myelin-basic-protein and Central-Nervous-System-Diseases

Viruses have often been associated with autoimmune diseases. One mechanism by which self-destruction can be triggered is molecular mimicry. Many examples of cross-reactive immune responses between pathogens and self-antigens have been described. This review presents two transgenic models of autoimmune disease induced by a virus through activation of anti-self lymphocytes. Viral antigens are expressed as transgenes either in beta-cells of the pancreas or in the oligodendrocytes of the CNS. Infection by a virus encoding the same gene activated autoreactive T cells that cleared the viral infection, and as a consequence of transgene expression resulted in organ-specific autoimmune disease. In both transgenic mouse models, autoreactive lymphocytes that escaped thymic negative selection were present in the periphery. Several factors are described that play a role in the regulation of the self-reactive process precipitated by a viral infection. These include the quantity of activated autoreactive T cells, the affinity of these T cells, the number of memory T cells generated following primary infection, costimulation by accessory molecules, and the types and locations of cytokines produced. In addition, unique barriers exist in target tissues that prevent or suppress autoreactive responses and define to a large extent the outcome of disease. Restimulation of autoreactive memory lymphocytes may be required to bypass these barriers and enhance autoimmune disease. Therapy directed at modifying these factors can reduce and even prevent autoimmune disease after it has been initiated.

Topics: Animals; Autoimmune Diseases; Central Nervous System; Central Nervous System Diseases; Diabetes Mellitus, Type 1; Disease Models, Animal; Humans; Insulin; Islets of Langerhans; Lymphocytic choriomeningitis virus; Mice; Mice, Transgenic; Myelin Basic Protein; Self Tolerance; Viruses

Immunofluorescence and immunoperoxidase (peroxidase-antiperoxidase, PAP) techniques for the demonstration of neural and non-neural cell markers are contributing greatly to increase the diagnostic accuracy of difficult tumors of the central nervous system. Well characterized nervous system markers include glial fibrillary acidic (GFA) protein, the three protein subunits of neurofilaments, neuron-specific enolase (NSE), myelin basic protein, and S-100 protein. The most important and reliable of these is GFA protein, which is widely in use for the immunohistochemical diagnosis of tumors of the glioma group. Its many practical applications are reviewed and illustrated. Other neural markers, in particular the specificity of NSE and S-100 protein, need to be critically evaluated. Problems related to the immunohistochemical diagnosis of central neuroepithelial tumors of putative neuroblastic origin remain complex and still need to be resolved. Non-neural markers, such as vimentin, desmin, cytokeratins, Factor VIII, alpha-fetoprotein, human chorionic gonadotropin, and immunoglobulins have well defined, although more restricted, applications in surgical neuropathology.

Topics: alpha-Fetoproteins; Antibodies, Monoclonal; Antigens; Carcinoma; Central Nervous System Diseases; Chorionic Gonadotropin; Cytoskeleton; Desmin; Factor VIII; Fluorescent Antibody Technique; Glial Fibrillary Acidic Protein; Histocytochemistry; Humans; Immune Sera; Immunoenzyme Techniques; Immunoglobulins; Intermediate Filament Proteins; Keratins; Lymphoma; Medical Oncology; Meningeal Neoplasms; Myelin Basic Protein; Neoplasm Metastasis; Neoplasms; Neoplasms, Germ Cell and Embryonal; Neurology; Oligodendroglia; Phosphopyruvate Hydratase; S100 Proteins; Sarcoma; Vascular Diseases; Vimentin; von Willebrand Factor

BackgroundPelizaeus Merzbacher disease (PMD) is a dysmyelinating disorder of the central nervous system caused by impaired differentiation of oligodendrocytes. This study was prompted by findings that antimuscarinic compounds enhance oligodendrocyte differentiation and remyelination in vitro. One of these compounds, clemastine fumarate, is licensed for treatment of allergic conditions. We tested whether clemastine fumarate can promote myelination in two rodent PMD models, the myelin-deficient and the PLP transgenic rat.MethodsPups were treated with daily injections of clemastine (10-30 mg/kg/day) on postnatal days 1-21. Neurologic phenotypes and myelination patterns in the brain, optic nerves, and spinal cords were assessed using histological techniques.ResultsNo changes in neurological phenotype or survival were observed even at the highest dose of clemastine. Postmortem staining with Luxol fast blue and myelin basic protein immunohistochemistry revealed no evidence for improved myelination in the CNS of treated rats compared to vehicle-treated littermates. Populations of mature oligodendrocytes were unaffected by the treatment.ConclusionThese results demonstrate lack of therapeutic effect of clemastine in two rat PMD models. Both models have rapid disease progression consistent with the connatal form of the disease. Further studies are necessary to determine whether clemastine bears a therapeutic potential in milder forms of PMD.

Topics: Animals; Animals, Genetically Modified; Animals, Newborn; Blood-Brain Barrier; Brain; Cell Differentiation; Central Nervous System; Central Nervous System Diseases; Clemastine; Demyelinating Diseases; Disease Models, Animal; Genotype; Injections, Subcutaneous; Male; Myelin Basic Protein; Myelin Sheath; Oligodendroglia; Optic Nerve; Phenotype; Rats; Spinal Cord

A 59-year-old man had been admitted to another hospital because of diplopia and thirst at the beginning of March and was diagnosed with diabetic ketoacidosis. He was referred to our hospital because he had limb weakness, dysarthria, and bilateral sensory impairment of the upper limbs, which worsened rapidly from the middle of March, although plasma glucose had been well controlled after the initiation of insulin therapy in the previous hospital. Contrast spinal MRI in our hospital revealed hyperintense lesions at the level of C4 to C5 and T10. The level of myelin basic protein was high (1,260 pg/ml) in the cerebrospinal fluid and serum anti-neurofascin antibody was negative. Nerve conduction study showed typical findings of demyelination at least 2 regions. Although anti-neurofascin antibody was negative, he was diagnosed with combined central and peripheral demyelination (CCPD) based on these clinical findings. After the repeated methylprednisolone pulse therapy for five times, the hyperintense lesions of the spinal cord disappeared gradually. He was bedridden at the beginning of his hospitalization but could ambulate with a cane on discharge 2 months after the admission. Then we received the result of anti-galactocerebroside antibody test as positive. This case suggested that high-dose steroid pulse therapy is safe and may be effective for anti-galactocerebroside antibody-positive CCPD.

Topics: Autoantibodies; Biomarkers; Cell Adhesion Molecules; Central Nervous System Diseases; Demyelinating Diseases; Galactosylceramides; Humans; Immunoglobulin G; Magnetic Resonance Imaging; Male; Methylprednisolone; Middle Aged; Myelin Basic Protein; Nerve Growth Factors; Peripheral Nervous System Diseases; Pulse Therapy, Drug; Treatment Outcome

Erythropoietin (EPO) plays a critical role in the development of the nervous system. In this study, the effects of EPO in carbon monoxide (CO) neurotoxicity were examined. Rats were exposed to 3000 ppm CO for 1 h and then different doses of EPO were administrated intraperitoneally. After 24 h, glial fibrillary acidic protein (GFAP) levels in the serum were determined and water content of brain and the extravasation of a tracer (Evans blue) were measured. Brain lipid peroxidation, myeloperoxidase activity Myelin basic protein (MBP) and BAX/BcL2 protein relative expressions were determined. Cation exchange chromatography was used to evaluate MBP alterations. Seven days after exposure, pathological assessment was performed after Klüver-Barrera staining. EPO reduced malondialdehyde levels at all doses (2500, 5000 and 10,000 u/kg). Lower doses of EPO (625, 1250, 2500 u/kg) significantly decreased the elevated serum levels of GFAP. EPO could not reduce the water content of the edematous poisoned brains. However, at 5000 and 10,000 u/kg it protected the blood brain barrier against integrity loss as a result of CO. EPO could significantly decrease the MPO activity. CO-mediated oxidative stress caused chemical alterations in MBP and EPO could partially prevent these biochemical changes. Fewer vacuoles and demyelinated fibers were found in the EPO-treated animals. EPO (5000 u/kg) could restore the MBP density. CO increased brain BAX/Bcl-2 ratio 38.78%. EPO reduced it 38.86%. These results reveal that EPO could relatively prevent different pathways of neurotoxicity by CO poisoning and thus has the potential to be used as a novel approach to manage this poisoning.

Topics: Animals; bcl-2-Associated X Protein; Blood-Brain Barrier; Brain; Carbon Monoxide; Carbon Monoxide Poisoning; Central Nervous System Diseases; Dose-Response Relationship, Drug; Erythropoietin; Gene Expression Regulation; Lipid Peroxidation; Male; Myelin Basic Protein; Proto-Oncogene Proteins c-bcl-2; Random Allocation; Rats; Rats, Wistar

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Animals; Axons; Cell Communication; Central Nervous System Diseases; Humans; Mice; Mice, Knockout; Models, Neurological; Myelin Basic Protein; Myelin Proteolipid Protein; Myelin Sheath; Poliomyelitis; Theilovirus; Virus Physiological Phenomena

Our objective was to follow the course of a dysmyelinating disease followed by partial recovery in transgenic mice using non-invasive high-resolution (117 x 117 x 70 microm) magnetic resonance (microMRI) and evoked potential of the visual system (VEP) techniques. We used JOE (for J37 golli overexpressing) transgenic mice engineered to overexpress golli J37, a product of the Golli-mbp gene complex, specifically in oligodendrocytes. Individual JOE transgenics and their unaffected siblings were followed from 21 until 75-days-old using non-invasive in vivo VEPs and 3D T2-weighted microMRI on an 11.7 T scanner, performing what we believe is the first longitudinal study of its kind. The microMRI data indicated clear, global hypomyelination during the period of peak myelination (21-42 days), which was partially corrected at later ages (>60 days) in the JOE mice compared to controls. These microMRI data correlated well with [Campagnoni AT (1995) "Molecular biology of myelination". In: Ransom B, Kettenmann H (eds) Neuroglia--a Treatise. Oxford University Press, London, pp 555-570] myelin staining, [Campagnoni AT, Macklin WB (1988) Cellular and molecular aspects of myelin protein gene-expression. Mol Neurobiol 2:41-89] a transient intention tremor during the peak period of myelination, which abated at later ages, and [Lees MB, Brostoff SW (1984) Proteins in myelin. In: Morell (ed) Myelin. Plenum Press, New York and London, pp 197-224] VEPs which all indicated a significant delay of CNS myelin development and persistent hypomyelination in JOE mice. Overall these non-invasive techniques are capable of spatially resolving the increase in myelination in the normally developing and developmentally delayed mouse brain.

Topics: Animals; Brain; Central Nervous System Diseases; Evoked Potentials, Visual; Longitudinal Studies; Magnetic Resonance Imaging; Mice; Mice, Neurologic Mutants; Mice, Transgenic; Myelin Basic Protein; Nerve Tissue Proteins; Transcription Factors

The goal of this investigation was to determine whether exposure to hyperbaric oxygen (HBO(2)) would ameliorate biochemical and functional brain abnormalities in an animal model of carbon monoxide (CO) poisoning. In this model, CO-mediated oxidative stress causes chemical alterations in myelin basic protein (MBP), which initiates an adaptive immunological response that leads to a functional deficit. CO-exposed rats do not show improvements in task performance in a radial maze. We found that HBO(2) given after CO poisoning will prevent this deficit, but not eliminate all of the CO-mediated biochemical alterations in MBP. MBP from HBO(2) treated CO-exposed rats is recognized normally by a battery of antibodies, but exhibits an abnormal charge pattern. Lymphocytes from HBO(2)-treated and control rats do not become activated when incubated with MBP, immunohistological evidence of microglial activation is not apparent, and functional deficits did not occur, unlike untreated CO-exposed rats. The results indicate that HBO(2) prevents immune-mediated delayed neurological dysfunction following CO poisoning.

Topics: Animals; Brain; Carbon Monoxide Poisoning; Central Nervous System Diseases; Disease Models, Animal; Hyperbaric Oxygenation; Male; Maze Learning; Myelin Basic Protein; Neurons; Oxidative Stress; Oxygen; Rats; Rats, Wistar

The cellular prion protein PrP(C) confers susceptibility to transmissible spongiform encephalopathies, yet its normal function is unknown. Although PrP(C)-deficient mice develop and live normally, expression of amino proximally truncated PrP(C) (DeltaPrP) or of its structural homolog Doppel (Dpl) causes cerebellar degeneration that is prevented by coexpression of full-length PrP(C). We now report that mice expressing DeltaPrP or Dpl suffer from widespread leukoencephalopathy. Oligodendrocyte-specific expression of full-length PrP(C) under control of the myelin basic protein (MBP) promoter repressed leukoencephalopathy and vastly extended survival but did not prevent cerebellar granule cell (CGC) degeneration. Conversely, neuron-specific PrP(C) expression under control of the neuron-specific enolase (NSE) promoter antagonized CGC degeneration but not leukoencephalopathy. PrP(C) was found in purified myelin and in cultured oligodendrocytes of both wild-type and MBP-PrP transgenic mice but not in NSE-PrP mice. These results identify white-matter damage as an extraneuronal PrP-associated pathology and suggest a previously unrecognized role of PrP(C) in myelin maintenance.

Topics: Age Factors; Animals; Blotting, Western; Central Nervous System Diseases; Glial Fibrillary Acidic Protein; GPI-Linked Proteins; In Situ Nick-End Labeling; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Mutation; Myelin Basic Protein; Nerve Degeneration; Neurons; Oligodendroglia; Phosphopyruvate Hydratase; Prions; Protein Conformation; Protein Processing, Post-Translational; PrPC Proteins

In human central nervous system (CNS) demyelinating diseases, spontaneous remyelination is often incomplete. Therefore, we have tested whether neutrotrophin-3 (NT-3) accelerates CNS myelin repair after a chemically-induced demyelination. One group of adult rats was injected in the corpus callosum (CC) with 1 microl of 1% lysophosphatidylcholine (LPC) and 1 microl of NT-3 (1 microg/microl), and 15 days after injury (D15) remyelination was compared to control rats (receiving 1 microl of LPC+1 microl of vehicle buffer of NT-3). The demyelinated volume decreased by 56% in NT-3-treated rats at D15, and immunohistochemistry showed an increase in mature MBP(+) oligodendrocytes (OL) (+66%) in treated animals (whereas less mature (CNP(+)) OL were unchanged). Since less than 3% axons degenerate in this model, and as astrocytic gliosis was not modified, these data suggest that NT-3 acts directly on cells of the OL lineage to enhance remyelination in vivo.

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Animals; Bromodeoxyuridine; Central Nervous System Diseases; Corpus Callosum; Demyelinating Diseases; Disease Models, Animal; Glial Fibrillary Acidic Protein; Immunohistochemistry; Lysophosphatidylcholines; Male; Myelin Basic Protein; Nerve Regeneration; Neurotrophin 3; Oligodendroglia; Rats; Rats, Wistar; Stem Cells; Time Factors

Axonal injury in the central nervous system (CNS) results in the degeneration of directly damaged fibers and also in the secondary degeneration of fibers that escaped the primary insult. Studies have shown that a protective T cell-mediated autoimmunity directed against myelin-related self-antigens is a physiological response to CNS insult, spontaneously elicited in strains that are constitutionally resistant to experimental autoimmune encephalomyelitis (EAE) but not in EAE-susceptible strains. The protective response following axonal injury can be induced in susceptible rats and boosted in resistant rats by passive or active immunization with myelin-related antigens. Here we show that oral administration of low-dose myelin basic protein (MBP) over a 5-day period is beneficial for post-traumatic survival of neurons in Lewis (EAE-susceptible) rats. Protection was accompanied by increased expression of the costimulatory molecule B7.2 in the traumatized nerves, similar to that seen after passive transfer of MBP-specific T cells. These results support the contention that properly controlled autoimmunity is the body's defense mechanism against non-infective insults. Oral immunization with MBP can be viewed as a way to control the autoimmunity capable of fighting off the consequences of CNS injury in EAE-susceptible strains.

Topics: Administration, Oral; Animals; Central Nervous System Diseases; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Humans; Macrophages; Myelin Basic Protein; Neurodegenerative Diseases; Optic Nerve; Rats; Rats, Inbred Lew; T-Lymphocytes

To study the biological role of the chemokine ligands CCL19 and CCL21, we generated transgenic mice expressing either gene in oligodendrocytes of the CNS. While all transgenic mice expressing CCL19 in the CNS developed normally, most (18 of 26) of the CCL21 founder mice developed a neurological disease that was characterized by loss of landing reflex, tremor, and ataxia. These neurological signs were observed as early as postnatal day 9 and were associated with weight loss and death during the first 4 wk of life. Microscopic examination of the brain and spinal cord of CCL21 transgenic mice revealed scattered leukocytic infiltrates that consisted primarily of neutrophils and eosinophils. Additional findings included hypomyelination, spongiform myelinopathy with evidence of myelin breakdown, and reactive gliosis. Thus, ectopic expression of the CC chemokine CCL21, but not CCL19, induced a significant inflammatory response in the CNS. However, neither chemokine was sufficient to recruit lymphocytes into the CNS. These observations are in striking contrast to the reported activities of these molecules in vitro and may indicate specific requirements for their biological activity in vivo.

Topics: Animals; Brain; Cell Movement; Central Nervous System Diseases; Cerebellum; Chemokine CCL19; Chemokine CCL21; Chemokines; Chemokines, CC; Cytokines; Demyelinating Diseases; Gliosis; Leukocytes; Medulla Oblongata; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Myelin Basic Protein; Neurodegenerative Diseases; Oligodendroglia; Phenotype; Spinal Cord

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

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

Poliovirus replicon vectors transiently express foreign proteins selectively in motor neurons of the anterior horn of the spinal cord. Here we intraspinally inoculated mice transgenic for the poliovirus receptor (PVR) with replicons encoding murine tumor necrosis factor alpha (mTNF-alpha). We detected high-level expression of mTNF-alpha in the spinal cords of these animals at 8-12 h post inoculation; this returned to background by 72 h. The mice exhibited ataxia and tail atony, whereas animals given a replicon encoding green fluorescent protein (GFP) exhibited no neurological symptoms. Histology of spinal cords from mice given the replicon encoding mTNF-alpha revealed neuronal chromatolysis, reactive astrogliosis, decreased expression of myelin basic protein, and demyelination. These animals recovered with only slight residual damage. This study shows that replicon vectors have potential for targeted delivery of therapeutic proteins to the central nervous system and provide a new approach for treatment of spinal cord trauma and neurological disease.

Topics: Animals; Astrocytes; Brain Diseases; Central Nervous System Diseases; Cytokines; Gene Transfer Techniques; Genetic Therapy; Green Fluorescent Proteins; HeLa Cells; Humans; Immunohistochemistry; Luminescent Proteins; Membrane Proteins; Mice; Mice, Transgenic; Microglia; Models, Genetic; Motor Neurons; Myelin Basic Protein; Myelin Sheath; Oligodendroglia; Poliovirus; Promoter Regions, Genetic; Receptors, Virus; Spinal Cord; Time Factors; Transduction, Genetic; Tumor Necrosis Factor-alpha

Inflammation of multiple sclerosis (MS) brain and spinal cord tissue consists of macrophages, T lymphocytes and cytokines as well as B lymphocytes and immunoglobulins (IgGs). IgG can be detected in high concentrations in both central nervous system tissue and cerebrospinal fluid (CSF). Using a sensitive radioimmunoassay (RIA), autoantibodies to myelin basic protein (anti-MBP) can be detected in the CSF of 90-95% of MS patients with active disease. The purpose of the present report was to determine whether these same autoantibodies can be reliably detected in non-MS patients. Between 1978 and 1998, CSF was collected from 1,968 control non-MS patients with psychiatric, inflammatory and noninflammatory neurological diseases as well as nonneurological systemic diseases, and anti-MBP were measured by the same RIA used to detect anti-MBP in MS CSF. Anti-MBP were undetectable in 98% of CSF samples from non-MS controls. In the remaining 2% of control samples, CSF IgGs capable of binding to MBP in vitro were unpredictably detected. This latter group included 1% of patients with miscellaneous diseases such as encephalomyelitis, 5 siblings with familial spastic paraparesis, rare patients with strokes, Wernicke-Korsakoff's syndrome, inherited leukodystrophy, motor neuron disease and some patients with miscellaneous spinal cord diseases. An additional 1% of patients included a group with neurological symptoms suggestive of early or predisseminated MS. The high prevalence of free and/or bound anti-MBP in the CSF of MS patients and the rare and unpredictable occurrence in the CSF of non-MS patients suggest that autoimmunity to MBP may be operative in the demyelination of MS. Molecular clones of anti-MBP with specificity towards variable surface or cryptic MBP epitopes in vivo may determine whether or not they are involved in the demyelinating process, and this variability may also be present within the MS population. Potential mechanisms of anti-MBP-mediated demyelination in MS patients are discussed.

Topics: Adult; Aged; Aged, 80 and over; Autoantibodies; Central Nervous System Diseases; Cerebrovascular Disorders; Child; Encephalomyelitis; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Neurodegenerative Diseases; Sclerosis; Spinal Cord Diseases

Molecular mass (M(r)) microheterogeneity of beta-trace protein (beta TP) in cerebrospinal fluid (CSF) from patients with various neurological disorders was analyzed by sodium dodecyl sulfate capillary gel electrophoresis. Under the conditions employed, beta TP with a M(r) distribution of 23,000-30,000 was roughly separated into two subfractions containing the major peaks with M(r) of 26,000 and 28,500, respectively. The peak area ratios of the two subfractions of the electropherograms varied among the samples examined, and elevation in the total beta TP level in the CSF from patients with organic diseases in the central nervous system (CNS) was often accompanied by changes in the ratios of the subfractions. The quantitative changes in the subfraction level in CSF beta TP are considered to reflect the pathological alterations in the CNS.

Topics: Adult; Aged; Beta-Globulins; Central Nervous System Diseases; Cerebrospinal Fluid Proteins; Cohort Studies; Electrophoresis, Capillary; Female; Humans; Intramolecular Oxidoreductases; Lipocalins; Male; Middle Aged; Myelin Basic Protein; Sodium Dodecyl Sulfate; Spinal Puncture

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

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

Memantine, a clinically employed drug with N-methyl-D-aspartate (NMDA) receptor antagonistic effects, dose-dependently ameliorates neurological deficits in Lewis rat experimental autoimmune encephalomyelitis (EAE). Interestingly, this therapeutic effect was not due to dampened CNS inflammation, as assessed by immunohistochemical evaluation of spinal cord tissue. Furthermore, numbers of interferon gamma (IFN gamma) mRNA expressing cells were not decreased, as assessed by in situ hybridization. Systemic immunity in terms of numbers of IFN gamma secreting cells in response to immunodominant myelin basic protein (MBP) peptides ex vivo was not reduced, and non-toxic doses of memantine did not affect lymphocyte proliferation or IFN gamma secretion in vitro. Considering these findings, we hypothesize that effector mechanisms responsible for reversible neurological deficits in EAE may involve NMDA receptors, and this highlights neurons as targets during autoimmune neuroinflammation.

Topics: Animals; Cell Division; Central Nervous System Diseases; Dose-Response Relationship, Drug; Encephalomyelitis, Autoimmune, Experimental; Excitatory Amino Acid Antagonists; Immunohistochemistry; Interferon-gamma; Male; Memantine; Myelin Basic Protein; Rats; Rats, Inbred Lew; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Spinal Cord; T-Lymphocytes

Chronic progression of autoimmune disease is accompanied by the acquisition of autoreactivity to new self-determinants. Recent evidence indicates that this process, commonly referred to as determinant spreading, may be pathogenic for chronicity. Our studies on experimental autoimmune encephalomyelitis (EAE), a murine model widely used in multiple sclerosis (MS) studies, have shown that determinant spreading develops as a predictable sequential cascade of neo-autoimmunity during progression to chronic disease. By 7-8 weeks after immunization of (SWR x SJL)F1 mice with the immunodominant myelin proteolipid protein determinant (PLP 139-151), splenocytes consistently respond to the immunodominant myelin basic protein determinant (MBP 87-99). In the present study, we directly address the pathogenicity of neo-autoimmunity resulting from endogenous self-priming during the course of disease. Our results indicate that T cells responding to the spreading MBP 87-99 determinant produce a proinflammatory cytokine profile consistent with type 1 helper T cells (Th1) cells. In addition, splenocytes activated to the spreading MBP 87-99 determinant consistently transfer acute EAE in naive recipients even when T cells reactive to the priming PLP 139-151 immunogen are eliminated by bromodeoxyuridine (BUdR)-mediated photolysis. Our data indicate that endogenous neo-autoantigen priming during chronic autoimmune disease generates type 1 helper T cells (Th1) cells that are autonomously pathogenic. These results provide further evidence supporting the view that determinant spreading is a pathogenic process that leads to chronic progression of autoimmune disease.

Topics: Adoptive Transfer; Animals; Antigen Presentation; Antimetabolites; Autoantigens; Bisbenzimidazole; Bromodeoxyuridine; Central Nervous System Diseases; Cytokines; Demyelinating Diseases; Encephalomyelitis, Autoimmune, Experimental; Epitopes; Female; Fluorescent Dyes; Immunization; Mice; Mice, Inbred Strains; Myelin Basic Protein; Myelin Proteins; Myelin Proteolipid Protein; Peptide Fragments; Photochemistry; Spleen; T-Lymphocytes, Helper-Inducer

In this study levels of neuron-specific enolase (NSE), S-100 protein (S-100) and myelin basic protein (MBP) in cerebrospinal fluid (CSF) of children and adults with distinct neurological disorders were examined. A previous study from our department demonstrated age related reference values for these brain-specific proteins in CSF. The median concentration level of the 3 proteins in 17 different neurological disease groups versus the reference group was compared. Significantly higher MBP values were observed in patients with multiple sclerosis (MS), cerebrovascular accident (CVA), metabolic disorder and infection. Furthermore, significantly higher values were demonstrated for S-100 in CVA and for NSE in metabolic diseases. In CVA, the NSE and S-100 values were significantly related with MBP values, whereas in MS the NSE and S-100 were not related with MBP values.

Topics: Adult; Central Nervous System Diseases; Child; Diagnosis, Differential; Female; Humans; Male; Myelin Basic Protein; Neurologic Examination; Phosphopyruvate Hydratase; Prognosis; Reference Values; S100 Proteins

A chronic relapsing model of demyelinating experimental allergic encephalomyelitis (EAE) was induced in Lewis rats by the repeated co-transfer of encephalitogenic, myelin basic protein (MBP)-specific T cells in combination with a demyelinating monoclonal antibody (mAb) specific for the myelin oligodendrocyte glycoprotein (MOG). In controls, repeated injections of 5 x 10(5) MBP-specific T cells at intervals of 18-21 days resulted in an increasing resistance to the induction of further episodes of EAE. However, intravenous injection of the mAb 4 days after each T cell transfer overcame this 'vaccination' effect and induced severe clinical relapses associated with an increasing and persistent neurological deficit. Histological examination revealed that four cycles of treatment with T cells and mAb were sufficient to result in the formation of large plaques of demyelination in the spinal cord that failed to undergo significant remyelination within 60 days of the final injection of mAb. These lesions consisted of a matrix of astrocytic scar tissue traversed by numerous naked axons. These observations demonstrate that the formation of large, persistently, demyelinated lesions in a T cell-mediated model of EAE in the Lewis rat is dependent on the presence of an appropriate anti-myelin autoantibody response.

Topics: Animals; Antibodies, Monoclonal; Cell Line; Central Nervous System Diseases; Demyelinating Diseases; Encephalomyelitis, Autoimmune, Experimental; Female; Membrane Glycoproteins; Myelin Basic Protein; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Nervous System; Rats; Rats, Inbred Lew; T-Lymphocytes

Triethyltin (TET) is a neurotoxicant that produces severe but transient cerebral edema, characterized ultrastructurally by vacuolation of the intraperiod line of central nervous system (CNS) myelin. TET has been reported to depress levels of myelin basic protein (MBP), a protein thought to play a critical role in myelin compaction. In the present study, the genomic expression (i.e., mRNA) of MBP was monitored throughout the pathogenesis of TET-induced myelin edema and recovery in Sprague-Dawley rats given a single injection of a neuropathic (8.0 mg/kg) or non-neuropathic (0.8 mg/kg) dose of TET-bromide. Levels of MBP-mRNA from the anterior and posterior brain were collected 1 hr, 3 hr, 2d, and 7d, postexposure. The optic nerve and caudal brainstem, representing anterior and posterior brain sites, respectively, were examined at the same time-points for ultrastructural evidence of edema and recovery. Our data indicate that neuropathic doses (8.0 mg/kg) of TET significantly stimulated MBP transcript throughout the brain at all exposure time-points. The magnitude and time-course of this stimulation differed in the anterior and posterior brain, with the latter region showing higher levels of MBP-mRNA. In the posterior brain, the highest levels of mRNA correlated with the appearance of edema in the caudal brainstem. In the anterior brain, MBP-mRNA levels were only marginally increased over controls. Ultrastructural evidence of myelin edema was confined to the brainstem in rats treated with neuropathic dose of TET. Intralamellar vacuolation appeared at 3 hr and 2d postexposure and could be correlated with peak levels of MBP transcript, whereas, recompacted myelin, which appeared by 7d postexposure, was associated with declining levels of the mRNA. Ultrastructural changes in the oligodendroglia were suggestive of metabolic stimulation and correlated with high MBP-mRNA levels. In summary, these data indicate that an initial genomic event in TET-induced myelin edema is stimulation of MBP transcript.

Topics: Animals; Blotting, Northern; Central Nervous System Diseases; DNA; DNA Probes; Edema; Male; Myelin Basic Protein; Myelin Sheath; Nucleic Acid Hybridization; Rats; Rats, Inbred Strains; RNA, Messenger; Triethyltin Compounds

The expression of the proteolipid protein (PLP) gene of the myelin deficient (md) and normal rat was studied during the myelination period. The sizes of the PLP transcripts (1.6 and 3.2 kb) in the md and normal rat were identical although the md PLP messenger RNA level was extremely reduced as shown by in situ hybridization and Northern blot hybridization analysis. The structure of the md proteolipid protein gene was analyzed on the cDNA and genomic level. The molecular basis of the myelin deficiency phenotype has been elucidated: a point mutation in exon III (A----C transversion) verified by cDNA and genomic DNA sequencing causes a mutation of Thr75 to Pro and creates an additional AvaII restriction site in exon III of the md rat. The threonine to proline mutation located within the second transmembranal alpha-helix might induce a conformational change and thereby prohibit the integration of PLP into the membrane with the clinical manifestation of dysmyelination leading to premature death within 3-6 weeks.

Topics: Amino Acid Sequence; Animals; Base Sequence; Blotting, Northern; Blotting, Southern; Brain; Brain Chemistry; Central Nervous System Diseases; DNA; Exons; Female; Gene Amplification; Male; Molecular Sequence Data; Mutation; Myelin Basic Protein; Myelin Proteins; Myelin Proteolipid Protein; Myelin Sheath; Oligodendroglia; Phenotype; Rats; Rats, Mutant Strains; RNA, Messenger

Topics: Animals; Autoantigens; Autoimmune Diseases; Cell Line; Central Nervous System Diseases; Encephalomyelitis, Autoimmune, Experimental; Epitopes; Histocompatibility Antigens Class II; Immunization; Killer Cells, Natural; Myelin Basic Protein; Rats; Rats, Inbred Lew; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Helper-Inducer

We studied 61 patients with complications of Semple-type postexposure rabies immunization. Thirty-six had neurologic signs, and 25 had only fever, headache, or myalgia. Thirty-two patients had CNS complications, and 4 had an acute peripheral neuropathy. Disease was acute and monophasic in 33, but 3 patients had progressive disease, including 1 patient with a relapsing-remitting course. No clinical features, including CSF content of myelin basic protein, were prognostic indicators. In three of six patients with encephalomyelitis, lymphocytes showed a proliferative response to myelin.

Topics: Central Nervous System Diseases; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Humans; Lymphocyte Activation; Myelin Basic Protein; Peripheral Nervous System Diseases; Rabies Vaccines

The pathogenesis of central nervous system complications in primary Sjögren's syndrome (CNS-SS) is unknown. In order to determine whether patients with active CNS-SS have cerebrospinal fluid (CSF) abnormalities indicative of CNS inflammation, CSF analyses from 30 patients with active CNS-SS (SSA) were contrasted with those from 20 SS patients without CNS involvement (SSI) and 20 patients with systemic lupus erythematosus and active CNS disease (SLEA). Elevations of total protein concentration, IgG concentration, IgG to total protein ratio, and IgG index were observed in patients with SSA, but not in those with SSI. Agarose gel electrophoresis results were abnormal, with 1 or more bands, in 25 of 29 SSA patients (86%), but in only 3 of 18 SSI patients (17%). Similar, but less striking, CSF abnormalities were seen in a minority of SLEA patients. Fifteen SSA patients (50%) had transient, mild-to-moderate CSF pleocytosis, while only 1 SSI patient and 2 SLEA patients had similar findings. Cytologic findings were abnormal in 18 SSA patients (60%); these included atypical mononuclear cells, lymphoblastoid cells, and plasma cells. The presence of immunocompetent cells and evidence for the intrathecal synthesis of IgG within the CSF of SSA, but not SSI, patients provide diagnostic parameters which are indicative of active disease and which can be monitored serially during therapy.

Topics: Central Nervous System Diseases; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Immunoglobulin G; Lymphocytes; Myelin Basic Protein; Sjogren's Syndrome

Cerebrospinal fluid (CSF) from 115 patients with several neurological disorders were tested for the presence of myelin basic protein (MBP), fragment P1 43-88. Cases were divided into groups according to neurological diagnosis. The control group (50 patients with chronic headache) presented normal CSF composition and presented no evidence of the presence of MBP. MBP was found in: four cases of the 44 of neurocysticercosis; three of the 8 cases of multiple sclerosis; one case of schistosomiasis with spinal cord involvement. Neuroimmunological data are discussed considering results found in this investigation.

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

A new B6C3 stock of shimld mutant mice is compared in terms of behavior and CNS morphology with both a B6C3 shi stock and reports on other shimld animals. Defects of B6C3 shimld myelination seen at postnatal day 21 (P-21) are comparable to those in B6C3 shi with respect to % axons myelinated, sheath thickness, errors in the wrapping and targeting of myelin and abnormal oligodendrocyte shape. The two mutations are similarly expressed in cerebellar organotypic cultures. However, the major dense line (MDL) is present in a few shimld myelin sheaths at P-21 and a few sheaths show myelin basic protein by immunocytochemistry, while neither phenomenon is seen in shi at this age in the same CNS regions. Shimld mice survive their disease significantly better than shi. The shimld stock currently under study elsewhere differs from this B6C3 stock in that MDL was reported only in older animals, and behavior and survival were severely compromised.

Topics: Alleles; Animals; Central Nervous System Diseases; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Neurologic Mutants; Microscopy, Electron; Myelin Basic Protein; Myelin Sheath; Oligodendroglia

Cerebrospinal fluid was examined from 70 children with acute lymphoblastic leukemia for evidence of active myelin breakdown based on the release of myelin basic protein (MBP). Fifty-three asymptomatic children were followed from diagnosis with serial MBP determinations. Eight (15.1%) of 53 children had abnormal elevations of MBP, six of eight before receiving presymptomatic central nervous system therapy. Long-term observations are in progress. For comparison, six children with clinical and radiologic findings of leukoencephalopathy had abnormal MBP determinations, whereas no abnormalities were detected in 11 children with meningeal leukemia.

Topics: Adolescent; Central Nervous System Diseases; Child; Child, Preschool; Humans; Leukemia, Lymphoid; Meningeal Neoplasms; Myelin Basic Protein; Necrosis; Prospective Studies

In 44 patients undergoing neurosurgical procedures for intracranial tumors, subarachnoid hemorrhage, or spinal and peripheral nerve lesions, serum myelin basic protein (MBP) immunoreactivity was measured preoperatively and serially in the first 10 postoperative days. The double-antibody radioimmunoassay method was used, with a detection limit of 2.5 ng/ml in serum. Clinical evaluation was carried out at admission and on successive days during the period of neurosurgical management; outcome was assessed later. In the early postoperative phase, there was a fall in MBP immunoreactivity in all groups of patients. In the groups with intracranial tumor and subarachnoid hemorrhage, there was a subsequent rise in MBP immunoreactivity before the end of the 10-day period, which was not found in the group with spinal and peripheral nerve lesions.

Topics: Adenoma; Brain Neoplasms; Central Nervous System Diseases; Female; Glioma; Humans; Male; Meningioma; Middle Aged; Myelin Basic Protein; Radioimmunoassay; Spinal Cord Diseases; Spinal Diseases; Subarachnoid Hemorrhage

Cerebrospinal fluid (CSF) from 18 multiple sclerosis (MS) patients, 13 subacute sclerosing panencephalitis (SSPE) patients, 22 other neurological disease (OND) patients, and 7 neurotic patients as controls were tested in an 125I-labeled anti-human F(ab')2 binding assay for the presence of antibodies to normal human brain cells from tissue culture, human fibroblasts, plasma membranes of MS and normal human brain, myelin basic protein (MBP) and bovine oligodendrocytes. Antibodies to MBP and to oligodendrocytes were found in the CSF of MS, SSPE and OND patients. Absorption of CSF with bovine CNS myelin significantly diminished binding activity to oligodendrocytes. Antibodies in the CSF against MBP and oligodendrocytes, on which some myelin determinants are expressed, seem to be a common feature of diseases in which demyelination is a component.

Topics: Antibodies; Antigen-Antibody Complex; Brain; Cell Membrane; Central Nervous System Diseases; Cerebrospinal Fluid; Fibroblasts; Humans; Multiple Sclerosis; Myelin Basic Protein; Neuroglia; Oligodendroglia; Subacute Sclerosing Panencephalitis

Myelin basic protein (BP) is a specific constituent of the myelin sheath. This structural protein cannot be detected in the cerebrospinal fluid (CSF) unless myelin is acutely degraded. In order to detect active demyelinating diseases, BP was measured in CSF samples of radioimmunoassay. The assay is specific and sensitive to as little as 1.5 to 2.5 ng/ml BP. A moderate non-parallelism between the standard curve and various dilutions of CSF samples indicates that in CSF BP is present in an altered state. Over 1000 CSF samples have been measured in a double-blind study, in which 100 patients were selected and their clinical records evaluated. Twenty-eight patients without demyelinating disease had BP levels lower than 2.5 ng/ml. 72 patients had values higher than 2.5 ng/ml. Among them, the most frequent causes of demyelination were multiple sclerosis (19 cases), brain tumors (22 cases) and cerebral or spinal vascular accidents (12 cases). During a single acute demyelinating episode, BP levels revert to background levels within a few days. In contrast to immunological anomalies observed in the CSF, the presence of BP is concomitant with the breakdown of myelin. The size and location of the lesion influence the level of BP in the CSF. Thus, the assay is useful for the detection of active demyelination in the central nervous system and in following the course of the disease, although normal values do not rule out the presence of demyelinating lesions. For the time being, therefore, this assay should be restricted to specialized neurological centers and selected patients.

Topics: Adult; Brain Diseases; Brain Neoplasms; Central Nervous System Diseases; Child; Demyelinating Diseases; Female; Humans; Male; Meningoencephalitis; Multiple Sclerosis; Myelin Basic Protein; Radioimmunoassay

Topics: Animals; Antigen-Antibody Complex; Blood-Brain Barrier; Central Nervous System Diseases; Immune Complex Diseases; Mice; Mice, Inbred C57BL; Myelin Basic Protein

Shiverer is an autosomal recessive mutant mouse characterized by abnormal and poor myelin formation of the central nervous system. Chimera mice were produced from wild-type control (C57BL/6N) and the shiverer mutant mice (BALB/C) by the aggregation technique in order to analyze the pathogenesis of the shiverer mutation. The coat color was a mosaic of both strains. Immunohistochemically we have examined sections of cerebellar white matter of the chimera using antiserum against myelin basic protein (MBP), since MBP is absent in the myelin of the shiverer. Patches of MBP-negative and positive sites were observed in cerebellar white matter. The myelin sheaths, both positive and negative to MBP staining, were well mixed in the white matter but each stained myelin sheath was clearly visible, even in the mixed part. The possibility that humoral factors caused dysmyelination could be eliminated, and it is suggested that the shiverer mutation occurs intrinsic to the cells themselves.

Topics: Animals; Central Nervous System; Central Nervous System Diseases; Chimera; Immunoenzyme Techniques; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Neurologic Mutants; Myelin Basic Protein; Myelin Sheath

Establishment of animal model of virus-induced encephalomyelitis was attempted in strain 13 guinea pigs sensitized with the homologous spinal cord antigen. Intracerebral inoculation of canine distemper virus alone or sensitization with the neural antigen alone did not induce significant clinical signs. Mild histological lesions were found in both the meninges and parenchyma of the central nervous system (CNS) of virus-infected animals, and in the meninges of the sensitized ones. In contrast, combination of virus infection and sensitization resulted in development of neurological signs of CNS disease as well as of marked histological lesions involving both the meninges and parenchyma. The potentiated CNS disease was successfully transferred by the lymph node cells of the sensitized animals into virus-infected ones. These results suggested that the virus-induced lesions in the CNS were potentiated by the lymphocytes sensitized with neural antigen. Depending on the time schedule of the sensitization and virus infection, different courses of CNS diseases including acute, subacute, and/or recurrent ones were induced, indicating the usefulness of this animal model for immunological and virological analysis of virus-induced CNS diseases.

Topics: Animals; Antigens; Central Nervous System Diseases; Distemper; Distemper Virus, Canine; Dogs; Female; Guinea Pigs; Lymphocytes; Male; Myelin Basic Protein; Neurons; Viral Plaque Assay

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; Central Nervous System Diseases; Demyelinating Diseases; Disease Models, Animal; Guinea Pigs; Mice; Mice, Neurologic Mutants; Myelin Basic Protein; Myelin Sheath; Schwann Cells

A subpopulation of T lymphocytes sensitized to human myelin basic protein in peripheral blood of patients with multiple sclerosis, central nervous system (CNS) tumors, and cerebrovascular accidents was demonstrated by the antigen-stimulated, rosette-forming T-cell assay. A significant increase in the percent of active rosette-forming T cells was detected after in vitro exposure of peripheral blood lymphocytes to human myelin basic protein but not to histones. In contrast, peripheral blood lymphocytes from healthy controls and from patients with benign and malignant breast diseases were unresponsive to stimulation by either antigen. These results demonstrate a functionally active T-lymphocyte subpopulation sensitized to myelin basic protein in patients with multiple sclerosis and in patients with certain other CNS diseases.

Topics: Adult; Aged; Breast Diseases; Breast Neoplasms; Central Nervous System Diseases; Cerebrovascular Disorders; Histones; Humans; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Rosette Formation; T-Lymphocytes

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

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

Proteolytic enzyme activity, present at both acid and neutral pH values, in cerebrospinal fluid, can be measured by a sensitive assay, which monitors the rate of 125I-basic protein breakdown on polyacrylamide gel electrophoresis. CSF cellular neutral proteinase and supernatant acid proteinase are increased in acute multiple sclerosis and in CNS infections.

Topics: Acute Disease; Central Nervous System Diseases; Humans; Hydrogen-Ion Concentration; Lymphocytes; Multiple Sclerosis; Myelin Basic Protein; Neutrophils; Peptide Hydrolases

Using a direct macrophage migration inhibition test the hypersensitivity against encephalitogenic protein and phytohaemagglubinin in normal persons, multiple sclerosis patients and patients with other diseases of the central nervous system were examined. It proved that the vast majority of patients were sensitised to brain antigen. The percentage of positive tests and the percentage of migration inhibition was related to the activity of the disease. No differences were found between lymphocytes of multiple sclerosis patients and of patients with the other neurological diseases patients. Foetal calf serum was proven to depress the hypersensitivity to phytohaemagglutinin as did multiple sclerosis serum on normal lymphocytes. The results did not support the hypothesis that multiple sclerosis is caused by a cell-mediated auto-immune process.

Topics: Autoimmune Diseases; Cell Migration Inhibition; Central Nervous System Diseases; Humans; Hypersensitivity, Delayed; Immune Sera; Lectins; Lymphocytes; Multiple Sclerosis; Myelin Basic Protein

A direct macrophage migration test is described, which proved to be useful for the detection of cellular hypersensitivity in man. We used a modification of the method described by Hughes & Paty (1972). In this method the MLR is abolished by 100 rad gamma-irradiation of the peritoneal exudate cells prior to pooling with human lymphocytes. Experiments with various intensity of irradiation, PPD, muscle antigen and encephalitogenic factor were performed to check this method. In a pilot study lymphocytes of patients with diseases of the central or peripheral nervous system or of muscle were tested. This proved that a hypersensitivity of Ef was present in various diseases of the CNS, while in muscle diseases positive tests were found using muscle antigen.

Topics: Antigens; Ascitic Fluid; Cell Migration Inhibition; Central Nervous System Diseases; Gamma Rays; Humans; Immunity, Cellular; Lymphocyte Culture Test, Mixed; Lymphocytes; Macrophages; Muscles; Muscular Diseases; Myelin Basic Protein; Peripheral Nervous System Diseases; Radiation Effects; Tuberculin; Tuberculin Test

Vaccinia virus infection was performed by scarification of the shaved skin (5 times 5 cm2) on the back of Pirbright guinea pigs. The macrophage migration inhibition test was performed with peritonealexudate cells 7, 11, 14 and 21 days after infection. Macrophage migration inhibition occurred after exposure of the cells to whole brain tissue antigen on the 7th, 11th, 14th day after infection (s. table 1). Lymphocyte transformation responses were examined by 14C-2-Thymidin uptake using blood cultures and basic encephalitogenic protein and whole brain tissue extract as antigens. A positive transformation response could be demonstrated from one to 8 weeks after infection (s. table 2). The specificity of the transformation response to brain antigen was established using control cultures stimulated with PHA or PPD. In no case stimulation occured with PPD. Stimulation with PHA was not altered. On the other hand the spontaneous lymphocyte transformation was enhanced at one week after infection and lymphocyte cultures exposed to heat inactivated vaccinia virus showed transformation from the 3th week after infection until the end of the observation period (i.e. 8 weeks) (s. table 2). The reason why cell mediated hypersensitivity to brain antigen is induced following vaccinia infection remains unknown. The most probable among several possible mechanisms seem a) the induction of virus-specific antigens on the surface of infected cells or b) the release of brain specific antigen through virus infection.

Topics: Administration, Topical; Animals; Antigens; Brain; Brain Diseases; Cell Migration Inhibition; Central Nervous System Diseases; Guinea Pigs; Immunity, Cellular; Immunization; Lectins; Lymphocyte Activation; Macrophage Migration-Inhibitory Factors; Macrophages; Myelin Basic Protein; Skin; Tuberculin; Vaccinia

29 guinea pigs, strain Pirbright, were infected with vaccinia virus, strain Elstree, by the dermal route. The observation period was 14 days. Thereafter, the animals were killed and their central nervous systems (CNS) histologically and immunohistologically, the blood fluorescence-serologically examined. Histological examination revealed meningitis, ependymitis or disseminated meningoencephalitis with slight perivascular cuffing in 72% of the animals. The viral antigen was found in 3 animals (10%). It was present most often in the cytoplasma of the arachnoidal and/or ependymal cells, as well as in the cells of the vessel walls and less often in the glial and/or nerve cells. The infected cells showed no severe degenerative changes. The blood-brain-barrier displayed localized disturbances. The examination of the myelin sheaths revealed disseminated foci of disappearance of myelin fluorescence in the perivascular, paraventricular and subcortical regions. Antibodies directed against myelin sheaths, or nerve cells could be detected in the sera of 48% of the animals. The results give evidence that the vaccinia infection is capable to induce a potentially pathogenic autoimmune reaction directed against brain. Such an immunomechanism can be triggered without any signs of acute lytic infection of the CNS. The mechanism and significance of this reaction are discussed.

Topics: Animals; Antibodies; Antibody Formation; Antigens; Autoimmune Diseases; Blood-Brain Barrier; Brain; Central Nervous System Diseases; Cerebrovascular Disorders; Ependyma; Guinea Pigs; Immune Sera; Immunity; Immunoglobulin G; Meningitis; Myelin Basic Protein; Vaccinia

Topics: Animals; Brain; Cell Differentiation; Central Nervous System Diseases; Cholesterol; Chromatography, Thin Layer; Demyelinating Diseases; Diffuse Cerebral Sclerosis of Schilder; Disease Models, Animal; DNA; Electrophoresis, Polyacrylamide Gel; Male; Mice; Mice, Inbred Strains; Myelin Basic Protein; Myelin Sheath; Nerve Fibers, Myelinated; Nerve Tissue Proteins; Neuroglia; Phospholipids; RNA; Sulfoglycosphingolipids

Topics: Animals; Animals, Newborn; Brain; Brain Chemistry; Central Nervous System Diseases; Disease Models, Animal; Electrophoresis, Polyacrylamide Gel; Lipoproteins; Mice; Mitochondria; Myelin Basic Protein; Myelin Sheath; Nerve Tissue Proteins; Synaptosomes