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PubMed1992

Interferon-gamma potentiates antibody-mediated demyelination in vivo.

The pathogenetic events leading to demyelination in experimental allergic encephalomyelitis and in human multiple sclerosis are still unclear. The involvement of anti-myelin antibodies and activated macrophages as effector cells has been postulated. We investigated the synergistic action of the monoclonal antibody 8-18C5 against myelin/oligodendrocyte glycoprotein and recombinant interferon-gamma on demyelination after simultaneous injection into the subarachnoid space of Sprague-Dawley rats. After combined injection of anti-myelin/oligodendrocyte glycoprotein antibody and interferon-gamma, electrophysiological and morphological evidence for demyelination was found. Cervical somatosensory evoked potentials and cervical short-latency somatosensory evoked potentials were significantly delayed, and the demyelinated area in the spinal cord was significantly enlarged when compared to control rats injected with either compound alone. Injection of either an irrelevant antibody and interferon-gamma or of peritoneal macrophages without anti-myelin/oligodendrocyte glycoprotein antibody and interferon-gamma did not induce demyelination. Our data suggest that the deleterious effect of interferon-gamma on multiple sclerosis may be not only due to its effect on antigen presentation but also due to potentiation of demyelination.

Animals↗
PubMed1993

Human class I major histocompatibility complex transgene prevents virus-induced demyelination in susceptible mutant B10.D2dml mice.

Theiler's murine encephalomyelitis virus (TMEV) induces immune-mediated demyelination in susceptible strains of mice, providing an excellent model for multiple sclerosis. Class I genes within the major histocompatibility complex locus (H-2D region) play a major role in determining whether strains of mice develop chronic demyelination and TMEV persistence. B10.D2dml mice with deletion in the 3' end of Dd and the 5' end of Ld genes develop the most prominent demyelination in comparison with resistant B10.D2 mice with normal complementation of H-2D region genes. We tested whether expression of a class I human transgene (HLA-B27) would modulate virus-induced demyelination in mutant B10.D2dml mice. Transgenic B10.D2dml (HLA-B27+) mice infected with virus showed dramatic decrease in the extent of demyelination (p < 0.0001) and virus antigen expression in spinal cord compared with littermate controls without the human class I transgene. These experiments demonstrate that transgenic expression of a human class I major histocompatibility complex locus molecule can prevent demyelination induced by a virus in mutant mice.

Animals↗
PubMed2004

Remyelination of cytokine- or antibody-demyelinated CNS aggregate cultures is inhibited by macrophage supplementation.

Remyelination in CNS aggregate cultures is determined both by macrophage enrichment and the mode of demyelination. Despite the same degree of myelin loss, accumulation of MBP in anti-MOG antibody-demyelinated aggregates overtakes that of controls, while recovery is significantly delayed following IFN-gamma-induced demyelination. In antibody-treated cultures, remyelination was associated with a significant increase in culture supernatant levels of TGF-beta1, FGF-2, and PDGF-AA as well as an induction of TNF-alpha immediately following removal of the demyelinating insult. The impaired recovery in IFN-gamma-treated cultures, denoted by a significant reduction in TGF-beta1, was reversed by treatment with hrTGF-beta1. Macrophage supplementation of the cultures prior to the addition of either demyelinating agent induced a greater degree of myelin loss followed by incomplete remyelination in both cases. This failure to remyelinate was associated in both groups with a several-fold elevation in TNF-alpha and with modest increases in PDGF-AA and FGF-2 in the antibody-treated cultures. In contrast, macrophage supplementation to mature cultures in the absence of any demyelinating treatment resulted in enhanced accumulation of MBP associated with a promyelinative growth factor and TNF-alpha profile similar to that in aggregates enriched with macrophages at the outset of the culture period. Hence, effector elements of the adaptive immune response appear to override promyelinogenic in favor of proinflammatory macrophage factors in mature CNS aggregates, counteracting the potential for myelin repair.

Animals↗
PubMed2007

T cells contribute to lysophosphatidylcholine-induced macrophage activation and demyelination in the CNS.

We have previously shown that intraspinal microinjection of lysophosphatidylcholine (LPC), a potent demyelinating agent, results in a rapid but brief influx of T cells (between 6 and 12 h). This is accompanied by a robust activation of macrophages/microglia that leads to demyelination by 48 h. In the present study, we examined whether this brief influx of T cells contributes to the activation of macrophages/microglia and demyelination by injecting LPC into the dorsal column white matter of athymic Nude mice that lack T cells. We show that there is a significant reduction in macrophage/microglial activation and myelin clearance after LPC injection in Nude mice as compared with wildtype controls. We also show that there is no difference in the recruitment of hematogenous macrophages into the spinal cord after LPC injection in the two mouse strains. Of the T cell cytokines assessed, there was a marked reduction in the mRNA expression of interleukin-2 (IL-2) in Nude mice compared with wildtype animals. Neutralizing IL-2 with function-blocking antibodies in wildtype animals resulted in a significant decrease in the number of phagocytic macrophages/microglia and a reduction in demyelination induced by LPC. While there may be other defects in Nude mice that might contribute to the effects shown here, these data suggest that the brief influx of T cells in this model of chemically-induced demyelination could play a role in macrophage/microglial activation and demyelination. These results may also have implications for remyelination in this and other types of CNS damage.

Adjuvants, Immunologic↗
PubMed2003

Spontaneous central nervous system remyelination is not altered in NFH-lacZ transgenic mice after chemical demyelination.

Harmonious functioning of the nervous system depends on neuron-glia interactions, particularly between the axons and their myelinating cells, i.e., oligodendrocytes (OL) in the central nervous system (CNS). In human demyelinating diseases such as multiple sclerosis (MS), demyelination may be associated with axonal damage, but alterations of the axonal cytoskeleton, which is composed mainly of neurofilaments (NF) and microtubules, are largely unknown, as are the consequences on remyelination. In a model of demyelination induced by lysophosphatidylcholine (LPC), we have shown that demyelination was correlated with a decrease in NF immunolabelling, and that these axonal abnormalities were reduced by platelet-derived growth factor (PDGF)-enhanced remyelination in adult rats. We have analysed the spontaneous remyelination after LPC stereotaxic injection in the CNS of transgenic NFH-lacZ mice, which present axonal atrophy caused by abnormal distribution of NF, associated with hypermyelination in the PNS, and normal myelin thickness in the CNS. Axonal atrophy in the CNS of NFH-lacZ mice was confirmed, but it was not worsened by demyelination. On the contrary, demyelination induced axonal atrophy in wild-type mice, demonstrating that NF are essential for axonal calibre determination. Moreover, an efficient spontaneous remyelination occurred in NFH-lacZ as well as in wild-type mice, indicating that the NF are not necessary for CNS remyelination. These findings point out that NF modifications observed in MS may not be responsible for the lack of remyelination in this disease.

Animals↗
PubMed2003

Dysregulation of axonal sodium channel isoforms after adult-onset chronic demyelination.

Demyelination results in conduction block through changes in passive cable properties of an axon and in the expression and localization of axonal ion channels. We show here that adult-onset chronic demyelination, such as occurs in demyelinating disorders and after nerve injury, alters the complement of axonal voltage-dependent Na+ (Nav) channel isoforms and their localization. As a model, we used heterozygous transgenic mice with two extra copies of the proteolipid protein gene (Plp/-). Retinal ganglion cell axons in these mice myelinate normally, with young Plp/- and wild-type mice expressing Nav1.2 at low levels, whereas Nav1.6 is clustered in high densities at nodes of Ranvier. At 7 months of age, however, Plp/- mice exhibit severe demyelination and oligodendrocyte cell death, leading to a profound reduction in Nav1.6 clusters, loss of the paranodal axoglial apparatus, and a marked increase in Nav1.2. We conclude that myelin is crucial not only for node of Ranvier formation, but also to actively maintain the proper localization and complement of distinct axonal Nav channel isoforms throughout life. The altered Nav channel isoform localization and complement induced by demyelination may contribute to the pathophysiology of demyelinating disorders and nerve injury.

Aging↗
PubMed2003

Chronic inflammatory demyelinating polyradiculoneuropathy in diabetic patients.

This retrospective analysis was undertaken to determine whether a subset of diabetic patients with demyelinating polyneuropathy were similar to patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Ten patients meeting the clinical criteria for idiopathic CIDP were compared to nine patients with diabetes and demyelinating polyneuropathy. The diabetic patients with demyelinating polyneuropathy displayed clinical, electrophysiologic, and histologic features that were similar to those in CIDP patients. All six patients with diabetes and demyelinating polyneuropathy who were treated with immunomodulatory therapy showed a favorable response. Our study highlights the importance of investigating diabetic patients with polyneuropathy in an attempt to identify patients with demyelinating polyneuropathy, because of the likelihood of benefit in these patients from immunomodulatory treatment.

Adjuvants, Immunologic↗
PubMedDate not supplied

Acquired versus familial demyelinative neuropathies in children.

The electrophysiologic differences between chronic acquired demyelinative neuropathy and the demyelinative form of Charcot-Marie-Tooth disease have recently been reported. The present report extends these observations to include the genetically determined demyelinating neuropathies seen in metachromatic leukodystrophy, Krabbe's leukodystrophy, and Cockayne's syndrome. The electrophysiologic features of metachromatic leukodystrophy (five patients), Krabbe's (four patients), and Cockayne's syndrome (three patients) were all similar. There was uniform slowing of conduction (both in different nerves and in different nerve segments), and conduction block was not seen. These findings are consistent with a uniform degree of demyelination in multiple nerves and throughout the entire length of individual axons. Thus, uniform slowing of nerve conduction constitutes strong evidence for a familial demyelinative neuropathy, as opposed to the multifocal slowing seen in acute and chronic acquired demyelinative neuropathy.

Adolescent↗
PubMed2003

PDGF and FGF2 regulate oligodendrocyte progenitor responses to demyelination.

Acute demyelination of adult CNS, resulting from trauma or disease, is initially followed by remyelination. However, chronic lesions with subsequent functional impairment result from eventual failure of the remyelination process, as seen in multiple sclerosis. Studies using animal models of successful remyelination delineate a progression of events facilitating remyelination. A universal feature of this repair process is extensive proliferation of oligodendrocyte progenitor cells (OPs) in response to demyelination. To investigate signals that regulate OP proliferation in response to demyelination we used murine hepatitis virus-A59 (MHV-A59) infection of adult mice to induce focal demyelination throughout the spinal cord followed by spontaneous remyelination. We cultured glial cells directly from demyelinating and remyelinating spinal cords using conditions that maintain the dramatically enhanced OP proliferative response prior to CNS remyelination. We identify PDGF and FGF2 as significant mitogens regulating this proliferative response. Furthermore, we demonstrate endogenous PDGF and FGF2 activity in these glial cultures isolated from demyelinated CNS tissue. These findings correlate well with our previous demonstration of increased in vivo expression of PDGF and FGF2 ligand and corresponding receptors in MHV-A59 lesions. Together these studies support the potential of these pathways to function in vivo as critical factors in regulating remyelination.

Animals↗
PubMed2000

HLA-DQ polymorphism influences progression of demyelination and neurologic deficits in a viral model of multiple sclerosis.

The importance of genetic susceptibility in determining the progression of demyelination and neurologic deficits is a major focus in neuroscience. We studied the influence of human leukocyte antigen (HLA)-DQ polymorphisms on disease course and neurologic impairment in virus-induced demyelination. HLA-DQ6 or DQ8 was inserted as a transgene into mice lacking endogenous expression of MHC class I (beta(2)m) and class II (H2-A(beta)) molecules. Following Theiler's murine encephalomyelitis virus (TMEV) infection, we assessed survival, virus persistence, demyelination, and clinical disease. Mice lacking expression of endogenous class I and class II molecules (beta(2)m(o) Abeta(o) mice) died 3 to 4 weeks postinfection (p.i.) due to overwhelming virus replication in neurons. beta(2)m(o) Abeta(o) DQ6 and beta(2)m(o) Abeta(o) DQ8 mice had increased survival and decreased gray matter disease and virus replication compared to nontransgenic littermate controls. Both beta(2)m(o) Abeta(o) DQ6 and beta(2)m(o) Abeta(o) DQ8 mice developed chronic virus persistence in glial cells of the white matter of the spinal cord, with greater numbers of virus antigen-positive cells in beta(2)m(o) Abeta(o) DQ8 than in beta(2)m(o) Abeta(o) DQ6 mice. At day 45 p.i., the demyelinating lesions in the spinal cord of beta(2)m(o) Abeta(o) DQ8 were larger than those in the beta(2)m(o) Abeta(o) DQ6 mice. Earlier and more profound neurologic deficits were observed in beta(2)m(o) Abeta (o) DQ8 mice compared to beta(2)m(o) Abeta(o) DQ6 mice, although by 120 days p.i. both strains of mice showed similar extent of demyelination and neurologic deficits. Delayed-type hypersensitivity and antibody responses to TMEV demonstrated that the mice mounted class II-mediated cellular and humoral immune responses. The results are consistent with the hypothesis that rates of progression of demyelination and neurologic deficits are related to the differential ability of DQ6 and DQ8 transgenes to modulate the immune response and control virus.

Acute Disease↗
PubMed1990

Changes in glial cell markers in recent and old demyelinated lesions in central pontine myelinolysis.

An immunohistochemical study was performed to compare glial reactions in recent and old lesions of central pontine myelinolysis (CPM). Regions of demyelination and destruction of oligodendrocytes, showed reduced immunoreactivity of myelin basic protein (MBP), myelin-associated glycoprotein (MAG), transferrin, and carbonic anhydrase C (CA C). In addition, labeling of glial fibrillary acidic protein (GFAP) and S-100 protein revealed distinct dystrophic alterations of the astroglia. Remarkably, immunolabeling of GFAP was drastically reduced in astrocytic cytoplasm within freshly demyelinated lesions. Immunostaining of vimentin revealed a differential intracytoplasmic decoration of hypertrophic and dystrophic astrocytes in recent and old CPM lesions. Immunolabeling of desmin failed to stain glial cells. Monoclonal antibodies against HNK-1 exhibited greatly increased immunoreactivity both of persisting oligodendrocytes and of reactive fibrillary astrocytes in old CPM foci. In freshly demyelinated lesions, enhanced immunoreactivity of the X-hapten (3-fucosyl-N-acetyllactosamine) was prominent in astroglia and oligodendrocytes. Simultaneously, reactive astrocytes revealed intracytoplasmic labeling of laminin. Quantitation of GFAP+ astroglia in fresh CPM and control cases revealed an increase in the number of astrocytes within the demyelinated foci and in the surrounding non-demyelinated pontine tissue of CPM cases. The occurrence of astroglial alterations in the demyelinated foci of CPM could be interpreted as "astroglial dystrophy" which may represent a pathogenic factor in CPM. Furthermore, it is possible that changes of the glial microenvironment may influence the astroglia to revert transiently back to an immature phenotype as indicated by the enhanced expression of the X-hapten and HNK-1, and the de novo synthesis of vimentin and laminin.

Adult↗
PubMed1989

In vivo CNS demyelination mediated by anti-galactocerebroside antibody.

The mechanism of antibody-mediated central nervous system (CNS) demyelination in vivo was studied using rabbit eyes. Injection of anti-galactocerebroside (Gal C) antiserum alone into the normal rabbit vitreous body induced demyelination in the epiretinal myelinated fibers. This activity of the antiserum disappeared after heat treatment at 56 degrees C for 30 min and was restored by supplement of normal fresh serum, suggesting the complement dependency of the activity. Heated anti-Gal C antiserum could induce demyelination, however, when macrophages were introduced by injecting lymphocyte supernatants together with antiserum. Electron microscopic study revealed penetration of macrophage process between the myelin lamella. These findings suggest that the cooperation of anti-Gal C antibody and macrophage can result in the antibody-dependent cell-mediated demyelination in the absence of complement. Because oligodendrocyte generally appeared normal, myelin, not oligodendrocyte is suspected to be the primary target by anti-Gal C antiserum. In contrast, neither anti-MBP nor anti-gangliosides antiserum had the in vivo-demyelinating activity. In CNS demyelination by anti-Gal C antibody, complement-mediated and macrophage-mediated mechanisms may cooperate in varying degrees.

Animals↗
PubMed1988

Observations on demyelinating lesions induced by Theiler's virus in CBA mice.

We examined demyelinating lesions in the spinal cord of CBA mice infected with the BeAn strain of Theiler's virus to see if it was possible to document the sequence of changes which result in demyelination. It was found that the lesions which develop in the late stages of the disease were progressive. Therefore, by examining the different zones of a single lesion, it was possible to follow a sequence of changes which lead to demyelination. There was a clear progression from normal myelin, to vacuolated myelin, to myelin phagocytosis, to demyelinated axons, to remyelinated axons. Virus was detected in degenerating oligodendrocytes in the area showing myelin vacuolation by both electron microscopy and immunocytochemistry, a finding which indicated that virus infection precedes demyelination. The area of normal myelin which surrounded the zone of vacuolated myelin was infiltrated by lymphocytes, indicating that lymphocytic infiltration preceded viral replication and oligodendrocyte degeneration. Our observations indicate that cells of the immune system may play a role in the initiation of virus replication which appears to be a prerequisite for demyelination.

Animals↗
PubMed1978

Corona virus induced subacute demyelinating encephalomyelitis in rats: a morphological analysis.

Thirty percent of weanling rats infected with JHM murine corona virus developed a subacute demyelinating encephalomyelitis approximately 3 weeks after intracerebral inoculation. Small demyelinating foci were located in the deep cerebral white matter and large, sharply demarcated demyelinating lesions were detectabll preserved in the demyelinating plaques in areas where the lesions extended to the gray matter. Perivascular cuffings, consisting of plasma cells and mononuclear cells, were frequently found. Viral antigen was found mostly in the white matter and in glial cells, leaving neurons unstained. Electron microscopic studies of the early lesions of white matter disclosed two different kinds of cell degeneration which developed prior to the myelin disruption and mononuclear cell infiltration. One was a small pyknotic cell, which is thought to be an oligodendrocyte and the other is a ballooned cell containing abundant microtubules. Virus particles could be demonstrated only in the latter cell type. Discussion about astrocytes as well as oligodendrocytes was made in relation to the initial stage of demyelination caused by virus infection. This animal model may be useful in the analysis of the mechanisms leading to demyelination in subacute or chronic infections.

Animals↗
PubMed1980

Plasmalogenase and phospholipase A1, A2, and L1 activities in white matter in canine distemper virus-associated demyelinating encephalomyelitis.

Three weeks after inoculation of 24-day-old gnotobiotic dogs with Snyder-Hill canine distemper virus, white matter samples were taken from the primary predilection sites for canine distemper virus-associated demyelination. The plasmalogenase activity in extracts was nearly 6-fold greater than control values for a dog with extensive demyelination and was not detectable in tissue from a dog with non-demyelinating lesions. Acid and neutral phospholipases A1 and A2 were assayed in homogenates and extracts with phosphatidyl ethanolamine substrates. Phospholipase A2 activities at both pH 4.3 and pH 6.8 were less in the dog with severe demyelinating lesions than in dogs with less severe lesions. Phospholipase A1 activities were generally similar for all four dogs. The marked elevation of plasmalogenase activity in demyelinating tissue may be associated with a release from the plasmalogens of arachidonic acid which is converted to oxygenated metabolites that may then be responsible for the inflammation. Phospholipases acting on phosphatidyl ethanolamine do not seem to be involved in the pathogenesis of demyelination associated with canine distemper virus.

Animals↗
PubMed2005

Demyelination in canine distemper virus infection: a review.

Canine distemper virus (CDV) causes severe immunosuppression and neurological disease in dogs, associated with demyelination, and is a model for multiple sclerosis in man. In the early stage of the infection, demyelination is associated with viral replication in the white matter. In acute demyelinating lesions there is massive down-regulation of myelin transcription and metabolic impairment of the myelin-producing cells, but there is no evidence that these cells are undergoing apoptosis or necrosis. Oligodendroglial change is related to restricted infection of these cells (transcription but no translation) and marked activation of microglial cells in acute lesions. Concomitant with immunological recovery during the further course of the disease, inflammation occurs in the demyelinating plaques with progression of the lesions in some animals. A series of experiments in vitro suggests that chronic inflammatory demyelination is due to a bystander mechanism resulting from interactions between macrophages and antiviral antibodies. Autoimmune reactions are also observed, but do not correlate with the course of the disease. The progressive or relapsing course of the disease is associated with viral persistence in the nervous system. Persistence of CDV in the brain appears to be favored by non-cytolytic selective spread of the virus and restricted infection, in this way escaping immune surveillance in the CNS. The CDV Fusion protein appears to play an important role in CDV persistence. Similarities between canine distemper and rodent models of virus-induced demyelination are discussed.

Animals↗
PubMed1997

Demyelination in severe combined immunodeficient mice by intracisternal injection of cerebrospinal fluid cells from patients with multiple sclerosis: neuropathological investigation.

Demyelinating lesions have been observed in severe combined immunodeficient (SCID) mice after intracisternal administration of cerebrospinal fluid cells (CSFC) from patients with multiple sclerosis (MS). Further investigation in our laboratory revealed that CSFC from 6 to 15 patients at exacerbation of MS caused demyelination. The factor leading to demyelination appears to be the high frequency of relapses during a short period, but not to the severity of the disease. Neuropathological and immunohistochemical studies revealed that a lack of inflammatory mononuclear cell infiltration within and around the demyelinating lesions or in leptomeninges was a common characteristic in all SCID mice with CSFC-induced demyelination. In affected mice killed 2-3 weeks after intracisternal administration of CSFC, foamy/vacuolar lesions with a small or moderate number of lipid-laden macrophages were seen in the white matter. Ultrastructurally, relative preservation of axons, in contrast to myelinoclastic features, as well as some remyelinated axons were observed. In affected SCID mice killed 4-6 weeks after intracisternal administration, more widespread foamy macrophages and necrotic foci with poor remyelination were seen. The findings were similar to those seen in experimental allergic encephalomyelitis, though without lymphocytic infiltration, but were quite different from the lesions observed in Theiler's murine encephalitis virus infection. The absence of an immunohistochemical reaction to the human leukocyte common antigen in the infiltrating mononuclear cells suggested that the graft-versus-host reaction was unlikely cause of the demyelinating lesions.

Adolescent↗
PubMed1982

Virus-induced demyelination in herpes simplex virus-infected mice.

Herpes simplex virus (HSV) infection of the mouse trigeminal ganglia and the brain stem is associated with demyelination of axons in the central part of the trigeminal root and inflammatory cell infiltration and perivascular demyelination in the brain stem. Cyclophosphamide (CPA) treatment prior to or soon after HSV inoculation caused increased axonal spread of infective virus from the peripheral site of inoculation, more widespread and severe demyelination and increased mortality, suggesting that by CPA the virus invasion of the CNS was facilitated. A direct cytocidal effect of HSV on myelinating cells seemed one plausible explanation for the demyelination. Influence on demyelination at late stages of infection by cytotoxic immune reactions are not excluded by the results reported but seemed not to dominate the picture. Schwann cells from the peripheral part of the nerve root invaded demyelinated areas in the brain stem and remyelinated the axons.

Animals↗