Human transaldolase and cross-reactive viral epitopes identified by autoantibodies of multiple sclerosis patients.
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Multiple sclerosis is mediated by an autoimmune process causing selective destruction of oligodendrocytes. Transaldolase, which is expressed in the brain selectively in oligodendrocytes, is a target of high affinity autoantibodies in serum and cerebrospinal fluid of multiple sclerosis patients. A three-dimensional model of human transaldolase was developed based on the crystal structure of the enzyme from Escherichia coli. To identify immunodominant epitopes, 33 peptides overlapping human transaldolase by 5 amino acids were synthesized. Ab 12484, raised against enzymatically active human transaldolase, recognized antigenic determinants corresponding to linear epitopes (residues 27-31 and 265-290) and alpha helices (residues 75-98 and 302-329). Four immunodominant peptides harboring charged amino acid residues with topographically exposed side chains were identified by sera from 13 multiple sclerosis patients with predetermined autoreactivity to transaldolase. Autoantibodies binding to the most prominent human transaldolase epitope, between residues 271 and 285, showed cross-reactivity with Epstein-Barr and herpes simplex virus type 1 capsid-derived peptides. Molecular mimicry between immunodominant autoepitopes and viral Ags may be a decisive factor in directing autoimmunity to transaldolase in multiple sclerosis patients. (+info)
Decrease in multiple sclerosis with acute transverse myelitis in Japan.
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Acute transverse myelitis (ATM) may be a manifestation of multiple sclerosis (MS) and was reported to be more common among Japanese MS patients than in Caucasian MS patients. Recently there are arguments whether clinical manifestations of MS may have changed. Therefore, we studied the frequency of ATM in MS and the clinical subtypes of MS in 86 clinically definite MS patients whose onsets were in 1970-1979, 1980-1989, and 1990-1998 in Sendai City, Japan. Fifty-six of the patients were women and 30 were men. Forty-four patients had the conventional form of MS (C-MS) commonly seen in Western countries, and 42 had optic-spinal or spinal forms of MS (OSS-MS). Twenty MS patients had ATM, and all of them were belong to optic-spinal form of MS. ATM was not seen in any cases of C-MS. The mean onset age (years) of the clinical subtypes was 25.5 in C-MS, 34.1 in OSS-MS without ATM, and 30.9 in OSS-MS with ATM. Among the patients whose onset of the disease was in 1970-1979, 60.0% of them were cases of OSS-MS with ATM, but such cases were markedly decreased to 5.3% in 1990-1998. In contrast, the frequency of C-MS increased to 63.2% in 1990-1998 compared with 20.0% in 1970-1979. Analysis of the data by the year of birth of the patients showed similar results. Our data suggest that the frequency of ATM in MS markedly decreased, and that of C-MS increased during the last 30 years in Sendai, Japan. Since the genetic background of Japanese has not changed, some exogenous factors, such as food, infectious microorganisms, and chemicals in our environment, may be responsible for the change. (+info)
A putative mechanism of demyelination in multiple sclerosis by a proteolytic enzyme, calpain.
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In autoimmune demyelinating diseases such as multiple sclerosis (MS), the degradation of myelin proteins results in destabilization of the myelin sheath. Thus, proteases have been implicated in myelin protein degradation, and recent studies have demonstrated increased expression and activity of a calcium-activated neutral proteinase (calpain) in experimental allergic encephalomyelitis, the corresponding animal model of MS. In the present study, calpain activity and expression (at translational and transcriptional levels) were evaluated in white matter from human patients with MS and Parkinson's and Alzheimer's diseases and compared with that of white matter from normal controls. Western blot analysis revealed that levels of the active form of calpain and calpain-specific degradation products (fodrin) were increased by 90.1% and 52.7%, respectively, in MS plaques compared with normal white matter. Calpain translational expression was up-regulated by 462.5% in MS plaques compared with controls, although levels of the specific endogenous inhibitor, calpastatin, were not altered significantly. At the transcriptional level, no significant changes in calpain or calpastatin expression were detected by reverse transcription-PCR. Using double immunofluorescent labeling, increased calpain expression was observed in reactive astrocytes, activated T cells, and activated mononuclear phagocytes in and adjacent to demyelinating lesions. Calpain activity and translational expression were not increased significantly in white matter from patients with Parkinson's or Alzheimer's diseases compared with that of normal controls. Because calpain degrades all major myelin proteins, the increased activity and expression of this proteinase may play a critical role in myelinolysis in autoimmune demyelinating diseases such as MS. (+info)
In vivo evidence for axonal dysfunction remote from focal cerebral demyelination of the type seen in multiple sclerosis.
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To test for axonal damage or dysfunction in white matter tracts remote from acute demyelinating lesions, we used brain proton magnetic resonance spectroscopic imaging to measure changes in N-acetyl aspartate (NAA), an index of neuronal integrity, in the white matter of the normal-appearing hemisphere of three patients with large, solitary brain demyelinating lesions of the type seen early in multiple sclerosis. During the acute phase of their disease, all patients showed normal ratios of NAA to creatine (Cr) resonance intensity throughout the hemisphere contralateral to the lesion. However, on examination 1 month later, all of the patients showed abnormally low NAA/Cr resonance intensity ratios (reduction of NAA/Cr by 22-35%) in voxels of the contralateral hemisphere which were homologous to the demyelinating lesion. Other voxels in the normal-appearing hemisphere showed normal NAA relative resonance intensities. The decrease in NAA/Cr in voxels of the normal-appearing hemispheres resolved in all patients after 6 months, with a time course similar to that observed for NAA from voxels within the lesions. We conclude that effects of damage or dysfunction to axons traversing inflammatory lesions can be transmitted over long distances in the normal-appearing white matter. Such remote, secondary effects may be an expression of dysfunction of axons in projection pathways or of the reorganization of functional pathways seen in brains recovering from an acute injury. (+info)
Correlation between morphological and functional retinal impairment in multiple sclerosis patients.
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PURPOSE: To assess whether a correlation exists between optic nerve fiber layer (NFL) thickness and the retinal or visual pathway function in multiple sclerosis (MS) patients previously affected by optic neuritis. METHODS: Fourteen patients with a diagnosis of definite MS were examined. All had been affected by optic neuritis (MSON) with complete recovery of visual acuity (14 eyes included in study). These were compared with 14 eyes from 14 age-matched control subjects. NFL thickness was measured by optical coherence tomography (OCT). Three different measurements in each quadrant (superior, inferior, nasal, and temporal) were taken and averaged. The data in all quadrants (12 values averaged) were identified as NFL Overall, whereas the data obtained in the temporal quadrant only (3 values averaged) were identified as NFL Temporal. Retinal and visual pathway function was assessed by simultaneously recording pattern electroretinograms (PERGs) and visual evoked potentials (VEPs) using high-contrast (80%) checkerboard stimuli subtending 15 minutes and 60 minutes of the visual arc (min arc) and reversed at the rate of two reversals per second. RESULTS: In MSON eyes there was a significant (P < 0.01) reduction in NFL thickness in both NFL Overall and NFL Temporal evaluations compared with the values observed in control eyes. PERG, (15-min arc checks) and VEP (15-min arc and 60-min arc checks), showed a significant (P < 0.01) delay in latency and reduction in amplitude. NFL Overall and NFL Temporal values were significantly correlated (P < 0.01) to the PERG P50 latency and P50 to N95 amplitude recorded with 15-min arc checks. No correlations (P > 0.01) between NFL values and the other electrophysiological data (PERG recorded with 60-min arc checks and VEP recorded with 15-min arc and 60-min arc checks) were found. CONCLUSIONS: There is a correlation between PERG changes and NFL thickness in MS patients previously affected by optic neuritis, but there is no correlation between VEP changes and NFL thickness. (+info)
Age dependence of clinical and pathological manifestations of autoimmune demyelination. Implications for multiple sclerosis.
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A prominent feature of the clinical spectrum of multiple sclerosis (MS) is its high incidence of onset in the third decade of life and the relative rarity of clinical manifestations during childhood and adolescence, features suggestive of age-related restriction of clinical expression. Experimental allergic encephalomyelitis (EAE), a model of central nervous system (CNS) autoimmune demyelination with many similarities to MS, has a uniform rapid onset and a high incidence of clinical and pathological disease in adult (mature) animals. Like MS, EAE is most commonly seen and studied in female adults. In this study, age-related resistance to clinical EAE has been examined with the adoptive transfer model of EAE in SJL mice that received myelin basic protein-sensitized cells from animals 10 days (sucklings) to 12 weeks (young adults) of age. A variable delay before expression of clinical EAE was observed between the different age groups. The preclinical period was longest in the younger (<14 days of age) animals, and shortest in animals 6 to 8 weeks old at time of transfer. Young animals initially resistant to EAE eventually expressed well-developed clinical signs by 6 to 7 weeks of age. This was followed by a remitting, relapsing clinical course. For each age at time of sensitization, increased susceptibility of females compared to males was observed. Examination of the CNS of younger animal groups during the preclinical period showed lesions of acute EAE. Older age groups developed onset of signs coincident with acute CNS lesions. This age-related resistance to clinical EAE in developing mice is reminiscent of an age-related characteristic of MS previously difficult to study in vivo. The associated subclinical CNS pathology and age-related immune functions found in young animals may be relevant to the increasing clinical expression of MS with maturation, and may allow study of factors associated with the known occasional poor correlation of CNS inflammation and demyelination and clinical changes in this disease. (+info)
Viral hyperinfection of the central nervous system and high mortality after hematopoietic stem cell transplantation for treatment of Theiler's murine encephalomyelitis virus-induced demyelinating disease.
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Theiler's murine encephalomyelitis virus (TMEV) establishes a persistent infection in the central nervous system (CNS) leading to an inflammatory demyelinating disease of the CNS in which the histology and clinical course is similar to multiple sclerosis (MS). Disease pathogenesis is primarily due to T-cell-mediated destruction of myelin, which has been attributed to cytopathic effects of the virus, but immune-mediated destruction of myelin mediated via both virus-specific and myelin-specific T cells appear to play the major role. To determine if bone marrow transplantation would be an effective therapy for a virus-initiated autoimmune disease and to better separate viral cytopathic effects from immune-mediated demyelination, we ablated the immune system of TMEV-infected animals with 1,100 cGy total body irradiation, and then the animal's immunity was reconstituted by transplantation of disease-susceptible SJL/J mice with syngeneic marrow or disease-susceptible DBA/2J with marrow from disease-resistant (C57Bl/6 x DBA/2)F1 (B6D2) donors. Hematopoietic transplant performed after onset of disease resulted in 42% mortality in SJL/J syngeneic transplants, 47% mortality in diseased DBA2 recipients restored with marrow from naive B6D2 donors, and 12% in diseased DBA2 recipients receiving marrow from B6D2 donors previously infected with TMEV. Delayed type hypersensitivity (DTH) to both virion and myelin proteins was decreased in surviving mice that underwent transplantation; however, CNS viral titers were significantly elevated compared with nontransplanted controls. We conclude that a functional immune system with appropriate T-cell responses are important in prevention of lethal cytopathic CNS effects from TMEV. Relevant to the clinical use of bone marrow transplantation, attempts to ablate the immune system in viral-mediated immune diseases or virus-initiated autoimmune disease may have acute and lethal consequences. Our results raise concern about the attempted use of autologous hematopoietic transplantation in patients with MS, an autoimmune disease with a suspected virus etiology, particularly if the graft is aggressively depleted of lymphocytes. (+info)
Interferon-beta-1a in relapsing-remitting multiple sclerosis: effect on hypointense lesion volume on T1 weighted images.
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OBJECTIVE: Recently, a strong correlation between the increase in hypointense lesion load on T1 weighted spin echo images, and the increase in disability was reported. Although the effect of interferon-beta has been demonstrated both in reducing exacerbation rate, frequency of enhancing lesions, and accumulation of disease burden on T2 weighted images, the impact on the accumulation of hypointense lesions has not yet been evaluated. The aims of the present study were: (a) to assess for the first time the effect of interferon-beta-1a on T1 weighted MRI hypointense lesion volume; and (b) to evaluate the relation between changes on hypointense, hyperintense, and enhancing lesion volume before and during interferon-beta-1a treatment in relapsing-remitting multiple sclerosis. METHODS: After a baseline scan and 6 month pretreatment period, 67 patients with relapsing-remitting multiple sclerosis were treated with interferon-beta-1a by subcutaneous injection three times a week during a 12 month treatment period. All patients had MRI every month during the 6 month pretreatment period and for the first 9 months of the treatment period. A final MRI was also performed at the end of the 12 month treatment period. RESULTS: There was a significant increase in the mean hyperintense lesion volume during the pretreatment phase (6 months) and a slight decrease during the treatment period (12 months), whereas the hypointense lesion volume increased significantly before treatment and remained substantially stable during treatment. There was a significant correlation between changes in hypointense and hyperintense lesion volume during the observation period, but not during treatment. The monthly mean volume of Gadolinium-DTPA enhancing lesions was significantly higher during the pretreatment than the treatment period, and the enhancing lesion volume correlated with changes of hyperintense and hypointense lesion volumes only during the observation period. CONCLUSION: These data suggest that interferon-beta-1a has a stabilising effect on T1 weighted hypointense lesion volume. (+info)