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PubMed1994

BALB/c substrain differences in susceptibility to Theiler's murine encephalomyelitis virus-induced demyelinating disease.

We report differences among BALB/c substrains in susceptibility to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease, an immune-mediated inflammatory demyelinating disease and experimental model for human multiple sclerosis. BALB/cJ and BALB/cAnNCr mice are susceptible, while BALB/cByJ and BALB/cCum are resistant. Hybrids between BALB/cBy and BALB/cAnNCr were intermediate, although closer to the resistant parent. Backcrosses gave results compatible with differential susceptibility being related to a single segregating locus. Exposure of resistant BALB/cByJ mice to low dose irradiation, 2 days prior to infection, rendered them susceptible to TMEV-induced demyelination. The susceptibility pattern of TMEV-induced demyelinating disease among BALB/c substrains is distinct from those of several autoimmune disorders.

Animals↗
PubMed1994

Magnetic resonance imaging of antibody-mediated demyelinating experimental allergic encephalomyelitis.

Two models of demyelinating experimental allergic encephalomyelitis (EAE) were studied on Lewis rats in whom the disease was induced by injections of either (i) lentil-lectin binding myelin glycoproteins plus myelin basic protein (MBP)-specific T cells (36 rats), or (ii) myelin/oligodendrocyte glycoprotein-specific monoclonal antibody plus MBP-specific T cells (16 rats). In our 24 control rats, 20 received MBP-specific T cells only, and four received myelin glycoproteins plus purified protein derivative-specific T cells. The extent of the resulting blood-brain barrier (BBB) permeability, vasogenic oedema and/or demyelination was assessed in vivo using magnetic resonance imaging (MRI) techniques. The results show that in both demyelinating EAE models the disease appeared more quickly, progressed very rapidly and was more severe than when induced with a similar number of MBP-specific T cells alone. Almost all animals developed hyperacute EAE, with a very high mortality rate. MRI showed a very intense BBB breakdown and vasogenic oedema in all the normally 'leaky' areas of the central nervous system, and focal lesions corresponding to plaque formation in the brain stem or spinal cord near the 'leaky' areas. During the 40-day observation period, the rare survivors of this hyperacute form of EAE presented a chronic form of EAE with serious sequelae. Our results demonstrate that the synergistic effect observed between MBP-specific T cells and antibodies to myelin glycoproteins, especially to myelin/oligodendrocyte glycoprotein, does not only induce demyelinating lesions and chronic clinical signs, but is further responsible, via the normally 'leaky areas', for the fatal increase of the BBB breakdown and vasogenic oedema of which there are ample acute clinical signs.

Animals↗
PubMed1995

Protracted, relapsing and demyelinating experimental autoimmune encephalomyelitis in DA rats immunized with syngeneic spinal cord and incomplete Freund's adjuvant.

Experimental autoimmune encephalomyelitis (EAE) is a model for multiple sclerosis (MS). However, MS is a chronic, relapsing and demyelinating disease, whereas EAE in rats is typically a brief and monophasic disorder showing little demyelination. We demonstrate here that DA rats develop severe, protracted and relapsing EAE (SPR-EAE) after a subcutaneous immunization at the tail base with syngeneic spinal cord and incomplete Freund's adjuvant (IFA). The neurological deficits were accompanied by demyelinating inflammatory lesions in the spinal cord, with infiltrating T lymphocytes and perivascular deposition of immunoglobulins and complement. The induction of SPR-EAE was associated with humoral autoreactivity to myelin oligodendrocyte glycoprotein (MOG) and cellular autoreactivity to the rat myelin basic protein (MBP) peptides 69-87 and 87-101. These two peptides, as well as whole rat MBP, were encephalitogenic. In conclusion, we believe that the presently described demyelinating SPR-EAE represents a useful model for MS.

Amino Acid Sequence↗
PubMed1991

The pathogenesis of demyelinating disease: insights from cell biology.

Cellular and humoral immune mechanisms have been implicated in the pathogenesis of human and experimental demyelinating diseases of the CNS. How these interact in the complex sequence of events that culminates in phagocytosis of myelin by macrophages has yet to be resolved. The relationship between leakage of the blood-brain barrier and demyelination, the reason why recurrent inflammatory demyelination occurs--seemingly in the absence of an antigen-specific immune response--and the lack of effective remyelination all require explanation if a coherent account of immunologically mediated demyelination is to be achieved. One approach to these problems is to study in vitro the developmental and cellular biology of oligodendrocytes--the glial cells responsible for the synthesis and maintenance of CNS myelin. This provides experimental opportunities not offered by more direct investigation of the intact nervous system, but carries the clear disadvantage that observations made in vitro cannot necessarily be extrapolated to humans.

Animals↗
PubMed1993

Sensitivity and specificity of diagnostic criteria for conduction block in chronic inflammatory demyelinating polyneuropathy.

Detection of conduction block (CB) has important clinical implications because it suggests segmental demyelination potentially reversible following treatment. There are no universally accepted criteria to define CB. We tested the sensitivity of two diagnostic criteria of partial motor CB in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and hereditary motor-sensory neuropathy type I (HMSN I) which are thought to be the prototypes of segmental and uniform demyelination respectively. Criterion I requires > 20% drop in negative peak amplitude and area and < 15% change in duration between proximal and distal compound muscle action potentials (CMAPs). Criterion II requires > 50% drop in negative peak amplitude and area of proximal CMAP independently from temporal dispersion. Twenty-eight percent of CIDP nerves and 65% of CIDP patients had CB according to criterion I. However, 29% of nerves and 61% of patients with HMSN I also fulfilled the same criterion. Thirty-four percent of CIDP nerves and 78% of CIDP patients and none of HMSN I patients fulfilled criterion II. Criterion II has the same sensitivity as criterion I, but seems to be highly specific in diagnosis of the segmental demyelination characteristic of CIDP. Therefore this criterion should be employed, as the diagnostic tool of CB, in chronic neuropathies presenting high stimulation threshold and coexisting axonal loss.

Action Potentials↗
PubMed1993

Directed migration of transplanted glial cells toward a spinal cord demyelinating lesion.

To investigate the migration of transplanted glial cells in normal adult mice with a focal demyelinating lesion, we have used A2G mice which have the autosomal dominant Mx-1 allele as donor. Mx-1 protein expression is inducible by interferon and is detected in a dotted pattern in the nucleus of A2G cells. A/J mice were used as recipient animals as they express the same major histocompatibility antigens as A2G but cannot express the Mx-1 protein. An acute demyelinating lesion was produced in the A/J spinal cord by intraspinal injection of lysolecithin. Mixed glial cultures derived from newborn A2G brain were treated with alpha/beta interferon for 24 hr. These Mx-1 expressing glial cells were then transplanted two intervertebral spaces away from the demyelinating lesion. The fate of the grafted cells was followed over the next 13 days, during which the induced Mx-1 protein can still be detected by immunocytochemistry. Grafted cells were found between the transplantation site and the lesion at 24 hr and some of the Mx-1+ cells reached the lesion at 4 days. The majority of the Mx-1+ migrating cells expressed GFAP and were located in the myelinated white matter and around the blood vessels. Scattered MBP+, Mx-1+ cells were detected in the lesion indicating that some of the transplanted cells may participate in the repair process. The Mx-1 is a useful marker to follow the migration events in the days after grafting and to determined what factors may attract transplanted cells toward a demyelinating lesion.

Animals↗
PubMed1987

Class II-restricted T cell responses in Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. II. Survey of host immune responses and central nervous system virus titers in inbred mouse strains.

Previous studies using mouse strains with limited genetic differences and H-2 haplotypes demonstrated that susceptibility to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease strongly correlated with chronically high levels of TMEV-specific delayed-type hypersensitivity (DTH), but not with TMEV-specific T cell proliferation (Tprlf), serum antibody responses, or with CNS virus titers. To determine if this correlation would be supported by analysis of these parameters in a more thorough genetic survey, ten inbred mouse strains, representing a wide variety of genetic backgrounds and H-2 haplotypes, were inoculated intracerebrally (i.c.) with the BeAn strain of TMEV. Significant TMEV-specific DTH was observed in all highly susceptible strains, but was not detectable in intermediate and resistant strains. TMEV-specific serum antibody titers also appeared to correlate with susceptibility to demyelinating disease, however even resistant strains had high antibody responses. Significant differences in CNS TMEV titers existed between strains, but did not correlate with disease susceptibility. DTH and Tprlf responses were observed in 3/4 resistant strains following peripheral immunization with UV-inactivated TMEV indicating that most resistant strains are genetically capable of mounting virus-specific cell-mediated immune (CMI) responses. The data extends our knowledge of host immune responses and virus titers in many different inbred mouse strains persistently infected with TMEV, supports the hypothesis that the demyelination in highly susceptible mice involves a TMEV-specific DTH response, and suggests that the genetic ability to mount specific DTH responses is necessary, but not sufficient for development of the demyelinating disease.

Animals↗
PubMed1987

Experimental demyelination induced by coronavirus JHM (MHV-4): molecular identification of a viral determinant of paralytic disease.

The molecular basis for demyelination induced by the neurotropic murine coronavirus JHM (JHMV or MHV4) is unknown. We have attempted to explore this issue by using neutralizing monoclonal antibodies specific for the major JHMV glycoprotein (E2) to select sets of neutralization resistant (NR) antigenic variant viruses. Monoclonal antibodies J.7.2 and J.2.2 bind to topographically distinct sites on E2. NR variants selected with J.7.2, like parental JHMV, predominantly cause a fatal encephalitis when given intracerebrally to mice, while J.2.2-selected NR variants cause a subacute disease characterized by paralysis and severe demyelination. We report here that consecutive selection with both J.2.2 and J.7.2 monoclonal antibodies results in NR variants which are markedly attenuated in both encephalitic potential and ability to induce demyelination. Analysis of the different variants suggests that the subregion of E2 bound by monoclonal antibody J.7.2 may be a critical viral determinant of paralysis and demyelination in this model system.

Animals↗
PubMed2006

Multifocal motor neuropathy with conduction block: Distribution of demyelination and axonal degeneration.

OBJECTIVE: Multifocal motor neuropathy with conduction block (MMN) is an immune-mediated neuropathy, characterized by progressive muscle weakness. Although demyelination is regarded as the underlying pathophysiologic mechanism of MMN, recently, it was reported that different pathophysiologic mechanisms were responsible for disease in the upper and lower limbs. Specifically, demyelination in the upper limbs and axonal loss in the lower limbs. Consequently, the aim of the present study was to assess, through clinical neurophysiology studies, whether different pathophysiologic mechanisms were occurring in the upper and lower extremities. Furthermore, we wanted to investigate whether the presence of conduction block (CB) correlated with axonal degeneration (AD), and to determine the electrophysiological abnormalities that correlate with muscle weakness. METHODS: We reviewed medical records of 18 patients with MMN for clinical features (using the Medical Research Council score and Guys Neurology Disability Scale) and neurophysiologic abnormalities (CB, AD prolongation of distal motor and F-wave latencies, and reduction of conduction velocity in the demyelinating range). RESULTS: Electrophysiological abnormalities deemed specific of demyelination were non-significantly different in the upper and lower extremities. The presence of axonal degeneration correlated significantly with conduction block (odds ratio 10.4, 95% CI 4.2-25.6), and both parameters correlated with muscle weakness (P<0.01). CONCLUSION: Our study suggests that the same pathophysiologic process occurs in the upper and lower extremity nerves. Moreover, one pathophysiologic process may be responsible for the development of CB and AD, and therefore muscle weakness. SIGNIFICANCE: The present study has established that both AD and CB occur in MMN, irrespective of extremity, and both correlate with muscle weakness.

Action Potentials↗
PubMed2005

Endogenous Nkx2.2+/Olig2+ oligodendrocyte precursor cells fail to remyelinate the demyelinated adult rat spinal cord in the absence of astrocytes.

Chronic demyelination is a pathophysiologic component of compressive spinal cord injury (SCI) and a characteristic finding in demyelinating diseases including multiple sclerosis (MS). A better characterization of endogenous cells responsible for successful remyelination is essential for designing therapeutic strategies aimed at restoring functional myelin. The present study examined the spatiotemporal response of endogenous oligodendrocyte precursor cells (OPCs) following ethidium bromide (EB)-induced demyelination of the adult rat spinal cord. Beginning at 2 days post-EB injection (dpi), a robust mobilization of highly proliferative NG2(+) cells within the lesion was observed, none of which expressed the oligodendrocyte lineage-associated transcription factor Nkx2.2. At 7 dpi, a significant up-regulation of Nkx2.2 by OPCs within the lesion was observed, 90% of which coexpressed NG2 and virtually all of which coexpressed the bHLH transcription factor Olig2. Despite successful recruitment of Nkx2.2(+)/Olig2(+) OPCs within the lesion, demyelinated axons were not remyelinated by these OPCs in regions lacking astrocytes. Rather, Schwann cell remyelination predominated throughout the central core of the lesion, particularly around blood vessels. Oligodendrocyte remyelination was observed in the astrogliotic perimeter, suggesting a necessary role for astrocytes in oligodendrocyte maturation. In addition, reexpression of the radial glial antigen, RC-1, by reactive astrocytes and ependymal cells was observed following injury. However, these cells did not express the neural stem cell (NSC)-associated transcription factors Sox1 or Sox2, suggesting that the endogenous response is primarily mediated by glial progenitors. In vivo electrophysiology demonstrated a limited and unsustained functional recovery concurrent with endogenous remyelination following EB-induced lesions.

Animals↗
PubMed2004

Coronavirus-induced demyelination occurs in the absence of CD28 costimulatory signals.

Infection of mice with mouse hepatitis virus (MHV) strain A59 results in acute encephalitis, hepatitis, and chronic demyelinating disease. T lymphocytes play an important role in MHV infection, and costimulatory signals are an important component of T cell function. To elucidate the role of the main costimulatory molecule, CD28, in MHV pathogenesis and demyelination, we examined the kinetics of MHV-A59 infection in CD28 knockout mice. MHV-A59-infected CD28 knockout mice developed acute encephalitis and hepatitis, and the same degree of chronic demyelination as normal C57Bl/6 (B6) mice. Thus, CD28, the costimulatory T cell molecule, is not required for MHV infection and MHV-induced demyelination.

Animals↗
PubMed2004

Microglial cell activation in demyelinating canine distemper lesions.

Microglia cells are the principal immune effector elements of the brain responding to any pathological event. To elucidate the possible role of microglia in initial non-inflammatory demyelination in canine distemper virus (CDV) infection, microglia from experimentally CDV infected dogs were isolated ex vivo by density gradient centrifugation and characterized immunophenotypically and functionally using flow cytometry. Results from dogs with demyelinating lesions were compared to results from recovered dogs and two healthy controls. CDV antigen could be detected in microglia of dogs with histopathologically confirmed demyelination. Microglia of these dogs showed marked upregulation of the surface molecules CD18, CD11b, CD11c, CD1c, MHC class I and MHC class II and a tendency for increased expression intensity of ICAM-1 (CD54), B7-1 (CD80), B7-2 (CD86), whereas no increased expression was found for CD44 and CD45. Functionally, microglia exhibited distinctly enhanced phagocytosis and generation of reactive oxygen species (ROS). It was concluded that in CDV infection, there is a clear association between microglial activation and demyelination. This strongly suggests that microglia contribute to acute myelin destruction in distemper.

Animals↗
PubMed2006

The pathologic role for COX-2 in apoptotic oligodendrocytes in virus induced demyelinating disease: implications for multiple sclerosis.

The objective of this study was examine whether the inducible isoform of the enzyme cyclooxygenase (COX-2) was expressed in dying oligodendrocytes in the Theiler's murine encephalomyelitis virus (TMEV) induced demyelinating disease (TMEV-IDD), an experimental animal model for multiple sclerosis (MS). COX-2 is an enzyme that is tightly coupled to neuronal excitotoxic death. Since neuronal expression of COX-2 contributes to the susceptibility of neurons to excitotoxic death, we asked whether COX-2 was expressed in oligodendrocytes in MS plaques and in lesions during TMEV-IDD. COX-2 was expressed in oligodendrocytes in chronic active lesions from two MS patients. Similar pathology was present in TMEV-IDD spinal cord lesions. COX-2 was expressed in oligodendrocytes four weeks after infection with TMEV coincident with the onset of demyelination. A marker for apoptotic death, activated caspase 3, was present in a subset of oligodendrocytes that expressed COX-2. Oligodendrocyte expression of COX-2 in TMEV-IDD and MS lesions is consistent with a pathological role for this enzyme in demyelination. The presence of the cell death marker (activated caspase 3) with COX-2 in oligodendrocytes is direct evidence linking COX-2 with cell death of oligodendrocytes in these demyelinating diseases.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2005

Functional imaging of a large demyelinating lesion.

PURPOSE: To determine the metabolic characterization of a large solitary demyelinating lesion. METHODS: Magnetic Resonance Spectroscopy (MRS) and Positron Emission Tomography (PET) studies with 2-deoxy-2-[F-18]fluoro-d-glucose (FDG), carbon-11-methionine (methionine) and carbon-11-choline (choline) were done on the demyelinating lesion. RESULTS: The demyelinating lesion exhibited a low glucose uptake, prominent methionine uptake and a minimal choline uptake on the PET studies. MRS data revealed an increased choline to creatine (cho/cr) ratio and a decreased N-acetyl-aspartate to creatine (NAA/cr) ratio, which demonstrated a return to near normal ratios on follow-up study. CONCLUSION: The report summarizes the metabolic characteristics of a demyelinating plaque.

Adult↗
PubMed2005

A technique for producing demyelination of the rat optic nerves.

Demyelination is a major cause of neurological disability within the human population, and the end product of a number of pathological processes, though the most common is the disease multiple sclerosis. This disease commonly affects the optic pathway, particularly the optic nerve and chiasm. This paper reports a novel technique of producing chemical glial toxin induced demyelination in the rat optic nerves and chiasm by the direct instillation of the glial toxin ethidium bromide into the rat cranial subarachnoid space causing demyelination of the optic nerves and chiasm. This model, because of its involvement of the optic pathways, will allow both histological and functional assessments of the processes of demyelination and remyelination in the rat animal model.

Animals↗
PubMed2006

Attenuated demyelination in the absence of the macrophage-restricted adhesion molecule sialoadhesin (Siglec-1) in mice heterozygously deficient in P0.

Mouse mutants heterozygously deficient for the myelin component P0 mimic some forms of inherited neuropathies in humans. We have previously shown that both T lymphocytes and macrophages contribute to the demyelinating neuropathy. Both cell types appear to influence each other mutually, i.e., impaired T lymphocyte development in RAG-1-deficient P0 mutants leads to decreased macrophage numbers and retarded macrophage activation causes reduced T lymphocyte numbers in the peripheral nerves of P0(+/-) mice. In the present study, we investigated the possible role of the macrophage-restricted sialic acid-binding Ig-like lectin sialoadhesin (Sn, Siglec-1) in the pathogenesis of inherited demyelination in P0(+/-) mice. We found that most peripheral nerve macrophages express Sn in the mutants. Myelin mutants devoid of Sn show reduced numbers of CD8+ T lymphocytes and macrophages in peripheral nerves and less severe demyelination, resulting in improved nerve conduction properties. Our findings are potentially important in the development of future treatment strategies for inherited demyelinating neuropathies.

Animals↗
PubMed2004

Immunohistochemical detection of osteopontin in the spinal cords of mice with Theiler's murine encephalomyelitis virus-induced demyelinating disease.

The spinal cords of mice that were infected with the BeAn 8386 strain of Theiler's murine encephalomyelitis virus (TMEV) were studied to elucidate the involvement of osteopontin in the course of TMEV-induced demyelination. Immunohistochemistry showed staining for osteopontin in the vessels of the normal spinal cords, and more intense immunoreactivity in the vessels within the demyelinating lesions. Intense osteopontin immunoreactivity was observed in the cell bodies, as well as in the extracellular space of the demyelinating lesions, where some glial cells, which included activated microglia/macrophages, were also immunopositive for osteopontin. These findings suggest that osteopontin is upregulated in the demyelinating spinal cord, and that osteopontin from either microglia or astrocytes may be involved in the chemotaxis of inflammatory cells and astrocytes, which ultimately leads to chronic inflammation and astrogliosis in this model system.

Animals↗
PubMed2005

Differences in the early inflammatory responses to toxin-induced demyelination are associated with the age-related decline in CNS remyelination.

CNS remyelination occurs more rapidly in young adult rats than in old rats. Since the inflammatory response initiated by demyelination is an important trigger for remyelination, we address whether ageing changes in remyelination are associated with changes in the inflammatory response. Using a toxin model of demyelination, where the inflammatory response largely comprises macrophages, we show that there is a delay in both recruitment and activation of OX-42+ and macrophage scavenger receptor B+ macrophages following demyelination in older rats (10-13 months) compared to young rats (8-10 weeks). This difference is associated with a slower onset of increased expression of several chemokine mRNAs. However, many inflammatory cytokines have similar mRNA expression patterns, with the exception of IL-1beta, IL-6 and TNF-alpha, which have prolonged expression in the older animals. Differences in IL-1beta mRNA expression, a cytokine specifically implicated in CNS remyelination, are not reflected in differences in protein expression detected by immunocytochemistry. These data relate the age-associated delay in remyelination efficiency to changes in the macrophage and inflammatory mediator response to demyelination.

Aging↗