antibiotic therapy was associated with better outcomes in both ceftiofur and enrofloxacin treated animals. Infection was associated with an increased likelihood of developing Th1(+) responses to MBP in non-infarcted brain (OR=2.94 [1.07, 8.12]; P=0.04), and Th1(+) responses to MBP in spleen and non-infarcted brain were independently associated with a decreased likelihood of stroke recovery (OR=0.16 [0.05, 0.51; P=0.002 and OR=0.32 [0.12, 0.84]; P=0.02, respectively).. Infection worsens stroke outcome in ceftiofur treated animals and increases Th1 responses to MBP. These data may help explain how infection worsens stroke outcome and suggest that treatment of infection may contribute to this outcome.

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Body Temperature; Body Weight; Cephalosporins; Cytokines; Disease Models, Animal; Enrofloxacin; Fluoroquinolones; Lymphocytes; Male; Myelin Basic Protein; Nervous System Diseases; Pneumonia; Rats; Rats, Inbred Lew; Staphylococcus aureus; Statistics, Nonparametric; Stroke

White matter injury induced by ischemic stroke elicits sensorimotor impairments, which can be further deteriorated by persistent proinflammatory responses. We previously reported that delayed and repeated treatments with omega-3 polyunsaturated fatty acids (n-3 PUFAs) improve spatial cognitive functions and hippocampal integrity after ischemic stroke. In the present study, we report a post-stroke n-3 PUFA therapeutic regimen that not only confers protection against neuronal loss in the gray matter but also promotes white matter integrity. Beginning 2 h after 60 min of middle cerebral artery occlusion (MCAO), mice were randomly assigned to receive intraperitoneal docosahexaenoic acid (DHA) injections (10 mg/kg, daily for 14 days), alone or in combination with dietary fish oil (FO) supplements starting 5 days after MCAO. Sensorimotor functions, gray and white matter injury, and microglial responses were examined up to 28 days after MCAO. Our results showed that DHA and FO combined treatment-facilitated long-term sensorimotor recovery and demonstrated greater beneficial effect than DHA injections alone. Mechanistically, n-3 PUFAs not only offered direct protection on white matter components, such as oligodendrocytes, but also potentiated microglial M2 polarization, which may be important for white matter repair. Notably, the improved white matter integrity and increased M2 microglia were strongly linked to the mitigation of sensorimotor deficits after stroke upon n-3 PUFA treatments. Together, our results suggest that post-stroke DHA injections in combination with FO dietary supplement benefit white matter restoration and microglial responses, thereby dictating long-term functional improvements.

Topics: Animals; Antigens, CD; Calcium-Binding Proteins; Cell Proliferation; Cerebrovascular Circulation; Corpus Callosum; Disease Models, Animal; Docosahexaenoic Acids; Eicosapentaenoic Acid; Ischemic Attack, Transient; Leukoencephalopathies; Male; Mice; Mice, Inbred C57BL; Microfilament Proteins; Microglia; Myelin Basic Protein; Nerve Tissue Proteins; Nervous System Diseases; Stroke; Time Factors

Very low birth weight (VLBW) premature infants experience numerous, often self-limited non-bradycardic episodes of intermittent hypoxemia (IH). We hypothesized that these episodes of IH affect postnatal white matter (WM) development causing hypomyelination and neurological handicap in the absence of cellular degeneration. Based on clinical data from ten VLBW neonates; a severity, daily duration and frequency of non-bradycardic IH episodes were reproduced in neonatal mice. Changes in heart rate and cerebral blood flow during IH were recorded. A short-term and long-term neurofunctional performance, cerebral content of myelin basic protein (MBP), 2'3' cyclic-nucleotide 3-phosphodiesterase (CNPase), electron microscopy of axonal myelination and the extent of cellular degeneration were examined. Neonatal mice exposed to IH exhibited no signs of cellular degeneration, yet demonstrated significantly poorer olfactory discrimination, wire holding, beam and bridge crossing, and walking-initiation tests performance compared to controls. In adulthood, IH-mice demonstrated no alteration in navigational memory. However, sensorimotor performance on rota-rod, wire-holding and beam tests was significantly worse compared to naive littermates. Both short- and long-term neurofunctional deficits were coupled with decreased MBP, CNPase content and poorer axonal myelination compared to controls. In neonatal mice mild, non-ischemic IH stress, mimicking that in VLBW preterm infants, replicates a key phenotype of non-cystic WM injury: permanent hypomyelination and sensorimotor deficits. Because this phenotype has developed in the absence of cellular degeneration, our data suggest that cellular mechanisms of WM injury induced by mild IH differ from that of cystic periventricular leukomalacia where the loss of myelin-producing cells and axons is the major mechanism of injury.

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Animals; Animals, Newborn; Caspase 3; Cerebrovascular Circulation; Disease Models, Animal; Gene Expression Regulation, Developmental; Heart Rate; Hypoxia; Leukoencephalopathies; Mice; Mice, Inbred C57BL; Muscle Strength; Myelin Basic Protein; Nerve Fibers, Myelinated; Nervous System Diseases; Oxygen; Psychomotor Performance; Statistics, Nonparametric; Time Factors

Oscillating field stimulation (OFS) has been used in attempts to treat spinal cord injury (SCI) and has been shown to improve remyelination after SCI in rats. However, some controversies regarding the effects of OFS have been presented in previous papers. Oligodendrocytes (OLs) are the main cell for remyelination and are derived from the differentiation of oligodendrocyte precursor cells (OPCs). To date, it has been unclear whether the differentiation of OPCs can be regulated by OFS. The goal of this study was to determine if OFS can improve the differentiation of OPCs and promote the recovery of neurological function after SCI in rats. Immature and mature OLs were observed in spinal cord slices through immunofluorescence staining. Levels of adenosine triphosphate (ATP) and the cytokine leukemia inhibitory factor (LIF) were detected by enzyme-linked immunosorbent assay (ELISA). Basso-Beattie-Bresnahan (BBB) scores and transcranial magnetic motor-evoked potentials (tcMMEPs) were used to evaluate the locomotor outcomes of rats after SCI. Our results showed a significant improvement in the differentiation of OPCs and the content of ATP and LIF in the injured spinal cord in the OFS group. Furthermore, BBB scores and tcMMEPs were significantly improved in the rats stimulated by OFS. These findings suggest that OFS can improve the differentiation of OPCs and promote the recovery of neurological function following SCI in rats.

Topics: Adenosine Triphosphate; Analysis of Variance; Animals; Blood-Brain Barrier; Cell Differentiation; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Evoked Potentials, Motor; Female; Leukemia Inhibitory Factor; Motor Activity; Myelin Basic Protein; Nervous System Diseases; Oligodendroglia; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Stem Cells; Time Factors; Transcranial Direct Current Stimulation

Citrullination is a protein PTM of arginine residues catalyzed by peptidylarginine deiminase. Protein citrullination has been detected in the CNS and associated with a number of neurological diseases. However, identifying citrullinated proteins from complex mixtures and pinpointing citrullinated residues have been limited. Using RP LC and high-resolution MS, this study determined in vitro citrullination sites of glial fibrillary acid protein (GFAP), neurogranin (NRGN/RC3), and myelin basic protein (MBP) and in vivo sites in brain protein extract. Human GFAP has five endogenous citrullination sites, R30, R36, R270, R406, and R416, and MBP has 14 in vivo citrullination sites. Human NRGN/RC3 was found citrullinated at residue R68. The sequence of citrullinated peptides and citrullination sites were confirmed from peptides identified in trypsin, Lys-C, and Glu-C digests. The relative ratio of citrullination was estimated by simultaneous identification of citrullinated and unmodified peptides from Alzheimer's and control brain samples. The site occupancy of citrullination at the residue R68 of NRGN ranged from 1.6 to 9.5%. Compared to CID, higher-energy collisional dissociation (HCD) mainly produced protein backbone fragmentation for citrullinated peptides. CID-triggered HCD fragmentation is an optimal approach for the identification of citrullinated peptides in complex protein digests.

Topics: Alzheimer Disease; Animals; Brain; Cattle; Chromatography, Liquid; Citrulline; Glial Fibrillary Acidic Protein; Humans; Hydrolases; Mass Spectrometry; Myelin Basic Protein; Nervous System Diseases; Neurogranin; Protein-Arginine Deiminases

Topics: Acclimatization; Adult; Altitude; Fatty Acid-Binding Proteins; Humans; Male; Middle Aged; Myelin Basic Protein; Nervous System Diseases; Occupational Exposure; Succinate Dehydrogenase

Purinergic ionotropic P2X(7) receptor is widely distributed in brain. Strong evidence suggests that this receptor is related to inflammatory and neurodegenerative changes in many pathological states of central nervous system (CNS), including multiple sclerosis (MS). Experimental autoimmune encephalomyelitis (EAE) is the commonly used animal model of MS. In this study we investigate the expression of P2X(7)R protein in rat brain in the symptomatic phase of EAE (day 10 post immunization) and after reversion of neurological symptoms (day 20 p.i.). We found the increased level of P2X(7)R protein in brain homogenates of EAE rats in both examined time windows. Immunohistochemical study revealed enhanced receptor's immunoreactivity. Immunoblots done with isolated cellular brain fractions indicated that the P2X(7)R overexpression is related to synaptosomal fraction in the symptomatic phase and to the glial (GPV) fraction in the recovery phase of EAE. Concomitantly, we noticed overexpression of astroglial marker GFAP in brain homogenates and astroglial fraction (GPV), so as its enhanced immunoreactivity in brain sections (10 days p.i.) which did not decline to control values in the recovery phase, similarly to P2X(7)R expression. Results suggest the involvement of P2X(7)R-mediated signaling in the pathomechanisms of EAE with the possible relevance of astrocytic pool of cells.

Topics: Analysis of Variance; Animals; Brain; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Freund's Adjuvant; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Myelin Basic Protein; Nervous System Diseases; Rats; Rats, Inbred Lew; Receptors, Purinergic P2X7; Synaptosomes; Time Factors

Loss of aquaporin 4 and glial fibrillary acidic protein (GFAP) with necrosis and demyelination is a prominent pathologic feature of neuromyelitis optica (NMO). However, the clinicopathologic significance of astrocytic damage and its relation with demyelination are unknown.. To analyze clinical and pathologic values of a CSF biomarker of astrocytic damage in NMO.. We measured the levels of GFAP, S100B, myelin basic protein (MBP), and neurofilament H (NF-H) in CSF obtained from patients with NMO (n = 33), multiple sclerosis (MS) (n = 27), acute disseminated encephalomyelitis (ADEM), ischemia, meningitis, and other neurologic disease controls (OND).. The CSF-GFAP levels during relapse in NMO (2,476.6 +/- 8,815.0 ng/mL) were significantly higher than those in MS (0.8 +/- 0.4 ng/mL) and OND (0.7 +/- 0.5 ng/mL), and much beyond those in ADEM (14.1 +/- 27.4 ng/mL). The sensitivity and specificity of CSF-GFAP for NMO was 90.9% and 76.9% in all, but the specificity improved above 90% in cases limited to demyelinating diseases. CSF-S100B showed a similar trend but was less remarkable. In contrast, MBP and NF-H are not different between NMO and MS. Following treatments, the CSF-GFAP rapidly decreased to a normal level, but CSF-MBP remained high. There were strong correlations between the CSF-GFAP, CSF-S100B, or CSF-MBP levels and Expanded Disability Status Scale (EDSS) or spinal lesion length in the acute phase (r > 0.6). Only CSF-GFAP correlated with EDSS at 6-month follow-up (r = 0.51) in NMO.. Astrocytic damage reflected by elevated CSF glial fibrillary acidic protein is a clinically relevant, primary pathologic process in neuromyelitis optica, and is far more severe than demyelination.

Topics: Adult; Aged; Antibodies; Aquaporin 4; Astrocytes; Biomarkers; Central Nervous System; Demyelinating Diseases; Disability Evaluation; Encephalomyelitis, Acute Disseminated; Female; Follow-Up Studies; Glial Fibrillary Acidic Protein; Humans; Male; Methylprednisolone; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Nerve Growth Factors; Nervous System Diseases; Neurofilament Proteins; Neuromyelitis Optica; Neuroprotective Agents; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Statistics, Nonparametric

Anamnestic recall of stroke-related deficits is a common clinical observation, especially during periods of systemic infection. The pathophysiology of this transient re-emergence of neurological dysfunction is unknown.. Male Lewis rats underwent 3 hours middle cerebral artery occlusion and were treated with lipopolysaccharide or saline at the time of reperfusion. The delayed-type hypersensitivity (DTH) response to myelin basic protein was examined 28 days after middle cerebral artery occlusion. Changes in behavioral outcomes were assessed after DTH testing and repeat administration of lipopolysaccharide or saline at 34 days. At the time of euthanasia (36 days), the immunologic response of splenocytes to myelin basic protein, neuron-specific enolase, and proteolipid protein was determined by enzyme-linked immunospot assay and the number of lymphocytes in the brain determined by immunocytochemistry.. Animals treated with lipopolysaccharide at middle cerebral artery occlusion had a greater DTH response to myelin basic protein than animals treated with saline. Among those animals that had fully recovered on a given behavioral test before DTH testing, those treated with lipopolysaccharide at middle cerebral artery occlusion displayed more neurological deterioration after DTH testing and had more CD8(+) lymphocytes within the ischemic core of the brain. Furthermore, the Th1 immune response to brain antigens in the spleen was more robust among those animals that deteriorated after DTH testing and there were more CD4(+) lymphocytes in the penumbral region of animals with a Th1 response to myelin basic protein.. Our data suggest that an immune response to the brain contributes to the phenomenon of anamnestic recall of stroke-related deficits after an infection. The contribution of the immune response to this phenomenon deserves further investigation.

Topics: Amnesia; Animals; Brain; Hypersensitivity, Delayed; Immune System; Infarction, Middle Cerebral Artery; Lipopolysaccharides; Male; Models, Animal; Myelin Basic Protein; Nervous System Diseases; Rats; Rats, Inbred Lew; Stroke; Th1 Cells; Time Factors

Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH yield the rare genetic disorder trichothiodystrophy (TTD). Although this syndrome was initially associated with a DNA repair defect, individuals with TTD develop neurological features, such as microcephaly and hypomyelination that could be connected to transcriptional defects. Here we show that an XPD mutation in TTD mice results in a spatial and selective deregulation of thyroid hormone target genes in the brain. Molecular analyses performed on the mice brain tissue demonstrate that TFIIH is required for the stabilization of thyroid hormone receptors (TR) to their DNA-responsive elements. The limiting amounts of TFIIH found in individuals with TTD thus contribute to the deregulation of TR-responsive genes. The discovery of an unexpected stabilizing function for TFIIH deepens our understanding of the pathogenesis and neurological manifestations observed in TTD individuals.

Topics: Animals; Brain; Cell Line, Transformed; Disease Models, Animal; DNA Footprinting; Gene Expression Regulation; In Situ Hybridization; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Transmission; Mutation; Myelin Basic Protein; Nerve Tissue Proteins; Nervous System Diseases; RNA, Small Interfering; Transcription Factor TFIIH; Transfection; Trichothiodystrophy Syndromes

Preferential brain white matter injury and hypomyelination induced by intracerebral administration of the endotoxin lipopolysaccharide (LPS) in the neonatal rat brain has been characterized as associated with the activation of microglia. To examine whether inhibition of microglial activation might provide protection against LPS-induced brain injury and behavioral deficits, minocycline (45 mg/kg) was administered intraperitoneally 12 hr before and immediately after an LPS (1 mg/kg) intracerebral injection in postnatal day 5 (P5) Sprague-Dawley rats and then every 24 hr for 3 days. Brain injury and myelination were examined on postnatal day 21 and the tests for neurobehavioral toxicity were carried out from P3 to P21. LPS administration resulted in severe white matter injury, enlarged ventricles, deficits in the hippocampus, loss of oligodendrocytes and tyrosine hydroxylase neurons, damage to axons and dendrites, and impaired myelination as indicated by the decrease in myelin basic protein immunostaining in the P21 rat brain. LPS administration also significantly affected physical development (body weight) and neurobehavioral performance, such as righting reflex, wire hanging maneuver, cliff avoidance, locomotor activity, gait analysis, and responses in the elevated plus-maze and passive avoidance task. Treatment with minocycline significantly attenuated the LPS-induced brain injury and improved neurobehavioral performance. The protective effect of minocycline was associated with its ability to attenuate LPS-induced microglial activation. These results suggest that inhibition of microglial activation by minocycline may have long-term protective effects in the neonatal brain on infection-induced brain injury and associated neurologic dysfunction in the rat.

Topics: Age Factors; Animals; Animals, Newborn; Avoidance Learning; Behavior, Animal; Brain; Brain Injuries; CD11b Antigen; Cell Count; Gait; Gene Expression Regulation, Developmental; Immunohistochemistry; Lateral Ventricles; Lectins; Lipopolysaccharides; Maze Learning; Microtubule-Associated Proteins; Minocycline; Motor Activity; Myelin Basic Protein; Nervous System Diseases; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Reflex; Staining and Labeling; Tyrosine 3-Monooxygenase

We studied CD4 T cell activation in patients with clinically isolated syndromes (CIS) suggesting an initial attack of multiple sclerosis. The percentage of blood CD26+ CD4 T cells was increased in these patients, and correlated with magnetic resonance imaging disease activity and clinical disease severity. In contrast, the percentage of CD25+ CD4 T cells in cerebrospinal fluid correlated negatively with the cerebrospinal fluid concentration of myelin basic protein and the presence of IgG oligoclonal bands. These results suggest that distinct systemic and intrathecal T cell activation states correlate with disease activity and risk of subsequently developing MS in CIS patients.

Topics: Adult; Antigens, Differentiation; CD4-Positive T-Lymphocytes; Dipeptidyl Peptidase 4; Disability Evaluation; Female; Flow Cytometry; Humans; Immunoglobulin G; Lymphocyte Activation; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Receptors, Interleukin-2

Idiotopic sequences are created after V, D and J recombinations and by somatic mutations during affinity maturation of immunoglobulin (Ig) molecules, and may therefore be potential immunogenic epitopes. Idiotope-specific T cells are able to activate and sustain the B cells producing such idiotopes. It is therefore possible that idiotope-specific intrathecal T cells could help maintain the persisting intrathecal synthesis of oligoclonal IgG observed in patients with multiple sclerosis (MS). This study was undertaken to examine T-cell responses to cerebrospinal fluid (CSF) IgG. Peripheral blood mononuclear cells (PBMC) from 14 of 21 MS patients and four of 17 control patients with other neurological diseases proliferated upon stimulation with autologous CSF IgG, while five and three, respectively, responded to serum IgG. By comparison, responses to myelin basic protein were recorded in only four MS and three control patients. Data from a limited number of patients indicate that the CSF IgG responsive cells were CD4+ and human leucocyte antigen DR restricted, that PBMC also respond to CSF IgG from other MS patients and that the CSF may contain T cells responding to autologous CSF IgG. This suggests that CSF IgG, or substances bound to this IgG, may represent T-cell immunogens, which could contribute to the intrathecal immune response in MS.

Topics: Adult; Case-Control Studies; CD4-Positive T-Lymphocytes; Cell Division; Female; HLA-DR Antigens; Humans; Immunoglobulin G; Male; Middle Aged; Monocytes; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; T-Lymphocytes

Topics: Biomarkers; Humans; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases

Radioimmunoassay for myelin basic protein in cerebrospinal fluid is commonly used as a biochemical marker of demyelination in multiple sclerosis patients. A sensitive enzyme-linked immunosorbent assay for myelin basic protein has been recently developed, which can make a clinical evaluation of myelin basic protein in cerebrospinal fluid of patients with multiple sclerosis and other neurological diseases. Most multiple sclerosis patients with acute exacerbation had markedly high myelin basic protein. Longitudinal studies of multiple sclerosis patients showed that myelin basic protein in CSF increases rapidly in agreement with acute relapse and then rapidly declines and disappears. Significantly higher cerebrospinal fluid myelin basic protein levels in human T-cell lymphotropic virus Type I-associated myelopathy/tropical spastic paraparesis patients were also detected. This enzyme-linked immunosorbent assay system can be used routinely to measure myelin basic protein in cerebrospinal fluid as a useful diagnostic indicator, not only for central active demyelination as in multiple sclerosis but, also for spinal cord demyelination as in human T-cell lymphotropic virus Type I-associated myelopathy/tropical spastic paraparesis.

Topics: Adolescent; Adult; Aged; Animals; Autoantigens; Autoimmune Diseases; Cattle; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Forecasting; Humans; Longitudinal Studies; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Paraparesis, Tropical Spastic; Reagent Kits, Diagnostic

The data herein demonstrate that in addition to the well-characterized myelin marker-positive, glial fibrillary acidic protein (GFAP)-negative, membrane sheet-bearing oligodendrocytes, another type of myelin marker-positive, process-bearing glia exists in normal and pathologic conditions. This second type of myelin marker-positive glia expresses GFAP, and therefore these cells have been referred to as mixed phenotype glia. Although mixed phenotype glia have been documented previously, their identity and function have remained a mystery. The goal of this immunocytochemical study was to further characterize these cells. Using the MBPlacZ transgenic mouse in which beta-galactosidase is under the control of the myelin basic protein (MBP) gene promoter, GFAP-positive/beta-galactosidase-positive and myelin/oligodendrocyte-specific protein (MOSP)-positive/beta-galactosidase-positive cells were detected in subcortical white matter and in perivascular locations within cerebral white and gray matter. In cultures prepared from highly enriched myelin marker-positive immature glia, mixed phenotype glia were detected that were GFAP-positive and either MOSP-, MBP-, O1-, and O4-positive. The expression of multiple myelin markers by mixed phenotype glia may suggest that these cells are of oligodendrocyte origin. Increased numbers of MOSP-positive/GFAP-positive mixed phenotype glia were detected in sections from adult hypomyelinated brain from shiverer, quaking, and PKU mice compared to myelinated control adult mouse brain. Similarly, cultures from control brain exposed to elevated pH for 2-3 weeks showed dramatically increased numbers of mixed phenotype glia (80%) compared to control (<10%). Increased numbers of mixed phenotype glia also were detected in shiverer cultures (40%). Since increases in the number of mixed phenotype glia occur in shiverer, quaking, and PKU mouse brain, these data suggest that mixed phenotype glia contribute to gliosis in pathologic white matter.

Topics: Animals; Brain; Cell Count; Cells, Cultured; Fluorescent Antibody Technique; Galactosidases; Glial Fibrillary Acidic Protein; Immunohistochemistry; Mice; Mice, Neurologic Mutants; Mice, Transgenic; Myelin Basic Protein; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Nervous System Diseases; Neuroglia; Oligodendroglia; Phenotype

The occurrence and role of autoantibodies to gangliosides and other lipid-containing components of the central nervous system in Multiple Sclerosis (MS) are unsettled. Using sensitive ELISAs, we measured IgG and IgM antibody titers and absorbances to the three major gangliosides GD1a, GD1b and GM1, and to sulfatides, cardiolipin and myelin proteins in paired serum and cerebrospinal fluid (CSF) from patients with untreated MS, optic neuritis (ON), acute aseptic meningo-encephalitis (AM) and other neurological diseases (OND). Twenty-three per cent of 30 MS (P<0.04) and 18% of 32 ON patients (P<0.05) presented elevated IgG antibody titers to GD1a in serum compared to 9% of patients with OND. Six (40%) of the patients with malignant MS had elevated serum IgG antibody titers to GD1a compared to one (6%) of the patients with benign MS (P<0.04). In CSF, elevated IgG antibody titers to GD1a were measured in 13% of MS and 20% of ON patients compared to 4% of patients with OND (P<0. 03 and P<0.02, respectively). The augmented IgG response to GD1a in serum also separated MS from Guillain-Barré syndrome. Compared to OND increased IgM absorbances to sulfatides and cardiolipin were observed in CSF of patients with MS, but also in AM. Elevated IgG antibody titers to myelin proteins were found more often in MS patients' serum and MS, ON and AM patients' CSF compared to OND. The data implicate that among the multitude of enhanced B-cell responses occurring in MS and ON, that directed to GD1a is common and more discriminative, and should be evaluated in future MS treatment studies.

Topics: Adult; Antibodies, Anticardiolipin; Autoantibodies; B-Lymphocytes; Cerebrovascular Disorders; Female; G(M1) Ganglioside; Gangliosides; Humans; Immunoglobulin G; Immunoglobulin M; Male; Meningoencephalitis; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Optic Neuritis; Recurrence; Sulfoglycosphingolipids

Pit, Oct, Unc (POU) homeo domain transcription factors have been implicated in various developmental processes, including cell division, differentiation, specification, and survival of specific cell types. Although expression of the transcription factor Oct-6 in oligodendroglia is confined to the promyelin stage and is downregulated at the myelin stage of development, the effect of Oct-6 overexpression on oligodendrocyte development has not been established. Here we show that transgenic animals overexpressing Oct-6 at late oligodendrocyte development develop a severe neurologic syndrome characterized by action tremors, recurrent seizures, and premature death. Axons in the central nervous system of Oct-6 transgenics were hypomyelinated, hypermyelinated, or dysmyelinated, and ultrastructural analyses suggested that myelin formation was premature. The vulnerability of developing oligodendroglia to Oct-6 deregulation provides evidence that the POU factor may play a direct role in myelin disease pathogenesis in the mammalian CNS.

Topics: Animals; Axons; Blotting, Northern; Blotting, Western; Central Nervous System; Cloning, Molecular; DNA; Gene Expression Regulation; Immunohistochemistry; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Microscopy, Electron; Mutagenesis, Insertional; Myelin Basic Protein; Myelin Sheath; Nervous System Diseases; Octamer Transcription Factor-6; Polymerase Chain Reaction; RNA; Transcription Factors

Central nervous system tissue from multiple sclerosis and non-multiple sclerosis subjects was studied for the expression of exon 2 myelin basic protein gene products at the protein and message levels by immunocytochemistry and in situ hybridization, respectively. The exon 2-encoded protein sequence is normally expressed during development (myelination) within the 21.5- and 20.2-kd isoforms of myelin basic protein and is downregulated in the adult central nervous system where the 18.5- and 17.2-kd isoforms predominate, the latter devoid of exon 2 owing to alternative splicing. Exon 2 myelin basic protein gene products were readily demonstrable in multiple sclerosis samples, the highest levels correlating with remyelination in chronic lesions while normal adult central nervous system and non-multiple sclerosis material showed very low levels and fetal human central nervous system tissue (a positive control) showed high levels. We conclude that recapitulation of ontogenetic events during myelin repair accounts for the increased expression of the exon 2-encoded protein sequence in the adult central nervous system during multiple sclerosis, an event that might underly the previously observed T-cell activation to this protein sequence during relapses.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Central Nervous System; Chronic Disease; Exons; Female; Fetus; Genes; Genes, Developmental; Humans; Immunohistochemistry; In Situ Hybridization; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Myelin Sheath; Nervous System Diseases

Somatic mutation as an index of in vivo T-cell amplification is a powerful tool to analyze the specificity and size of the autoreactive T-cell repertoire. Using this strategy, we determined the precursor frequency of T cells reactive to myelin basic protein (MBP) and overlapping MBP peptides spanning regions p84-168 in patients with MS and controls in the HPRT mutant T-cell population. Among 19 MS patients, nine had estimatable frequencies to MBP or MBP peptides, p93-112, p124-142 and p143-168 in the HPRT mutant T-cell population. Only one of the 10 controls showed measurable frequency to MBP in the HPRT mutant T-cell population. These studies suggest that increased frequency of T cells reactive to MBP and MBP peptides might indicate putative disease-related epitopes in MS.

Topics: Adolescent; Adult; Amino Acid Sequence; Cells, Cultured; Female; Histocompatibility Testing; HLA-DR Antigens; Humans; Hypoxanthine Phosphoribosyltransferase; Male; Middle Aged; Molecular Sequence Data; Multiple Sclerosis; Mutation; Myelin Basic Protein; Nervous System Diseases; Peptide Fragments; Reference Values; T-Lymphocytes

Chemokines (pro-inflammatory chemoattractant cytokines) are expressed in pathological conditions of the central nervous system (CNS). Previous studies suggested that the CNS is relatively resistant to leukocyte diapedesis after chemokine injection, leaving their functional role unresolved. The CNS function of N51/KC, a neutrophil-selective chemokine, was addressed by expressing N51/KC under control of the myelin basic protein (MBP) promoter in transgenic (tg) mice (MBP-N51/KC mice). CNS-specific N51/KC expression produced remarkable neutrophil infiltration into perivascular, meningeal, and parenchymal sites, demonstrating that this chemokine exerts the multiple functions in vivo required to recruit leukocytes into the CNS. MBP-N5 1/KC mice represent an incisive model for the molecular dissection of neutrophil entry into the CNS. Unexpectedly, MBP-N51/KC mice developed a neurological syndrome of pronounced postural instability and rigidity at high frequency beginning at 40 days of age, well after peak chemokine expression. 68/182 mice in one tg fine were found dead before one year of age, with prominent neurological symptoms premortem in 26 (38%). Florid microglial activation and blood-brain barrier disruption without dysmyelination were the major neuropathological alterations. Late-onset neurological symptoms in MBP-N51/KC mice may indicate unanticipated consequences of CNS chemokine expression.

Topics: Animals; Astrocytes; Base Sequence; Brain; Chemokine CXCL1; Chemokines; Chemokines, CXC; Chemotactic Factors; Cytokines; DNA Primers; Female; Growth Substances; Intercellular Signaling Peptides and Proteins; Introns; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred ICR; Mice, Transgenic; Microscopy, Electron; Molecular Sequence Data; Myelin Basic Protein; Nervous System Diseases; Neuroglia; Neutrophils; Oligodendroglia; Polymerase Chain Reaction; Posture; Promoter Regions, Genetic; Recombinant Fusion Proteins; Restriction Mapping

Simplified enzyme-linked immunoadsorbent assays (ELISA) for myelin basic protein (MBP) and antibodies to myelin basic protein (Anti-MBP) have been used to test 337 patients with diseases of the nervous system including 36 compressive diseases (CMP), 33 multiple sclerosis (MS), 34 cerebrovascular diseases (CVD), 31 inflammatory diseases of central nervous system (ID), 161 epilepsy (EP) and 42 other nervous diseases (OND). Comparison of results among various groups indicates that serum mean MBP values of CMP, MS, CVD, ID and EP groups are significantly higher than those of OND group and normal control (P < 0.01). The serum mean MBP value of 33 acute trauma patients with spine fracture and paraplegia, the majority of CMP group, is the highest compared with MS group (P < 0.05), CVD, ID and EP groups (P < 0.01). CSF mean MBP value of 15 CVD patients is markedly greater than that of OND group (P < 0.05). No statistically significant differences are found in serum MBP values between OND group and normal control, and in serum and CSF Anti-MBP values among six groups by using our method.

Topics: Autoantibodies; Enzyme-Linked Immunosorbent Assay; Epilepsy, Tonic-Clonic; Humans; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Spinal Cord Compression

The cytotoxic cytokines tumor necrosis factor alpha (TNF-alpha) and lymphotoxin (LT) possess toxic activity against myelin and/or oligodendrocytes in vitro. Multiple sclerosis (MS) plaques within the central nervous system (CNS) are infiltrated by peripheral blood mononuclear cells (PBMC). In this study the production of TNF-alpha and LT by PBMC in active MS were measured. PBMC were isolated from the blood of MS patients in relapse and also patients with other neurological diseases (OND) and healthy controls (HC). Isolated cells were cultured unstimulated or stimulated with phytohemagglutinin A (PHA), lipopolysaccharide (LPS) and myelin basic protein (MBP)--a hypothetical autoantigen for MS. Cytokine production was assessed using ELISA method. In the MS group, PBMC without stimulation as well as after stimulation with MBP displayed a significantly increased production of TNF-alpha. LT production was similar in MS and control groups. These results suggest that TNF-alpha but not LT is overproduced by PBMC during MS relapse.

Topics: Adolescent; Adult; Autoimmune Diseases; Cells, Cultured; Female; Humans; Lipopolysaccharides; Lymphocyte Activation; Male; Middle Aged; Monocytes; Multiple Sclerosis; Myelin Basic Protein; Myelin Proteins; Nervous System Diseases; Oligodendroglia; Phytohemagglutinins; T-Lymphocytes, Cytotoxic; Tumor Necrosis Factor-alpha

Equal numbers of CD4+ T cells recognizing myelin basic protein (MBP) and proteolipid protein (PLP) are found in the circulation of normal individuals and multiple sclerosis (MS) patients. We hypothesized that if myelin-reactive T cells are critical for the pathogenesis of MS, they would exist in a different state of activation as compared with myelin-reactive T cells cloned from the blood of normal individuals. This was investigated in a total of 62 subjects with definitive MS. While there were no differences in the frequencies of MBP- and PLP-reactive T cells after primary antigen stimulation, the frequency of MBP or PLP but not tetanus toxoid-reactive T cells generated after primary recombinant interleukin (rIL-2) stimulation was significantly higher in MS patients as compared with control individuals. Primary rIL-2-stimulated MBP-reactive T cell lines were CD4+ and recognized MBP epitopes 84-102 and 143-168 similar to MBP-reactive T cell lines generated with primary MBP stimulation. In the cerebrospinal fluid (CSF) of MS patients, MBP-reactive T cells generated with primary rIL-2 stimulation accounted for 7% of the IL-2-responsive cells, greater than 10-fold higher than paired blood samples, and these T cells also selectively recognized MBP peptides 84-102 and 143-168. In striking contrast, MBP-reactive T cells were not detected in CSF obtained from patients with other neurologic diseases. These results provide definitive in vitro evidence of an absolute difference in the activation state of myelin-reactive T cells in the central nervous system of patients with MS and provide evidence of a pathogenic role of autoreactive T cells in the disease.

Topics: Adult; Antigens, CD; Cell Line; Female; Flow Cytometry; HLA-DQ Antigens; HLA-DR Antigens; Humans; Interleukin-2; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Myelin Proteins; Myelin Proteolipid Protein; Nervous System Diseases; Recombinant Proteins; T-Lymphocyte Subsets; T-Lymphocytes

Human immunodeficiency virus type 1 (HIV-1)-infected individuals frequently develop a broad spectrum of neurological syndromes, classified as HIV-1-associated cognitive/motor complex. Diffuse demyelination of hemispheric white matter is a commonly observed in HIV-1 infected brain, but the events leading to myelin destruction are still obscure. Since oligodendrocyte infection by HIV-1 is not proven as yet, myelin damage in HIV-1 infection may result from indirect mechanisms such as the excessive release of myelinotoxic substances or the triggering of autoimmune responses directed to myelin constituents. To verify the latter hypothesis, we searched for elevated anti-myelin basic protein (MBP) IgG levels in the cerebrospinal fluid (CSF) and serum of 25 patients with HIV-1 infection, 12 with multiple sclerosis (MS), and 9 with non-inflammatory neurological diseases (NIND). CSF, but not serum, anti-MBP IgG levels were more frequently elevated in HIV-1+ (16/25, 64%) than in MS (3/12, 25%) or NIND (0/9) patients. By using the anti-MBP IgG index, the anti-MBP IgG antibody specificity index (ASI), and the search for anti-MBP oligoclonal IgG, we ascertained that anti-MBP IgG were produced within the CNS in 13 of 25 (52%) HIV-1+, in 6 of 12 (50%) MS, and in none of NIND patients. The incidence of increased CSF anti-MBP IgG levels was higher among HIV-1+ patients at stage II-III (4/4, 100%) or at stage IV B (7/9, 78%) than among those at stage IV C-IV D (5/12, 42%). Although our data indicate that intrathecal anti-MBP IgG may occur early during HIV-1 infection and that they are more common in patients with HIV-1-associated cognitive/motor complex, the possible demyelinating role of these antibodies remains to be demonstrated.

Topics: AIDS Dementia Complex; Autoantibodies; Blood-Brain Barrier; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; HIV Seropositivity; HIV-1; Humans; Immunoglobulin G; Immunoglobulins; Multiple Sclerosis; Myelin Basic Protein; Myelin Sheath; Nervous System Diseases; Neurologic Examination; Neuropsychological Tests; Oligoclonal Bands

Degradation of purified myelin basic protein (MBP) was studied by SDS gel electrophoresis after addition of CSF samples obtained from HIV-1-infected patients. An increase in MBP degradation was detected in patients with neurological complications, such as AIDS dementia complex (ADC) or progressive multifocal leukoencephalopathy (PML), when compared with patients with no neurological symptoms (NA) or with other neurological opportunistic infections (OI). In the ADC and PML patients, in addition to CSF proteolytic activity, an increase in CSF-MBP levels and presence of white matter lesions were also observed by neuroimaging (MRI). In other opportunistic infections of the brain, MBP levels but not anti-MBP proteolytic activity increased. Results suggest the involvement of proteases in the virus-induced demyelination.

Topics: Adult; AIDS Dementia Complex; AIDS-Related Opportunistic Infections; Cerebrospinal Fluid; Demyelinating Diseases; HIV Infections; HIV-1; Humans; Leukoencephalopathy, Progressive Multifocal; Myelin Basic Protein; Nervous System Diseases; Peptide Hydrolases

Some heavy metals have been suspected of playing a role in the pathogenesis of nervous system diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. In these disorders, autoantibodies against neural proteins are evident at some stage of the disease. Lead is known to affect both the immune and nervous systems. Work in our laboratory has shown that lead exposure leads to the production of autoantibodies against neural proteins, including myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP). We hypothesize that lead aggravates neurological disease by enhancing the immunogenicity of nervous system proteins, including MBP and GFAP. To test this hypothesis, lead-altered protein was prepared by incubating MBP or GFAP with lead acetate for 24 hr. On days 0, 14, and 28, mice received inoculations with either saline, native protein, or lead-altered protein. Anti-MBP and anti-GFAP, isotypes IgM and IgG, were measured in sera by ELISA on day 38. Sera of mice treated with lead-altered MBP had statistically higher anti-MBP IgG titers than both control and native MBP-immunized mice. An analogous response was seen in mice immunized with lead-altered GFAP. Supernatants from lectin-stimulated splenocytes were also examined for antibody titers and for interleukin 2 (IL-2) and interleukin 6 (IL-6) levels. A significant increase in IL-6 production was seen in mice immunized with lead-altered MBP but not with lead-altered GFAP. No changes were observed in the IL-2 levels of mice immunized with either lead-altered protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Autoantibodies; Culture Techniques; Enzyme-Linked Immunosorbent Assay; Female; Glial Fibrillary Acidic Protein; Immunoglobulin G; Immunoglobulin M; Interleukin-2; Interleukin-6; Lead; Mice; Mice, Inbred CBA; Myelin Basic Protein; Nervous System Diseases; Spleen

Monosymptomatic unilateral optic neuritis (ON) is a common first manifestation of multiple sclerosis (MS) in which increased numbers of autoimmune T and B cells, recognizing different myelin autoantigens including myelin basic protein (MBP) and its peptides, have been implicated in a hypothetical immunopathogenesis. Using an immunospot assay to detect specific antibodies secreted by individual cells, we analyzed the B-cell repertoire to MBP and its amino acid residues 1-20, 63-88, 110-128, and 148-165 in blood and CSF from patients with ON and MS, and from controls. There were cells secreting IgG antibodies to MBP and the four peptides in blood at mean numbers of 0.9 to 4.6 per 10(5) mononuclear cells, without differences between the three patient groups. Mostly, more than 100-fold more B cells with these specificites per 10(5) cells were found in CSF from the patients with ON and MS, without differences between these two groups but with many fewer in CSF from controls. None of the four included MBP peptides represented an immunodominant B-cell epitope in either ON or MS, and the B-cell response was not more restricted in ON than in MS. The autonomy of the autoimmune B-cell response in CSF was further supported by the pronounced asynchrony of the repertoire to the four MBP peptides in CSF compared with blood in individual patients. The large numbers of MBP- and MBP peptide-reactive B cells in CSF in early MS, as manifested by ON, could play a major role in the immunopathogenesis and perpetuation of MS. Alternatively, they could represent myelin breakdown or restoration.

Topics: Adult; Antibodies, Anti-Idiotypic; B-Lymphocytes; Female; Humans; Immunoglobulin A; Immunoglobulin M; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Optic Neuritis

A panel of autoantigens (myosin, actin, myelin basic protein MBP, and thyroglobulin) was used to analyze antigen recognition by the peripheral blood leukocytes (PBL) of patients with active and stable multiple sclerosis (MS), patients with other neurological diseases (OND) and healthy individuals. The immune responsiveness was studied by examining the in vitro cell proliferation and the increase in the expression of two T-cell-surface activation markers (the interleukin-2 receptor IL-2R, and a late activation antigen recognized by the 19.2 monoclonal antibody). In MS, autoantigen recognition occurred more frequently than in the other groups and it was manifested by moderate proliferation or marked elevation of the expression of the IL-2R, whereas autoantigen recognition in the other groups concerned essentially the expression of the late activation antigen. Results similar to those described above were obtained with enriched T lymphocytes either in the presence or absence of IL-2. Our results suggest that the peripheral immune system in MS patients may recognize and can be activated by different autoantigens and not only by MBP, and that this response is quantitatively and qualitatively different from that of PBL from OND patients and healthy individuals.

Topics: Actins; Adult; Animals; Autoantigens; Autoimmune Diseases; Biomarkers; Cattle; Cells, Cultured; Female; Humans; Lymphocyte Activation; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Myosins; Nervous System Diseases; Receptors, Interleukin-2; T-Lymphocytes; Thyroglobulin

Immune complexes from sera of MS patients, other neurological diseases, and healthy donors were precipitated using polyethyleneglycol and analyzed by sodium dodecylsulfate-polyacrylamide gel electrophoresis. Silver staining evidenced additional protein bands whose molecular weights were 14-16, 38, and 43 kDa. These IC proteins were present in most MS patients studied. To identify their nature, immunoblotting was performed with antihuman immunoglobulins A, M, G antibodies. No immunoreactivity was found below a molecular weight of 66 kDa on a nitrocellulose sheet having the transferred protein pattern of MS IC. Using purified human myelin, MS IC transferred to an immobilon sheet and antihuman myelin basic protein antibodies, an immunoreactivity was seen only on purified human MBP. The small proteins of 14-16 kDa and the others of 38, 43 kDa were not immunoreactive. Identification of the nature of these additional proteins in MS IC is in progress.

Topics: Antigen-Antibody Complex; Epitopes; Humans; Molecular Weight; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases

Recent evidence supports the possible involvement of myelin basic protein (BP) as one of the target autoantigens in multiple sclerosis (MS), including elevated frequencies of MS blood and cerebrospinal fluid (CSF) T cells, and the presence in MS plaque tissue of V beta gene sequences and CDR3 motifs characteristic of BP-reactive T cells. Because of its proximity to the target organ, the CSF has long been thought to harbor T cells involved in the pathogenic process. In order to evaluate their frequency and response characteristics, BP-reactive T cells were isolated by limiting dilution from the CSF of patients with MS and other neurological diseases (OND) for quantitation and determination of epitope specificity and V alpha and V beta gene expression. In addition to isolates responsive to intact BP epitopes that were present at a significantly higher frequency in MS versus OND CSF, we here describe a second clonotype responsive to 'cryptic' BP epitopes that is present at approximately equal frequencies in MS and OND patients. In spite of their difference in recognition of intact versus 'cryptic' BP determinants, both clonotypes predominantly recognized epitopes in the N terminal half of human BP, using a similar V gene repertoire that included biased use of V alpha 2 and to a lesser degree V beta 7 and V beta 18. These V gene biases were not related to the epitope specificity of the T cells, indicating that V gene selection is not epitope-driven. These data suggest that there is differential recognition of intact versus 'cryptic' BP determinants in MS versus OND patients that may be related to the processing and presentation of BP to the immune system.

Topics: Adult; Cerebrospinal Fluid; Epitopes; Female; Gene Expression; Humans; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Receptors, Antigen, T-Cell, alpha-beta; T-Lymphocytes

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

Antibodies against the nicotinic acetylcholine receptor (AChR) of the neuromuscular junction are detectable in most patients with myasthenia gravis (MG) and assumed to participate in the destruction of the AChR, thereby, causing the characteristics signs and symptoms of the disease. The extent and importance of T cell responses to AChR and its subunits in MG are still unsettled. We have now examined T cell reactivities using human recombinant AChR-alpha subunit as antigen. Upon recognition of appropriate antigen in an MHC-class II-restricted fashion, memory T cells secrete interferon-gamma (IFN-gamma). Adopting this principle in an immunospot assay we found that 73% of MG patients had recombinant human AChR-alpha subunit-reactive T cells at a median value of 1 per 56,000 blood mononuclear cells, while only 27% of the MG patients responded to the alpha subunit in a conventional lymphocyte proliferation assay. This compares with even lower numbers of AChR-reactive T cells and 14% positivity in the proliferation assay among control subjects. The T cell responses to the control antigens purified protein derivative and myelin basic protein did not differ between MG and controls, underlining the specificity of an augmented T cell reactivity to AChR-alpha subunit in MG. Alpha Subunit-specific T cell lines and clones propagated from patients with MG and healthy controls yielded a high proportion of alpha subunit-reactive T cells in the IFN-gamma immunospot assay. Their appearance was inhibited by the addition of monoclonal anti-MHC class II antibodies, demonstrating that an MHC-restricted T cell response was measured. Our data underline that the AChR-alpha subunit is a major T cell autoantigen in MG.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibody Specificity; Cell Division; Female; Humans; Immunity, Cellular; Interferon-gamma; Male; Middle Aged; Myasthenia Gravis; Myelin Basic Protein; Nervous System Diseases; Phytohemagglutinins; Receptors, Cholinergic; Recombinant Proteins; T-Lymphocytes; Tuberculin

An autoimmune response to myelin basic protein (MBP) has been proposed to participate in the development of the chronic neurologic manifestations that may accompany Borrelia burgdorferi-induced Lyme disease. Using an immunospot assay, we counted cells secreting antibodies to MBP. Anti-MBP IgG antibody-secreting cells were detected in CSF from eight of 13 consecutive patients with Lyme neuroborreliosis irrespective of stage of disease. The numbers were between 1/370 and 1/5,000 CSF cells (mean, 1/1,250 in the 13 patients). The highest numbers were encountered in two patients with severe signs of CNS involvement. The numbers decreased in parallel with clinical improvement after treatment. Anti-MBP IgG antibody-secreting cells were also observed in the CSF from patients with a variety of other inflammatory diseases of the nervous system, and their role in the development of tissue damage remains unsettled. Anti-MBP IgG antibody-secreting cells were not detected in the patients' blood, reflecting accumulation of this autoantibody response to CSF.

Topics: Adult; Aged; Antibody-Producing Cells; Humans; Immunoglobulin G; Lyme Disease; Middle Aged; Myelin Basic Protein; Nervous System Diseases

Anti-myelin antibodies can be found in sera from patients with neurologic disorders of suspected immune-mediated pathogenesis such as multiple sclerosis and inflammatory polyneuropathies. However, the specificity of these findings is controversial. In the present study, in vitro synthesis of antibodies to myelin components was compared to their presence in sera in diverse neurological disorders. Epstein-Barr virus was used to activate B lymphocytes for in vitro antibody production. Anti-myelin basic protein and anti-galactocerebroside antibodies were secreted in vitro by B lymphocytes derived from patients with neurological disorders of various etiologies and pathogenetic mechanisms. Anti-myelin basic protein antibodies were detected in many more cell culture supernatants than in sera from the same patients. In vitro secretion of antibodies to myelin antigens, as well as the presence of these antibodies in body fluids, are apparently non-specific for disease type and may be secondary to neural tissue damage.

Topics: Aged; Aged, 80 and over; Antibody Formation; Antigens, Viral; B-Lymphocytes; Branchial Region; Facial Paralysis; Female; Galactosylceramides; Herpesvirus 4, Human; Humans; Lymphocyte Activation; Male; Myasthenia Gravis; Myelin Basic Protein; Myelin Sheath; Nervous System Diseases; Neuritis; Radioimmunoassay

Development of neurologic complications after Semple rabies vaccine is closely linked to development of antibody to myelin basic protein (MBP). The portions of MBP against which the antibodies are directed were analyzed by enzyme immunoassay in sera and cerebrospinal fluid from 27 patients with vaccine complications. Most of the antibody was directed to regions of MBP peptides 45-89 and 90-170. There was no apparent correlation between antibody specificity for MBP peptides 1-44, 45-89 and 90-170 and the type of post-vaccinal neurologic complication. We conclude that the immunoglobulin repertoire in human B lymphocytes for responding to human MBP favors the portion of the MBP molecule containing residues 45-170.

Topics: Antibodies; Encephalomyelitis; Humans; Immunoenzyme Techniques; Myelin Basic Protein; Nervous System Diseases; Neuropeptides; Rabies Vaccines

Inclusion of 1.1% tellurium in the diet of developing rats causes a highly synchronous primary demyelination of peripheral nerves, which is followed closely by a period of rapid remyelination. The demyelination is related to the inhibition of squalene epoxidase activity, which results in a block in cholesterol synthesis and accumulation of squalene. We now report that the demyelination resulting from this limiting of the supply of an intrinsic component of myelin (cholesterol) leads to repression of the expression of mRNA for myelin-specific proteins. Tellurium exposure resulted in an increase in total RNA (largely rRNA) in sciatic nerve, which could not be accounted for by cellular proliferation; these increased levels of rRNA may be a reactive response of Schwann cells to toxic insult and may relate to the higher levels of protein synthesis required during remyelination. In contrast, steady-state levels of mRNA, determined by Northern blot analysis, for P0 and myelin basic protein were markedly decreased (levels after 5 days of tellurium exposure were only 10-15% of control levels as a fraction of total RNA and 25-35% of control levels when the increased levels of total RNA were taken into account). Message levels increased during the subsequent period of remyelination and reached near-normal levels 30 days after beginning tellurium exposure. Although message levels for the myelin-associated glycoprotein showed a similar temporal pattern, levels did not decrease as greatly and subsequently increased sooner than did levels for P0 and myelin basic protein. The coordinate alterations in message levels for myelin proteins indicate that Schwann cells can down-regulate and then up-regulate the synthesis of myelin in response to alterations in the supply of membrane components.

Topics: Animals; Blotting, Northern; Diet; Gene Expression Regulation; Male; Models, Biological; Myelin Basic Protein; Myelin Proteins; Myelin Sheath; Nervous System Diseases; Rats; RNA, Messenger; Schwann Cells; Sciatic Nerve; Tellurium

Cerebrospinal fluid (CSF) and sera from 17 patients with primary Sjögren's syndrome (PSS) with or without clinical evidence of nervous system involvement were studied. Intrathecal IgG synthesis as measured by oligoclonal IgG bands on agarose isoelectric focusing or elevated IgG index in CSF was found in 6 of 8 patients with clinical nervous system involvement but also in 5 of 9 patients without clinical nervous system involvement. Elevated IgM-index in CSF was found in 7 of 8 patients with clinical nervous system involvement and in 6 of 9 patients without clinical nervous system involvement. By immunoblotting, CSF IgG-antibodies against myelin basic protein (MBP) were found in 3 of 12 patients with multiple sclerosis (MS), but in none of the patients with PSS or in the 12 controls. Intrathecal anti-viral IgG-antibodies, as measured by immunoblotting against measles, mumps, varicella or herpes simplex, were found in 8 of 17 patients with PSS, and in 7 of 12 patients with MS, but were not detected in the controls. Our observations support the concept that the central nervous system (CNS) is included in the multiple immunological phenomena of PSS. Interestingly, in some PSS patients intrathecal IgG synthesis occurred without overt clinical nervous system involvement and thus the clinical significance of intrathecal IgG synthesis in PSS is uncertain. The similarities with MS regarding intrathecal antiviral antibody production may be interpreted as the result of polyclonal B-cell activation.

Topics: Adult; Aged; Antibodies, Viral; Autoantibodies; Autoimmune Diseases; Headache; Humans; Immunoglobulin G; Immunoglobulin M; Lymphocyte Activation; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Sjogren's Syndrome

High dose methylprednisolone (50 mg kg-1, daily) was administered to Lewis rats with experimental allergic neuritis from onset of the disease. Disease severity was reduced and recovery was significantly more rapid than that in saline-injected controls. Histological examination showed reduction of endoneurial edema, cellular infiltration, and demyelination. The results provide experimental evidence supporting the trial of high dose steroids in human demyelinating polyradiculoneuropathy.

Topics: Animals; Antibodies; Ganglia, Spinal; Immunization; Male; Methylprednisolone; Myelin Basic Protein; Myelin P2 Protein; Nervous System; Nervous System Diseases; Neuritis, Autoimmune, Experimental; Rats; Rats, Inbred Lew

Peripheral blood T lymphocytes from patients with multiple sclerosis (MS) and other neurological diseases (OND) were tested for primary in vitro proliferation in response to four synthetic peptides derived from the sequence of human myelin basic protein (HuMBP) and to HuMBP 45-89 peptide fragment, using a [3H]thymidine incorporation assay. The synthetic peptides used corresponded to residues HuMBP 15-31, 75-96, 83-96 and 131-141 of human myelin basic protein. Significant proliferation of T lymphocytes to peptides was noted only in the MS group (with the exception of peptide 131-141): the majority of control subjects and OND patients did not respond to the above-mentioned peptides. The sensitized T lymphocytes in MS patients displayed the inducer/helper phenotype and required autologous monocytes for optimal proliferation. An anti-HLA-DR monoclonal antibody, directed against a monomorphic determinant of DR molecules, was able to block the responses in a dose-dependent fashion. These results suggest that autoimmune inducer/helper T lymphocytes in the peripheral blood of MS patients may initiate and/or regulate the demyelination process in patients with MS. Furthermore, our data demonstrate that monocytes and HLA-DR molecules are essential for activation of these cells. Finally primary in vitro T cell proliferation to HuMBP synthetic peptide may be used as an additional diagnostic test in MS.

Topics: Female; HLA-DR Antigens; Humans; Lymphocyte Activation; Male; Monocytes; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Peptide Fragments; Reference Values; T-Lymphocytes

Topics: Adolescent; Adult; Female; Humans; Male; Methotrexate; Middle Aged; Myelin Basic Protein; Nervous System Diseases; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Fifteen HIV seropositive patients were studied. It was possible to enhance detection of HIV antigen and HIV and myelin basic protein (MBP) antibodies after dissociation of immune complexes by acid hydrolysis. HIV p24 antigen was then detected in four patients, three of whom were previously antigen negative. In 14 patients the treatment resulted in increased anti-HIV IgG subclass levels. Anti-MBP IgG was detected in 12 patients. Intrathecal synthesis of anti-MBP IgG subclasses was found in eight patients, five of whom had symptoms from the central nervous system.

Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Antigen-Antibody Complex; Blood-Brain Barrier; Enzyme-Linked Immunosorbent Assay; HIV Antibodies; HIV Antigens; HIV Core Protein p24; HIV Seropositivity; Humans; Immunoglobulin G; Middle Aged; Myelin Basic Protein; Nervous System Diseases; Retroviridae Proteins

In animals, the selection in vitro of T cell lines to myelin basic protein (MBP) can define immunodominant and encephalitogenic epitopes which are preferentially associated with class II major histocompatibility (MHC) molecules. These principles were used to evaluate the specificity and MHC restriction of 14 human MBP-reactive T cell lines selected from normal individuals and patients with multiple sclerosis (MS) and other neurological diseases (OND). The four normal T cell lines recognized single, separate immunodominant MBP epitopes which were restricted by MHC molecules from the DR or in one case the DP class II locus. In contrast, the MS and OND T cell lines recognized multiple MBP epitopes, each in association with a discrete class II MHC molecule from the DR or DQ locus. Overall, HLA-DR molecules were used preferentially to associate with epitopes on human MBP, restricting 26/33 responses. As predicted from animal studies, T cells from genetically disparate individuals responded to different immunodominant epitopes on human MBP in association with distinct MHC class II molecules. HLA-DR2, which is overrepresented in MS patients, possessed an unusual capacity to restrict all eight epitopes identified on MBP in this study. These data provide the first evidence of genetically restricted human T cell recognition of potentially encephalitogenic epitopes of MBP.

Topics: Adult; Cell Line; Epitopes; Female; Histocompatibility Antigens Class II; Humans; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; T-Lymphocytes

Cerebrospinal fluid myelin basic protein and cerebrospinal fluid and peripheral blood T-cell subsets have been studied in patients with multiple sclerosis and other inflammatory and non-inflammatory nervous system diseases. These biological parameters have been correlated with clinical disease activity. No changes in peripheral blood T-cell subsets were seen in multiple sclerosis patients. Low cerebrospinal fluid T8+ cells occurred only in multiple sclerosis, while high cerebrospinal fluid T4+ cells were detected both in clinically active multiple sclerosis and in inflammatory nervous system diseases. A close relationship was found between cerebrospinal fluid T4/T8 ratio and myelin basic protein in relapsing multiple sclerosis patients.

Topics: Adolescent; Adult; CD4-Positive T-Lymphocytes; Cerebrospinal Fluid; Child; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; T-Lymphocytes; T-Lymphocytes, Regulatory

Protein methyltransferases, rich in most mammalian brains, were studied in human cerebrospinal fluid (CSF). Among several well-characterized groups of methyltransferases, protein methylase I (S-adenosylmethionine:protein-arginine N-methyltransferase, EC 2.1.1.23) was found in significant amounts in human CSF samples. Both myelin basic protein (MBP) -specific and histone-specific protein methylase I activities were observed, the latter being generally higher in most CSF. S-Adenosyl-L-homocysteine, a potent product inhibitor for the methyltransferase, inhibited approximately 90% of MBP-specific protein methylase I activity at a concentration of 1 mM. The optimum pH of the MBP-specific protein methylase I was found to be around 7.2. Identity of exogenously added MBP as the methylated substrate for CSF enzyme was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. An amino acid analysis of the [methyl-3H]protein hydrolysate showed two major radioactive peaks cochromatographing with monomethyl- and dimethyl (symmetric)-arginine. Human CSF contained relatively high endogenous protein methylase I activity (activity measured without added substrate protein): The endogenous substrate can be immunoprecipitated by antibody raised against calf brain MBP. Finally, CSF from several neurological patients were analyzed for protein methylase I, and the results are presented.

Topics: Humans; Methylation; Molecular Weight; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Protein Methyltransferases; Reference Values; S-Adenosylhomocysteine; Substrate Specificity

To measure myelin basic protein (MBP)-like material in cerebrospinal fluid, we compared two radioimmunoassays, both using the same antiserum to MBP but one using peptide (45-89) as the radioligand and standard (peptide assay), and the other using purified MBP as the radioligand and standard (MBP assay), with respect to their diagnostic sensitivity. Cerebrospinal fluid specimens from 185 patients with definite multiple sclerosis (MS) (n = 27), possible MS (n = 63), probable MS (n = 24), and other neurological disease (n = 71) were analyzed using both assays. The diagnostic sensitivity of the peptide assay was significantly better than that of the MBP assay in those with definite MS (sensitivity 59% and 30%, respectively); there was no significant difference in specificity. The peptide assay also showed better correlation with disease activity than the MBP assay: 14 patients classified as having active MS showed significantly higher sensitivity (78.6% versus 38%, p less than 0.04) when compared to patients with inactive disease. The MBP assay showed no significant difference between these two groups. Besides the increase in sensitivity, the actual molar concentrations of immunoreactive MBP detected using this peptide assay were considerably higher than those found using the MBP assay. These results show that the use of MBP antisera capable of recognizing epitopes present in the carboxyl half of MBP peptide (45-89) results in more sensitive detection of immunoreactive MBP when used with MBP peptide (45-89) as radiolabeled ligand in the assay.

Topics: Humans; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Peptide Fragments; Radioimmunoassay

The characteristics and heterogeneity of the myelin basic protein (MBP)-like material appearing in cerebrospinal fluid (CSF) after acute central nervous system (CNS) myelin injury are unresolved. Antigenic material containing an epitope in the carboxyl-terminal portion of human MBP peptide 45-89 (from the intact molecule of 170 residues) is a prominent species of the MBP-like material present. In an effort to define further the MBP-like material in CSF and to enhance its detection, a modified double-antibody radioimmunoassay has been developed using a radioligand of human MBP synthetic peptide 69-89. This assay is more sensitive with results paralleling those of previously used MBP assays for CNS myelin damage. Results with this assay provide additional confirmation of the presence of an epitope of MBP in the decapeptide of MBP 80-89 but in a conformation simulating that of intact MBP in CSF after CNS myelin injury. Unexpected buffer effects were noted to influence the immunochemical behavior of some of the small peptides of MBP.

Topics: Binding, Competitive; Buffers; Epitopes; Humans; Myelin Basic Protein; Nervous System Diseases; Oligopeptides; Peptides; Radioimmunoassay; Structure-Activity Relationship

Topics: Antibody-Producing Cells; B-Lymphocytes; Cerebrospinal Fluid; Humans; Immunoglobulin G; Measles virus; Multiple Sclerosis; Myelin Basic Protein; Myelin Sheath; Nervous System Diseases

The immunomodulatory effects of cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS) and other neurologic diseases (OND) were determined by measuring their abilities to suppress alloantigen-specific and nonspecific (IL-2 mediated) proliferative responses. An alloantigen primed, IL-2-dependent line of human T-cells (PLT) was used as indicator. CSF from both patient groups significantly suppressed alloantigen-specific and nonspecific PLT proliferative response. However, patterns of suppression differed between the two groups. While alloantigen-specific proliferative responses were suppressed similarly by MS and controls, CSF from MS patients had significantly less suppressing effect on nonspecific lymphocyte proliferation than did control CSF. The degree of suppression of alloantigen-stimulated proliferation by MS CSF correlated with the concentrations of gamma-globulin and myelin basic protein as well as with the Ig index. Suppression of alloantigen-stimulated proliferation by control CSF correlated only with the concentration of alpha 1-globulin. Sera from 3 MS patients and 7 OND patients were also tested in our system. Only MS sera significantly suppressed the alloantigen stimulated proliferative responses of the PLT. Neither serum group affected nonspecific (IL-2 mediated) proliferation. Our data suggest that there are immunomodulatory factors present in both MS and control CSF, but MS CSF may be relatively lacking in a factor controlling nonspecific lymphocyte proliferation. Deficiency of this factor(s) may contribute to the increased numbers of activated lymphocytes in MS CSF.

Topics: Adjuvants, Immunologic; Adult; Cerebrospinal Fluid Proteins; Humans; Interleukin-2; Lymphocyte Activation; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; T-Lymphocytes

Migration properties and occurrence of antibodies against myelin basic protein (MBP) in paired CSF and serum specimens from patients with multiple sclerosis (MS) were demonstrated after agarose isoelectric focusing, immunoblot transfer, and immunoperoxidase staining. Oligoclonal IgG antibody bands directed against MBP were found in the CSF of 9 of 28 patients with MS (32%), but not in the CSF of any of 34 patients with other neurologic diseases. No serum showed anti-MBP antibody bands. The CSF anti-MBP antibodies migrated to the anodal region of the IgG area in a different fashion from oligoclonal IgG and anti-measles IgG antibodies, which were detected in parallel. The anti-MBP bands were transient in three of seven patients whom we studied consecutively. Enzyme-linked immunosorbent assay (ELISA) of serum and CSF for detection of IgG reactivity against MBP showed absorbance values above 2 standard deviations of controls in 44% of the MS patients and in 21% of those with other neurologic diseases. Results of this assay correlated partly with those of the immunoblot assay. ELISA positive and immunoblot negative results might be due to a broad polyclonal anti-MBP antibody response.

Topics: Adult; Antibodies; Electrophoresis, Agar Gel; Female; Humans; Immunoglobulin G; Immunologic Techniques; Isoelectric Focusing; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases

A polyclonal antiserum has been produced that can detect nanogram amounts of myelin basic protein (MBP)-like material in unconcentrated human urine. The urinary immunoreactive material is cross-reactive with human MBP peptides 45-89 and 69-89, dialyzable, heat resistant, and is not artifact of either degradation of radioligand or salt effect. An octapeptide, MBP peptide 82-89, was demonstrated to be the smallest peptide containing the main epitope against which this antiserum was directed. This epitope differed from the major epitope recognized by antisera detecting MBP-like material in cerebrospinal fluid, implying that the MBP-like material is altered, presumably degraded, in the kidney. Results of gel filtration and high-performance liquid chromatography suggested a size of 1,000 daltons or less and a charge similar to that of human MBP peptide 80-89. In a group of 39 persons with multiple sclerosis, 48 with other neurological diseases, and 26 normal control subjects, the concentration of urinary MBP-like material, related to the concentration of urinary creatinine, was significantly higher in the multiple sclerosis group (22.0 ng MBP-like material/mg creatinine) than in the other neurological diseases or control groups, in which the values were 7.0 and 3.9 ng MBP-like material/mg creatinine, respectively. Variations in the level of MBP-like material appearing in the urine may provide a clinically feasible test for myelin damage. The precise identification of the chemical nature of the urinary MBP-like material may also furnish a means for further analyzing the in vivo catabolism of the potentially autoantigenic MBP.

Topics: Antibody Specificity; Humans; Molecular Weight; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Peptide Fragments; Radioimmunoassay

The levels of myelin basic protein (MBP) in the cerebrospinal fluid (CSF) have been evaluated as a method of detecting central nervous system (CNS) demyelination. MBP levels were measured in the CSF of 129 patients with neurological illnesses of whom 26 had a demyelinating illness. High levels of MBP were found in 81% of patients with recent episodes of demyelination but were not seen in patients with multiple sclerosis that was clinically stable or in remission. Patients with CNS trauma also had high levels of MBP in their CSF. The detection of a high level of MBP in CSF may be useful in the diagnosis of acute CNS demyelination but the finding is not specific for multiple sclerosis.

Topics: Demyelinating Diseases; Diagnosis, Differential; Humans; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases

We describe a method which uses protein blots of whole animal sections to map the distribution of exogenous and endogenous antigens to specific nuclei and tracts within the nervous system (NS). We propose this method as a new approach to analysis of the expression of NS gene products during development and to charting the course and molecular pathogenesis of infectious and immune disorders of the NS.

Topics: Animals; Antigens; Antigens, Viral; Guinea Pigs; Immune Sera; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Mammalian orthoreovirus 3; Mice; Mice, Inbred BALB C; Myelin Basic Protein; Nervous System; Nervous System Diseases; Reoviridae Infections

The nervous system specific proteins glial fibrillary acidic protein (GFAp), S-100 and myelin basic protein (MBP) were determined in 535 human cerebrospinal fluid (CSF) samples. The level of all three proteins was increased in CSF of patients with nonselective destructive central nervous tissue disease such as encephalitis, cerebrovascular disease or tumoural compression. The increases in GFAp were more constant, making it a better marker of CNS pathology. Increases in MBP in CSF of patients with acute demyelinating disease were confirmed. S-100 did not seem to give more information as GFAp. Isolated increases of GFAp could be demonstrated in patients with dementia (Alzheimer type or multi-infarct dementia) or syringomyelia. Since CNS of these patients is very rich in fibrillary astrocytes, containing large amounts of GFAp, it is suggested that GFAp is to be considered as a specific marker of fibrillary gliosis in CSF and can be used as a diagnostic tool in dementia and syringomyelia.

Topics: Cerebrovascular Disorders; Dementia; Glial Fibrillary Acidic Protein; Humans; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Nervous System Neoplasms; Polyradiculoneuropathy; S100 Proteins; Syringomyelia

Platelet aggregation (PA) stimulated by encephalitogenic peptide (EP) and PA induced by ADP were measured in 83 multiple sclerosis (MS) patients and 70 control subjects with other neurological diseases (OND). EP-stimulated PA was significantly increased in MS patients as compared with the controls. There was no significant difference in ADP-induced PA between patients with MS and OND. The results are discussed in terms of EP-stimulated platelets playing a role in the pathogenesis of MS by affecting the venular permeability of the brain.

Topics: Adenosine Diphosphate; Adolescent; Adult; Aged; Capillary Permeability; Demyelinating Diseases; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Platelet Aggregation; Polyradiculopathy

Prevalence and titer of total, free, and bound cerebrospinal fluid anti-myelin basic protein (MBP) antibodies as well as free/bound ratios were determined in four groups of patients with multiple sclerosis (MS) and three groups of controls. All patients with clinically active MS have elevated levels of total anti-MBP, which may be present in either free or bound form. Patients whose disease is in remission have undetectable anti-MBP levels, and some patients with clinically stable disease with residual disability may have detectable antibody titers. Chronically progressive MS is usually associated with high levels of antibody in the bound rather than the free form, resulting in a low or normal free/bound ratio. In contrast, MS exacerbations are characterized by relatively high levels of free anti-MBP in the cerebrospinal fluid, resulting in a high free/bound antibody ratio. Bound anti-MBP was also detected in elevated levels in 1 patient with subacute sclerosing panencephalitis and 2 of 8 patients with postinfectious encephalomyelitis. Although elevated levels of cerebrospinal fluid anti-MBP are not specific for MS, they are strongly associated with disease activity and may be involved in the pathogenesis of demyelination in patients with MS.

Topics: Autoantibodies; Central Nervous System; Humans; Immunoglobulin G; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Neurotic Disorders

Cell-mediated and humoral immunity to purified nerve proteins has been assessed in GBS patients and compared with that of patients with other neurological diseases and healthy controls. A strong and specific cell-mediated response to the neuritogenic basic protein P2 occurred in 13/16 GBS patients tested. Extremely low levels of P2 (0.01 micrograms/culture) induced monocyte/macrophage procoagulant activity (MPCA) on peripheral blood mononuclear cells (PBM) from GBS patients (P = 0.007) whereas higher concentrations (2 micrograms/culture) of myelin basic protein (MBP) and sciatic nerve myelin (SNM) were required to stimulate similar levels of activity. These concentrations of nerve antigens failed to induce significant MPCA on peripheral blood mononuclear cells of patients with other neuropathies or healthy controls. Lipopolysaccharide, a non-specific stimulant of macrophage procoagulant activity, induced similar procoagulant levels on PBM from each group. The MPCA assay was a sensitive, quantitative and specific indicator of cell-mediated immunity to the neuritogenic peptide, P2 in GBS patients. Serum antibodies to P2, P0 and SNM were detected by a sensitive solid-phase radioimmunoassay. Naturally occurring antibodies to peripheral nerve antigens were observed in sera of healthy subjects and these levels were not significantly different from patients with GBS or those with other neuropathies. Our results indicate that the autoimmune cell-mediated response to the neuritogenic peptide P2 plays a major role in the pathogenesis of GBS.

Topics: Adolescent; Adult; Aged; Antigens; Blood Coagulation Factors; Female; Humans; Immunity, Cellular; Macrophages; Male; Middle Aged; Monocytes; Myelin Basic Protein; Myelin P2 Protein; Myelin Sheath; Nervous System Diseases; Peripheral Nerves; Polyradiculoneuropathy; Sciatic Nerve

A double antibody sequential radioimmunoassay for human myelin basic protein (MBP) has been developed. The assay utilizes a rabbit antibody to human MBP and purified rabbit MBP as the radiolabelled antigen. This assay was used to analyze cerebrospinal fluid (CSF) from 22 patients with severe head injury, 61 other cases of various neurological disorders, and 106 normal controls. The results showed that closed head trauma caused moderate to severe elevations in CSF MBP, and elevated CSF MBP was detectable in several diseases which involve CNS myelin.

Topics: Craniocerebral Trauma; Humans; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Radioimmunoassay

Topics: Female; Humans; Lymphoma; Methotrexate; Middle Aged; Myelin Basic Protein; Nervous System Diseases

Myelin-deficient (mld) mutant mice were treated with phenobarbital between 60 and 90 d of age. The survival rate at 90 d increased from 1.4% in untreated mutants to 46% in those who received phenobarbital. This is evidence that apneic spells during tonic seizures are a major cause of death in mld mice. Myelin basic protein (MBP) content of brain homogenates from treated mld mice increased significantly between 30 and 90 d. MBP was present in myelin purified from the 90-d-old treated mld mice. These results demonstrate that the MBP increase, which occurs after the active phase of myelin formation is completed, is a general phenomenon and is not caused by the selection of a small and mildly affected subpopulation of mutants.

Topics: Animals; Brain Chemistry; Mice; Mice, Neurologic Mutants; Myelin Basic Protein; Myelin Sheath; Nervous System Diseases; Phenobarbital

Topics: Antigen-Antibody Reactions; Antigens; Antigens, Viral; Brain; Humans; Leukocyte Adherence Inhibition Test; Measles virus; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases

Patients admitted to the neurosurgical wards for the management of nervous system tumours, subarachnoid and intracerebral haemorrhage, head injury, spinal and peripheral nerve lesions, and other miscellaneous neurosurgical conditions, were studied by assay of serum immunoreactivity for myelin basic protein. Of 171 patients, 70% proved to have elevated myelin basic protein activity. In cerebral cases the extent of brain damage assessed by clinical methods appeared to correlate with the appearance of elevated serum myelin basic protein. In spinal and peripheral nerve cases no similar elevation of myelin basic protein was observed.

Topics: Adolescent; Adult; Brain Diseases; Brain Neoplasms; Child; Child, Preschool; Female; Humans; Infant; Male; Middle Aged; Myelin Basic Protein; Nervous System Diseases; Peripheral Nervous System Diseases; Postoperative Complications; Prognosis; Radioimmunoassay; Spinal Cord Diseases

Normal human kidney contains a neutral endopeptidase that can degrade human myelin basic protein peptide 43-88. In the present study, renal homogenates prepared from postmortem tissue obtained from four persons with multiple sclerosis, two with amyotrophic lateral sclerosis, one each with olivopontocerebellar atrophy, subacute sclerosing panencephalitis, and Guillain-Barré syndrome, and four controls were analyzed for the enzymes present that degrade human myelin BP peptide 43-88. There was no evidence that the activity in renal tissue for degrading human BP peptide 43-88 is qualitatively different in persons with MS, other neurologic diseases, or controls. Gel filtration of digested peptide demonstrated the action of an endopeptidase capable of hydrolyzing BP peptide 43-88 into large fragments.

Topics: Adolescent; Adult; Aged; Amyotrophic Lateral Sclerosis; Cerebellar Diseases; Endopeptidases; Female; Humans; Kidney; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Peptide Fragments; Polyradiculoneuropathy; Subacute Sclerosing Panencephalitis

A solid phase radioimmunoassay (RIA) was used to detect antibodies to myelin or myelin basic protein (MBP) in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) or other neurological diseases (OND). When measured at the same IgG concentration, MS samples had higher binding values than OND against myelin, but not against MBP. Using F(ab')2 fragments purified from pools of MS and OND CSF there was no difference in binding to myelin between MS and OND samples. These results indicate that anti-MBP antibodies are nt a feature of MS and binding of CSF IgG to myelin is not due to specific antibody, but is probably the result of non-specific binding to Fc receptors.

Topics: Humans; Immunoglobulin Fab Fragments; Immunoglobulin G; Multiple Sclerosis; Myelin Basic Protein; Myelin Sheath; Nervous System Diseases; Radioimmunoassay

Topics: Epitopes; Humans; Multiple Myeloma; Myelin Basic Protein; Nervous System Diseases

Peripheral blood lymphocytes from patients with multiple sclerosis (MS) or other neurological diseases and from healthy individuals were separated by density gradient sedimentation into several subfractions. Individual cell populations were cultured in the presence of several human brain tissue antigens. In comparison to controls, mononuclear cells with a density of less than 1.077 gm/cm3 from MS patients displayed a significantly increased sensitivity after incubation with purified human myelin basic protein (MBP) but not with other brain tissue antigens. In particular, the lymphocytes of patients suffering from MS for more than four years reacted positively with MBP, suggesting that the reaction dependent. No difference between MS patients and controls in sensitivity to any brain tissue antigen could be detected with cells of lower density (i.e., 1.073 to 1.069 gm/cm3 or less than 1.069 gm/cm3). Comparable lymphocyte activity was found to antigens isolated from both MS and control brain tissue. These results suggest that patients with chromic progressive MS have a secondary immune activity to MBP.

Topics: Adult; Aged; Antigens; Autoantigens; Brain; Humans; Immunity, Cellular; Lymphocyte Activation; Lymphocytes; Middle Aged; Myelin Basic Protein; Nervous System Diseases

Cerebrospinal fluid (CSF) and peripheral blood (PB) lymphocyte sensitization to rabbit myelin basic protein (MBP) in 44 multiple sclerosis (MS) patients, 21 patients with other neurological diseases (OND) and 14 persons with neurosis was studied with the antigen-active rosette forming cells (Ag-ARFC) assay. The frequency of sensitization of CSF lymphocytes to MBP in groups of MS patients in the relapse stage and the chronic progressive stage was higher than in the group of MS patients in the stable stage and the OND patients. None of the healthy subjects showed a positive reaction with MBP. In BP there were no differences in the incidence of sensitization to MBP between patients in various stages of the disease, but it was higher than in the group of patients with OND and neuroses. In the patients who had suffered from MS for less than 4 years, sensitization to MBP was more common in CSF lymphocytes than in BP lymphocytes. The results suggest that primary sensitization to MBP occurs in CSF, and is probably secondary to myelin damage. However at present it is difficult to determine the extent to which sensitization of CSF and PB lymphocytes to MBP play a role in further demyelination processes.

Topics: Adolescent; Adult; Aged; Follow-Up Studies; Humans; Lymphocytes; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Psychotic Disorders

Topics: Adolescent; Adult; Aged; Antibodies; Child; Child, Preschool; Female; Humans; Male; Middle Aged; Myelin Basic Protein; Nervous System Diseases; Rabies Vaccines

Cerebrospinal fluid (CSF) from 105 patients was analyzed by radioimmunoassay for the presence of material cross-reactive with peptide 89-169 of bovine myelin basic protein (BP). In a group of 72 multiple sclerosis patients, 52 showed higher BP content than the control group, i.e. more than 2 ng/ml CSF. Increased BP or BP fragments could be detected in CSF from almost all patients who recently (within 2 weeks) had had an acute episode, or after deterioration in the progressive form of the disease. Fifteen to 30 days after the onset of exacerbation or in a stable period, BP content decreases and in the slowly progressive form was in the range of the control group with one exception. BP content was also elevated in the CSF of patients with other neurological diseases. The presence of BP in the CSF from patients with isolated retrobulbar neuritis is of particular interest. Thus the presence of material cross-reactive with BP fragment 89-169 is not specific for multiple sclerosis, but is a useful parameter in diagnosis and evaluation of MS.

Topics: Cerebrovascular Disorders; Humans; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Neurosyphilis; Optic Neuritis; Polyradiculoneuropathy; Radioimmunoassay

A solid phase radioimmunoassay is described which employs 125I-protein-A to detect the presence of antibodies against a panel of cellular and soluble central nervous system (CNS) specific antigens coated onto polyvinylchloride Microtiter plates. Serum antibodies from rabbits immunized against myelin, myelin basic protein (MBP), glial acidic fibrillary protein (GFAP), astroglioma cells, and cerebellar cells were easily detected, and high specificity for each antiserum and antigen was also demonstrable. The assay is applicable to cerebrospinal fluid (CSF) from patients with neurological diseases to detect antibodies against CNS-specific antigens. The assay should be useful for examining cell lines derived from CNS tissue for the presence of brain proteins.

Topics: Adolescent; Adult; Aged; Animals; Antigens; Astrocytes; Autoantibodies; Cattle; Central Nervous System; Cerebellum; Child, Preschool; Female; Glial Fibrillary Acidic Protein; Humans; Infant; Male; Mice; Middle Aged; Myelin Basic Protein; Myelin Sheath; Nerve Tissue Proteins; Nervous System Diseases; Rabbits; Radioimmunoassay; Rats

Cerebrospinal fluid from 582 persons was analyzed by a double-antibody radioimmunoassay for the presence of material cross-reactive with peptide 43-88 of human myelin basic protein (BP). In a group of 104 patients with multiple sclerosis (MS), 23 of 33 individuals clinically judged to have had an exacereation within two weeks prior to the time CSF was obtained had detectable material ranging from 2 to 200 ng/ml. In the remaining 71 MS patients who either were stable or had had an exacerbation more than two weeks before, only 1 patient had a marginally elevated level of immunoreactive material. CSF from 53 persons with cerebrovascular disease was studied, and 13 of 29 with recent infarctions had values of 2 to 540 ng/ml. The degree of elevation in strokes generally paralleled the predicted volume of the lesion, but the amounts detected did not correlate quite so closely temporally with onset as they did with the periods of active disease in MS. Of the remaining 425 patients, 29 had immunoreactive material of 2 to 400 ng/ml in their CSF. Most of these patients with detectable material had acute diseases known to affect the myelin sheath. Eight of 10 persons with acute disseminated encephalomyelitis had no detectable material. The presence in CSF of material cross-reactive with BP peptide 43-88 does not have diagnostic specificity for MS but can be used as a means for determining recent myelin injury. The type of BP peptide formed and mechanisms for clearance of BP and BP peptides may be important in determining the biological consequences following release of this potentially immunogenic material from the central nervous system.

Topics: Antigen-Antibody Reactions; Central Nervous System Diseases; Demyelinating Diseases; Humans; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Radioimmunoassay

Topics: Animals; Cattle; Cerebrovascular Disorders; Humans; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Radioimmunoassay; Spinal Cord Diseases

Topics: Brain Neoplasms; Humans; Immunity, Cellular; Immunization; Lymphocytes; Lymphokines; Meningoencephalitis; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases

Topics: Animals; Antigen-Antibody Reactions; Autoimmune Diseases; B-Lymphocytes; Encephalomyelitis, Autoimmune, Experimental; Freund's Adjuvant; Guinea Pigs; Humans; Models, Biological; Myelin Basic Protein; Nervous System Diseases; Rats; T-Lymphocytes; Thyroiditis

Circulating lymphocyte populations were examined in 85 patients with multiple sclerosis (MS), 26 of whom showed exacerbations; 48 patients with other neurological diseases (OND); 14 patients suffering from psychiatric disorders; and 2 normal subjects. The study involved the assay of early (active, high-affinity rosetting) T-cells, myelin basic protein (MBP)-reactive early T-cells, late (total, 24-hour rosetting) T-cell levels were significantly lower in MS (p less than 0.01) than in OND subjects. Exacerbations in MS were usually accompanied by further decreases in early T-cells. The lower levels of early T-cells in MS and their fluctuations are believed to reflect disease activity. MBP-reactive early T-cells were more frequently increased in MS (75% of cases) than OND (50%), and while this might be indicative of increased sensitization against myelin antigens, it was found not to be an MS-specific phenomenon.

Topics: Adult; B-Lymphocytes; Female; Humans; Immunity, Cellular; Male; Mental Disorders; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Remission, Spontaneous; T-Lymphocytes

Cerebrospinal fluid contains several proteolytic enzymes that can degrade myelin basic protein (BP) under physiological conditions into peptide fragments of various sizes which still contain antigenic determinants capable of binding antibodies to BP. These enzymes are optimally active in either acid (pH 4) or nuetral (pH 7 to 8) conditions and can be characterized by the nature of the BP peptide fragments produced. Proteinases resembling cathepsin D, thrombin, plasmin (fibrinolysin), or kallikrein are present in variable amounts in CSF. No relationship to any particular disease has yet been established.

Topics: Cathepsins; Epitopes; Fibrinolysin; Humans; Hydrogen-Ion Concentration; Kallikreins; Myelin Basic Protein; Nervous System Diseases; Peptide Hydrolases; Thrombin

Components in cerebrospinal fluid that are antigenically related to myelin basic protein have been identified by a technique described recently [Barbarese, E., Braun, P. E. & Carson, J. H. (1977) Proc. Natl. Acad. Sci. USA 74, 3360-3364] involving separating the cerebrospinal fluid proteins by sodium dodecyl sulfate/polyacrylamide gel electrophoresis and measuring the individual components by radioimmunoassay for myelin basic protein. Samples of cerebrospinal fluid from 48 different patients (23 with definite multiple sclerosis, 4 with suspected multiple sclerosis, and 21 with other neurological diseases) were examined by this technique. The results indicate that cerebrospinal fluid can contain at least three separate components that are detected by radioimmunoassay for myelin basic protein. On the basis of their apparent molecular weights, the three components were identified as follows: component I, intact myelin basic protein; component II, proteolytic fragments of myelin basic protein; and component III, a protein of unknown origin with an apparent molecular weight of 50,000. Most samples of cerebrospinal fluid (45 of 48) from patients with multiple sclerosis and from patients with other neurological diseases contained components I and II. Component III was detected in all of the samples from patients with definite multiple sclerosis, in three of four samples from patients with suspected multiple sclerosis, and in none of the samples from patients with other neurological diseases. Some implications of these findings are discussed.

Topics: Humans; Isoelectric Point; Molecular Weight; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Radioimmunoassay

Topics: Humans; Myelin Basic Protein; Nervous System Diseases

Topics: Age Factors; Animals; Brain Chemistry; Mice; Mutation; Myelin Basic Protein; Nervous System Diseases

Topics: Adult; Antigens, Neoplasm; Cell Migration Inhibition; Cross Reactions; Female; HeLa Cells; Humans; Immunity, Cellular; Male; Middle Aged; Myelin Basic Protein; Neoplasms; Nervous System Diseases; Serotonin

The number of lymphocytes in the blood sensitized to encephalitogenic factor (EF) is less in multiple sclerosis than it is in general paralysis of the insane. The number appears related to the extent of parenchymatous destruction. The study offers no support for the view that lymphocyte sensitization to EF is of pathogenetic significance in multiple sclerosis.

Topics: Adolescent; Adult; Aged; Child; Dementia; Female; Humans; Lymphocyte Activation; Lymphocytes; Macrophages; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Syphilis

Circulating lymphocytes from patients with multiple sclerosis are sensitized to saline homogenate of human thymus. They also show a minor degree of sensitization to lymph node extract. The sensitization to thymus is greater in multiple sclerosis than it is in other neurological disease (except dementia paralytica) and this may be related to the degree of parenchymatous destruction which provides the antigen stimulus or to astroglial overgrowth in these diseases. The observations support the view that human brain and thymus may share antigen(s) of the type known as ø-antigen in mice.

Topics: Adolescent; Adult; Aged; Antigens; Brain; Cell Migration Inhibition; Female; Humans; Lymph Nodes; Lymphocyte Activation; Macrophages; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Thymus Gland

Topics: Binding, Competitive; Cross Reactions; Epitopes; Hallucinogens; Humans; Indoles; Lymphocytes; Lysergic Acid Diethylamide; Multiple Sclerosis; Myelin Basic Protein; Nerve Tissue Proteins; Nervous System Diseases; Receptors, Drug; Serotonin; Tryptamines