myelin-basic-protein and Acute-Disease

A previously healthy 19-month-old boy developed acute encephalopathy, thrombocytopenia and hepatic dysfunction. Human herpesvirus-6 (HHV-6) DNA was found in his CSF during the acute stage of the disease by means of the polymerase chain reaction. T2-weighted MRI revealed high signal intensity in the left thalamus and left parieto-occipital deep white matter. The myelin basic protein concentration in the CSF was elevated suggesting acute demyelination. The patient is now 2.5 years old and has no sequelae.. Since clinical course and neuroimaging after HHV-6 infection are similar to those in acute disseminated encephalomyelitis, clinicians must pay attention to primary HHV-6 infection in patients under 2 years old with white matter lesions.

Topics: Acute Disease; Brain; Brain Diseases; Child, Preschool; Demyelinating Diseases; DNA, Viral; Dominance, Cerebral; Encephalitis, Viral; Follow-Up Studies; Herpesviridae Infections; Herpesvirus 6, Human; Humans; Infant; Liver Function Tests; Magnetic Resonance Imaging; Male; Myelin Basic Protein

Multiple sclerosis may ultimately be effectively treated using appropriate immunosuppressive regimens. Both cytotoxic drugs and therapeutic apheresis may constitute important therapeutic options. A number of studies are currently underway which will hopefully clarify the exact role of these treatment modalities in patients at different stages of disease.

Topics: Acute Disease; Adrenocorticotropic Hormone; Adult; Antilymphocyte Serum; Azathioprine; Cell Separation; Chronic Disease; Cyclophosphamide; Female; Humans; Immunosuppressive Agents; Lymphocyte Depletion; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Plasmapheresis; Prednisone; Recurrence

Topics: Acute Disease; Adjuvants, Immunologic; Age Factors; Animals; Antigens; Bone Marrow Transplantation; Cyclophosphamide; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Immunization, Passive; Lymphocyte Transfusion; Lymphocytes; Myelin Basic Protein; Neutrophils; Pertussis Vaccine; Rats; Species Specificity; Transplantation Immunology

Although multiple sclerosis (MS) is considered primarily as a demyelinating disease, neuronal damage is abundant and correlates with the neurological deficit. Therefore, we investigated the frequency and characteristics of human T cells specific for synapsin-a neuronal protein highly conserved among species. Synapsin specific T cell responses were detected at a frequency similar to that of MBP specific T cells in MS patients, one patient with acute demyelinating encephalomyelitis (ADEM) and controls. Long-term T cell lines specific for synapsin exhibited a CD3(+), CD4(+), CD8(-) phenotype and produced high amounts of tumor-necrosis-factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) after antigen specific stimulation, whereas lymphotoxin (LT), interleukin-4 (IL-4) and interleukin-10 (IL-10) were detectable in smaller quantities.

Topics: Acute Disease; CD3 Complex; CD4 Antigens; Cell Line; Dose-Response Relationship, Immunologic; Encephalomyelitis, Acute Disseminated; Humans; Immunophenotyping; Interferon-gamma; Interleukin-10; Interleukin-4; Lymphotoxin-alpha; Multiple Sclerosis; Myelin Basic Protein; Synapsins; T-Lymphocytes; Tumor Necrosis Factor-alpha

Intrathecal immunoglobulin synthesis and activation of the complement cascade occurs in patients with multiple sclerosis (MS). The present study aimed at further studying the relation between intrathecal immunoglobulin synthesis and complement activation. We compared total intrathecal synthesis of IgA, IgG, and IgM, the number of cells secreting anti-myelin basic protein (MBP) and anti-proteolipid protein (PLP) antibodies of the IgG isotype and intrathecal activation of the complement cascade in patients with possible onset symptoms of MS (n = 18) or clinically definite MS (n = 30). Early activation of the complement cascade correlated with intrathecal synthesis of IgM. Intrathecal IgG, IgA and IgM synthesis also correlated weakly with the presence of cells secreting anti-MBP or anti-PLP autoantibodies. Full activation of the complement cascade did not correlate with any measures of intrathecal antibody synthesis. These findings suggest a complex relation between different immunoglobulin isotypes and complement activation which may have similarly complex roles in the pathogenesis of MS.

Topics: Acute Disease; Adult; Complement Activation; Female; Humans; Immunoglobulins; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Myelin Proteolipid Protein; Optic Neuritis

Acute relapses of multiple sclerosis (MS) are characterized by elevated Free (F)/Bound (B) anti-MBP ratios during the initial phase, followed by a steady decline of F antibody as the recovery/remission phase develops. The (human) MBP epitope for MS anti-MBP is: Pro85-Val-Val-His-Phe-Phe-Lys-Asn-Ile-Val-Thr-Pro96. In phase one clinical research, synthetic peptides (p) containing this epitope, namely pMBP86-95 and/or pMBP82-98, were intrathecally administered to MS patients with monosymptomatic or polysymptomatic relapses to determine the dosage, frequency and duration of administration which will immediately neutralize F circulating CSF anti-MBP. Patients with monosymptomatic relapses required 50 mg of peptide administered daily for 4-5 days. In patients with polysymptomatic relapses, F anti-MBP can be neutralized with dosages between 50 mg peptide daily for 4 days up to 100 mg twice a day for 2 days; however due to the prolonged nature of polysymptomatic relapses, antibody neutralization could not be maintained by these short courses of intrathecal peptide administration. Intravenous administration of these same peptides did not prevent occurrence of future relapses.

Topics: Acute Disease; Adult; Autoantibodies; Epitopes; Humans; Injections, Intravenous; Injections, Spinal; Male; Multiple Sclerosis; Myelin Basic Protein; Peptides; Protein Binding; Recurrence

In the current study, it was aimed to evaluate the changes in myelinated and unmyelinated nerve fibers in retinal ischemia‑reperfusion injuries caused by acute ocular hypertension and to determine the sequence of these changes. Adult healthy New Zealand white rabbits were randomized to the hemodynamic group [n=12; used to determine the optimal intraocular pressure (IOP) for the subsequent experiments] and the hypertension group (n=6; 70‑mmHg hypertension induced in one eye). IOP was adjusted using a cannula and saline. Doppler ultrasound was used to measure the velocity of the optic artery under different intraocular pressures. Immunohistochemistry for myelin basic protein (MBP) was performed. Apoptosis of retinal cells was detected by terminal deoxynucleotidyl transferase biotin‑dUTP nick end labeling (TUNEL) assay. Electron microscopy was used to investigate the changes in myelinated and unmyelinated nerve fibers. IOP of the hypertension eyes was maintained at 70.2±1.0 mmHg, while IOP of control eyes was 7‑14 mmHg. Doppler ultrasound demonstrated an obvious decline of peak systolic velocity and an increase of resistance index of retinal bloodstream under a 70‑mmHg IOP. MBP immunohistochemistry and electron microscopy demonstrated obvious injuries to the myelin fibers. TUNEL indicated a significantly higher apoptosis rate in the hypertension eyes compared with control eyes. The apoptosis rate of retinal ganglion cells and bipolar cells in unmyelinated regions was higher than in myelinated regions. In conclusion, an IOP of 70 mmHg led to incomplete retinal ischemia but was the threshold for retinal ischemia, leading to obvious injuries to the myelin fibers.

Topics: Acute Disease; Animals; Disease Models, Animal; Intraocular Pressure; Male; Microscopy, Electron; Myelin Basic Protein; Nerve Fibers, Unmyelinated; Ocular Hypertension; Optic Nerve; Rabbits; Retina; Ultrasonography, Doppler

At present, the great attention is given to the neurospecific markers as their elevated level in the cerebrospinal fluid corresponds to the degree of destruction of relevant CNS cells. Therefore, actual direction of the studies of the pathogenesis and diagnosis of CNS diseases is to determine levels of neurospecific markers in the cerebrospinal fluid (CSF). The purpose of the study was to evaluate the diagnostic and prognostic role of NSE, S-100 protein, GFAP and MBP levels in CSF of patients with acute bacterial meningitis. S-100 protein, NSE, GFAP and MBP levels in CSF of patients with acute pneumococcal and meningococcal meningitis were determined during admission and after 10-12 days of treatment. Patients were divided into groups depending on the etiology and severity of the disease. 60 cases of acute bacterial meningitis, as a study group, and 12 cases with acute respiratory infection and meningism, as a control group, were analyzed. It is shown that CSF levels of NSE, S-100 protein, GFAP and MBP on the first day of admission were significantly increased (P<0,05), depending on the severity of the disease. The highest levels of neurospecific markers have been identified in non-survivors (P<0,001). The concentration changes of CSF neurospecific markers are found to be helpful as a diagnostic and prognostic marker in acute bacterial meningitis.

Topics: Acute Disease; Adolescent; Adult; Aged; Biomarkers; Glial Fibrillary Acidic Protein; Humans; Meningitis, Bacterial; Meningitis, Meningococcal; Meningitis, Pneumococcal; Middle Aged; Myelin Basic Protein; Phosphopyruvate Hydratase; S100 Proteins; Severity of Illness Index; Young Adult

Delayed neurologic sequelae (DNS) after carbon monoxide (CO) poisoning manifest as a relapse of neurologic deficits. However, the long-term outcome of DNS has not been fully clarified. Myelin basic protein (MBP) levels in the cerebrospinal fluid (CSF) have been reported to be elevated in DNS. However, the precise timing and clinical value of the CSF examination have not been fully evaluated. We aimed to clarify the long-term outcome and the factors predicting the outcome of DNS and to evaluate the utility of CSF-MBP for predicting the development and severity of DNS.. This work was designed as a single-center, prospective, observational study. We graded DNS severity as Grade 1 (consistent independence), Grade 2 (temporary dependence), or Grade 3 (persistent dependence). We analyzed the percentage categorized in each grade and the parameters associated with outcome.. Of 100 patients experiencing acute CO poisoning (median age: 46 years; 69% male), 20 (20%) developed DNS, including six Grade 1 (30%), ten Grade 2 (50%), and four Grade 3 (20%) cases. The Grade 3 patients [median: 77 years; interquartile range (IQR): 76-82] were older than the Grade 1 patients [42; 30-46] (P<0.01); the DNS onset of the Grade 1 patients [median interval after poisoning: 35 days; IQR: 32-56] occurred later than that of the Grade 3 patients [10; 9-13] P<0.001) and the Grade 2 patients [25; 23-27] (P<0.05). The CSF-MBP levels of the DNS patients were higher than those of the non-DNS patients (P<0.0001). The 1-month CSF-MBP levels of the Grade 3 patients were higher than those of the Grade 1 patients (P<0.05); the MBP index, defined as [(Age)×(1-month CSF-MBP)], was higher in the Grade 3 patients than in the Grade 1 patients (P<0.01). Severe DNS were associated with advanced age (>72.5 years), earlier onset (<18 days), higher 1-month CSF-MBP (>252 pg/ml), and higher MBP index (>20.9 year × ng/ml).. Poor DNS outcomes were associated with advanced age and earlier onset. CSF-MBP can serve as a sensitive predictor of both the development and outcomes of DNS.

Topics: Acute Disease; Adult; Age Factors; Aged; Aged, 80 and over; Biomarkers; Carbon Monoxide Poisoning; Female; Humans; Japan; Magnetic Resonance Imaging; Male; Middle Aged; Myelin Basic Protein; Neurotoxicity Syndromes; Predictive Value of Tests; Prognosis; Prospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Time Factors; Young Adult

Topics: Acute Disease; Adult; Aged; Biomarkers; Carbon Monoxide Poisoning; Cytokines; Female; Humans; Male; Middle Aged; Myelin Basic Protein; Neurotoxicity Syndromes; Prognosis; S100 Calcium Binding Protein beta Subunit

Thymosin β4 (Tβ4) is a 5K actin binding peptide. Tβ4 improves neurological outcome in a rat model of embolic stroke and research is now focused on optimizing its dose for clinical trials. The purpose of this study was to perform a dose-response study of Tβ4 to determine the optimal dose of neurological improvement in a rat model of embolic stroke.. Male Wistar rats were subjected to embolic middle cerebral artery occlusion (MCAo). Rats were divided into 4 groups of 10 animals/group: control, 2, 12 and 18 mg/kg. Tβ4 was administered intraperitoneally 24h after MCAo and then every 3 days for 4 additional doses in a randomized controlled fashion. Neurological tests were performed after MCAo and before treatment and up to 8 weeks after treatment. The rats were sacrificed 56 days after MCAo and lesion volumes measured. Generalized estimating equation was used to compare the treatment effect on long term functional recovery at day 56. A quartic regression model was used for an optimal dose determination.. Tβ4 significantly improved neurological outcome at dose of 2 and 12 mg/kg at day 14 and extended to day 56 (p-values <0.05). The higher dose of 18 mg/kg did not show significant improvement. The estimated optimal dose of 3.75 mg/kg would provide optimal neurological improvement.. This study shown that Tβ4 significantly improved the long term neurological functional recovery at day 56 after MCAo with an optimal dose of 3.75 mg/kg. These results provide preclinical data for human clinical trials.

Topics: Acute Disease; Adenomatous Polyposis Coli; Animals; Brain; Bromodeoxyuridine; Disease Models, Animal; Dose-Response Relationship, Drug; Infarction, Middle Cerebral Artery; Male; Myelin Basic Protein; Neuroimaging; Neurologic Examination; Rats; Stroke; Thymosin; Time Factors; Treatment Outcome; Versicans

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Carbon Monoxide Poisoning; Female; Humans; Interleukin-6; Male; Middle Aged; Myelin Basic Protein; Neurotoxicity Syndromes; Prospective Studies; Young Adult

Here, we assessed the effects of acute experimental autoimmune encephalomyelitis (EAE) on the rat hippocampal somatostatinergic system and whether administration of an ethanolamine phosphate salt could prevent the appearance of the clinical signs and the impairment of the somatostatinergic system in this pathological condition. Female Lewis rats were injected in both hindlimb footpads with myelin basic protein from guinea pig brain and complete Freund's adjuvant and were sacrificed when limp tail (grade 1 EAE) or severe hindlimb paralysis (grade 3 EAE) were observed. One group was injected daily with ethanolamine phosphate, starting two days prior to immunization and for 15 days thereafter. The animals were sacrificed 15 days post-immunization. Acute EAE in grade 3 increased anti-myelin basic protein antibodies in rat serum as well as tumor necrosis factor-α and interferon-γ levels in hippocampal extracts. In addition, it decreased the somatostatin receptor density, somatostatin receptor subtype 2 mRNA and protein content, and the inhibitory effect of somatostatin on adenylyl cyclase activity in the hippocampus. The protein levels of the inhibitory G protein subunits αi(1-3), the G protein-coupled receptor kinase isoforms 2, 5 and 6, the phosphorylated cyclic AMP-binding protein and the somatostatin-like immunoreactivity content were unaltered in this brain area. Acute EAE in grade 1 did not modify any of these parameters. Ethanolamine phosphate administration prevented the clinical expression of acute EAE as well as the decrease in the somatostatin receptor density, somatostatin receptor subtype 2 expression and the capacity of somatostatin to inhibit adenylyl cyclase activity at the time-period studied. Furthermore, it blunted the rise in serum anti-myelin basic protein antibodies and hippocampal interferon-γ and tumor necrosis factor-α levels. Altogether, these data suggest that ethanolamine phosphate might provide protection against acute EAE.

Topics: Acute Disease; Adenylyl Cyclases; Animals; Cyclic AMP Response Element-Binding Protein; Cytokines; Encephalomyelitis, Autoimmune, Experimental; Ethanolamines; Female; GTP-Binding Proteins; Hippocampus; Myelin Basic Protein; Rats; Rats, Inbred Lew; Receptors, Somatostatin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Somatostatin

Anti-myelin basic protein (MBP) antibodies in pediatric-onset MS and controls were characterized. Serum samples were obtained from 94 children with MS and 106 controls. Paired CSF and serum were obtained from 25 children with MS at time of their initial episode of acute demyelinating syndrome (ADS). Complementary assays were applied across samples to evaluate the presence, and the physical binding properties, of anti-MBP antibodies. While the prevalence and titers of serum anti-MBP antibodies against both immature and mature forms of MBP were similar in children with MS and in controls, binding characteristics and formal Surface Plasmon Resonance (SPR) studies indicated surprisingly high binding affinities of all pediatric anti-MBP antibodies. Serum levels of anti-MBP antibodies correlated significantly with their CSF levels, and their presence in children with MS was associated with significantly increased risk of an acute disseminated encephalomyelitis-like initial clinical presentation. While antibodies to both immature and mature forms of MBP can be present as part of the normal pediatric humoral repertoire, these anti-myelin antibodies are of surprisingly high affinity, can access the CNS during inflammation, and have the capacity to modulate disease expression. Our findings identify an immune mechanism that could contribute to the observed heterogeneity in spectrum of clinical presentations in early-onset MS.

Topics: Acute Disease; Adolescent; Autoantibodies; Biomarkers; Child; Child, Preschool; Female; Humans; Infant; Male; Multiple Sclerosis; Myelin Basic Protein; Myelin Sheath; Nerve Tissue Proteins; Risk Factors; Syndrome; Transcription Factors; Young Adult

Experimental autoimmune encephalomyelitis (EAE) is mediated by CD4+ Th1 cells that mainly secrete IFN-gamma and TNF-alpha, important cytokines in the pathophysiology of the disease. Spontaneous remission is, in part, attributed to the down regulation of IFN-gamma and TNF-alpha by TGF-beta. In the current paper, we compared weight, histopathology and immunological parameters during the acute and recovery phases of EAE to establish the best biomarker for clinical remission. Female Lewis rats were immunised with myelin basic protein (MBP) emulsified with complete Freund's adjuvant. Animals were evaluated daily for clinical score and weight prior to euthanisation. All immunised animals developed the expected characteristics of EAE during the acute phase, including significant weight loss and high clinical scores. Disease remission was associated with a significant reduction in clinical scores, although immunised rats did not regain their initial weight values. Brain inflammatory infiltrates were higher during the acute phase. During the remission phase, anti-myelin antibody levels increased, whereas TNF-alpha and IFN-gamma production by lymph node cells cultured with MBP or concanavalin A, respectively, decreased. The most significant difference observed between the acute and recovery phases was in the induction of TNF-alpha levels in MBP-stimulated cultures. Therefore, the in vitro production of this cytokine could be used as a biomarker for EAE remission.

Topics: Acute Disease; Animals; Biomarkers; Encephalomyelitis, Autoimmune, Experimental; Female; Interferon-gamma; Lymph Nodes; Myelin Basic Protein; Rats; Rats, Inbred Lew; Spleen; Time Factors; Tumor Necrosis Factor-alpha; Weight Loss

An immuno-enzyme assay of NSE and MBP in the cerebrospinal fluid (CFS) and blood serum of rats during the development of acute experimental autoimmune encephalomyelitis revealed the increase of NSE, a neuronal marker, and MBP, a marker for myelin. The investigation has shown that the increased level of NSE in CSF was prior to the increased concentration of MBP. The changes of these neurospecific proteins (NSP) in the serum were not the same as in the CSF. The analysis of the ratio between NSP concentrations in CSF to serum revealed the initial marked decrease of BBB permeability to MBP but not to NSE.

Topics: Acute Disease; Animals; Autoimmune Diseases; Biomarkers; Blood-Brain Barrier; Disease Models, Animal; Encephalomyelitis; Female; Myelin Basic Protein; Nerve Tissue Proteins; Oligodendroglia; Phosphopyruvate Hydratase; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Transcription Factors

Chronic exposure to the copper-chelating agent, cuprizone (CPZ), is an increasingly popular model for producing demyelination. More importantly, cessation of cuprizone exposure allows for full remyelination, which represents a window of opportunity for determining the influence of environmental factors on regenerative processes. In the present study, CPZ-treated animals were assessed for functional status of systemic and central cytokine responsiveness to LPS, as well as assessment for signs of body weight changes. Exposure of male C57BL/6J mice to 5 weeks of 0.2% CPZ in the diet was optimal in producing demyelination and microglial activation, as measured by myelin basic protein, CD11b, and CD45 immunohistochemistry. Acute challenge with LPS at the end of 5 weeks CPZ treatment did not alter IL-1beta, IL-6, nor TNFalpha responses in the spleen and corpus callosum. Similarly, repeated exposure to LPS during the remyelination phase (CPZ removal) did not influence these measures to LPS. Plasma corticosterone was unaffected following acute challenge of CPZ-pretreated animals, but after repeated LPS treatment, there was a significant augmentation of the corticosterone response in CPZ-pretreated mice. Interestingly, the basal concentration of IL-1beta in the corpus callosum of CPZ treated animals was significantly increased, which was in keeping with the increase in activated microglial cells. In conclusion, the cuprizone model of demyelination and remyelination does not appear to influence the systemic nor central IL-1, IL-6, and TNF responses to acute nor repeated LPS. This opens up the possibility for studying the contribution of systemic inflammatory processes on remyelination after cessation of CPZ treatment.

Topics: Acute Disease; Animals; Body Weight; CD11b Antigen; Chelating Agents; Chronic Disease; Corpus Callosum; Corticosterone; Cuprizone; Cytokines; Demyelinating Diseases; Disease Models, Animal; Leukocyte Common Antigens; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Microglia; Myelin Basic Protein; Myelin Sheath; Nerve Regeneration; Spleen

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

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

Biochemical markers of acute neuronal injury may aid in the diagnosis and management of acute ischemic stroke. Serum samples from the National Institute for Neurological Disorders and Stroke (NINDS) recombinant tissue plasminogen activator Stroke Study were analyzed for the presence of 4 biochemical markers of neuronal, glial, and endothelial cell injury. These biochemical markers, myelin basic protein (MBP), neuron-specific enolase (NSE), S100beta, and soluble thrombomodulin, were studied for an association with initial stroke severity, infarct volume, and functional outcome.. In the original NINDS study, serum samples were drawn from all patients on presentation to the Emergency Department and at approximately 2 and 24 hours after initiation of study therapy. In this analysis, stored serum samples were available for 359 patients; 107 patients had samples for all 3 time points. Serum marker concentrations were measured by ELISA techniques. We examined the relation between serum concentrations of each marker and the degree of baseline neurological deficit, functional outcome, and infarct size on computed tomography at 24 hours and the effect of fibrinolytic therapy.. Higher 24-hour peak concentrations of MBP, NSE, and S100beta were associated with higher National Institutes of Health Stroke Scale baseline scores (r=0.186, P<0.0001; r=0.117, P=0.032; and r=0.263, P<0.0001, respectively). Higher peak concentrations of MBP and S100beta (r=0.209, P<0.0001; r=0.239, P<0.0001) were associated with larger computed tomography lesion volumes. Patients with favorable outcomes had smaller changes in MBP and S100beta (P<0.05) concentrations in the first 24 hours. Soluble thrombomodulin was not associated with any severity or outcome measure.. This study corroborates previous work demonstrating correlations of MBP, NSE, and S100beta with clinical and radiographic features in acute stroke. Despite significantly better outcomes in the tissue plasminogen activator-treated group, we found no difference in the early release of the 4 biomarkers between treatment groups. Further study will define the role of biomarkers in acute stroke management and prognostication.

Topics: Acute Disease; Adult; Aged; Biomarkers; Brain Damage, Chronic; Brain Infarction; Brain Ischemia; Double-Blind Method; Endothelial Cells; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Myelin Basic Protein; Nerve Growth Factors; Neuroglia; Neurons; Phosphopyruvate Hydratase; Randomized Controlled Trials as Topic; Recombinant Proteins; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Thrombomodulin; Time Factors; Tissue Plasminogen Activator; Tomography, X-Ray Computed; Treatment Outcome

Local inflammation may be a precipitating event in autoimmune processes. In this study, we demonstrate that regulated influx of monocytes and dendritic cells (DC) into the CNS causes an acute neurological syndrome that results in a demyelinating encephalomyelitis. Expansion of monocytes and DC by conditional expression of Flt3 ligand in animals expressing CCL2 in the CNS promoted parenchymal cell infiltration and ascending paralysis in 100% of the mice within 9 days of Flt3 ligand induction. Depletion of circulating monocytes and DC reduced disease incidence and severity. Unlike the classical models of experimental autoimmune encephalomyelitis, depletion of CD4+ and CD8+ T cells did not affect disease induction. T cells and demyelinating lesions were observed in the CNS at a later stage as a result of organ-specific inflammation. We propose that alterations in the numbers or function of monocytes and DC coupled to dysregulated expression of chemokines in the neural tissues, favors development of CNS autoimmune disease.

Topics: Acute Disease; Animals; Cell Movement; Chemokine CCL2; Chronic Disease; Dendritic Cells; Doxycycline; Encephalomyelitis, Autoimmune, Experimental; Leukocyte Count; Ligands; Membrane Proteins; Meningoencephalitis; Mice; Mice, Transgenic; Monocytes; Myelin Basic Protein; Spinal Cord

Topics: Acute Disease; Animals; Disease Models, Animal; Drug Administration Schedule; Humans; Multiple Sclerosis; Myelin Basic Protein; Myelin Sheath; Nerve Fibers, Myelinated; Nerve Regeneration; Oligodendroglia; Rats; Thyroid Hormones; Time Factors

Topics: Acute Disease; Carbon Monoxide Poisoning; Cerebral Cortex; Cerebral Hemorrhage; Cerebral Infarction; Diffusion Magnetic Resonance Imaging; Globus Pallidus; Humans; Iron; Myelin Basic Protein; Nerve Fibers, Myelinated; Prospective Studies

In humans, studies of autoreactive T cells that mediate multiple sclerosis have been largely confined to testing peripheral blood lymphocytes. Little is known how such measurements reflect the disease-mediating autoreactive T cells in the CNS. This information is also not available for murine experimental allergic encephalomyelitis (EAE); the low number of T cells that can be obtained from the blood or the brain of mice prevented such comparisons. We used single-cell resolution IFN-gamma ELISPOT assays to measure the frequencies and functional avidities of myelin basic protein (MBP:87-99)-specific CD4 cells in SJL mice immunized with this peptide. Functional MBP:87-99-specific IFN-gamma-producing cells were present in the CNS during clinical signs of EAE, but not during phases of recovery. In contrast, MBP:87-99-specific T cells persisted in the blood during all stages of the disease, and were also present in mice that did not develop EAE. Therefore, the increased frequency of MBP:87-99-reactive T cells in the blood reliably reflected the primed state, but not the inflammatory activity of these cells in the brain. The functional avidity of the MBP:87-99-reactive T cells was identical in the brain and blood and did not change over 2 mo as the mice progressed from acute to chronic EAE. Therefore, high-affinity T cells did not become selectively enriched in the target organ, and avidity maturation of the MBP:87-99-specific T cell repertoire did not occur in the observation period. The data may help the interpretation of measurements made with peripheral blood lymphocytes of multiple sclerosis patients.

Topics: Acute Disease; Animals; Autoantigens; Autoimmunity; Central Nervous System; Chronic Disease; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Interferon-gamma; Lymph Nodes; Male; Mice; Myelin Basic Protein; Peptide Fragments; Spleen; T-Lymphocyte Subsets; Time Factors

We investigated the apoptosis of myelin basic protein (MBP)-specific T lymphocytes in multiple sclerosis (MS) patients with acute (AMS) or stable (SMS) MS by evaluating the expression of apoptosis markers on peripheral cells. Cells of healthy controls (HC) were evaluated as well. Results showed that mitogen-stimulated apoptosis was comparable among patients and controls, whereas MBP-stimulated CD4+ and CD8+ 7-AAD+ and 7-AAD+ Fas+ cell (apoptotic cells) were significantly reduced in AMS patients. A reduction of the apoptotic rate of myelin-specific CD4+ and CD8+ T lymphocytes could be involved in the immune-mediated destruction of the myelin sheath seen in AMS patients.

Topics: Acute Disease; Adult; Apoptosis; Biomarkers; Case-Control Studies; CD4-Positive T-Lymphocytes; fas Receptor; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Proto-Oncogene Proteins c-bcl-2; Tetradecanoylphorbol Acetate

Serotonin (5-hydroxytryptamine, 5-HT) is one of the most extensively studied neurotransmitters of the central nervous system. It also has been identified in constituents of the immune system. Therefore serotonin has been suggested to serve as a mediator of bidirectional interactions between the nervous system and the immune system. We investigated this interaction in experimental autoimmune encephalomyelitis (EAE), a well-defined animal model of autoimmune disease of the central nervous system (CNS) mimicking features of the human disease multiple sclerosis. EAE was induced by immunization with the autoantigens myelin basic protein (MBP) or the immunodominant peptide of myelin oligodendrocyte glycoprotein (MOG) spanning amino acids 35-55 (MOGp 35-55). We studied EAE in knockout (KO) mice lacking the 5-HT transporter (5-HTT) on a C57.BL/6 background, in comparison with wild-type C57.BL/6 animals. After immunization with MOGp 35-55, or with rat MBP, the disease courses of the 5-HTT knockout mice were attenuated as compared to wildtype control mice. This difference was more pronounced in female animals. To dissect potential immune mechanisms underlying this phenomenon, histological studies of the CNS and cytokine measurements in mononuclear cells from the spleens of 5-HTT KO mice and wild-type controls were performed. We found a reduction of the inflammatory infiltrate in the CNS and of the neuroantigen-specific production of IFN-gamma in splenocytes, again accompanied by a gender difference. These findings suggest a potential role of extracellular 5-HT homeostasis in the fine-tuning of neuroantigen-specific immune responses.

Topics: Acute Disease; Animals; Autoantigens; Cell Division; Central Nervous System; Disease Susceptibility; Encephalomyelitis, Autoimmune, Experimental; Epitopes; Female; Glycoproteins; Immunohistochemistry; Interferon-gamma; Interleukins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin Basic Protein; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Rats; Serotonin; Sex Factors; T-Lymphocytes

To elucidate the pathomechanisms of relapses of autoimmune disorders and to develop immunotherapy against relapses, we induced acute monophasic and chronic relapsing (CR) experimental autoimmune encephalomyelitis (EAE) in DA rats. Immunopathological and cytokine-chemokine analyses demonstrated that the number of infiltrating macrophages was significantly elevated in the CR-EAE than in acute EAE lesions and that IFN-gamma and IP-10 in the spinal cord were significantly upregulated during the first attack and relapse of CR-EAE, respectively, than at the peak of acute EAE. In vivo administration of decoy chemokine receptor plasmid DNAs encoding the binding sites of CXCR3 and CCR2 suppressed the development of relapse of CR-EAE. Importantly, multiple injections of DNAs did not elicit the antibody production against chemokine receptors. Taken together, these findings demonstrated that neutralization therapy with decoy chemokine receptor DNAs is effective to control autoimmune diseases.

Topics: Acute Disease; Animals; Antigens; Cell Movement; Cell Proliferation; Central Nervous System; Chemokines; Chronic Disease; Cytokines; DNA; Down-Regulation; Encephalomyelitis, Autoimmune, Experimental; Genetic Therapy; Immunization; Immunotherapy; Macrophages; Myelin Basic Protein; Myelin Proteins; Myelin Sheath; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Rats; Rats, Inbred Strains; Receptors, Chemokine; Recurrence; RNA, Messenger; T-Lymphocytes

Experimental allergic encephalomyelitis (EAE) is the animal model for multiple sclerosis. The present study underlines the importance of sodium phenylacetate (NaPA), a drug approved for urea cycle disorders, in inhibiting the disease process of adoptively transferred EAE in female SJL/J mice at multiple steps. Myelin basic protein (MBP)-primed T cells alone induced the expression of NO synthase (iNOS) and the activation of NF-kappaB in mouse microglial cells through cell-cell contact. However, pretreatment of MBP-primed T cells with NaPA markedly inhibited its ability to induce microglial expression of iNOS and activation of NF-kappaB. Consistently, adoptive transfer of MBP-primed T cells, but not that of NaPA-pretreated MBP-primed T cells, induced the clinical symptoms of EAE in female SJL/J mice. Furthermore, MBP-primed T cells isolated from NaPA-treated donor mice were also less efficient than MBP-primed T cells isolated from normal donor mice in inducing iNOS in microglial cells and transferring EAE to recipient mice. Interestingly, clinical symptoms of EAE were much less in mice receiving NaPA through drinking water than those without NaPA. Similar to NaPA, sodium phenylbutyrate, a chemically synthesized precursor of NaPA, also inhibited the disease process of EAE. Histological and immunocytochemical analysis showed that NaPA inhibited EAE-induced spinal cord mononuclear cell invasion and normalized iNOS, nitrotyrosine, and p65 (the RelA subunit of NF-kappaB) expression within the spinal cord. Taken together, our results raise the possibility that NaPA or sodium phenylbutyrate taken through drinking water or milk may reduce the observed neuroinflammation and disease process in multiple sclerosis patients.

Topics: Acute Disease; Administration, Oral; Adoptive Transfer; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Differentiation; Cell Line; Cell Movement; Chronic Disease; Disease Progression; Encephalomyelitis, Autoimmune, Experimental; Enzyme Inhibitors; Female; Growth Inhibitors; Immunosuppressive Agents; Injections, Intraperitoneal; Lymphocyte Activation; Mice; Mice, Inbred Strains; Microglia; Myelin Basic Protein; NF-kappa B; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Phenylacetates; Phenylbutyrates; Severity of Illness Index; Spinal Cord; T-Lymphocyte Subsets; Transcription Factor RelA; Tyrosine

Experimental autoimmune encephalomyelitis (EAE) is a major animal model of human multiple sclerosis (MS). CD4+ T cells are thought to play a pivotal role in the pathogenesis of EAE and MS. In order to investigate the depletion of CD4+ T cells from the systemic circulation as an effective strategy for the treatment of MS, we performed extracorporeal CD4+ T cell adsorption, using a filter to which anti-CD4+ antibody is immobilized as a ligand, in adoptively transferred EAE. Rats treated with CD4+ T cell removal filter (CD4RF) exhibited milder clinical signs of EAE and earlier recovery than those receiving sham treatment. Moreover, the thymic cells from EAE rats treated with CD4RF exhibited a suppressed proliferative response and IFN-gamma production to myelin basic protein. These results suggest that depletion of CD4+ T cells from the systemic circulation by extracorporeal treatment is a potentially useful strategy for treatment of acute phase and relapsing MS.

Topics: Acute Disease; Adoptive Transfer; Animals; CD4-Positive T-Lymphocytes; Cell Line; Cytapheresis; Encephalomyelitis, Autoimmune, Experimental; Interferon-gamma; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein; Rats; Rats, Inbred Lew; Thymus Gland

The ICAM-1-mediated brain endothelial cell (EC)-signaling pathway induced by adherent lymphocytes is a central element in facilitating lymphocyte migration through the tight endothelial barrier of the brain. Rho proteins, which must undergo posttranslational prenylation to be functionally active, have been shown to be an essential component of this signaling cascade. In this study, we have evaluated the effect of inhibiting protein prenylation in brain ECs on their ability to support T lymphocyte migration. ECs treated in vitro with protein prenylation inhibitors resulted in a significant reduction in transendothelial T lymphocyte migration. To determine the therapeutic potential of this approach, an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis, was induced in Biozzi ABH mice. Animals treated before disease onset with protein prenylation inhibitors exhibited a dramatic and significant reduction in both leukocyte infiltration into the CNS and clinical presentation of disease compared with untreated animals. These studies demonstrate, for the first time, the potential for pharmacologically targeting CNS EC signaling responses, and particularly endothelial Rho proteins, as a means of attenuating leukocyte recruitment to the CNS.

Topics: Acute Disease; Animals; Benzamides; Brain; Cell Line; Cell Membrane; Cell Movement; Dimethylallyltranstransferase; Disease Models, Animal; Drug Combinations; Encephalomyelitis, Autoimmune, Experimental; Endothelium, Vascular; Enzyme Inhibitors; Guinea Pigs; Leukocytes; Methionine; Mice; Mice, Inbred Strains; Multiple Sclerosis; Myelin Basic Protein; Protein Prenylation; Rats; Rats, Inbred Lew; rho GTP-Binding Proteins; T-Lymphocytes

It has been suggested that Golli proteins, structurally related to myelin basic proteins (MBPs), have a role in autoimmune processes. We studied the expression of these proteins in multiple sclerosis (MS) and determined that the number of Golli-immunoreactive (ir) cells was significantly higher around lesions of chronic MS than in control white matter. Golli proteins were expressed in the adult oligodendrocyte precursor cells (OPCs), activated microglia/macrophages, and some demyelinated axons around MS lesions. Their expression in adult OPCs indicates remyelination attempts, whereas the expression in the subpopulation of microglia/macrophages suggests roles in the immune processes of MS. In addition, Golli proteins may be markers of axonal transection, which is characteristic for MS.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Brain; Brain Chemistry; Chronic Disease; Female; Humans; Immunohistochemistry; Macrophages; Male; Microglia; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Nerve Tissue Proteins; Oligodendroglia; Stem Cells; Transcription Factors

Type I diabetes and multiple sclerosis (MS) are distinct autoimmune diseases where T cells target either islet or CNS self-proteins. Unexpectedly, we found that autoreactive T cells in diabetic patients, relatives with high diabetes risk, nonobese diabetic (NOD) mice, and MS patients routinely target classical islet as well as CNS autoantigens. The pathogenic potential of CNS autoreactivity was testable in NOD mice. Pertussis holotoxin, without additional Ags or adjuvants, allowed development of an NOD mouse-specific, autoimmune encephalitis with variable primary-progressive, monophasic, and relapsing-remitting courses. T cells from diabetic donors transferred CNS disease to pertussis toxin-pretreated NOD.scid mice, with accumulation of CD3/IFN-gamma transcripts in the brain. Diabetes and MS appear more closely related than previously perceived. NOD mouse-specific, autoimmune encephalitis provides a new MS model to identify factors that determine alternative disease outcomes in hosts with similar autoreactive T cell repertoires.

Topics: Acute Disease; Adoptive Transfer; Adult; Amino Acid Sequence; Animals; Autoantigens; Cell Division; Cytokines; Diabetes Mellitus, Type 1; Encephalomyelitis, Autoimmune, Experimental; Female; Follow-Up Studies; Humans; Islets of Langerhans; Lymphocyte Activation; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Inbred NZB; Mice, SCID; Molecular Sequence Data; Multiple Sclerosis; Myelin Basic Protein; Organ Specificity; Prospective Studies; Recurrence; Species Specificity; T-Lymphocyte Subsets

Lewis rats immunized with myelin basic protein (MBP) develop experimental autoimmune encephalomyelitis (EAE) and associated anterior uveitis (AU), which can relapse without recurring of EAE. In this study, we analyzed the repertoire of MBP epitopes that play a role in acute and recurrent AU by injection of MBP synthetic peptides. In addition to the encephalitogenic epitopes 69-89 and 87-99, several cryptic epitopes were found to be strongly uveitogenic in Lewis rats upon immunization with synthetic peptides, including 100-120, 121-140 and 142-167. However, the peptide corresponding to the MBP residues 1-20 was uniquely capable of inducing AU without EAE. Immunization with intact MBP was not essential for the induction of the recurrence of AU. The responses of T cells from lymph nodes and spleens showed a dominant response to the original disease-induced epitope with responses to secondary epitopes. In conclusion, the analysis of pathogenic determinants important for the induction of uveitis provides further evidence that MBP-specific T cells also contribute to the pathogenesis of anterior uveitis. Moreover, this also suggests that a distinct immunoregulatory mechanism exists in the eye and spinal cord because of the uniqueness of the epitope 1-20 in AU but not EAE, and the capability of MBP-specific T cells of inducing AU without EAE.

Topics: Acute Disease; Animals; Cell Division; Encephalomyelitis, Autoimmune, Experimental; Epitopes; Female; Immunization; Myelin Basic Protein; Peptide Fragments; Rats; Rats, Inbred Lew; Recurrence; Uveitis, Anterior

The development of severe CNS damages including encephalitis is highly probable in some respiratory and exanthemata viral infections (measles, rubella, parotitis). A high level of IgG antibodies to the myelin basic protein was found in patients with parotitis meningitis and rubella encephalitis but it was not high in 80% of patients with encephalitis of the unclear etiology and in 25% of cases with rubella encephalitis. More accurate analysis of clinical, neurovisual and immunologic data revealed a link of appearance of such complications with both the presence of more pronounced demyelinization and prolongation of the disease.

Topics: Acute Disease; Adolescent; Antibodies, Bacterial; Child; Child, Preschool; Encephalitis, Viral; Female; Humans; Immunoglobulin E; Immunoglobulin G; Male; Meningitis, Bacterial; Myelin Basic Protein; Prognosis

Lewis rats, on recovery from monophasic clinical experimental allergic encephalomyelitis (EAE), can be induced to develop repeated paralytic relapses with a graded reduction in clinical severity following intraperitoneal administration of IL-12. By the time of the third relapse, the number and size of inflammatory cuffs in the spinal cord were reduced with the makeup of the cellular infiltrate shifting to a significantly increased number of B cells. Serum levels of myelin basic protein (MBP)-specific IgG1 and IgG2b were found to rise over time while MBP and MBP peptide-positive macrophages and microglia became evident in perivascular cuffs and in spinal cord parenchyma, indicative of myelin phagocytosis. Axonal death was observed in semithin and EM sections of spinal cord in third relapse animals in association with iNOS and tPA immunostaining throughout gray and white matter. These neurotoxic or excitotoxic agents may contribute to axonal damage directly or indirectly by activated microglia and macrophages, leading to limited damage of the axonal-myelin unit.

Topics: Acute Disease; Animals; Autoantibodies; Axons; Encephalomyelitis, Autoimmune, Experimental; Female; Immunoglobulin G; Interleukin-12; Interleukins; Leukocyte Count; Macrophage Activation; Myelin Basic Protein; Myelin Sheath; Paralysis; Rats; Rats, Inbred Lew; Recurrence; Spinal Cord; Tissue Plasminogen Activator; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Biomarkers; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Myelin Basic Protein; Phosphopyruvate Hydratase; S100 Proteins; Stroke

The immunological effects of high-dose methylprednisolone in attacks of multiple sclerosis and acute optic neuritis have only been examined in a few randomized, controlled trials. We studied immunological changes in 50 patients with optic neuritis or multiple sclerosis who underwent lumbar puncture before and 1 week after completing a 15-day course of oral high-dose methylprednisolone treatment. Treatment resulted in a decrease in the concentration of myelin basic protein, a decrease in the serum concentration of immunoglobulin G (IgG) and intrathecal IgG synthesis, an increase in the cerebrospinal fluid concentration of transforming growth factor-beta1, and changes in the expression of CD25, CD26, and human leukocyte antigen-DR (HLA-DR) on CD4 T-cells. No effect was seen on the cerebrospinal fluid leucocyte count or the cerebrospinal fluid activity of matrix metalloproteinase-9 (MMP-9). The lack of a persistent effect on cerebrospinal fluid leucocyte recruitment and MMP-9 activity, despite changes in IgG synthesis, T-cell activation, and cytokine production, suggests that modulation of the function of inflammatory cells may contribute to the clinical efficacy of oral high-dose methylprednisolone treatment in optic neuritis and multiple sclerosis.

Topics: Acute Disease; Administration, Oral; Adult; Anti-Inflammatory Agents; Antigens; CD4-Positive T-Lymphocytes; Dose-Response Relationship, Drug; Female; Flow Cytometry; Humans; Immune System; Immunoglobulin G; Leukocyte Count; Male; Matrix Metalloproteinase 9; Methylprednisolone; Multiple Sclerosis; Myelin Basic Protein; Optic Neuritis; Randomized Controlled Trials as Topic; Spinal Cord; Spinal Puncture; Transforming Growth Factor beta

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

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

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

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

During the progression of relapsing experimental autoimmune encephalomyelitis (R-EAE), in SJL mice, disease relapses are mediated by T cells specific for non-cross-reactive myelin epitopes, a process termed 'epitope spreading'. CTLA-4, a negative regulator of T cell function modulates R-EAE, in that CTLA-4 blockade exacerbates clinical R-EAE. Herein, we show that CTLA-4-mediated signaling negatively regulates the dynamic spread of autoreactive T cell responses during the course of autoimmune disease. Anti-CTLA-4 mAb, administration at various points during the progression of R-EAE exacerbated subsequent clinical disease and enhanced T cell reactivity to both inducing and relapse-associated epitopes. In addition, CTLA-4 blockade during acute disease inhibited clinical remission. Thus, CTLA-4-mediated events are critical for intrinsic regulation of epitope spreading during autoimmune disease.

Topics: Abatacept; Acute Disease; Amino Acid Sequence; Animals; Antibodies, Monoclonal; Antigens, CD; Antigens, Differentiation; Autoantigens; Cross Reactions; CTLA-4 Antigen; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Epitopes, T-Lymphocyte; Flow Cytometry; Hypersensitivity, Delayed; Immunization; Immunoconjugates; Mice; Mice, Inbred Strains; Molecular Sequence Data; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein; Phospholipids; Recurrence; Remission, Spontaneous; T-Lymphocytes

Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model for multiple sclerosis (MS). EAE is typically initiated by CD4(+) T helper cell type 1 (Th1) autoreactivity directed against a single priming immunodominant myelin peptide determinant. Recent studies have shown that clinical progression of EAE involves the accumulation of neo-autoreactivity, commonly referred to as epitope spreading, directed against peptide determinants not involved in the priming process. This study directly addresses the relative roles of primary autoreactivity and secondary epitope spreading in the progression of both EAE and MS. To this end we serially evaluated the development of several epitope-spreading cascades in SWXJ mice primed with distinctly different encephalitogenic determinants of myelin proteolipid protein. In a series of analogous experiments, we examined the development of epitope spreading in patients with isolated monosymptomatic demyelinating syndrome as their disease progressed to clinically definite MS. Our results indicate that in both EAE and MS, primary proliferative autoreactivity associated with onset of clinical disease invariably regresses with time and is often undetectable during periods of disease progression. In contrast, the emergence of sustained secondary autoreactivity to spreading determinants is consistently associated with disease progression in both EAE and MS. Our results indicate that chronic progression of EAE and MS involves a shifting of autoreactivity from primary initiating self-determinants to defined cascades of secondary determinants that sustain the self-recognition process during disease progression.

Topics: Acute Disease; Adult; Animals; Antigenic Variation; Autoantigens; Autoimmune Diseases; Autoimmunity; Brain; Chronic Disease; Disease Models, Animal; Disease Progression; Encephalomyelitis, Autoimmune, Experimental; Epitopes; Female; Humans; Immunity, Cellular; Immunization; Immunodominant Epitopes; Male; Mice; Models, Immunological; Multiple Sclerosis; Myelin Basic Protein; Myelin Proteins; Myelin Proteolipid Protein; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Self Tolerance; Spinal Cord; Spleen; Th1 Cells

Multiple sclerosis (MS) is an autoimmune disease in which the myelin sheath of the central nervous system is degraded, and the 18.5 kDa isoform of myelin basic protein (MBP) is reduced in cationicity. In a unique case of acute, fulminating MS (Marburg's variant), MBP is considerably less cationic than MBP from both normal, and chronic MS-afflicted individuals. This electron microscopical study has identified that, in vitro, the less cationic Marburg MBP isomer forms a more extended protein-lipid complex than MBP from healthy or chronic MS-afflicted individuals. This correlation implies that chemical modifications to MBP in vivo contribute directly to the structural instability of myelin, and subsequent autoantigenic presentation of this protein, observed in vivo in MS.

Topics: Acute Disease; Autoantigens; Citrulline; Humans; Image Processing, Computer-Assisted; Microscopy, Electron; Microscopy, Electron, Scanning Transmission; Multiple Sclerosis; Myelin Basic Protein; Protein Conformation; Protein Isoforms

Experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats by inoculation with myelin basic protein (MBP) and adjuvants. Rats were treated with second daily injections of saline or cyclosporin A (CsA) from the day of inoculation. Saline-treated rats had an acute episode of disease followed by clinical recovery. Rats treated with CsA 16 or 32 mg/kg had minimal signs of EAE at the usual time after inoculation, but developed signs of disease after treatment was ceased. Rats treated with CsA 8 mg/kg had a delayed first episode of disease and then developed a relapsing or a chronic persistent course of disease. CsA 4 mg/kg delayed the onset of disease. To study the effects of CsA on the inflammatory infiltrate, cells were extracted from the spinal cords of rats with EAE, 16 h after a single injection of CsA or saline. Extracted cells were labelled with antibodies to T cells, CD11b/c (macrophages/microglia), CD95 (Fas) and Fas ligand. CsA 4 mg/kg did not alter the composition of the inflammatory infiltrate. Treatment with higher single doses of CsA caused a dose-dependent decline in the percentage of T cell receptor (TCR) alphabeta+ cells in the inflammatory infiltrate. All doses of CsA caused a significant increase in the number and percentage of cells that were apoptotic. CsA treatment caused an increase in the percentages of CD5+ and TCR alphabeta+ cells that were apoptotic. There was a decline in the percentage of apoptotic T cells that were Vbeta8.2+, compared to the percentage of non-apoptotic T cells that were Vbeta8.2+, in CsA treated rats compared to saline-treated controls. This suggests that, while CsA treatment caused a non-specific increase in the overall level of T cell apoptosis in the spinal cord, it abrogated the selective apoptosis of Vbeta8.2+ encephalitogenic T cells that normally occurs during spontaneous recovery from acute EAE.

Topics: Acute Disease; Animals; Apoptosis; Cyclosporine; Encephalomyelitis, Autoimmune, Experimental; Flow Cytometry; G1 Phase; G2 Phase; Immunization; Immunosuppressive Agents; Male; Mitosis; Myelin Basic Protein; Rats; Rats, Inbred Lew; Resting Phase, Cell Cycle; S Phase; Spinal Cord; T-Lymphocytes

Myelin basic protein (MBP), is a major component of the central nervous system (CNS) myelin. MBP can stimulate T cells that migrate into the CNS, initiating a cascade of events that result in perivascular infiltration and demyelination. EAE is an inflammatory and demyelinating autoimmune disease of the CNS that serves as a model for the human disease Multiple Sclerosis (MS). Taking advantage of the fact that EAE can be mediated by T cells, able to recognize MBP or its peptides, we developed a new approach to target anti-MBP T cells by fusing an MBP-sequence to a toxin. In the new chimeric protein, an oligonucleotide coding for the guinea pig MBP encephalitogenic moiety (residues 68-88) was fused to a cDNA encoding a truncated form of the PE gene (PE40). The chimeric gene termed MBP-PE was expressed in E. coli and highly purified. MBP-PE chimeric protein was cytotoxic to various anti-MBP T cells. Moreover, treatment with the novel MBP-toxin blocked the clinical signs of EAE as well as CNS inflammation and demyelination. A chimeric protein such as MBP-PE40 presents a novel prototype of chimeric proteins, composed of antigen/peptide-toxin, that could prove to be an efficient and specific immunotherapeutic agent for autoimmune diseases in which a known antigen is involved.

Topics: Acute Disease; ADP Ribose Transferases; Animals; Cell Line; Encephalomyelitis, Autoimmune, Experimental; Exotoxins; Female; Immunotoxins; Mice; Myelin Basic Protein; Recombinant Fusion Proteins; T-Lymphocytes

T cell co-stimulation through the CD28 receptor on T cells is critical to the induction of experimental autoimmune encephalomyelitis (EAE). In this study, expression of the co-stimulatory ligands B7-1 (CD80) and B7-2 (CD86), as well as the receptors CD28 and CTLA-4, were quantitated in central nervous system (CNS) tissues from mice at various stages of EAE. Immunohistochemistry and flow cytometry of CNS-infiltrating cells revealed a high percentage of infiltrating T cells expressing B7-1 and B7-2 during acute, chronic and relapsing EAE. Of the infiltrating cells 10-20% were CTLA-4(+), most of which were CD4(+) T cells. B7-1 and B7-2 expression within the CNS during active EAE might increase the potential for local activation of autoimmune T cells; however, the high level of expression of B7 molecules may also provide a mechanism for the autoregulation of activated CTLA-4(+) T cells.

Topics: Abatacept; Acute Disease; Animals; Antigens, CD; Antigens, Differentiation; B7-1 Antigen; B7-2 Antigen; CD28 Antigens; CTLA-4 Antigen; Encephalomyelitis, Autoimmune, Experimental; Female; Flow Cytometry; Immunoconjugates; Immunohistochemistry; Lymph Nodes; Membrane Glycoproteins; Mice; Mice, Inbred Strains; Myelin Basic Protein; Recurrence; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spinal Cord; T-Lymphocytes

The administration of soluble myelin proteins is an effective way of down-regulating the inflammation in the central nervous system (CNS) in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. To shed more light on the mechanism of this antigen-specific therapy, we determined the effect of the intraperitoneal (i.p.) injection of soluble myelin basic protein (MBP) on Tcell apoptosis in the CNS and peripheral lymphoid organs of Lewis rats with EAE induced by inoculation with MBP and complete Freund's adjuvant. In particular we assessed the level of apoptosis of Vbeta8.2+ Tcells, which constitute the predominant encephalitogenic MBP-reactive T cell population in the Lewis rat. The daily i.p. injection of MBP for 3 days from the onset of neurological signs inhibited the further development of neurological signs of EAE. Using two-color flow cytometry we found that a single i.p. injection of MBP increased the level of apoptosis of the Vbeta8.2+ T cell population in the CNS to 26.2% compared to 7.4% in saline-treated rats and 7.6% in ovalbumin-treated rats. In contrast, treatment with MBP did not increase the level of apoptosis of the Vbeta8.2+ population in the popliteal lymph node draining the inoculation site (1.4%) or in the spleen (1.6%) above that occurring in saline-treated rats (1.6% and 1.1%, respectively). Limiting dilution analysis revealed that the frequency of T cells reactive to the major encephalitogenic epitope, MBP72-89, was decreased in the CNS but not in the popliteal lymph node by this treatment. Three-color flow cytometry in MBP-treated rats demonstrated that CNS Vbeta8.2+ T cells expressing Fas (CD95) and Fas ligand were highly vulnerable to apoptosis compared to Vbeta8.2+ Tcells not expressing these proteins. We conclude that the i.p. injection of MBP increases the spontaneously occurring Fas-mediated activation-induced apoptosis of autoreactive T cells in the CNS in EAE and that this contributes to the therapeutic effect of the injection.

Topics: Acute Disease; Amino Acid Sequence; Animals; Apoptosis; Autoantigens; Encephalomyelitis, Autoimmune, Experimental; Fas Ligand Protein; fas Receptor; Female; Guinea Pigs; Ligands; Lymphocyte Count; Lymphoid Tissue; Membrane Glycoproteins; Molecular Sequence Data; Myelin Basic Protein; Organ Specificity; Rats; Rats, Inbred Lew; Receptors, Antigen, T-Cell, alpha-beta; Solubility; Spinal Cord; T-Lymphocyte Subsets

In this study we report for the first time that nasal administration of the Th2 cell-related cytokine interleukin-10 (IL-10), at concentrations of 1.5 microg/rat and 15 microg/rat, suppressed clinical signs of acute experimental allergic encephalomyelitis (EAE) in Lewis rats and prevented the development and relapse of protracted-relapsing EAE (PR-EAE) in DA rats. In contrast, subcutaneous injection of IL-10 (15 microg/rat) did not inhibit acute EAE. The IL-10-mediated suppression of EAE was associated with decreased myelin antigen-specific T-cell proliferative responses and IFN-gamma secretion in both acute and PR-EAE. In sections of spinal cords derived from rats nasally pretreated with IL-10, there were no infiltrating CD4+ T cells or macrophages, which are considered as major encephalitogenic or inflammatory cells. Most interestingly, nasally administered IL-10 also inhibited MHC class II expression in microglia, indicating that IL-10 administration by the nasal route prevents the activation of microglia. Administration of cytokines via the nasal route offers an exciting alternative in the prevention and treatment of autoimmune diseases.

Topics: Acute Disease; Administration, Intranasal; Animals; Biomarkers; CD4-Positive T-Lymphocytes; Dose-Response Relationship, Drug; Encephalomyelitis, Autoimmune, Experimental; Guinea Pigs; Histocompatibility Antigens Class II; Immunohistochemistry; Immunotherapy; Interferon-gamma; Interleukin-10; Lymphocyte Activation; Macrophages; Microglia; Myelin Basic Protein; Rats; Rats, Inbred Lew; Recurrence; Spinal Cord

Experimental autoimmune encephalomyelitis (EAE), a model for human multiple sclerosis, is an inflammatory disease of the CNS mediated by autoreactive T lymphocytes directed against the neuroantigen, myelin basic protein (MBP). EAE is inducible in the Lewis rat, which exhibits an acute monophasic disease, and in selected mouse strains, which show a remitting-relapsing or chronic course of paralysis. We examined the effects of neuroendocrine modulation by restraint stress on these models of EAE. In Lewis rats, daily cycles of restraint resulted in significant suppression of both clinical and histopathologic changes of EAE. Suppression of EAE was more pronounced in the female than in the male rat, which follows from the higher endogenous corticosterone levels in the female. Mechanistic studies suggested that stress affected the processing of MBP or the T-cell idiotype. In the relapsing murine model of EAE, B10.PL mice were restrained beginning either before MBP challenge or after the establishment of relapsing disease. We observed a striking inhibition of EAE clinical signs in mice stressed before challenge relative to nonstressed controls. Interestingly, approximately 10 days after termination of the stress period, clinical signs returned and were as severe or more severe than in control nonstressed animals. Stress administered after relapsing EAE was established had no protective effect. In vitro parameters revealed that only stress initiated before disease induction significantly reduced the frequency of MBP-specific lymphocytes in the spleen and lymph nodes. Both Th1 and Th2 cytokine responses were suppressed in stressed mice. T-cell receptor transgenic mice exposed to restraint showed a marked decreased in the number and functional activity of transgene-positive lymphocytes. In summary, elevated levels of endogenous neuroendocrine hormones exert a profoundly suppressive effect on both acute and chronic models of autoimmune CNS injury.

Topics: Acute Disease; Animals; Chronic Disease; Encephalomyelitis, Autoimmune, Experimental; Female; Male; Mice; Mice, Inbred Strains; Mice, Transgenic; Myelin Basic Protein; Neurosecretory Systems; Rats; Rats, Inbred Lew; Receptors, Antigen, T-Cell; Recurrence

The effect of a synaptosomal fraction isolated from bovine brain was examined on acute experimental allergic encephalomyelitis (EAE) in Wistar rats. Intraperitoneal administration of the animals with low doses of saline-soluble synaptosomal antigens 10 and 3 days previous to the active induction of the disease was an effective way of suppressing EAE. This treatment diminished the incidence and severity of EAE, reverted the appearance of central nervous system histological and biochemical alterations, and produced changes in the autoimmune humoral response against the encephalitogenic myelin basic protein. The phenomenon observed by treatment with synaptosomal fraction is similar to the previously described suppression mediated by myelin antigens. Taking into account that affinity-purified antibodies and T lymphocytes specific for myelin basic protein can also recognize several neuronal proteins, among them the specific synaptosomal protein synapsin I, can be suggested that antigen-driven bystander suppression could be a mechanism by which synaptosomal proteins suppress the response against myelin antigens.

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Acute Disease; Animals; Antigens; Brain Chemistry; Encephalomyelitis, Autoimmune, Experimental; Female; Immunohistochemistry; Injections, Intraperitoneal; Male; Myelin Basic Protein; Nerve Tissue Proteins; Rats; Rats, Wistar; Synapsins; Synaptosomes

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

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

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

Cerebrospinal fluid (CSF) may provide markers of severity and outcome of optic neuritis.. We examined the CSF from 29 patients with acute monosymptomatic optic neuritis (AMON) for content of myelin basic protein-like material (MBPLM) and correlated the levels with results of cranial magnetic resonance imaging. The length of the time from onset of AMON to the time of CSF collection did not exceed four weeks.. Only two patients (7%), one of whom developed an acute myelopathy one month after AMON, showed an elevated value of CSF MBPLM. No MBPLM was detected in 6 patients (21%), and other 21 (72%) had detectable levels of MBPLM but below the upper limit of normal of 0.1 ng/ml. The value of MBPLM was not significantly correlated with the interval to CSF sampling from onset of AMON or with severity of decreased visual acuity. The highest values of CSF MBLPM were observed among patients with severely decreased visual acuity and among patients with an abnormal MRI (13 of 27 i.e. 48%).. CSF MBPLM was rarely abnormal in AMON. However, CSF MBPLM may have potential value in reflecting disease activity, as the highest values were obtained among patients with CSF sampled soon after the maximum visual dysfunction was reached, with severe visual impairment, and with an abnormal MRI.

Topics: Acute Disease; Adolescent; Adult; Child; Female; Humans; Immunoglobulin G; Magnetic Resonance Imaging; Male; Middle Aged; Myelin Basic Protein; Neurologic Examination; Optic Neuritis; Predictive Value of Tests; Severity of Illness Index; Time Factors; Visual Acuity

The role of epitope spreading in the pathology of relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) was examined. Using peripherally induced immunologic tolerance as a probe to analyze the neuropathologic T cell repertoire, we show that the majority of the immunopathologic reactivity during the acute phase of R-EAE in SJL/J mice induced by active immunization with the intact proteolipid (PLP) molecule is directed at the PLP139-151 epitope and that responses to secondary encephalitogenic PLP epitopes may contribute to the later relapsing phases of disease. Intermolecular epitope spreading was demonstrated by showing the development of T cell responses to PLP139-151 after acute disease in mice in which R-EAE was initiated by the transfer of T cells specific for the non-cross-reactive MBP84-104 determinant. Intramolecular epitope spreading was demonstrated by showing that endogenous host T cells specific for a secondary encephalitogenic PLP epitope (PLP178-191) are demonstrable by both splenic T cell proliferative and in vivo delayed-type hypersensitivity responses in mice in which acute central nervous system damage was initiated by T cells reactive with the immunodominant, non-cross-reactive PLP139-151 sequence. The PLP178-191-specific responses are activated as a result of and correlate with the degree of acute tissue damage, since they do not develop in mice tolerized to the initiating epitope before expression of acute disease. Most importantly, we show that the PLP178-191-specific responses are capable of mediating R-EAE upon adoptive secondary transfer to naive recipient mice. Furthermore, induction of tolerance to intact PLP (which inhibits responses to both the initiating PLP139-151 epitope and to the PLP178-191 epitope) after the acute disease episode is sufficient to prevent relapsing disease. These results strongly support a contributory role of T cell responses to epitopes released as a result of acute tissue damage to the immunopathogenesis of relapsing clinical episodes and have important implications for the design of antigen-specific immunotherapies for the treatment of chronic autoimmune disorders in humans.

Topics: Acute Disease; Amino Acid Sequence; Animals; Autoimmune Diseases; Cross Reactions; Desensitization, Immunologic; Encephalomyelitis, Autoimmune, Experimental; Female; Immunodominant Epitopes; Immunotherapy, Adoptive; Lymphocyte Activation; Mice; Mice, Inbred Strains; Molecular Sequence Data; Myelin Basic Protein; Myelin Proteins; Myelin Proteolipid Protein; Peptide Fragments; Recurrence; Th1 Cells

Neuron-specific enolase (NSE) and myelin basic protein (MBP) in the peripheral venous blood (PVB) have been reported to be sensitive markers for judging the prognosis of patients with head injury. However, to our knowledge, the levels of NSE and MBP in the internal jugular venous blood (IJVB) have never been studied.. In 25 patients with acute head injury, blood samples were taken from the internal jugular vein and the peripheral vein at the same time before any medical or surgical procedure was performed. The levels of NSE and MBP in the both venous blood samples were measured. The time interval between injury and sampling was 1.5-8.0 hours (mean 4.3 hours). The levels of NSE and MBP in the IJVB were compared to those in the PVB. The relationship between the clinical outcome and the serum levels of those was evaluated.. The levels of NSE and MBP in the IJVB were almost equal to those in the PVB. The levels of NSE and MBP were significantly higher in the patients who died than in those who survived. In the survivors, the levels of NSE and MBP in the IJVB were 17.6 +/- 11.4 ng/ml and 1.4 +/- 1.5 ng/ml, whereas in the patients who died, both levels were elevated to 51.3 +/- 27.3 ng/ml (p < 0.005) and to 11.3 +/- 9.5 ng/ml (p < 0.01), respectively.. The assay of serum NSE and MBP levels provides a reliable laboratory indicator of the degree of brain damage and allows early prediction of the prognosis in patients with acute head injury.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Brain Injuries; Female; Glasgow Coma Scale; Humans; Jugular Veins; Male; Middle Aged; Myelin Basic Protein; Phosphopyruvate Hydratase; Regression Analysis

Acute and monophasic experimental autoimmune encephalomyelitis (EAE) was induced in rats by immunization with myelin basic protein (MBP). Proliferative responses of lymph node cells to major and minor encephalitogenic and nonencephalitogenic determinants of the MBP molecules were measured at various time intervals after the immunization. Results of these experiments revealed that additional responses to minor determinants which had been observed at the late stage of mouse EAE (Lehmann et al., Nature 356, 155, 1992) were very weak and short-lived in the rat. Furthermore, the response to the minor encephalitogenic determinant was not recognized throughout the course of EAE. Coimmunization with synthetic peptides, corresponding to the major and minor determinants, induced T-cell response only to the major determinant. These findings suggest that poor generation of T cells reactive with the minor encephalitogenic epitope is attributable to peptide competition between these two determinants. The present results, together with those reported in mice, strongly suggest that differences in the clinical course of EAE, i.e., acute monophasic or chronic relapsing, is closely related to the presence or absence of "determinant spread" to minor encephalitogenic epitope(s).

Topics: Acute Disease; Amino Acid Sequence; Animals; Chronic Disease; Encephalomyelitis, Autoimmune, Experimental; Epitopes; Lymph Nodes; Molecular Sequence Data; Myelin Basic Protein; Peptide Fragments; Rats; T-Lymphocytes

Interleukin 4 (IL-4)- and interferon gamma (IFN gamma)-secreting peripheral blood cells were enumerated by immunospot assay in 13 multiple sclerosis (MS) patients during exacerbations, in 24 patients with progressive multiple sclerosis (CPMS), and in 20 controls. Cells that spontaneously secreted IFN gamma were significantly higher in MS patients experiencing an attack (P < 0.001) than in controls or in CPMS (P < 0.04). IL-4-secreting cell numbers were elevated significantly and to a comparable extent in both MS groups compared to controls. Our finding of increased numbers of IFN gamma-secreting cells is in keeping with prior work showing increased IFN gamma levels in the circulation prior to and during MS attacks and increased release of IFN gamma to the supernatant in bulk cultured blood cells from MS patients. What role an increase in IL-4-secreting cells might play in MS is unclear, but it could relate to immune system regulation. Following in vitro exposure to MBP, IFN gamma-secreting cell number rose above levels observed in the absence of stimulation in controls and in both MS groups with the rise in acutely exacerbating MS patients being significantly greater than in controls. Our results provide further evidence for reactivity to MBP in MS, the significance of which in terms of pathogenesis remains clouded.

Topics: Acute Disease; Adult; Female; Humans; Interferon-gamma; Interleukin-4; Leukocytes, Mononuclear; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein

An epitope present in the 71-90 sequence of basic protein (BP) has been identified as the dominant epitope recognized by most Lewis rat encephalitogenic T cells isolated during experimental autoimmune encephalomyelitis (EAE). In the present study, we investigated the BP epitopes recognized by Lewis rat T cells in naive rats, in rats suffering from acute EAE, and in recovered rats. T cells isolated from the spinal cord lesions and from the lymph nodes were studied using T cell lines and bulk cultures. Virulence of the T cells was assayed by adoptive transfer. We now report that naive and recovered Lewis rats are populated with T cells reactive to a variety of BP epitopes and only a minority are specific for the 71-90 epitope. In contrast, the induction of EAE was associated with a predominance of T cells reactive to the 71-90 epitope. T cells recovered from naive, diseased, or recovered rats were found to be virulent upon passive transfer. Some of these virulent T cells were specific to BP epitopes other than the 71-90 epitope. There was no major difference in the BP specificities of T cells isolated from the lesions and from the lymph nodes. Thus, natural T cell reactivity to BP is heterogeneous and pathogenicity is not confined to one particular epitope, active disease is characterized by a dominant response to the 71-90 epitope, and recovery is marked by a return to heterogeneity.

Topics: Acute Disease; Amino Acid Sequence; Animals; Cell Line; Clone Cells; Encephalomyelitis, Autoimmune, Experimental; Female; Immunodominant Epitopes; Lymph Nodes; Lymphocyte Activation; Male; Molecular Sequence Data; Myelin Basic Protein; Peptide Fragments; Rats; Spinal Cord; T-Lymphocytes

To characterize the role of B lymphocytes in the pathogenesis of Multiple Sclerosis (MS), we have isolated mononuclear cells from cerebrospinal fluid (CSF) and stimulated them with a polyclonal B-cell mitogen (pokeweed mitogen). This study has been done with MS patients selected for the occurrence of an acute attack in the course of the disease and with patients hospitalized for other neurological diseases. Five of the 11 MS patients had B lymphocytes producing in vitro antibodies (Abs) directed against purified human myelin basic protein (hMBP), as revealed by Western blot analysis. None of the 20 patients with other neurological diseases showed such a reactivity. The produced Abs recognized only 1 or 2 hMBP peptides without dominance for a certain peptide. This result emphasizes the presence of B cells producing Abs against MBP in CSF of MS patients and shows the interest of studying mononuclear cells of CSF as a good marker of the pathogenesis.

Topics: Acute Disease; Adult; Aged; Autoantibodies; B-Lymphocytes; Biomarkers; Blotting, Western; Brain Diseases; Cells, Cultured; Cerebrospinal Fluid; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lymphocyte Activation; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Pokeweed Mitogens

Elevated titers of anti-myelin basic protein (anti-MBP) are highly associated with acute idiopathic unilateral optic neuritis as well as acute relapses of multiple sclerosis (MS). During acute phases of optic neuritis, free/bound antibody ratios are generally above unity, with high titers of free anti-MBP and relatively low or undetectable values of bound antibody. Three to 5 months after the acute phase when the majority of patients have recovered, free/bound anti-MBP ratios are below unity with low titers of free antibody and relatively higher levels of bound anti-MBP. Anti-MBP purified from cerebrospinal fluid of patients with optic neuritis are neutralized by synthetic peptides of human MBP containing overall amino acid residues 61-106 and do not react with synthetic peptides corresponding to residues 1-60 and 107-170. Anti-MBP may either have multiple epitopes in the region corresponding to residues 61-106 or it may react with a discontinuous epitope in this range. The mechanism of the optic nerve demyelination may be associated with anti-MBP binding in situ to MBP in the 61-106 amino acid region.

Topics: Acute Disease; Amino Acid Sequence; Antibody Specificity; Autoantibodies; Autoimmune Diseases; Cerebrospinal Fluid Proteins; Convalescence; Epitopes; Humans; Immunoglobulin G; Molecular Sequence Data; Multiple Sclerosis; Myelin Basic Protein; Optic Neuritis; Peptide Fragments

In an attempt to understand the mechanisms underlying disease progression in adoptively transferred experimental allergic encephalomyelitis (EAE), and perhaps multiple sclerosis (MS), this study has examined the transfer of EAE serially from primary to secondary and tertiary recipients using myelin basic protein (MBP)-responsive lymphocytes. It was found that EAE could be serially transferred only when there was acute or relapsing disease activity in the donor animal. Cells from donors with quiescent disease did not transfer EAE. Autoradiographic attempts to locate primary adoptively transferred cells in the central nervous system of secondary and tertiary recipients were uniformly unsuccessful. These findings implicate the requirement of effector cell activation in the donor and the recruitment of augmenting autoimmune cells in lesion formation.

Topics: Acute Disease; Animals; Autoradiography; Carbon Radioisotopes; Cell Line; Central Nervous System; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Immunization, Passive; Isotope Labeling; Lymph Nodes; Mice; Myelin Basic Protein; Recurrence; Spleen; T-Lymphocytes

To determine the factors which may alter NMR relaxation times in multiple sclerosis (MS) lesions we measured the proton T1 and T2, specific gravity (SG), and histology in the central nervous system (CNS; 13-19 levels per animal) in the myelin basic protein (MBP) and CNS-induced acute and relapsing EAE models in 44 juvenile Hartley guinea pigs. In the MBP model, T1 is unchanged but T2 is prolonged before symptoms and pathological changes occur. T2 remains prolonged during the acute phase of MBP-induced EAE. In the acute CNS model, T1 and T2 were not different from control despite advanced pathological changes of inflammation and demyelination and changes in specific gravity, indicating a marked change in tissue water content. No single variable, pathological or SG, could predict T1 or T2 values in the CNS-induced model. In active disease in the MBP model, when edema occurs in the presence or absence of parenchymal infiltration, T2 values are increased. However, as the factors which influence tissue NMR characteristics are complex in these MS models, it is likely difficult to infer specific pathological events from MRI findings in patients with MS.

Topics: Acute Disease; Animals; Central Nervous System; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Guinea Pigs; Magnetic Resonance Spectroscopy; Myelin Basic Protein; Time Factors

Chronic relapsing experimental allergic encephalomyelitis was induced by the passive transfer of [14C]thymidine-labeled myelin basic protein (MBP)-sensitized lymphocytes from MBP-immunized mice to naive syngeneic recipients. Labeled lymphocytes were localized and quantitated in the central nervous system during acute and chronic disease and clinical relapses. The results have shown that MBP-immune T cells home to the central nervous system endothelium 24 hours prior to and during initial clinical disease (5 to 7 days posttransfer). Unexpectedly, labeled MBP-immune cells never migrated far from blood vessels and, despite the presence of massive parenchymal inflammatory cell infiltration, almost invariably remained within the perivascular area. Quantitation revealed that labeled cells represented a minority (usually 1% to 4%) of the inflammatory cells during acute and early chronic disease. Furthermore, labeled cells could not be demonstrated in the central nervous system at the time of clinical relapse. We conclude that in this model, MBP-immune lymphocytes act exclusively from a perivascular location to orchestrate the influx of inflammatory cells that are predominantly of recipient derivation.

Topics: Acute Disease; Animals; Cell Movement; Central Nervous System; Chronic Disease; Encephalomyelitis, Autoimmune, Experimental; Endothelium; Female; Immunization, Passive; Mice; Mice, Inbred Strains; Myelin Basic Protein; Spinal Cord; T-Lymphocytes

Using a passively transferred acute model of experimental allergic encephalomyelitis (EAE) in the rat, inflammatory central nervous system (CNS) lesions were shown to develop rapidly, peak and then resolve. An unusual feature of the lesions in the CNS was the presence of pyknotic cells within myelin sheaths. A sequence of observations indicated that such cells were lymphocytes which had insinuated themselves into the myelin sheath by passage along the interperiod line. The presence of lymphocytes within myelin sheaths, a process which did not lead to demyelination, was considered to represent a change which reflects the specificity of the immune response in this disease. The detection of this change in other CNS autoimmune diseases, notably those associated with virus infections, may be important as an indicator of pathogenetically relevant lymphocyte-myelin interactions.

Topics: Acute Disease; Animals; Cell Communication; Cell Nucleus; Encephalomyelitis, Autoimmune, Experimental; Immunization, Passive; Lymphocyte Transfusion; Lymphocytes; Male; Myelin Basic Protein; Myelin Sheath; Rats; Rats, Inbred Lew; Spinal Cord

In order to determine if free (F) and bound (B) levels of autoantibodies to myelin basic protein (anti-MBP) are present from the onset of multiple sclerosis (MS), 201 patients referred to our clinic were clinically divided into a group diagnosed as having an initial MS relapse and a group of non-MS controls. Ninety-four of 106 patients thought to have an initial MS relapse had increased CSF anti-MBP, while only 14 of 95 controls had elevated antibody levels; 9 of these 14 positive controls were subsequently shown to have MS by magnetic resonance imaging and/or clinical follow-up. CSF anti-MBP was more frequently abnormal than 3 estimates of intrathecal IgG synthesis in the group with suspected MS. Kinetics of F and B CSF anti-MBP were determined in a group of 29 patients with clinically definite MS during an acute relapse and 97.4 +/- 54 days later in the subsequent convalescent phase when in clinical remission. F and B anti-MBP levels were highly dependent on the timing of the CSF sampling; generally, as patients entered into clinical remission F anti-MBP declined, B antibody levels rose and F/B anti-MBP ratios initially above unity gradually declined towards zero. These data suggest that anti-MBP may be involved in the mechanism of MS.

Topics: Acute Disease; Autoantibodies; Convalescence; Demyelinating Diseases; Humans; Kinetics; Multiple Sclerosis; Myelin Basic Protein; Time Factors

We evaluated 130 consecutive HIV-infected neurologically asymptomatic individuals for intrathecal IgG production and myelin basic protein (MBP) levels. Although 56.7% of immunologically normal and 68.8% of immunocompromised patients had some CSF abnormality, no patient had an abnormal MBP level. The lack of MBP elevation in the CSF of these patients suggests that the production of intrathecal IgG is not related to active demyelination.

Topics: Acquired Immunodeficiency Syndrome; Acute Disease; Adult; Dementia; Demyelinating Diseases; Follow-Up Studies; Humans; Immunoglobulin G; Male; Myelin Basic Protein; Neurologic Examination

Demyelinating inflammatory disease of the central nervous system-(CNS) can be a multifactorial process mediated by cellular and antibody-mediated immune processes. In rats, hyperacute disease progression and severe demyelination can be induced in experimental allergic encephalomyelitis (EAE)-diseased animals by injection of a monoclonal antibody, 8-18C5, specific for an oligodendrocyte cell surface glycoprotein. Here we demonstrate that this antibody-induced hyperacute EAE can be prevented by 'vaccination' with myelin basic protein (MBP)-specific T cells. Thus, the 8-18C5 antibody-mediated disease process is critically dependent on inflammatory processes induced by T lymphocytes and T cell vaccination is highly effective in preventing the development of demyelinating CNS lesions.

Topics: Acute Disease; Animals; Antibodies, Monoclonal; Brain; Cell Line; Encephalomyelitis, Autoimmune, Experimental; Myelin Basic Protein; Rats; Rats, Inbred Lew; Spinal Cord; T-Lymphocytes; Vaccination

The cellular mechanisms of recovery and relapses in experimental allergic encephalomyelitis (EAE) are not known. In order to determine the role of the suppressor/cytotoxic T lymphocytes (Lyt-2+) in EAE we studied the effect of in vivo depletion of this subset using monoclonal antibodies. Intraperitoneal injection of 1 mg of monoclonal antibody 2.43 resulted in rapid depletion of Lyt-2+ cells from lymph node, spleen and blood. Depletion of this subset had no effect on the kinetics of development, severity, and duration of acute EAE. Furthermore, following recovery from acute EAE administration of 2.43 did not result in development of relapses that were different in onset or severity from control animals. These results suggest that T cells of the Lyt-2 phenotype do not play a significant role in the immunoregulation of EAE.

Topics: Acute Disease; Animals; Antibodies, Monoclonal; Antigens, Ly; Encephalomyelitis, Autoimmune, Experimental; Female; Immunization, Passive; Lymphocyte Depletion; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Myelin Basic Protein; Recurrence; Spinal Cord; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Regulatory; Tissue Extracts

Strain 13 guinea pigs were immunized with galactocerebroside, asialo-GM1 (GA1) or GM4 ganglioside in association with myelin basic protein (MBP) in complete Freund's adjuvant (CFA) to produce experimental autoimmune encephalomyelitis (EAE). The clinical and pathological features, serum antibodies, and lipid compositions of affected brains and spinal cords were compared with those of guinea pigs immunized with MBP, in CFA, alone. Perivascular demyelination was seen in brains from all guinea pigs immunized with GA1/MBP. The incidence and degree of demyelination in this group were significantly higher than in the group immunized with only MBP. The onset of EAE was slightly, but significantly, retarded in groups of animals immunized with GM4/MBP and there was no detectable demyelination. Otherwise, no significant differences were detected between groups. Augmentation of EAE by myelin glycolipids may provide some important clues in understanding the mechanism of demyelinating diseases.

Topics: Acute Disease; Animals; Autoantibodies; Brain Chemistry; Encephalomyelitis, Autoimmune, Experimental; Glycosphingolipids; Guinea Pigs; Lipids; Myelin Basic Protein; Spinal Cord

We used a new version of experimental autoimmune encephalomyelitis (EAE) in the rat to investigate immunotherapy of demyelination during autoimmune disease of the central nervous system (CNS). Encephalitis was induced by immunization of rats with myelin basic protein (MBP), and demyelination by systemic injection of a monoclonal antibody, 8-18C5, specific for a myelin/oligodendrocyte glycoprotein (MOG). Antibody injection resulted in hyperacute disease progression and extensive demyelination throughout the CNS. Immunotherapy of antibody-induced demyelination was possible with another monoclonal antibody, pta-3, specific for activated rat T cells. These findings demonstrate the synergy of T cell-mediated and antibody-dependent processes in rat CNS demyelination in vivo. Histologically, immunotherapy reduced the numbers of meningeal mononuclear cell inflammatory foci, but not parenchymal inflammation in the early phase of demyelinating disease. Animals which had received pta-3 antibody had less inflammation than untreated rats in the convalescent phase. Multiple pta-3 treatments most effectively suppressed inflammation. Furthermore, antibody-treated rats with demyelination developed a series of neurologic signs, including pronounced spasticity; that were not observed in control EAE rats and thus appears to be associated with the demyelinating process.

Topics: Acute Disease; Animals; Antibodies, Monoclonal; Brain; Encephalomyelitis, Autoimmune, Experimental; Freund's Adjuvant; Leukocytes, Mononuclear; Lymphocyte Activation; Myelin Basic Protein; Rats; Rats, Inbred Lew; T-Lymphocytes

Acute and chronic relapsing forms of experimental allergic encephalomyelitis (EAE) can be induced in SJL/J mice following transfer of myelin basic protein (MBP)-sensitized T cells which have been challenged in vitro with MBP. In this study, addition of specific anti I-A antibody during the culture blocked the antigen-specific proliferation of T cells and inhibited the transfer of both acute and relapsing EAE. Treatment of T cell recipients with anti I-As antibody daily for 10 days suppressed the induction of acute EAE. Further treatment of mice with anti I-As antibody reduced the number of relapses and improved their conditions. We conclude that MBP-sensitized T cells interact with Ia positive cells, both in vitro and in vivo, to induce acute and chronic relapsing EAE, respectively. The mechanism of this interaction and its role in the disease process are discussed.

Topics: Acute Disease; Animals; Antibodies, Monoclonal; Autoantibodies; Cells, Cultured; Chronic Disease; Encephalomyelitis, Autoimmune, Experimental; Female; Galactosylceramides; Histocompatibility Antigens Class II; Immunization, Passive; Immunosuppressive Agents; Mice; Mice, Inbred Strains; Myelin Basic Protein; Recurrence; T-Lymphocytes

The premise that acute non-fatal viral infections of the central nervous system (CNS) predispose to the subsequent development of chronic immune-mediated neurologic disease was investigated. Adult C57Bl/6 mice inoculated peripherally with 10(4) PFU of the A774 strain of Semliki Forest virus (SFV) develop a transient encephalomyelitis and sporadic (less than 20%) mild symptoms of paralysis with demyelination in the cerebellum from which they recover. Such recovered mice were found to develop signs characteristic of experimental allergic encephalomyelitis (EAE) 2 to 8 wk after either immunization with myelin basic protein (MBP) or receipt of 1 to 2 X 10(7) lymph node cells from MBP-primed syngeneic donors. These two methods of disease induction were unsuccessful when applied to normal B6 mice or those previously inoculated with noninfectious SFV. These findings suggest the possibility that virus-induced damage to CNS tissue may facilitate subsequent priming or clonal expansion of pre-existing myelin-reactive lymphoid cells.

Topics: Acute Disease; Animals; Demyelinating Diseases; Disease Susceptibility; Encephalomyelitis; Encephalomyelitis, Autoimmune, Experimental; Female; Immunization, Passive; Mice; Mice, Inbred C57BL; Myelin Basic Protein; Semliki forest virus; Togaviridae Infections

The recovery mechanism of acute experimental allergic encephalomyelitis (EAE) in Lewis rats was studied by using an encephalitogenic T cell line specific for myelin basic protein. Antigen-activated line cells were highly encephalitogenic, but unstimulated line cells were not encephalitogenic. The activated line cells returned to the unstimulated state in a few days in culture medium without antigen. This decline of proliferative and encephalitogenic activities of the activated line cells was also observed even if the activated line cells were continuously stimulated with the antigen. In addition, rats during the convalescent stage from acute EAE showed only mild clinical signs of EAE even by transfer of almost a lethal dose of activated line cells. Thus, self-limiting capacity of autoaggressive cells and attenuation of effector cell function during the convalescent stage seem to be involved in the recovery mechanism of EAE.

Topics: Acute Disease; Animals; Antigen-Presenting Cells; Cell Line; Cells, Cultured; Encephalomyelitis, Autoimmune, Experimental; Epitopes; Female; Guinea Pigs; Immunization, Passive; Lymphocyte Activation; Lymphocyte Cooperation; Myelin Basic Protein; Rats; Rats, Inbred Lew; T-Lymphocytes; T-Lymphocytes, Regulatory

We previously reported that the thymolysis was observed in acute experimental allergic encephalomyelitis (EAE) rats immunized with brain tissue homogenates in complete Freund adjuvant. This observation has led us to suppose that the central nervous system (CNS) has high antigenicity for self. To keep from the high antigenicity of CNS, the blood brain barrier (BBB) and cerebrospinal fluid (CSF) which maintain CNS in isolated state are essential for self. If the BBB is destroyed and brain tissue is disseminated in CSF, is oneself sensitized by CNS? In this experiment, we produced cerebral contusion in rats and the BBB was partially destroyed and brain tissue was disseminated in CSF. No clinical signs of EAE were observed by cerebral contusion was exposed to encephalitogen one week later, EAE was remarkably suppressed compared with those in controls or sham operated groups (p less than 0.001). Almost 80% of the rats with cerebral contusion showed no response to EAE. These results seen to show that self is sensitized by autologous brain tissue and CNS has high antigenicity.

Topics: Acute Disease; Animals; Autoantigens; Blood-Brain Barrier; Brain Concussion; Encephalomyelitis, Autoimmune, Experimental; Immune Tolerance; Myelin Basic Protein; Rats; Rats, Inbred Lew; Spinal Cord

Chronic relapsing experimental allergic encephalomyelitis was induced in SJL mice by adoptive transfer of long-term cultured T cell lines. The T cells which were activated with myelin basic protein (MBP) derived from various species, all induced chronic relapsing experimental allergic encephalomyelitis with a similar high incidence. During the relapsing stage, lymphocytes obtained from the spleen responded well to MBP and were capable of transferring experimental allergic encephalomyelitis, whereas thymus lymphocytes did not respond to MBP. There was no difference in the proliferative response of splenocytes to MBP when splenocytes were isolated either from mice with clinical relapse or from mice that did not relapse. Pathological examination revealed a transient appearance of inflammatory cells during the acute stage. Similar cell infiltrates were also observed at the relapsing stage. The I-region associated (Ia) antigens appeared on vessels and astrocytes in the acute inflammatory lesions which coincided with the appearance of inflammatory cell infiltrates. Ia antigen expression diminished with the disappearance of inflammatory cells. During the relapsing stage, the Ia antigens were also expressed on the vessels and astrocytes in the fresh lesions. Our data indicate that MBP-reactive T cells persist at least in the spleen, for a long time. They may be reactivated by certain mechanisms probably in the central nervous system associated with the Ia-antigen expression, which facilitates the effector phase again. The initial event that triggers the Ia-expression is not known as yet.

Topics: Acute Disease; Animals; Cell Division; Cell Line; Central Nervous System; Chronic Disease; Encephalomyelitis, Autoimmune, Experimental; Female; Histocompatibility Antigens Class II; Histocytochemistry; Immunoenzyme Techniques; Mice; Myelin Basic Protein; Recurrence; Spleen; T-Lymphocytes; Thymus Gland

Of 66 patients (31 female and 35 male) with demyelinating inflammatory polyradiculoneuropathy (DIP), 12% (8/66) had a chronic relapsing and/or progressive course (CR-DIP) and 88% (58/66) had an acute monophasic illness (acute Guillain-Barré syndrome or GBS). Ten (15%) of the 66 had one or more associated putative autoimmune diseases; of these ten, five had CR-DIP and five had GBS. Cell-mediated immune responsiveness (CMI) of 30 cases with DIP was tested in vitro by lymphocyte transformation. Peripheral nervous system neuritogenic protein (NP) and central nervous system encephalitogenic myelin basic protein were the challenge antigens. Eighteen (60%) of the 30 patients had CMI to NP of human peripheral nervous system origin when a stimulation index (SI) of 2 or more was evaluated as positive; eight 27% (1) had CMI to NP when a positive SI was 3 or more. Of the 44 control patients with other neuropathies, only two (4.6%) demonstrated CMI to NP (SI, greater than or equal to 2). The in vitro response of patients with DIP to myelin basic protein (7/30) was not significantly different from that of the control population (16/44). The high incidence of DIP associated with autoimmune diseases and the CMI to NP in this group suggest that DIP may be an autoimmune disease with NP as one possible major antigen.

Topics: Acute Disease; Adolescent; Adult; Aged; Autoimmune Diseases; Central Nervous System; Child; Child, Preschool; Chronic Disease; Demyelinating Diseases; Female; Humans; Immunity, Cellular; Infant; Lymphocyte Activation; Lymphocytes; Male; Middle Aged; Myelin Basic Protein; Peripheral Nerves; Polyradiculoneuropathy

Acute demyelinating and relapsing demyelinating lesions from spinal cords of mice infected with the WW strain of Theiler's encephalomyelitis virus (TMEV) were studied immunocytochemically with antisera to various myelin constituents. Acute lesions were studied for differences in the distribution of myelin basic protein (MBP) and myelin associated glycoprotein (MAG). Relapsing lesions, characterized by demyelination of areas previously remyelinated by Schwann cells, were studied for differences in the distribution of P0 and MAG. In both instances the earliest lesions were characterized by preferential disappearance of MBP and P0 respectively when compared to MAG. In well-developed lesions, MAG, MBP and P0 were absent in essentially equal proportion. These observations are in agreement with previous findings suggesting a primary loss of myelin rather than a direct attack on oligodendrocytes as the main pathogenetic mechanism of demyelination in this viral model.

Topics: Acute Disease; Animals; Demyelinating Diseases; Enterovirus Infections; Histocytochemistry; Male; Maus Elberfeld virus; Mice; Myelin Basic Protein; Myelin P0 Protein; Myelin Proteins; Myelin-Associated Glycoprotein; Recurrence

The current report describes a new technique for producing chronic experimental allergic encephalomyelitis (EAE)+ accompanied by demyelination in adult strain 13 guinea pigs. The disease is induced by a combination of passive transfer of lymph node cells sensitized to myelin basic protein (BP) and active challenge of the recipients with homologous spinal cord in Freund's complete adjuvants. The clinical-pathologic spectrum ranges from a progressively fatal form of chronic EAE leading to death in 4-7 wk, through a remitting-relapsing form, to a chronic-stable form lasting many months. In all of these forms large subpial plaques of demyelination occur in the spinal cord with active phagocytosis of myelin debris, especially at the edges. The axons are swollen, but remain intact throughout. The histologic appearances of the lesions suggest that lysis of myelin occurs before phagocytosis, one of the hypotheses proposed for the pathogenesis of lesions occurring in humans with multiple sclerosis.

Topics: Acute Disease; Animals; Axons; Chronic Disease; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Guinea Pigs; Immunization, Passive; Multiple Sclerosis; Myelin Basic Protein; Myelin Sheath; Spinal Cord

Cerebrospinal fluid (CSF) from 221 patients with multiple sclerosis (MS) and 85 patients with other neurological disorders (OND) was examined using a competitive radioimmunoassay for myelin basic protein (MBP) immunoreactivity. MBP was found in 46 of 55 MS patients (84%) examined within six weeks of relapse but in only 11 of 85 patients (13%) with OND. There was a significant correlation between the concentration of MBP in the CSF and relapse severity in patients seen within four weeks of the onset of symptoms (p less than 0.01). Of 44 patients in remission, MBP was detected in 12, and these patients had a significantly higher tendency to subsequent relapse (p less than 0.05). In 72 patients with progressive disease the presence of MBP in the CSF reflected the confidence of clinical diagnosis. The results of this study suggest that measurement of MBP in the CSF gives an objective method of monitoring disease activity in patient with MS.

Topics: Acute Disease; Brain Diseases; Female; Humans; Male; Multiple Sclerosis; Myelin Basic Protein; Peripheral Nervous System Diseases; Recurrence; Remission, Spontaneous; Time Factors

To investigate the sequence of immunopathologic events during lesion formation in acute experimental allergic encephalomyelitis (EAE), SJL/J mice were inoculated with isogeneic spinal cord in complete Freund's adjuvant (CFA) and with Bordetella pertussis on Days 1 and 3 postinoculation (PI). Mice were sampled at different time points PI and T cells, T-cell subsets. Ia+ cells, Ig+ cells, albumin, and Ig deposits were localized in frozen sections by the avidin-biotin complex (ABC) method and direct fluorescence. Furthermore, samples were stained for Ia antigen, myelin basic protein (MBP), and galactocerebroside (GC) localization on endothelial cells by the ABC technique. Clinical and pathologic observations were correlated with the immunopathologic results. It was found that early in the disease process myelin and Ia-antigens were demonstrable on endothelial cells within the central nervous system (CNS). Simultaneously, damage to the blood-brain barrier was apparent, as indicated by albumin deposits, and small numbers of infiltrating T cells, T-cell subsets, and Ia+ cells were found. With time PI, the density of infiltrating total T cells (Thy-1.2+), helper/inducer (Lyt-1+), and suppressor/cytotoxic (Lyt-2+) T cells increased; Lyt-1+ and Lyt-2+ cells were detectable in meningeal as well as parenchymal infiltrates, while later on, Lyt-1+ cells showed some predilection for the CNS parenchyma and Lyt-2+ cells for meninges. Ia+ cells (B cells, macrophages, activated T cells) were present in small numbers only. Ig+ cells (B cells and macrophages) appeared shortly before onset of signs and persisted in moderate numbers. These results reconfirm the importance of early T-cell involvement for the development of EAE; they might also indicate a secondary role for Ig+ cells and are consistent with the concept that presentation of myelin antigens to T cells might occur locally on Ia-bearing endothelial cells within the CNS.

Topics: Acute Disease; Animals; Antibodies, Monoclonal; Antigen-Presenting Cells; Blood-Brain Barrier; Encephalomyelitis, Autoimmune, Experimental; Endothelium; Female; Galactosylceramides; Histocompatibility Antigens Class II; Histocytochemistry; Immunoenzyme Techniques; Mice; Mice, Inbred Strains; Myelin Basic Protein; T-Lymphocytes; Time Factors

The molecular size of myelin basic protein (MBP) immunoactivity in spinal fluid from patients with multiple sclerosis, acute stroke or who had gone through neurosurgery was determined by gel filtration. Gel filtration fractions were analysed for MBP by radioimmunoassay. Spinal fluid from all patients demonstrated a broad range of MBP immunoactivity. The neurosurgery and stroke cases had high MBP immunoactivity in the higher molecular range, around 67 000 daltons. The spinal fluid from MS patients had increased levels of low molecular size MBP immunoactivity, around 10-13 000 daltons. The results suggest that different forms of demyelinating processes give rise to various kinds of MBP fragments and/or different proteolytic activity on MBP within the spinal fluid space.

Topics: Acute Disease; Adolescent; Adult; Aged; Albumins; Animals; Cerebrovascular Disorders; Chromatography, Gel; Epitopes; Histones; Humans; Immunoglobulin G; Middle Aged; Molecular Weight; Multiple Sclerosis; Myelin Basic Protein; Rabbits; Radioimmunoassay

Normal CSF-MBP levels as determined by a RIA were less than 6.2 ng/ml CSF (mean 3.9). Eighty percent of patients with acute optic neuritis have CSF-MBP levels greater than 6.2 ng/ml (mean 7.6 ng/ml CSF). Five of 7 patients with acute internuclear ophthalmoplegia due to an initial exacerbation of demyelination have CSF-MBP levels above 6.2 ng/ml (mean 6.8 ng/ml). Fifty percent of MS patients with chronic progressive disease have CSF-MBP levels above 6.2 ng/ml (mean 6.7 ng/ml). MS patients experiencing monosymptomatic exacerbations show elevated CSF-MBP levels in 75% in 75% of cases (mean 8.2 ng/ml). MS patients experiencing polysymptomatic exacerbations show significantly higher levels of CSF-MBP (mean 22.3 ng/ml) than the patients with monosymptomatic exacerbations. Ninety-five percent of MS patients experiencing polysymptomatic exacerbations have elevated levels of CSF-MBP.

Topics: Acute Disease; Adolescent; Adult; Aged; Female; Humans; Leukemia, Lymphoid; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Ophthalmoplegia; Optic Neuritis; Radioimmunoassay

After addition of encephalitogenic peptide to the blood of multiple sclerosis patients a factor X with platelet aggregation activating property could be demonstrated in the supernatant serum. Factor X was able to induce a platelet aggregation or to enhance an ADP-induced platelet aggregation. These findings suggest an explanation for the well-known platelet alterations found in multiple sclerosis.

Topics: Acute Disease; Adenosine Diphosphate; Humans; Multiple Sclerosis; Myelin Basic Protein; Platelet Aggregation

Possible sensitisation of peripheral blood mononuclear cells from multiple sclerosis (MS) patients was studied in the presence of both normal and MS brain subcellular fractions. Myelin, synaptosomal and microsomal fractions and myelin basic protein were prepared by sucrose density gradient centrifugation from normal and MS brain. These preparations were added to mononuclear cell microcultures from the peripheral blood of nine acute and six chronic MS patients, 10 patients with other neurological diseases and 10 normal subjects. There was no significant increment in the peripheral blood mononuclear cell transformation of any of the acute MS patients with any of the fractions. Therefore there is no evidence that immunity to antigens in any of the fractions of MS or normal brain is of primary pathogenetic importance. A small increment in peripheral blood mononuclear cell transformation in the presence of several fractions was observed in two of six chronic MS patients, which might indicate the development of a secondary immune response after prolonged disease.

Topics: Acute Disease; Adult; Antigens; Brain; Cells, Cultured; Chronic Disease; Female; Humans; Lymphocyte Activation; Lymphocytes; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Subcellular Fractions

To study the distribution of myelin-associated glycoprotein (MAG) in human nervous tissue and in multiple sclerosis (MS) lesions, we used paraffin sections and our modification of the peroxidase-antiperoxidase technique. Sections of MS lesions also were treated with antiserum to basic protein (BP) and with histological stains for axons and myelin sheaths. In tissue from normal developing central nervous system, oligodendroglia, their processes, and wwly formed myelin sheaths were intensely stained by MAG antiserum. In adults, MAG was found in periaxonal regions of myelinated fibers of the central and peripheral nervous system. The most striking finding in MS lesions was the extension of decreased MAG immunostaining into white matter that appeared normal when treated with BP antiserum or luxol fast blue. In acute early MS lesions the decrease in MAG immunostaining extended far beyond the margin of acute demyelination, where the BP staining of degenerating sheaths often was increased. In chronic inactive plaques, this decrease in periaxonal MAG immunostaining was limited to relatively few fibers in a thin rim around each lesion. These observations suggest that in MS, immunoreactivity of periaxonal MAG is altered before myelin breakdown begins. Early in degeneration, myelin sheaths and their fragments often were more intensely stained by BP antiserum than normal sheaths; later the staining intensity decreased. In shadow plaques, BP antiserum stained some oligodendroglia. Their appearance and location among thinly myelinated axons suggested that these oligondendroglia were forming new sheaths around previously demyelinated axons.

Topics: Acute Disease; Adolescent; Adult; Aged; Animals; Autolysis; Central Nervous System; Child; Child, Preschool; Chronic Disease; Glycoproteins; Histological Techniques; Humans; Immunoenzyme Techniques; Infant; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Myelin Sheath; Oligodendroglia; Rats; Staining and Labeling

MBP-reactive early T cells were determined simultaneously in the circulation and in inflammatory cells from the meninges of guinea pigs with acute EAE. In addition, early and late T cells as well as B cells were estimated in both compartments. Within the circulation, early T cells were found to decrease at the onset of clinical signs, and MBP-reactive early T cells were significantly higher than in normals. Different changes were found in inflammatory cells from the meninges. In this cell population, early T cells were increased but did not show significant, further elevation after incubation with MBP. This may indicate that the majority of early T cells in meningeal infiltrates had been previously activated by MBP in vivo.

Topics: Acute Disease; Animals; B-Lymphocytes; Encephalomyelitis, Autoimmune, Experimental; Epitopes; Guinea Pigs; Male; Myelin Basic Protein; T-Lymphocytes

To obtain more information about early events in central nervous system myelin injury in multiple sclerosis (MS), a comparative study was conducted of the distribution of myelin basic protein (BP) in tissue lesions of both MS and experimental allergic encephalomyelitis (EAE). Sixteen postmortem specimens containing lesions from 4 persons with MS and the brains of 14 guinea pigs with acute EAE induced with BP were studied. Cryostat sections of quick-frozen material were fixed, treated with rabbit antibody to BP, and processed by immunoperoxidase techniques. The reaction of antibody to BP was reduced or absent in MS lesions but normal in uninvolved surrounding tissue. Alterations in BP generally paralleled changes in staining of myelin by histological methods. Marked diminution of reactivity with anti-BP occurred in early lesions of MS and extended far beyond any identifiable inflammatory elements. In both parenchyma and perivascular areas, lipid-laden macrophages in MS plaques frequently contained BP material in addition to a variable amount of endogenous peroxidatic activity. Compared with MS, BP was relatively well preserved in brains of guinea pigs with EAE. At the light microscopy level, normal-appearing patterns of BP existed adjacent to the perivascular cellular infiltrates, and macrophages containing BP material were rare. The results of this study suggest differences between MS and acute EAE in both removal of BP from the central nervous system and its subsequent disposal.

Topics: Acute Disease; Adult; Animals; Antibody Specificity; Brain; Encephalomyelitis, Autoimmune, Experimental; Female; Guinea Pigs; Histocytochemistry; Humans; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Staining and Labeling

We have previously reported that myelin basic protein appears in CSF during acute attacks of multiple sclerosis. These studies have been extended to over 700 patients, 91 with multiple sclerosis. The data continues to indicate that myelin basic protein is released into cerebrospinal fluid during acute attacks of multiple sclerosis. We are currently characterizing the basic protein in the CSF.

Topics: Acute Disease; Epitopes; Humans; Multiple Sclerosis; Myelin Basic Protein; Optic Neuritis

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

A modified electrophoretic mobility (EM) test was performed in 150 children to examine their lymphocyte sensitization to myelin basic protein (encephalitogenic factor). Measurements in the cytopherometer were facilitated by using devitalized sheep erythrocytes as indicator particles instead of macrophages. A significant decrease in EM was found in 29/30 children with acute lymphoblastic leukaemia and in 67/75 children with solid tumours, thus giving a false negative rate in malignant disease of 9/105=8-6%, as compared to 6 false positives among 45 children with non-malignant disorders; 5 of the later "false/positive" 6 patients had autoimmune disease. Results of the EM test in the children with leukaemia were compared with those in 9 patients with non-Hodgkin's lymphoma and 2 with Hodgkin's disease at different stages, but no striking change was seen between different diseases, or after cessation of long-term immunosuppressive chemotherapy. Percentage of "slowing" ranged from 4 to 30%. These results indicate that patients with lymphoid malignancies still have lymphocytes which had been sensitized by a common antigen of the malignant cell clone at the beginning of the disease. The EM test, furthermore, could serve as an additional diagnostic aid in differentiating benign from malignant masses in the abdomen, extremities or intracranial disease.

Topics: Abdominal Neoplasms; Acute Disease; Antigens; Child; Electrophoresis; Humans; Leukemia, Lymphoid; Lymphocytes; Lymphoma; Myelin Basic Protein; Neoplasms

Lymphocytes from patients with acute transverse myelopathy (ATM) were shown to undergo a specific and significant transformation when cultured in vitro in the presence of either the central nervous myelin basic encephalitogenic protein (BE) or the peripheral nerve myelin P2 protein. A similar pattern of response was demonstrated in acute disseminated encephalomyelitis and in acute myeloradiculitis. Lymphocytes from patients suffering from other autoimmune neurological disorders or other neurological diseases affecting the spinal cord showed no response to there immunologically related antigens, which have previously been found to have the capacity of inducing experimental allergic encephalomyelitis, either alone or with experimental allergic neuritis, when injected into animals. The specific in vitro response to BE and P2 suggests that in vivo sensitization of lymphocytes to such self-antigens occurs in ATM and than a cell-mediated, probably postinfecious autoimmune mechanism may be an important factor in the pathogenesis of the disease.

Topics: Acute Disease; Adolescent; Adult; Autoimmune Diseases; Encephalomyelitis; Female; Humans; Immunity, Cellular; Lymphocyte Activation; Male; Middle Aged; Myelin Basic Protein; Myelin Proteins; Myelitis; Myelitis, Transverse

The macrophage migration inhibitory factor (MIF) assay and the lymphoblastic transformation (LBT) technique were utilized simultaneously to measure immune responses to peptide Y, the 17 amino acid C-terminal fragment of basic myelin protein, in patients with multiple sclerosis (MS). Ten normals and 67 MS patients from the Montreal Neurological Hospital and affiliated institutions were examined. A prospective attempt was made to correlate the measured responses with phasic clinical activity of the disease. The LBT results indicate some degree of cellular sensitization to peptide Y which parallels the clinical course of the illness, and resembles earlier positive findings obtained with the whole basic myelin protein molecule. These findings, however, are in contrast to a negative MIF response to the Y peptide used in the present study and further contrast the positive MIF results obtained earlier using the whole protein. It is not evident from the results of the present study whether sensitization may be of any pathogenetic significance, but the findings show that differing portions of the basic myelin protein molecule may selectively stimulate specific lymphokine elaboration by sensitized lymphocytes.

Topics: Acute Disease; Animals; Guinea Pigs; Humans; Lymphocyte Activation; Lymphocytes; Macrophage Migration-Inhibitory Factors; Macrophages; Multiple Sclerosis; Myelin Basic Protein; Peptides; Time Factors

Topics: Acute Disease; Animals; Antigens; Autoantigens; Dose-Response Relationship, Immunologic; Encephalomyelitis, Autoimmune, Experimental; Epitopes; Female; Guinea Pigs; Methylation; Myelin Basic Protein; Peptides; Rats; Structure-Activity Relationship

Topics: Acute Disease; Antibodies; Brain Diseases; Chronic Disease; Encephalomyelitis; Female; Humans; Immunity, Cellular; Immunodiffusion; Iodine Radioisotopes; Lectins; Lymphocyte Activation; Male; Multiple Sclerosis; Myelin Basic Protein; Polyradiculopathy; Tritium

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