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PubMed1988

Schwann cell vulnerability to demyelination is associated with internodal length in tellurium neuropathy.

The frequency of demyelinated fibers in mixed nerve and cutaneous nerve and the relationship of the frequency of demyelination to internodal length were assessed in a model of tellurium neuropathy in the rat. Twenty-day-old Long-Evans rats were fed chow containing 1.25% elemental tellurium for seven days and subsequently killed at 34 or 41 days of age. Teased-fiber preparations revealed a higher frequency of demyelinated fibers in sciatic nerve (mixed nerve) than in sural nerve (cutaneous nerve). The frequency of demyelinated fibers was positively associated with internodal length in both nerves. The type of nerve (mixed or cutaneous) was not a significant predictor of the frequency of demyelinated fibers once internodal length had been taken into account. These data indicate that there is a hierarchy of vulnerability within the population of myelinating Schwann cells to tellurium toxicity, and that this hierarchy is related to internodal length. The hierarchy of vulnerability may reflect intrinsic differences among Schwann cells, such as the volume of myelin each cell is synthesizing and maintaining, or a gradient of unrecognized axonal abnormalities.

Animals↗
PubMed2000

Osmotic demyelination disorders: central pontine and extrapontine myelinolysis.

Focal symmetric demyelination in the central nervous system may be precipitated by aggressive correction of a hyper- or hypo-osmolar state and until recently has been associated with a high rate of morbidity and mortality. Specific anatomical locations are more susceptible to demyelination than others, although the mechanism of injury is unknown. Classic clinical and anatomical descriptions associated with a central pontine location have been supplemented by descriptions of patients with unusual symptoms associated with demyelinating lesions in extrapontine locations. The separation of patients with myelinolysis in central pontine and extrapontine locations is possible on the basis of clinical symptoms, and may direct specific pharmacological treatment. Patients at risk of central myelinolysis who are subjected to aggressive osmolar correction may be rescued with appropriate fluid management before brain injury has occurred; once injury is suspected on the basis of neurological symptoms, additional forms of intervention may still improve the outcome. Recent investigation of the molecular basis of the demyelinating process and the adaptive responses of the brain to dysosmolar challenge has allowed for the refinement of standard treatments and has made the osmotic demyelination syndrome a treatable condition with a better than expected prognosis.

Demyelinating Diseases↗
PubMed1987

Semliki Forest virus-induced, immune-mediated demyelination: adoptive transfer studies and viral persistence in nude mice.

Adoptive transfer experiments in athymic nude mice demonstrated that the demyelination seen in the central nervous system (CNS) following Semliki Forest virus (SFV) infection was directly dependent upon sensitized T lymphocytes. Antibodies generated during the infection did not seem to be involved in the demyelination, but thymus-dependent antibodies (IgG) were responsible for the reduction of brain virus titres. In the absence of a T cell response and T cell-dependent antibody production, virus persisted in the CNS for several months. Despite persistence of high virus titres for this time, only mice eventually developing a CNS inflammatory response developed lesions of demyelination. In the absence of an inflammatory response no demyelination was apparent even after several months of persistent infection. Administration of anti-SFV hyperimmune serum intracerebrally to both infected and control mice did not produce demyelination but resulted in CNS tissue degeneration with marked pycnosis.

Animals↗
PubMedDate not supplied

Ethidium bromide induced demyelination in the spinal cord of the cat.

Small volumes of ethidium bromide were injected into the dorsal column of the spinal cord of cats. Oligodendrocytes and astrocytes showed morphological evidence of intoxication by ethidium bromide from 2 days after injection. However, apart from around the point of injection and the needle tract, demyelination did not occur until between 8 and 14 days. Both oligodendrocytes and astrocytes were absent from the demyelinated area at 14 days and all but a small number of demyelinated axons were remyelinated by Schwann cells. These cells first appeared in the lesion at 10 days, but axon association and myelination did not occur until 16 days. This model of experimental demyelination indicates once again that Schwann cell invasion of demyelinated areas in the CNS occurs if both oligodendrocytes and astrocytes are destroyed. None of the lesions in the present investigation were in continuity with root entry zones, indicating that this location is not a prerequisite for Schwann cell invasion of the CNS.

Animals↗
PubMed1993

Failure of remyelination in areas of demyelination produced in the spinal cord of old rats.

The extent of remyelination was determined one month after injecting 1 microliter of 1.0% lysolecithin into the dorsal columns of adult rats of three age groups--juvenile, young and old. In the juvenile group (2 months) all axons were remyelinated by either oligodendrocytes or Schwann cells. In the young rats (5 months) nearly all axons were remyelinated. However, in the oldest age group (> 12 months) many axons remained demyelinated and there was a decrease in both oligodendrocyte and Schwann cell remyelination. Also, myelin sheaths formed by oligodendrocytes in the old rats were thinner than those found in the young rats; evidence of impaired Schwann cell remyelination was also seen. The appearance of the lesions in the old animals was variable and many contained myelin debris despite the presence of macrophages within the demyelination area. Although some astrocytes were present in the lesion, many of the demyelinated axons were not separated by astrocyte processes. It is suggested that the failure of remyelination in the old rats following lysolecithin-induced demyelination may be related to sluggish responses of astrocytes and/or macrophages to demyelination. However, a lack of recruitable myelin-forming cells in old animals cannot be excluded.

Aging↗
PubMed1994

Oligodendrocyte reactions and cell proliferation markers in human demyelinating diseases.

We have carried out immunocytochemical reactions using antibodies to markers of oligodendrocytes, astrocytes, microglia and proliferating cells (PCNA) in sections of human brain in a variety of demyelinating conditions and human immunodeficiency virus (HIV) infection. In the acute phases of demyelinating diseases we found marked reactive changes in oligodendrocytes with hyperplasia and an increased cytoplasmic reaction using antibodies to enzymes involved in myelin formation. Proliferative responses were implied by the hyperplasia and the common finding of clusters of two or three adjacent oligodendrocytes at sites of acute myelin damage. This was borne out by studies using the PCNA antibody which gave negative reactions in normal brain but positive reactions in acute demyelination. Double staining for PCNA and cell markers showed that cells that had entered the cell proliferation cycle were to be found among astrocytes, microglia/macrophages and oligodendrocytes. In chronic demyelinating conditions, numbers of oligodendrocytes were reduced and cells in the proliferative cycle were not present, suggesting that the reactive potential of oligodendrocytes or their precursors and their capacity to respond to demyelination is limited.

Biomarkers↗
PubMed2005

Repopulation of oligodendrocyte progenitor cell depleted tissue in a model of chronic demyelination.

Some, but not all chronically demyelinated MS lesions are depleted of oligodendrocyte progenitor cells (OPCs) suggesting that OPCs are destroyed during the process of demyelination and some factor impedes OPC repopulation of the depleted tissue. The chronically demyelinated axons in MS lie in an astrocytic environment and it has been proposed that this might impede entry of OPCs into such regions. By depleting a short length of spinal cord of its OPCs using 40 Gy of X-irradiation in both normal rats and rats with progressive myelin loss accompanied by an astrocytosis (taiep rats), we investigated whether such changes affect the ability of OPCs to repopulate OPC-depleted tissue. In both taiep and normal rats, the rate of repopulation decreases with age, but no difference was detected in the rate at which OPCs repopulated normally myelinated and chronically demyelinated and astrocytosed tissue. This indicates that, if the astrocytic environment of the taiep CNS is comparable to that found in MS lesions, then the presence of chronically demyelinated axons and astrocytosis in chronic MS lesions does not represent a barrier to repopulation of the tissue by OPCs. However, similar to the situation in the normal adult rodent CNS, the rate of repopulation by endogenous OPCs in aged taiep rats is very slow, approximately 0.2 mm per week.

Age Factors↗
PubMed1995

Expression of the highly polysialylated neural cell adhesion molecule during postnatal myelination and following chemically induced demyelination of the adult mouse spinal cord.

We have investigated the expression of the highly polysialylated neural cell adhesion molecule in the mouse spinal cord during postnatal myelination and in the adult after chemically induced demyelination. By double immunohistochemistry, using a monoclonal antibody (anti-Men B) which specifically recognizes polysialic acid (PSA) units on neural cell adhesion molecule (N-CAM), and an anti-myelin basic protein, a caudorostral gradient of expression of PSA-NCAM was observed at postnatal day 1 (P1), which was inversely related to the gradient of myelination. At P7, PSA-NCAM labelling decreased relative to P1. In white matter, this decrease was correlated with the progression of myelination. PSA-NCAM immunoreactivity persisted in as yet unmyelinated structures, i.e. the corticospinal tract, the dorsomedial part of the ventral funiculus and the lateral funiculi, and decreased with the onset of myelination of these structures at P15. In the adult, PSA-NCAM expression remained in discrete structures, i.e. laminae I and II of the dorsal horn and lamina X around the central canal. The ependymal cells and the astrocyte endfeet under the meninges were also labelled. In addition, PSA-NCAM expression was reinduced on various cells and structures after lysolecithin-induced demyelination of the adult mouse spinal cord. At early times after demyelination, PSA-NCAM was expressed on glial cells around the lesion but also at a distance from this zone. Seven days after injection, cellular PSA-NCAM expression was found around but also within the lesion. This expression was totally abolished 15 days after injection. Double immunohistochemistry for PSA and cell-specific markers showed that the cells which expressed PSA-NCAM after demyelination were oligodendrocyte precursors, reactive astrocytes and Schwann cells. PSA-NCAM re-expression on all cell types was transient and ceased when myelin repair was accomplished. The spatial and temporal regulation of PSA-NCAM expression during development and after demyelination suggests a role for PSA-NCAM in glial plasticity during the myelination and remyelination processes.

Aging↗
PubMed2006

Guillain-Barré syndrome in Pakistan: similarity of demyelinating and axonal variants.

Guillain-Barré syndrome (GBS) comprises multiple subtypes whose nosological and pathophysiologic interrelationships are unclear. In an attempt to better understand the relationship between the disease's major subtypes, we reviewed the characteristics of GBS cases consecutively admitted to a tertiary care hospital in Karachi, Pakistan, over a 13-year period. Of 175 cases, 80 (46%) were demyelinating and 55 (31%) axonal, whilst 40 (23%) had ambiguous electrophysiological findings precluding classification. The three groups differed in severity of weakness at presentation (axonal approximately ambiguous > demyelinating; P = 0.002 for arm strength and P = 0.025 for leg strength); mean age (demyelinating > axonal > ambiguous; P = 0.05); and mean cerebrospinal fluid protein concentration (demyelinating > ambiguous > axonal; P = 0.05). However, they were similar in several other respects, including gender ratio, proportion of pediatric cases, history of antecedent infection, length of hospital stay, need and duration of mechanical ventilation, and functional outcome at discharge. Stool culture data was available for 146 (83%) cases in the study; none was positive for Campylobacter jejuni. GBS in Pakistan comprises a high proportion of axonal cases. Similarity of outcomes in axonal and demyelinating variants and lack of C. jejuni stool culture positivity are atypical features.

Adolescent↗
PubMed1994

Upper limb pain in chronic demyelinating polyneuropathy: electrophysiological correlates.

Pain is not usually considered a symptom of chronic relapsing demyelinating polyneuropathy. We report two patients with chronic demyelinating polyneuropathies in whom clinical and electrophysiological worsening was associated with the development of deep and distressing upper limb aching discomfort. One patient had a MGUS-associated hypertrophic demyelinating and prednisone-dependent polyneuropathy, followed over a course of two and a half years. His discomfort regularly predicted electrophysiological relapse of neuropathy, before more obvious clinical signs had emerged. Resolution of the discomfort also predicted subsequent clinical and electrophysiological improvement. Upper limb pain may be an important feature of early relapse in some patients with demyelinating polyneuropathies. Standardized serial electrophysiological testing in patients with chronic demyelinating polyneuropathy can be an important management tool in conjunction with clinical signs and symptoms.

Arm↗
PubMed1999

Demyelination: the role of reactive oxygen and nitrogen species.

This review summarises the role that reactive oxygen and nitrogen species play in demyelination, such as that occurring in the inflammatory demyelinating disorders multiple sclerosis and Guillain-Barré syndrome. The concentrations of reactive oxygen and nitrogen species (e.g. superoxide, nitric oxide and peroxynitrite) can increase dramatically under conditions such as inflammation, and this can overwhelm the inherent antioxidant defences within lesions. Such oxidative and/or nitrative stress can damage the lipids, proteins and nucleic acids of cells and mitochondria, potentially causing cell death. Oligodendrocytes are more sensitive to oxidative and nitrative stress in vitro than are astrocytes and microglia, seemingly due to a diminished capacity for antioxidant defence, and the presence of raised risk factors, including a high iron content. Oxidative and nitrative stress might therefore result in vivo in selective oligodendrocyte death, and thereby demyelination. The reactive species may also damage the myelin sheath, promoting its attack by macrophages. Damage can occur directly by lipid peroxidation, and indirectly by the activation of proteases and phospholipase A2. Evidence for the existence of oxidative and nitrative stress within inflammatory demyelinating lesions includes the presence of both lipid and protein peroxides, and nitrotyrosine (a marker for peroxynitrite formation). The neurological deficit resulting from experimental autoimmune demyelinating disease has generally been reduced by trial therapies intended to diminish the concentration of reactive oxygen species. However, therapies aimed at diminishing reactive nitrogen species have had a more variable outcome, sometimes exacerbating disease.

Animals↗
PubMed2000

CD40L is critical for protection from demyelinating disease and development of spontaneous remyelination in a mouse model of multiple sclerosis.

Theiler's murine encephalomyelitis virus (TMEV) induces acute neuronal disease followed by chronic demyelination in susceptible strains of mice. In this study we examined the role of a limited immune defect (deletion or blocking of CD40 ligand [CD40L]) on the extent of brain disease, susceptibility to demyelination, and the ability of demyelinated mice to spontaneously remyelinate following TMEV infection. We demonstrated that CD40L-dependent immune responses participate in pathogenesis in the cerebellum and the spinal cord white matter but protect the striatum of susceptible SJL/J mice. In mice on a background resistant to TMEV-induced demyelination (C57BL/6), the lack of CD40L resulted in increased striatal disease and meningeal inflammation. In addition, CD40L was required to maintain resistance to demyelination and clinical deficits in H-2b mice. CD40L-mediated interactions were also necessary for development of protective H-2b-restricted cytotoxic T cell responses directed against the VP2 region of TMEV as well as for spontaneous remyelination of the spinal cord white matter. The data presented here demonstrated the critical role of this molecule in both antibody- and cell-mediated protective immune responses in distinct phases of TMEV-mediated pathology.

Animals↗
PubMed2003

A 40-cM region on chromosome 14 plays a critical role in the development of virus persistence, demyelination, brain pathology and neurologic deficits in a murine viral model of multiple sclerosis.

Theiler virus persists and induces immune-mediated demyelination in susceptible mice and serves as a model of multiple sclerosis. Previously, we identified 4 markers--D14Mit54, D14Mit60, D14Mit61, and D14Mit90--in a 40-cM region of chromosome 14 that are associated with demyelination in a cross between susceptible DBA/2 and resistant B10.D2 mice. We generated congenic-inbred mice to examine the contribution of this 40-cM region to disease. DBA Chr.14B10 mice, containing the chromosomal segment marked by the microsatellite polymorphisms, developed less spinal cord demyelination than did DBA/2 mice. More demyelination was found in the reciprocal congenic mouse B10.D2 Chr.14D2 than in the B10.D2 strain. Introduction of the DBA/2 chromosomal region onto the B10.D2 genetic background resulted in more severe disease in the striatum and cortex relative to B10.D2 mice. The importance of the marked region of chromosome 14 is indicated by the decrease in neurological performance using the Rotarod test during chronic disease in B10.D2 Chr.14D2 mice in comparison to B10.D2 mice. Viral replication was increased in B10.D2 Chr.14D2 mice as determined by quantitative real-time RT-PCR. These results indicate that the 40-cM region on chromosome 14 of DBA/2 mice contributes to viral persistence, subsequent demyelination, and loss of neurological function.

Animals↗
PubMed1982

Uncoupled relationship between demyelination and primary infection of myelinating cells in Theiler's virus encephalomyelitis.

Theiler's virus infection in mice produces a chronic demyelinating disease which appears to be based on an immune pathogenesis rather than on direct viral destruction of myelin-supporting cells. The purpose of the present study is to ascertain whether viral antigen is present in the cytoplasm of such cells in areas of demyelination. Because of the difficulty of identifying oligodendrocytes in tissues rich in infiltrating mononuclear cells and fixed for immunohistochemistry, I turned to a recently described form of Theiler's virus encephalomyelitis which follows inoculation with the attenuated ww strain and is characterized by extensive spinal cord remyelination by invading Schwann cells and by recurrent demyelination of Schwann cell-remyelinated axons. The unlabeled antibody peroxidase-antiperoxidase technique was employed to study whether such spinal cord Schwann cells were primarily infected by virus at the time when recurrent demyelination was occurring. Whereas other types of cells, including neurons, astrocytes, and macrophages, contained abundant viral antigen, no positive immune reaction was observed in Schwann cells. These results correlate with our previous studies which had suggested that demyelination in this viral model is not dependent on primary viral attack on myelinating cells but is probably dependent on the host immune response.

Animals↗
PubMed2000

Coronavirus-induced demyelination occurs in the absence of inducible nitric oxide synthase.

Demyelination induced by mouse hepatitis virus (MHV), strain JHM, is in large part immune mediated, but little is known about the mechanisms involved in this process. Previous results suggest that inducible nitric oxide synthase (NOS2) contributes transiently to MHV-induced demyelination. Herein, we show that equivalent amounts of demyelination were evident at day 12 after MHV infection in mice genetically deficient in NOS2 (NOS2(-/-)) and in C57BL/6 mice. Furthermore, using an established adoptive transfer model and pharmacological inhibitors of NOS2 function, we could demonstrate no effect on MHV-induced demyelination. These results indicate that NOS2 function is not required for demyelination in mice infected with MHV.

Adoptive Transfer↗
PubMed2000

A central role for CD4(+) T cells and RANTES in virus-induced central nervous system inflammation and demyelination.

Infection of C57BL/6 mice with mouse hepatitis virus (MHV) results in a demyelinating encephalomyelitis characterized by mononuclear cell infiltration and white matter destruction similar to the pathology of the human demyelinating disease multiple sclerosis. The contributions of CD4(+) and CD8(+) T cells in the pathogenesis of the disease were investigated. Significantly less severe inflammation and demyelination were observed in CD4(-/-) mice than in CD8(-/-) and C57BL/6 mice (P < or = 0.002 and P < or = 0.001, respectively). Immunophenotyping of central nervous system (CNS) infiltrates revealed that CD4(-/-) mice had a significant reduction in numbers of activated macrophages/microglial cells in the brain compared to the numbers in CD8(-/-) and C57BL/6 mice, indicating a role for these cells in myelin destruction. Furthermore, CD4(-/-) mice displayed lower levels of RANTES (a C-C chemokine) mRNA transcripts and protein, suggesting a role for this molecule in the pathogenesis of MHV-induced neurologic disease. Administration of RANTES antisera to MHV-infected C57BL/6 mice resulted in a significant reduction in macrophage infiltration and demyelination (P < or = 0.001) compared to those in control mice. These data indicate that CD4(+) T cells have a pivotal role in accelerating CNS inflammation and demyelination within infected mice, possibly by regulating RANTES expression, which in turn coordinates the trafficking of macrophages into the CNS, leading to myelin destruction.

Animals↗
PubMed2002

Transgenic expression of Theiler's murine encephalomyelitis virus genes in H-2(b) mice inhibits resistance to virus-induced demyelination.

We investigated the role of the immune system in protecting against virus-induced demyelination by generating lines of transgenic B10 (H-2(b)) congenic mice expressing three independent contiguous coding regions of the Theiler's murine encephalomyelitis virus (TMEV) under the control of a class I major histocompatibility complex (MHC) promoter. TMEV infection of normally resistant B10 mice results in virus clearance and development of inflammatory demyelination in the spinal cord. Transgenic expression of the viral capsid genes resulted in inactivation of virus-specific CD8(+) T lymphocytes (class I MHC immune function) directed against the relevant peptides, but it did not affect production of virus capsid-specific antibodies or lymphocyte proliferation to the virus antigen (class II MHC immune functions). Following intracerebral infection with TMEV, all three lines of mice survived the acute encephalitis but transgenic mice expressing VP1 (or the cluster of virus capsid proteins [VP4, VP2, and VP3] mapping to the left of VP1 in the TMEV genome) developed virus persistence and subsequent demyelination in spinal cord white matter. Transgenic mice expressing noncapsid proteins mapping to the right of VP1 (2A, 2B, 2C, 3A, 3B, 3C, and 3D) cleared the virus and did not develop demyelination. These results are consistent with the hypothesis that virus capsid gene products of TMEV stimulate class I-restricted CD8(+) T-cell immune responses, which are important for virus clearance and for protection against myelin destruction. Presented within the context of self-antigens, inactivation of these cells by ubiquitous expression of relevant virus capsid peptides partially inhibited resistance to virus-induced demyelination.

Animals↗
PubMed2005

Important roles for gamma interferon and NKG2D in gammadelta T-cell-induced demyelination in T-cell receptor beta-deficient mice infected with a coronavirus.

gammadelta T cells mediate demyelination in athymic (nude) mice infected with the neurotropic coronavirus mouse hepatitis virus strain JHM. Now, we show that these cells also mediate the same process in mice lacking alphabeta T cells (T-cell receptor beta-deficient [TCRbeta(-/-)] mice) and demyelination is gamma interferon (IFN-gamma) dependent. Most strikingly, our results also show a major role for NKG2D, expressed on gammadelta T cells, in the demyelinating process with in vivo blockade of NKG2D interactions resulting in a 60% reduction in demyelination. NKG2D may serve as a primary recognition receptor or as a costimulatory molecule. We show that NKG2D(+) gammadelta T cells in the JHM-infected central nervous system express the adaptor molecule DAP12 and an NKG2D isoform (NKG2D short), both required for NKG2D to serve as a primary receptor. These results are consistent with models in which gammadelta T cells mediate demyelination using the same effector cytokine, IFN-gamma, as CD8 T cells and do so without a requirement for signaling through the TCR.

Animals↗