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PubMed2000

Open-ring imaging sign: highly specific for atypical brain demyelination.

OBJECTIVE: To test the specificity for demyelination of a new neuroimaging sign: contrast enhancement shaped as an open ring or a crescent circumscribed to the white matter. BACKGROUND: Brain demyelination can cause ring enhancement mimicking neoplasm or infection on CT or MRI. METHODS: A MEDLINE search of pathology-proved demyelination yielded 32 illustrated cases of ring-enhancing lesions published between 1981 and 1995. Controls consisted of the same number of published images of neoplasms and infections, pathology proved, and matched by year of publication, and age and gender of the patient. Two neuroradiologists read the images twice independently 1 year apart. RESULTS: Interrater agreement was good (kappa = 0.64 and 0.66 for either reading). Test-retest reliability was high (kappa = 0.75 and 0.74 for either rater). The open-ring sign clearly distinguished demyelinating lesions from neoplasms and infections. For demyelination versus neoplasm or infection, the specificity of the reading by the first neuroradiologist was 93.8 (95% CI, 86 to 98), and that of the second was 84.4 (95% CI, 74 to 92). The likelihood ratio of demyelination versus neoplasm averaged 5.2, and versus infection, 17.2. That is, if the lesions had the same incidence in the population, in the presence of an open-ring sign demyelination would be five times more likely than neoplasm and 17 times more likely than infection. However, given the much higher incidence of neoplasms and infections, these lesions are still frequently responsible for open-ring enhancement. CONCLUSIONS: The open-ring sign is often present in large, contrast-enhancing demyelinating lesions and helps to differentiate them from neoplasms and infections.

Adult↗
PubMed1996

Pathogenesis of mouse hepatitis virus-induced demyelination.

Infection of rodents with neurotropic mouse hepatitis virus (MHV) may result in lethal encephalitis or paralytic demyelinating disease resembling the human disease multiple sclerosis. The outcome of MHV infection is dependent on a number of variables, including the passage history of the viral isolate, dose and route of inoculation, and the age and immune status of the host. Alterations in surface glycoproteins, especially the spike protein, can profoundly influence pathogenesis. Innate resistance to MHV infection may be related to the expression of cellular receptors or to immunological factors. The immune system plays a major role in MHV pathogenesis, affecting encephalitis, viral clearance, and demyelination. Antiviral antibodies, CD4+ T lymphocytes, or CD8+ T lymphocytes may protect infected animals from lethal encephalitis, but both CD4+ and CD8+ T lymphocytes are required for effective viral clearance. Demyelination in MHV-infected animals has been attributed to the cytolytic effects of viral infection on myelin-producing oligodendrocytes, but more recent evidence supports an immunopathological mechanism for demyelination. Immunopathological models for demyelination include autoimmunity, direct immune cytotoxicity, and indirect 'bystander' damage. Although evidence exists supporting all of these models, the authors favor the bystander demyelination model. Much remains to be revealed about the processes leading to demyelination in MHV-infected mice, and information gained from these investigations may aid in the study of demyelinating disease in humans.

Animals↗
PubMed2000

Contributions of CD8+ T cells and viral spread to demyelinating disease.

Acute and chronic demyelination are hallmarks of CNS infection by the neurotropic JHM strain of mouse hepatitis virus. Although infectious virus is cleared by CD8+ T cells, both viral RNA and activated CD8+ T cells remain in the CNS during persistence potentially contributing to pathology. To dissociate immune from virus-mediated determinants initiating and maintaining demyelinating disease, mice were infected with two attenuated viral variants differing in a hypervariable region of the spike protein. Despite similar viral replication and tropism, one infection was marked by extensive demyelination and paralysis, whereas the other resulted in no clinical symptoms and minimal neuropathology. Mononuclear cells from either infected brain exhibited virus specific ex vivo cytolytic activity, which was rapidly lost during viral clearance. As revealed by class I tetramer technology the paralytic variant was superior in inducing specific CD8+ T cells during the acute disease. However, after infectious virus was cleared, twice as many virus-specific IFN-gamma-secreting CD8+ T cells were recovered from the brains of asymptomatic mice compared with mice undergoing demyelination, suggesting that IFN-gamma ameliorates rather than perpetuates JHM strain of mouse hepatitis virus-induced demyelination. The present data thus indicate that in immunocompetent mice, effector CD8+ T cells control infection without mediating either clinical disease or demyelination. In contrast, demyelination correlated with early and sustained infection of the spinal cord. Rapid viral spread, attributed to determinants within the spike protein and possibly perpetuated by suboptimal CD8+ T cell effector function, thus ultimately leads to the process of immune-mediated demyelination.

Animals↗
PubMed2000

CD4 and CD8 T cells have redundant but not identical roles in virus-induced demyelination.

A chronic demyelinating disease results from murine infection with the neurotropic strain JHM of mouse hepatitis virus (MHV-JHM). Demyelination is largely immune mediated. In this study, the individual roles of CD4 and CD8 T cells in MHV-induced demyelination were investigated using recombination-activating gene 1-/- (RAG1-/-) mice infected with an attenuated strain of MHV-JHM. These animals develop demyelination only after adoptive transfer of splenocytes from mice previously immunized to MHV. In this study, we show that, following adoptive transfer, virus-specific CD4 and CD8 T cells rapidly infiltrate the CNS of MHV-JHM-infected RAG1-/- mice. Adoptive transfer of CD4 T cell-enriched donors resulted in more severe clinical disease accompanied by less demyelination than was detected in the recipients of undepleted cells. Macrophage infiltration into the gray matter of CD4 T cell-enriched recipients was greater than that observed in mice receiving undepleted splenocytes. In contrast, CD8 T cell-enriched recipients developed delayed disease with extensive demyelination of the spinal cord. MHV-JHM-infected RAG1-/- mice receiving donors depleted of both CD4 and CD8 T cells did not develop demyelination. These results demonstrate that the development of demyelination following MHV infection may be initiated by either CD4 or CD8 T cells. Furthermore, they show that CD4 T cells contribute more prominently than CD8 T cells to the severity of clinical disease, and that this correlates with increased macrophage infiltration into the gray matter.

Adoptive Transfer↗
PubMed1991

Expression of human HLA-B27 transgene alters susceptibility to murine Theiler's virus-induced demyelination.

Infection of certain strains of mice with Theiler's murine encephalomyelitis virus results in persistence of virus and an immune-mediated primary demyelination in the central nervous system that resembles multiple sclerosis. Because susceptibility/resistance to demyelination in B10 congeneic mice maps strongly to class I MHC genes (D region) we tested whether expression of a human class I MHC gene (HLA-B27) would alter susceptibility to Theiler's murine encephalomyelitis virus-induced demyelination. Transgenic HLA-B27 mice were found to co-express human and endogenous mouse class I MHC genes by flow microfluorimetry analysis of PBL. In the absence of the human transgene, H-2stf, or v mice but not H-2b mice had chronic demyelination and persistence of virus at 45 days after infection. No difference in degree of demyelination, meningeal inflammation, or virus persistence was seen between transgenic HLA-B27 and nontransgenic littermate mice of H-2f or H-2v haplotype. In contrast, H-2s (HLA-B27+) mice showed a dramatic decrease in extent of demyelination and number of virus-Ag+ cells in the spinal cord compared with H-2s (HLA-B27-) littermate mice. In addition, none of the eight H-2s mice homozygous for HLA-B27 gene had spinal cord lesions even though infectious virus was isolated chronically from their central nervous system. Expression of HLA-B27 transgene did not interfere with the resistance to demyelination normally observed in B10 (H-2b) mice. These experiments demonstrate that expression of a human class I MHC gene can modulate a virus-induced demyelinating disease process in the mouse.

Animals↗
PubMed1994

A predominant viral epitope recognized by T cells from the periphery and demyelinating lesions of SJL/J mice infected with Theiler's virus is located within VP1(233-244).

The intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) into susceptible strains of mice results in a chronic, immune-mediated demyelinating disease that shares many features with human multiple sclerosis. As with human MS, T lymphocytes seem to be critically important for the pathogenesis of this virally induced, demyelinating disease. Therefore, determining the fine specificity of the T cell response may be essential for elucidating the mechanism(s) involved in demyelination. By using fusion proteins and synthetic peptides, we have initially identified a region within the amino acid residues 233 to 250 of the VP1 capsid protein of Theiler's virus that is recognized by T cells from either TMEV-immunized or TMEV-infected, demyelination-susceptible SJL/J mice. A T lymphocyte precursor frequency analysis indicates that a major TMEV-reactive T cell population in the periphery of virus-infected mice recognizes this VP1 region. The fine epitope specificity has been further determined to be within VP1(233-244) using additional synthetic peptides. VP1(233-244)-specific T cells seem to represent a significant population of TMEV-reactive T lymphocytes within the demyelinating lesions, because such T cells have been cloned from the spinal cords of infected mice. Interestingly, all TMEV-specific T cell clones derived from the demyelinating lesions, regardless of epitope specificity, produce IFN-gamma on stimulation and thus may play a critical role in the recruitment and activation of inflammatory cells leading to demyelination. Taken together, these data suggest that a T cell response against VP1(233-244) is involved in the pathogenesis of TMEV-induced demyelinating disease.

Animals↗
PubMed1994

[The pathomechanisms of virus-induced demyelination].

The pathomechanisms of virus-induced demyelination have been widely studied, especially in animal models, in order to elucidate the pathogenesis of a human demyelinating disease, multiple sclerosis. The recent development of molecular biology has partially defined the genomic segment responsible for demyelination in some viruses. It is, however, still unclear, how such a segment causes demyelination. Three main issues have been addressed regarding the mechanisms of demyelination, i.e., oligodendrocyte lytic viral infection, immune-mediated demyelination with oligodendrocyte viral infection, and immune-mediated demyelination without oligodendrocyte viral infection. Immune responses of the host are, therefore, critical, as well as viral replication and propagation in virus-induced demyelination.

Animals↗
PubMedDate not supplied

Interaction of immune and central nervous systems: contribution of anti-viral Thy-1+ cells to demyelination induced by coronavirus JHM.

The murine coronavirus JHM (JHMV or MHV-4) has been intensively studied as an experimental model of viral-induced demyelination; nonetheless, the degree to which demyelination results from direct viral cytolysis of oligodendroglia or immunological mechanisms remains controversial. To examine the contribution of immunity to the pathogenesis of JHMV in the central nervous system (CNS), mice were exposed to immunosuppressive doses of x-irradiation 3 days post infection and observed for clinical and pathological evidence of acute and subacute demyelination. Irradiated mice were found to have a nearly thousand-fold increase in central nervous system virus titer, as well as the presence of both abundant virus and viral antigen in white matter cells with the morphological characteristics of oligodendrocytes. Nonetheless, infected, irradiated mice had little or no evidence of demyelination or destruction of CNS cells. Adoptive transfers of spleen cells from syngeneic JHMV-immunized donors into irradiated JHMV-infected mice were carried out in order to determine the effect of immune reconstitution on pathogenesis. Splenocytes from JHMV-immune donors, but not naive donors or donors immunized with irrelevant antigen, completely restored demyelination in irradiated, JHMV-infected recipients. Depletion of Thy-1+ cells by treatment with monoclonal antibody and complement abolished the ability to transfer demyelination. We conclude that: 1) JHMV infection of the CNS does not result in acute or subacute demyelination in the absence of an intact immune response, and 2) viral-specific Thy-1+ cells are an essential element in the induction of demyelinating CNS lesions that result from JHMV infection.

Animals↗
PubMed1996

The balance between persistent virus infection and immune cells determines demyelination.

We addressed the contributions of persistent virus infection and immune cells to the pathogenesis of Theiler's virus-induced demyelination, a model for human multiple sclerosis. We developed a model involving the transfer of spleen cells into immunodeficient C.B-17-scid (SCID) mice, which normally die of overwhelming virus encephalitis without demyelination when infected with Theiler's virus. Adoptive transfer of nonimmune spleen cells from BALB/c mice into SCID mice resulted in the survival of all mice. However, these mice developed extensive demyelination and virus Ag/RNA persistence in the spinal cord white matter. The most demyelination was observed when mice received an intermediate number of spleen cells (1.8-7.5 x 10(6)), whereas too few cells (0.5 x 10(6)) did not ameliorate the SCID phenotype, and too many cells (30 x 10(6)) resulted in almost complete viral clearance with minimal demyelination. Adoptive transfer of spleen cells depleted of either CD4+ or CD8+ T cells produced vacuolar demyelination associated with virus persistence. In contrast, reconstitution with both CD4+ and CD8+ T cells produced less severe demyelination and partial clearance of virus. These experiments support the hypothesis that demyelination is the result of a balance between persistent virus infection and immune injury mediated by either CD4+ or CD8+ T cells.

Adoptive Transfer↗
PubMed1998

Response of the oligodendrocyte progenitor cell population (defined by NG2 labelling) to demyelination of the adult spinal cord.

Elucidation of the response of oligodendrocyte progenitor cell populations to demyelination in the adult central nervous system (CNS) is critical to understanding why remyelination fails in multiple sclerosis. Using the anti-NG2 monoclonal antibody to identify oligodendrocyte progenitor cells, we have documented their response to antibody-induced demyelination in the dorsal column of the adult rat spinal cord. The number of NG2+ cells in the vicinity of demyelinated lesions increased by 72% over the course of 3 days following the onset of demyelination. This increase in NG2+ cell numbers did not reflect a nonspecific staining of reactive cells, as GFAP, OX-42, and Rip antibodies did not co-localise with NG2 + cells in double immunostained tissue sections. NG2 + cells incorporated BrdU 48-72 h following the onset of demyelination. After the onset of remyelination (10-14 days), the number of NG2+ cells decreased to 46% of control levels and remained consistently low for 2 months. When spinal cords were exposed to 40 Grays of x-irradiation prior to demyelination, the number of NG2+ cells decreased to 48% of control levels by 3 days following the onset of demyelination and remained unchanged at 3 weeks. Since 40 Grays of x-irradiation kills dividing cells, these studies illustrate a responsive and nonresponsive NG2+ cell population following demyelination in the adult spinal cord and suggest that the responsive NG2+ cell population does not renew itself.

Animals↗
PubMed1989

Conduction along myelinated and demyelinated nerve fibres during the recovery cycle: model investigations.

The membrane excitability changes as well as the underlying mechanisms of these changes in a normal and in a systematically paranodally demyelinated nerve fibre have been investigated by paired stimulation during the first 30 ms of the recovery cycle. The ionic current kinetics determining the observed changes in the action potential parameters are presented also. The simulation of the conduction in the normal fibre is based on the Frankenhaeuser and Huxley (1964) and Goldman and Albus (1968) equations, while in the case of a demyelinated fibre according to the same equations modified by Stephanova (1988a). It has been shown for the demyelinated membrane that increased demyelination increases both the threshold current for the second potential as well as the absolute refractory period. With increasing interpulse interval, the subnormality of the membrane excitability is followed by supernormality in the case of the demyelinated membrane. For the recovery cycle of 30 ms under consideration no supernormality of the normal membrane excitability is obtained. With interpulse interval from 8.8 to 10.9 ms, the highest degree of demyelination (l = 30 microns) is accompanied by a refractory period of transmission. The membrane properties of the normal and demyelinated fibres recover 20 ms after the first pulse. For short interpulse intervals, the amplitude of the second action potential is decreased, and a slower propagation velocity is obtained. The most sensitive phenomenon is the excitability of the demyelinated membrane, which remains unrecovered 30 ms after the first pulses has been applied.

Computer Simulation↗
PubMedDate not supplied

Serum and cells from Theiler's virus-infected mice fail to injure myelinating cultures or to produce in vivo transfer of disease. The pathogenesis of Theiler's virus-induced demyelination appears to differ from that of EAE.

Intracerebral inoculation of SJL mice with Theiler's Murine Encephalomyelitis virus (TMEV) results in a biphasic disease characterized by early grey matter involvement followed by late, chronic white matter inflammation and demyelination. Morphological parameters of TMEV-induced demyelination are essentially identical to those of experimental allergic encephalomyelitis (EAE) and immunosuppression has been shown to prevent demyelination. To test whether the pathogenesis of demyelination in TMEV infection is based on an autoimmune attack on myelin as in EAE, we tested sera and cells from infected animals for their ability to produce in vitro demyelination and cells for their ability to transfer disease in vivo. Isogeneic organotypic cultures were exposed to either serum or splenocytes from diseased animals. Neither serum nor splenocytes demyelinated or prevented myelination in these cultures. Splenocytes from diseased animals were also incubated with basic protein or whole spinal cord and assayed for their proliferative response or their ability to transfer disease to naive recipients. Neither proliferation nor transfer of disease was observed. These results show that the immunopathology of demyelination in the Theiler's model differs from that of EAE in a number of important parameters and support the contention that demyelination in this viral infection is produced by immunological mechanisms different from those operating in EAE.

Animals↗
PubMed1988

Demyelinating experimental allergic encephalomyelitis (EAE) in the rat: treatment with a monoclonal antibody against activated T cells.

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.

Acute Disease↗
PubMedDate not supplied

The response of NG2-expressing oligodendrocyte progenitors to demyelination in MOG-EAE and MS.

Remyelination of primary demyelinated lesions is a common feature of experimental models of multiple sclerosis (MS) and is also suggested to be the normal response to demyelination during the early stages of MS itself. Many lines of evidence have shown that remyelination is preceded by the division of endogenous oligodendrocyte precursor cells (OPCs) in the lesion and its borders. It is suggested that this rapid response of OPCs to repopulate the lesion site and their subsequent differentiation into new oligodendrocytes is the key to the rapid remyelination. Antibodies to the NG2 chondroitin sulphate proteoglycan have proved exceedingly useful in following and quantitating the response of endogenous OPCs to demyelination. Here we review the literature on the response of NG2-expressing OPCs to demyelination and provide some new evidence on their response to the chronic inflammatory demyelinating environment seen in recombinant myelin oligodendrocyte glycoprotein (MOG) induced experimental allergic encephalomyelitis (EAE) in the DA rat. NG2-expressing OPCs responded to the inflammatory demyelination in this model by becoming reactive and increasing in number in a very focal manner. Evidence of NG2+ OPCs in lesioned areas beginning to express the oligodendrocyte marker CNP was also seen. The response of OPCs appeared to occur following successive relapses but did not always lead to remyelination, with areas of chronic demyelination observed in the spinal cord. The presence of OPCs in the adult human CNS is clearly of vital importance for repair in multiple sclerosis (MS). As in rat tissue, the antibody labels an evenly distributed cell population present in both white and grey matter, distinct from HLA-DR+ microglia. NG2+ cells are sparsely distributed in the centre of chronic MS lesions. These cells apparently survive demyelination and exhibit a multi-processed or bipolar morphology in the very hypocellular environment of the lesion.

Animals↗
PubMed1998

Absence of neurological deficits following extensive demyelination in a class I-deficient murine model of multiple sclerosis.

Demyelination alone has been considered sufficient for development of neurological deficits following central nervous system (CNS) disease. However, extensive demyelination is not always associated with clinical deficits in patients with multiple sclerosis (MS), the most common primary demyelinating disease in humans. We used the Theiler's murine encephalomyelitis virus model of demyelination to investigate the role of major histocompatibility complex (MHC) class I and class II gene products in the development of functional and neurophysiological deficits following demyelination. We measured spontaneous clinical activity by two independent assays and recorded hind-limb motor-evoked potentials in infected class I-deficient and class II-deficient mice of an identical genetic background as well as in highly susceptible SJL/J mice. The results show that despite a similar distribution and extent of demyelinated lesions in all mice, only class I-deficient mice were functionally normal. We propose that the mechanism by which demyelinated class I-deficient mice maintain neurologic function results from increased sodium channel densities and the relative preservation of axons. These findings are the first to implicate a role for MHC class I in the development of neurological deficits following demyelination.

Animals↗
PubMed1978

Conduction through demyelinated plaques in multiple sclerosis: computer simulations of facilitation by short internodes.

Clinical and laboratory observations both suggest that it may be possible for action potentials to traverse, in a continuous manner and without interruption, demyelinated zones along some axons. This continuous mode of conduction requires the presence of sufficient numbers of sodium channels in the demyelinated region. One of the factors which will tend to prevent such conduction is the impedance mismatch at sites of focal demyelination, which may result in a reduction in current density sufficient to cause conduction failure. As part of an effort to examine the conditions which would promote conduction into, and beyond, the demyelinated region, we examined, using computer simulations, the effects of reduction in length of the proximal internodes closest to the demyelinated region. Our results indicate that reduction in length of the two internodes closest to the demyelinated region. to approximately one-third of normal length or less, will facilitate conduction beyond the plaque. The results suggest that reductions in internode length, which have been histologically observed along some demyelinated fibres, may have functional significance in terms of facilitating conduction past focally demyelinated zones.

Action Potentials↗
PubMed2002

The membrane attack complex of complement causes severe demyelination associated with acute axonal injury.

Complement is implicated in pathology in the human demyelinating disease multiple sclerosis and in animal models that mimic the demyelination seen in multiple sclerosis. However, the components of the complement system responsible for demyelination in vivo remain unidentified. In this study, we show that C6-deficient (C6-) PVG/c rats, unable to form the membrane attack complex (MAC), exhibit no demyelination and significantly reduced clinical score in the Ab-mediated experimental autoimmune encephalomyelitis model when compared with matched C6-sufficient (C6+) rats. In C6+ rats, perivenous demyelination appeared, accompanied by abundant mononuclear cell infiltration and axonal injury. Neither demyelination nor axonal damage was seen in C6- rats, whereas levels of mononuclear cell infiltration were equivalent to those seen in C6+ rats. Reconstitution of C6 to C6- rats yielded pathology and clinical disease indistinguishable from that in C6+ rats. We conclude that demyelination and axonal damage occur in the presence of Ab and require activation of the entire complement cascade, including MAC deposition. In the absence of MAC deposition, complement activation leading to opsonization and generation of the anaphylatoxins C5a and C3a is insufficient to initiate demyelination.

Animals↗
PubMed1993

Experimental paraprotein neuropathy, demyelination by passive transfer of human IgM anti-myelin-associated glycoprotein.

Circulating monoclonal IgM antibodies that react with myelin-associated glycoprotein are strongly associated with a specific type of human peripheral nerve demyelination. There has been great interest in this syndrome because, if the paraprotein could be shown to cause the demyelination, then it would be the first proven example of antibody-mediated demyelination in humans. Systemic transfusion of chickens with monoclonal IgM antibody isolated from one of these patients produced peripheral demyelination highly characteristic of the human syndrome. The experimental lesion consists of segmental demyelination and remyelination with minimal inflammation, specific antibody bound to myelin, and widening of the myelin lamellae. In the experimental model, antibody is concentrated in specialized myelin structures, the nodes of Ranvier, and Schmidt-Lanterman incisures, suggesting that myelin-associated glycoprotein may be the antigenic target in vivo. This demonstration that human myelin-associated glycoprotein antibodies cause demyelination in vivo is the final information needed to prove that this type of human demyelination is antibody mediated. This strengthens the proposition that nerve antibodies, present in other human neurological syndromes, may also cause disease.

Animals↗