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At least 1,009 records · Page 56Linked to original sources
PubMed1991

Serum antibodies to GM1 and GM3-gangliosides in systemic lupus erythematosus with chronic inflammatory demyelinating polyradiculoneuropathy.

Acute symmetric demyelinating polyneuropathy of the Guillain-Barré type is known in systemic lupus erythematosus (SLE). Chronic idiopathic demyelinating polyneuropathy (CIDP) has been reported rarely with SLE. A case is reported of CIDP accompanying SLE with autoantibodies against GM1- and GM3-gangliosides. There was no historical evidence to suggest SLE, and CIDP was the first manifestation of SLE. The 38-year-old patient had elevated CSF-protein, slow nerve conduction velocities, sural nerve biopsy revealed mixed axon loss with demyelination and CIDP white matter lesions were observed in magnetic resonance imaging, the GM1- and GM3-autoantibodies may play a role in the pathogenesis of CIDP in SLE.

Adult↗
PubMed1995

Increased CSF C4d in demyelinating neuropathy indicates the radicular involvement.

Plasma and cerebrospinal fluid (CSF) levels of C4d and the circulating immune complex (CIC) to C1q were measured in 12 patients with chronic inflammatory demyelinating polyneuropathy and Guillain-Barré syndrome. CSF C4d values more than 2 SD from the mean of 8 cervical spongylosis cases were demonstrated in the patients with proximal demyelination. The CSF C4d probably originated from both intrathecal synthesis and the systemic circulation. CSF levels of C4d may serve as a sensitive indicator for the radicular involvement in demyelinating polyneuropathy.

Adult↗
PubMed1988

Mechanisms of virus-induced demyelination and remyelination.

Viral models of demyelination and remyelination provide important clues to the pathogenesis of multiple sclerosis. Determining the precise viral polypeptides recognized by T cells during the demyelinating process will be important in understanding the mechanisms of viral-induced myelin destruction. Isolation, purification, and characterization of factors that promote remyelination and proliferation of oligodendrocytes may provide hope in the treatment of patients with chronic demyelinating disorders.

Animals↗
PubMed1996

Regulation of oligodendrocyte development and CNS myelination by growth factors: prospects for therapy of demyelinating disease.

Multiple sclerosis (MS), the most common neurological disorder diagnosed in young adults, is characterized by autoimmune demyelination in the central nervous system (CNS). Promotion of remyelination in the brain and spinal cord is a potential strategy for therapeutic intervention in MS and other demyelinating diseases. Recent studies have shown that the development of oligodendrocytes, the myelin-forming cells of the CNS, is extensively controlled by growth factors. These factors regulate the proliferation, migration, differentiation, survival and regeneration of oligodendroglial cells and the synthesis of myelin, and often interact in a complex manner. Moreover, insulin-like growth factor I (IGF-I) has proven effective for therapy of experimental autoimmune encephalomyelitis (EAE), an animal model of autoimmune demyelination. In this review we summarize recent findings on the regulation of oligodendrocyte development and CNS myelination by growth factors, and discuss these findings in the context of possible clinical application for the therapy of neurological disease in humans.

Animals↗
PubMed2003

Quantifying the early stages of remyelination following cuprizone-induced demyelination.

The demyelinating toxin cuprizone is used increasingly in mouse studies of central nervous system remyelination. The value of this model for such studies depends on an accurate description of its quantifiable features. We therefore investigated histology and ultrastructure during the early oligodendrocyte differentiation phase of remyelination in mice given cuprizone and allowed to recover for 2 weeks. Limiting the dose of cuprizone to 0.2% overcame significant mouse morbidity and weight loss seen with a 0.4% dose, but the distribution of cuprizone-induced demyelination was anatomically variable. The caudal corpus callosum and dorsal hippocampal commissure mostly demyelinated at this dose, but the rostral corpus callosum and rostral cerebellar peduncles did not. This variable response, together with small axon diameters and hence thin myelin sheaths, hindered analysis of the progress of early remyelination. The proportion of myelinated and unmyelinated axons in defined regions followed expected trends, but there was pronounced variation between animals. Furthermore, group mean G ratios did not change as expected during the early stages of remyelination, and regression analysis revealed a complex relationship between axon diameter and myelin sheath thickness during this period. We also noted axonal pathology that persisted for at least 2 weeks after cuprizone withdrawal.

Animals↗
PubMed2005

ES cell-derived glial precursors contribute to remyelination in acutely demyelinated spinal cord lesions.

Pluripotent embryonic stem (ES) cells have emerged as a powerful tool for disease modeling and neural regeneration. Transplantation studies in rodents indicate that ES cell-derived glial precursors (ESGPs) efficiently restore myelin in dysmyelinating mutants and chemically induced foci of myelin loss. Here we explore the myelination potential of ESGPs in an antibody/complement-induced demyelination model. Microinjection of an antibody to myelin oligodendrocyte glycoprotein (MOG) and complement was employed to generate circumscribed areas of demyelination in the adult rat spinal cord. ESGPs transplanted into 2-day-old lesions were found to survive and differentiate into both oligodendrocytes and astrocytes. The engrafted cells remained largely confined to the lesion site and showed no evidence of tumor formation up until 4 weeks after transplantation. Within areas of pronounced microglial activation and macrophage extravasation, engrafted ES cell-derived oligodendrocytes contacted and enwrapped host axons and alongside endogenous glia, contributed to the formation of new myelin sheaths. These findings demonstrate that ESGPs transplanted into acutely demyelinated lesions can contribute to myelin repair.

Animals↗
PubMed1970

Demyelinating encephalomyelopathy associated with lead poisoning in nonhuman primates.

Lead poisoning was diagnosed in four primates by the finding of toxic amounts of lead in tissues. Abnormalities in the brain and spinal cord were characterized by vascular lesions and demyelination. These findings suggest a new animal model for the study of demyelination and strengthen the supposition that lead may be a factor in some idiopathic demyelinating diseases.

Animals↗
PubMed1981

Rapid correction of hyponatremia causes demyelination: relation to central pontine myelinolysis.

The human demyelinative disorder central pontine myelinolysis may be an iatrogenic disease caused by a rapid rise in serum sodium, usually when hyponatremia is corrected. Rats treated with hypertonic saline after 3 days of vasopressin-induced hyponatremia had demyelinative lesions in the corpus striatum, lateral hemispheric white matter, cerebral cortex, hippocampal fimbria, anterior commissure, thalamus, brainstem tegmentum, and cerebellum. Thus, rapid correction of hyponatremia can lead to demyelinative lesions and may be the cause of central pontine myelinolysis in man.

Animals↗
PubMed1973

Myelin-specific autoantibodies associated with central nervous system demyelination in canine distemper virus infection.

Sera from dogs with spontaneously occurring and experimentally produced canine distemper virus-associated demyelinating encephalitis were examined for antibodies to central nervous system myelin by the complement fixation and indirect immunofluorescent methods. Complement-fixing immunoglobulin M antibodies and non-complement-fixing immunoglobulin G antibodies were found in 97% of the spontaneous cases. In comparison, only 28% of control sera contained these antibodies; furthermore, mean antibody titers in the control groups were significantly lower (P < 0.005) when compared to the distemper group. Complement-fixing antimyelin antibodies were also demonstrated in gnotobiotic dogs with experimentally induced distemper virus-associated demyelination. The antibody response could be correlated with clinicopathological features of the disease produced. Results of this study indicate that demyelination in canine distemper may proceed by immune mechanisms.

Absorption↗
PubMed1984

Persistence of mouse hepatitis virus A59 RNA in a slow virus demyelinating infection in mice as detected by in situ hybridization.

Mouse hepatitis virus strain A59 produces chronic central nervous system demyelination in rodents. As late as 6 months after intracerebral inoculation of mice 4 to 6 weeks old, when infectious virus cannot be recovered and viral antigens cannot be detected in the central nervous systems and livers of these animals, primary demyelination is still evident. Using cloned virus-specific DNAs and the highly sensitive and specific technique of in situ hybridization, we have detected low levels of mouse hepatitis virus A59 RNA in the central nervous systems and livers of mice 10 months after inoculation. We suggest that viral persistence may play a role in mouse hepatitis virus A59-induced chronic demyelination.

Animals↗
PubMed1986

Demyelinating lesions due to Theiler's virus are associated with ongoing central nervous system infection.

We used in situ hybridization and immunocytochemistry to look for a correlation between virus expression and white matter lesions during late demyelinating disease due to persistent Theiler's virus infection. We found the following. (i) Tissue lesions developed at the site of virus infection. This correlation was not explained by infection of lymphocytes and macrophages. (ii) Large differences in the extent of pathology existed between mice. The amount of inflammation paralleled the number of cells containing viral RNA or viral capsid antigens. (iii) C57BL/6 mice, which are resistant to demyelination, were able to eradicate the infection. Our results are strongly in favor of a mechanism of demyelination in which viral gene products play a central role.

Animals↗
PubMed1990

Genetic mapping of the ability of Theiler's virus to persist and demyelinate.

Theiler's virus, a murine picornavirus, is responsible for two different types of disease: strains DA, BeAn, and WW persist for more than a year in the white matter of the central nervous system and cause primary demyelination; strains GDVII and FA, on the other hand, cause an acute encephalitis that kills the host in a matter of days. To map the regions of the viral genome responsible for persistence and demyelination, cDNA clones of the entire genomes of the DA and GDVII strains were constructed and cloned into Bluescript plasmid (A. McAllister, F. Tangy, C. Aubert, and M. Brahic, Microb. Pathogen. 7:381-388, 1989; F. Tangy, A. McAllister, and M. Brahic, J. Virol. 63:1101-1106, 1989). We constructed chimeric viruses obtained by exchanging regions between the cDNA clones. Analysis of the disease phenotypes produced by the chimeric viruses allowed us to map persistence and demyelination to a genome segment coding for the VP1 capsid protein and 27 amino acids of protein 2A.

Animals↗
PubMed1995

Identification of a major T-cell epitope within VP3 amino acid residues 24 to 37 of Theiler's virus in demyelination-susceptible SJL/J mice.

Intracerebral inoculation of susceptible strains of mice with Theiler's murine encephalomyelitis virus (TMEV) results in a chronic, immunologically mediated demyelinating disease that shares many features with human multiple sclerosis. CD4+ T lymphocytes play a critical role in the pathogenesis of virus-induced demyelinating disease. We have identified a region within amino acid residues 24 to 37 of the VP3 capsid protein of TMEV (VP3(24-37)) that is recognized by T lymphocytes from the demyelination-susceptible SJL/J strain of mice. The T-cell response to VP3(24-37) represents a predominant Th-cell response against the virus from either TMEV-immunized or TMEV-infected SJL/J mice, and viral epitopes VP1(233-250), VP2(74-86), and VP3(24-37) account for most of the Th-cell response to TMEV.

Amino Acid Sequence↗
PubMed1995

The predominant virus antigen burden is present in macrophages in Theiler's murine encephalomyelitis virus-induced demyelinating disease.

Theiler's murine encephalomyelitis virus (TMEV) produces a persistent central nervous system infection and chronic, inflammatory demyelinating disease in susceptible mice. TMEV antigen(s) and RNA genome have been detected in astrocytes, oligodendrocytes, and macrophages during persistence. Whether there is a predominant cell type in which TMEV persists has not been resolved. Since TMEV-induced demyelinating lesions are infiltrated with macrophages and a number of other persistent viruses show near-exclusive tropism for these phagocytic cells, we used two-color immunofluorescent staining with conventional and confocal microscopy to colocalize TMEV to cells that stain with monoclonal antibodies (MOMA-2) [unknown antigen], Mac-1 [CD11b], FA-11 [CD66], and 2F8 [scavenger receptor]) to macrophages in BeAn-infected SJL mice. A predominant virus antigen burden within macrophages infiltrating demyelinating lesions was seen. A dichotomy of cells staining for virus antigen(s) was found with infected cells containing either a large or small virus antigen load. Ninety percent of cells with a large virus antigen load were large phagocytes (20 to 50 microns) that were readily detected at low power (5x objective). Cells with smaller amounts of virus antigen(s) turned out to be either these same large phagocytic cells or much smaller cells, approximately equal to 10 microns in diameter. Forty percent of cells with a small virus antigen load were macrophages. The unidentified approximately equal to 10-microns cells that are virus antigen positive and macrophage negative in this study could still be macrophages, or they may be oligodendrocytes. The fact that virus was detected in the cytoplasm and not phagolysosomes of macrophages and the sheer mass of fluorescently stained virus proteins in some macrophages suggest that TMEV persists in these phagocytic cells by active virus replication.

Animals↗
PubMed1997

Major linear antibody epitopes and capsid proteins differentially induce protective immunity against Theiler's virus-induced demyelinating disease.

Theiler's murine encephalomyelitis virus-induced immunologically mediated demyelinating disease (TMEV-IDD) in susceptible mice provides a relevant infectious model for multiple sclerosis. Previously, we have identified six major linear antibody epitopes on the viral capsid proteins. In this study, we utilized fusion proteins containing individual capsid proteins and synthetic peptides containing the linear antibody epitopes to determine the potential role of antibody response in the course of virus-induced demyelination. Preimmunization of susceptible mice with VPI and VP2 fusion proteins, but not VP3, resulted in the protection from subsequent development of TMEV-IDD. Mice free of clinical symptoms following preimmunizations with fusion proteins displayed high levels of antibodies to the capsid proteins corresponding to the immunogens. In contrast, the level of antibodies to a particular linear epitope, A1C (VP1(262-276)), capable of efficiently neutralizing virus in vitro increased with the progression of disease. Further immunization with synthetic peptides containing individual antibody epitopes indicated that antibodies to the epitopes are differentially effective in protecting from virus-induced demyelination. Taken together, these results suggest that antibodies to only certain linear epitopes are protective and such protection may be restricted during the early stages of viral infection.

Animals↗
PubMed2003

Infection with Theiler's murine encephalomyelitis virus directly induces proinflammatory cytokines in primary astrocytes via NF-kappaB activation: potential role for the initiation of demyelinating disease.

Theiler's virus infection in the central nervous system (CNS) induces a demyelinating disease very similar to human multiple sclerosis. We have assessed cytokine gene activation upon Theiler's murine encephalomyelitis virus (TMEV) infection and potential mechanisms in order to delineate the early events in viral infection that lead to immune-mediated demyelinating disease. Infection of SJL/J primary astrocyte cultures induces selective proinflammatory cytokine genes (interleukin-12p40 [IL-12p40], IL-1, IL-6, tumor necrosis factor alpha, and beta interferon [IFN-beta]) important in the innate immune response to infection. We find that TMEV-induced cytokine gene expression is mediated by the NF-kappaB pathway based on the early nuclear NF-kappaB translocation and suppression of cytokine activation in the presence of specific inhibitors of the NF-kappaB pathway. Further studies show this to be partly independent of dsRNA-dependent protein kinase (PKR) and IFN-alpha/beta pathways. Altogether, these results demonstrate that infection of astrocytes and other CNS-resident cells by TMEV provides the early NF-kappaB-mediated signals that directly activate various proinflammatory cytokine genes involved in the initiation and amplification of inflammatory responses in the CNS known to be critical for the development of immune-mediated demyelination.

Animals↗
PubMed2005

Increased epitope-specific CD8+ T cells prevent murine coronavirus spread to the spinal cord and subsequent demyelination.

CD8+ T cells are important for clearance of neurotropic mouse hepatitis virus (MHV) strain A59, although their possible role in A59-induced demyelination is not well understood. We developed an adoptive-transfer model to more clearly elucidate the role of virus-specific CD8+ T cells during the acute and chronic phases of infection with A59 that is described as follows. C57BL/6 mice were infected with a recombinant A59 virus expressing the gp33 epitope, an H-2Db-restricted CD8+ T-cell epitope encoded in the glycoprotein of lymphocytic choriomeningitis virus, as a fusion with the enhanced green fluorescent protein (RA59-gfp/gp33). P14 splenocytes (transgenic for a T-cell receptor specific for the gp33 epitope) were transferred at different times pre- and postinfection (p.i.). Adoptive transfer of P14 splenocytes 1 day prior to infection with RA59-gfp/gp33, but not control virus lacking the gp33 epitope, RA59-gfp, reduced weight loss and viral replication and spread in the brain and to the spinal cord. Furthermore, demyelination was significantly reduced compared to that in nonrecipients. However, when P14 cells were transferred on day 3 or 5 p.i., no difference in acute or chronic disease was observed compared to that in nonrecipients. Protection in mice receiving P14 splenocytes prior to infection correlated with a robust gp33-specific immune response that was not observed in mice receiving the later transfers. Thus, an early robust CD8+ T-cell response was necessary to reduce virus replication and spread, specifically to the spinal cord, which protected against demyelination in the chronic phase of the disease.

Animals↗
PubMed2006

Predicting response to treatment in chronic inflammatory demyelinating polyradiculoneuropathy.

OBJECTIVE: To discover whether Inflammatory Neuropathy Cause and Treatment Group (INCAT) electrophysiological criteria for demyelinating neuropathy predict response to immunotherapy in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: This was a retrospective case note study of patients who had attended Guy's Hospital Peripheral Nerve Clinic between January 2001 and March 2004, been diagnosed as having CIDP, and given treatment with corticosteroids, intravenous immunoglobulin (IVIg), or plasma exchange (PE). Patients' nerve conduction studies (NCS) were reviewed for evidence of demyelination and whether the abnormalities fulfilled modified INCAT electrophysiological criteria. Patients whose NCS fulfilled the criteria were assigned to the neurophysiologically definite CIDP group, while those that did not were labelled as neurophysiologically probable CIDP. Responses to any of the three immunotherapy agents were compared between the two groups. RESULTS: Out of 50 patients, 27 (54%) were classified as neurophysiologically definite and 23 (46%) as neurophysiologically probable CIDP patients. Twenty (74%) neurophysiologically definite and 17 (73.9%) neurophysiologically probable CIDP patients responded to treatment. CONCLUSIONS: INCAT electrophysiological criteria did not predict a higher rate of response to immunotherapy. Neurophysiologically probable CIDP patients should be given a trial of immunotherapy.

Adolescent↗