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PubMed2000

Positive association between blood brain barrier disruption and osmotically-induced demyelination.

Rapid correction of chronic hyponatremia can cause osmotic brain demyelination in animals and humans. Why demyelination develops is unknown, but blood brain-barrier disruption might expose oligodendrocytes to substances normally excluded from the brain. To test this hypothesis, chronic hyponatremia was induced and corrected using a new, reproducible rat model for producing osmotic brain demyelination. Blood brain barrier integrity was assessed by NMR imaging at either 3, 16 or 24 h during the first day of correction. Demyelination was determined histopathologically 5 - 6 days later. Of 96 rats studied, demyelination developed 5 - 6 days later in 37 rats, 89% of whom showed barrier disruption. In the 59 rats who did not develop demyelination, 45 (76%) had no barrier disruption. Thus, blood-brain barrier disruption during the first 24 h of correction was associated with a 70% risk of developing demyelination. By contrast, the risk of developing subsequent demyelination was only 8% when the barrier was intact. This strong association between barrier disruption and subsequent demyelination provides new insights into the role of blood brain barrier function in demyelinative disorders such as the osmotic demyelination syndrome and by extension to other demyelinative disorders such as multiple sclerosis.

Animals↗
PubMed2003

Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients.

Three genes commonly causing Charcot-Marie-Tooth disease (CMT) encode myelin-related proteins: peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and connexin 32 (Cx32). Demyelinating versus axonal phenotypes are major issues in CMT associated with mutations of these genes. We electrophysiologically, pathologically and genetically evaluated demyelinating and axonal features of 205 Japanese patients with PMP22 duplication, MPZ mutations or Cx32 mutations. PMP22 duplication caused mainly demyelinating phenotypes with slowed motor nerve conduction velocity (MCV) and demyelinating histopathology, while axonal features were variably present. Two distinctive phenotypic subgroups were present in patients with MPZ mutations: one showed preserved MCV and exclusively axonal pathological features, while the other was exclusively demyelinating. These axonal and demyelinating phenotypes were well concordant among siblings in individual families, and MPZ mutations did not overlap among these two subgroups, suggesting that the nature and position of the MPZ mutations mainly determine the axonal and demyelinating phenotypes. Patients with Cx32 mutations showed intermediate slowing of MCV, predominantly axonal features and relatively mild demyelinating pathology. These axonal and demyelinating features were present concomitantly in individual patients to a variable extent. The relative severity of axonal and demyelinating features was not associated with particular Cx32 mutations. Median nerve MCV and overall histopathological phenotype changed little with disease advancement. Axonal features of diminished amplitudes of compound muscle action potentials (CMAPs), axonal loss, axonal sprouting and neuropathic muscle wasting all changed as disease advanced, especially in PMP22 duplication and Cx32 mutations. Median nerve MCVs were well maintained independently of age, disease duration and the severity of clinical and pathological abnormalities, confirming that median nerve MCV is an excellent marker for the genetically determined neuropathic phenotypes. Amplitude of CMAPs was correlated significantly with distal muscle strength in PMP22 duplication, MPZ mutations and Cx32 mutations, while MCV slowing was not, indicating that clinical weakness results from reduced numbers of functional large axons, not from demyelination. Thus, the three major myelin-related protein mutations induced varied degrees of axonal and demyelinating phenotypic features according to the specific gene mutation as well as the stage of disease advancement, while clinically evident muscle wasting was attributable to loss of functioning large axons.

Action Potentials↗
PubMed2000

Transplanted glial cells migrate over a greater distance and remyelinate demyelinated lesions more rapidly than endogenous remyelinating cells.

Glial cell transplantation offers a means of remyelinating areas of demyelination in situations where endogenous remyelination fails. How effective such a strategy would be if undertaken in human demyelinating disease is not yet clear since it is very difficult to create large areas of demyelination in adult rodents that would mimic the situation found in a human disease such as multiple sclerosis. When CNS tissue is subjected to 40 Grays of X-irradiation, remyelination is suppressed in the X-irradiated area unless cells migrate into, or are introduced into the X-irradiated area. In the present experiments, by appropriate positioning of lead shielding we have created a "starting gate" from which oligodendrocyte progenitors must depart in order to colonise areas of demyelination. When the starting gate is located at one end of the area of demyelination, endogenous cells fail to colonise throughout an area of demyelination over the ensuing month. In contrast, when transplanted oligodendrocyte precursors are faced with the same situation, the whole area of demyelination is remyelinated over the same period. To determine how far transplanted cells can migrate to areas of demyelination and also to study how quickly the cells can colonise areas of demyelination we injected cells at some distance from areas of demyelination made in X-irradiated tissue. In these experiments, we found that transplanted cells could repopulate up to 9 mm in 2 months compared to 4 mm recorded for endogenous cells (Franklin et al. [1997] J. Neurosci. Res. 50:337-344). These experiments demonstrate that transplanted cells have a far greater ability to colonise areas of demyelination than endogenous cells.

Animals↗
PubMed2003

The presence of astrocytes in areas of demyelination influences remyelination following transplantation of oligodendrocyte progenitors.

To date, most experiments examining the myelination potential of transplanted cells have been undertaken into either the immature nervous system or into acutely demyelinating lesions. Since these are situations where myelination or remyelination are occurring, such studies provide little information on the likely outcome of introducing myelinogenic cells into area of chronic demyelination. In an attempt to gain a greater understanding of the interaction between astrocytes and oligodendrocyte progenitors in areas of demyelination, we undertook transplantation experiments in which an identical preparation of oligodendrocyte progenitors (OPCs) was (1) transplanted directly into astrocyte-free areas of acute demyelination (3 days after induction), (2) transplanted cranial to similar areas of demyelination (20 days after induction) or (3) transplanted cranial to areas of demyelination (20 days after induction) that had been injected with astrocytes at 3 days to confront OPCs with demyelinated axons in an astrocytic environment. The acute astrocyte-free lesions were remyelinated by oligodendrocytes and Schwann cells while the delayed interaction of OPCs with demyelinating lesions resulted in only oligodendrocyte remyelination, the extent of which was reduced when the area of demyelination contained astrocytes. The results of these experiments illustrate that the introduction of OPCs into an astrocyte-free area of demyelination soon after its induction favours Schwann cell differentiation while the presence of established astrocytes in an area of demyelination has an inhibitory effect on the extent of oligodendrocyte remyelination achieved by OPCs.

Animals↗
PubMed2000

Demyelination determinants map to the spike glycoprotein gene of coronavirus mouse hepatitis virus.

Demyelination is the pathologic hallmark of the human immune-mediated neurologic disease multiple sclerosis, which may be triggered or exacerbated by viral infections. Several experimental animal models have been developed to study the mechanism of virus-induced demyelination, including coronavirus mouse hepatitis virus (MHV) infection in mice. The envelope spike (S) glycoprotein of MHV contains determinants of properties essential for virus-host interactions. However, the molecular determinants of MHV-induced demyelination are still unknown. To investigate the mechanism of MHV-induced demyelination, we examined whether the S gene of MHV contains determinants of demyelination and whether demyelination is linked to viral persistence. Using targeted RNA recombination, we replaced the S gene of a demyelinating virus (MHV-A59) with the S gene of a closely related, nondemyelinating virus (MHV-2). Recombinant viruses containing an S gene derived from MHV-2 in an MHV-A59 background (Penn98-1 and Penn98-2) exhibited a persistence-positive, demyelination-negative phenotype. Thus, determinants of demyelination map to the S gene of MHV. Furthermore, viral persistence is insufficient to induce demyelination, although it may be a prerequisite for the development of demyelination.

Animals↗
PubMed1997

5-Fluorouracil and levamisole exacerbate demyelination in susceptible mice infected with Theiler's virus.

A multifocal inflammatory leukoencephalopathy is associated with the administration of 5-fluorouracil (5-FU), a pyrimidine analogue, and levamisole (LE), an immunomodulator, in patients receiving adjuvant therapy for colon cancer. Cerebral biopsy demonstrated features indistinguishable from multiple sclerosis. We tested whether administration of these agents directly resulted in inflammatory demyelination in mice or whether they exacerbated demyelination in a host predisposed to myelin injury. We used mice intracerebrally infected with Theiler's murine encephalomyelitis virus (TMEV) which serves as an excellent model for multiple sclerosis. Varying dosages of 5-FU (240 micrograms-2.4 mg) and LE (40 micrograms-1 mg) were administered alone or in combination on a fixed schedule to 52 normal SJL mice and 61 Theiler's virus-infected mice (51 SJL/J mice susceptible to demyelination; 10 C57BL10 mice resistant to demyelination). Controls included 6 noninfected SJL and 26 infected mice (16 susceptible; 10 resistant) treated with phosphate-buffered saline (PBS). Inflammation or demyelination was not detected in brains or spinal cords of noninfected SJL mice treated with 5-FU and/or LE. TMEV-susceptible SJL mice treated with LE alone or in combination with 5-FU demonstrated more extensive inflammation and demyelination at Day 45 than mice treated with PBS. Demyelination was accelerated in infected animals treated with these agents at 45 days but at 70 days a significant difference in extent of demyelination was no longer appreciated between treatment and control groups. Treatment with 5-FU and LE did not convert normally resistant TMEV-infected C57BL/10 mice to demyelination. These experiments support the hypothesis that 5-FU and LE may exacerbate inflammatory demyelination in a susceptible host.

Adjuvants, Immunologic↗
PubMed1998

A quantifiable model of axonal regeneration in the demyelinated adult rat spinal cord.

Strategies to increase the extent of axonal regeneration in the adult CNS must address an array of intrinsic and environmental factors which influence neuritic outgrowth. In order to develop an in vivo model of axonal regeneration in which potential therapies may be assessed, we have quantified growth cones within demyelinated regions in the dorsal funiculus of the spinal cord, following a discrete axotomy. Demyelinated lesions were produced by the intraspinal injection of galactocerebroside antibodies plus serum complement proteins. Axonal integrity was not compromised by the demyelination protocol. Axonal injury was induced at the caudal extent of the demyelinated region using a micromanipulator-controlled Scouten knife. The severity of axonal injury was varied in different animals at the time of surgery and was quantified 8 days later by counting degenerate axons in transverse 1-microm resin sections. Evidence of axonal regeneration within these animals was assessed by an electron microscopic analysis of growth cone frequency and position relative to the site of axotomy. Growth cones were identified within the region of demyelination only; no growth cones were identified within the dorsal column white matter adjacent to the demyelinated region, or rostral or caudal to the region of demyelination, or in animals with an injury but no demyelination. Quantification of growth cones within regions of demyelination indicated a strong linear relationship (P < 0.001) between the number of growth cones and the number of axons severed. These findings indicate that demyelination facilitates axonal regeneration in the adult rat CNS and illustrate a quantifiable method of assessing axonal regeneration.

Age Factors↗
PubMed2000

Magnetically evoked motor potentials in demyelinating and axonal polyneuropathy: a comparative study.

We investigated the value of magnetically evoked motor potentials (MEPs) for the differentiation of demyelinating and axonal polyneuropathies. The study population comprised 107 patients, with polyneuropathy verified by electromyography (EMG) and nerve conduction study (NCS), who had also been examined by means of MEP. MEPs were evoked by magnetic stimulation of the cortex and the spinal roots and were recorded from three upper limb muscles and two lower limb muscles bilaterally. From the EMG/NCS results 53 patients were characterized as having primary demyelination (demyelinating patients) and 54 as having axonal involvement (axonal patients). Demyelinating patients were classified as acute (acute inflammatory demyelinating polyradiculoneuropathy: AIDP) or chronic (chronic inflammatory demyelinating polyradiculoneuropathy: CIDP) according to the duration of illness. A series of indices were calculated from MEP results. One demyelinating patient and two axonal patients had normal MEPs. The MEPs of the demyelinating patients showed significantly longer peripheral conduction times, larger interside differences and lower amplitudes than the axonal patients. The central conduction index and the amplitudes upon cortical stimulation were significantly higher in patients with CIDP than in those with AIDP. Peripheral conduction time prolonged by more than 85% in at least one of the 10 muscles studied or a peripheral conduction index of above 9.4 were pathognomonic for demyelination. By combining all criteria 75% of the patients could be categorized as CIDP vs. AIDP in accordance with the EMG/NCS diagnosis. Likewise, 83% were categorized correctly as demyelinating versus axonal according to the EMG/NCS data.

Acute Disease↗
PubMed1991

Macrophage apolipoprotein synthesis and endoneurial distribution as a response to segmental demyelination.

The synthesis and endoneurial distribution of apolipoproteins in response to myelin degradation was elucidated morphologically and biochemically in rodent models of segmental demyelination. At the onset of acute demyelination induced by tellurium (Te) poisoning, macrophages infiltrated the endoneurium and then began to express cytoplasmic immunoreactivity for apolipoprotein E (apo E). When demyelinating nerve slices were incubated with S35-methionine, radiolabeled apo E was released, showing that apo E was actively synthesized by the macrophages. Macrophages secreted apo E into the endoneurial spaces, leading to dense endoneurial accumulations. Other apolipoproteins (apo A1 and albumin) were not synthesized in the endoneurium, but they entered edematous nerves, presumably through an early breakdown in the blood-nerve barrier. During the phagocytosis of myelin, plasma-derived apolipoproteins accumulated within some of the macrophages. In chronic demyelination caused by lead poisoning, the cellular and extracellular distribution of apolipoproteins was similar to Te neuropathy; the amount of apo E accumulation and the macrophage density were proportional to the prevalence of active demyelination in teased fibers. Similar patterns of endoneurial apo E were present in an inherited form of demyelination in the twitcher mouse, after antibody-mediated demyelination, and in demyelination secondary to axonal degeneration. Human sural nerve biopsies had patterns of apolipoprotein E antigenicity that were comparable to the rodent models. We conclude that secretion of apo E by infiltrating macrophages is a generalized response to demyelination, and that endoneurial edema leads to the accumulation of certain plasma apolipoproteins within macrophages. These data suggest that endoneurial apolipoproteins and macrophages might mediate important functions in patients recovering from primary and secondary demyelination.

Animals↗
PubMed1997

Identification of post-mitotic oligodendrocytes incapable of remyelination within the demyelinated adult spinal cord.

In order to investigate the remyelinating potential of mature oligodendrocytes in vivo, we have developed a model of demyelination in the adult rat spinal cord in which some oligodendrocytes survive demyelination. A single intraspinal injection of complement proteins plus antibodies to galactocerebroside (the major myelin sphingolipid) resulted in demyelination followed by oligodendrocyte remyelination. Remyelination was absent when the spinal cord was exposed to 40 Grays of x-irradiation prior to demyelination, a procedure that kills dividing cells. Quantitative Rip immunohistochemical analysis revealed a similar density of surviving oligodendrocytes in x-irradiated and nonirradiated lesions 3 days after demyelination. Rip and bromodeoxyuridine double immunohistochemical analysis of demyelinated lesions indicated that Rip+ oligodendrocytes did not divide as an acute response to demyelination. Oligodendrocytes were also identified by Rip immunostaining and electron microscopy at late time points (3 weeks) within x-irradiated areas of demyelination. These oligodendrocytes extended processes that engaged axons, and on occasion formed myelin membranes, but did not lay down new myelin sheaths. These studies demonstrate that (a) oligodendrocytes that survive within a region of demyelination are not induced to divide in the presence of demyelinated axons, and (b) fully-differentiated oligodendrocytes are therefore postmitotic and do not contribute to remyelination in the adult CNS.

Animals↗
PubMed2001

Classification of demyelinating diseases at the interface between etiology and pathogenesis.

The classical demyelinating diseases include the 'autoimmune' inflammatory demyelinating diseases, the inflammatory demyelinating diseases of infectious aetiology, and the demyelinating or dysmyelinating diseases of genetic/hereditary background. In addition, primary demyelination is present in other conditions, such as brain ischaemia and intoxication. Irrespective of the primary aetiology, selective demyelination can be mediated through various pathogenetic pathways: the immune-mediated inflammatory pathway; the metabolic pathway; and the ischaemic/excitotoxic pathway. These pathways are only partly segregated with distinct aetiologies of demyelinating diseases, but they also reflect the way in which the patient copes with the disease-inciting event in relation to their particular genetic background. For future therapeutic strategies it will be important to interfere with the specific pathogenetic pathways of demyelination, which may be common to various demyelinating diseases, but may differ in subgroups of patients who suffer from a particular clinical demyelinating disease entity.

Animals↗
PubMed2001

Viral induced demyelination.

Viral induced demyelination, in both humans and rodent models, has provided unique insights into the cell biology of oligodendroglia, their complex cell-cell interactions and mechanisms of myelin destruction. They illustrate mechanisms of viral persistence, including latent infections in which no infectious virus is readily evident, virus reactivation and viral-induced tissue damage. These studies have also provided excellent paradigms to study the interactions between the immune system and the central nervous system (CNS). Although of interest in their own right, an understanding of the diverse mechanisms used by viruses to induce demyelination may shed light into the etiology and pathogenesis of the common demyelinating disorder multiple sclerosis (MS). This notion is supported by the persistent view that a viral infection acquired during adolescence might initiate MS after a long period of quiescence. Demyelination in both humans and rodents can be initiated by infection with a diverse group of enveloped and non-enveloped RNA and DNA viruses (Table 1). The mechanisms that ultimately result in the loss of CNS myelin appear to be equally diverse as the etiological agents capable of causing diseases which result in demyelination. Although demyelination can be a secondary result of axonal loss, in many examples of viral induced demyelination, myelin loss is primary and associated with axonal sparing. This suggests that demyelination induced by viral infections can result from: 1) a direct viral infection of oligodendroglia resulting in cell death with degeneration of myelin and its subsequent removal; 2) a persistent viral infection, in the presence or absence of infectious virus, resulting in the loss of normal cellular homeostasis and subsequent oligodendroglial death; 3) a vigorous virus-specific inflammatory response wherein the virus replicates in a cell type other than oligodendroglia, but cytokines and other immune mediators directly damage the oligodendroglia or the myelin sheath; or 4) infection initiates activation of an immune response specific for either oligodendroglia or myelin components. Virus-induced inflammation may be associated with the processing of myelin or oligodendroglial components and their presentation to the host's own T cell compartment. Alternatively, antigenic epitopes derived from the viral proteins may exhibit sufficient homology to host components that the immune response to the virus activates autoreactive T cells, i.e. molecular mimicry. Although it is not clear that each of these potential mechanisms participates in the pathogenesis of human demyelinating disease, analysis of the diverse demyelinating viral infections of both humans and rodents provides examples of many of these potential mechanisms.

Animals↗
PubMed1998

CD4(+) and CD8(+) T cells make discrete contributions to demyelination and neurologic disease in a viral model of multiple sclerosis.

Following intracerebral infection with Theiler's murine encephalomyelitis virus (TMEV), susceptible strains of mice (SJL and PLJ) develop virus persistence and demyelination similar to that found in human multiple sclerosis. Resistant strains of mice (C57BL/6) clear virus and do not develop demyelination. To resolve the controversy about the role of CD4(+) and CD8(+) T cells in the development of demyelination and neurologic deficits in diseases of the central nervous system, we analyzed TMEV infection in CD4- and CD8-deficient B6, PLJ, and SJL mice. Genetic deletion of either CD4 or CD8 from resistant B6 mice resulted in viral persistence and demyelination during the chronic stage of disease. Viral persistence and demyelination were detected in all strains of susceptible background. Although genetic deletion of CD8 had no effect on the extent of demyelination in susceptible strains, deletion of CD4 dramatically increased the degree of demyelination observed. Whereas strains with deletions of CD4 showed severe neurologic deficits, mice with deletions of CD8 showed minimal or no deficits despite demyelination. In all strains, deletion of CD4 but not CD8 resulted in a decreased delayed-type hypersensitivity response to viral antigen. We conclude that each T-cell subset makes a discrete and nonredundant contribution to protection from viral persistence and demyelination in resistant strains. In contrast, in susceptible strains, CD8(+) T cells do not provide protection against chronic demyelinating disease. Furthermore, in persistent TMEV infection of the central nervous system, neurologic deficits appear to result either from the absence of a protective class II-restricted immune response or from the presence of a pathogenic class I-restricted response.

Animals↗
PubMed1992

Primary demyelination induced by exposure to tellurium alters Schwann cell gene expression: a model for intracellular targeting of NGF receptor.

Exposure of developing rats to tellurium results in a highly synchronous segmental demyelination of peripheral nerves with sparing of axons; this demyelination is followed closely by a period of rapid remyelination. Demyelination occurs subsequent to a tellurium-induced block in the synthesis of cholesterol, the major myelin lipid. We utilized the techniques of Northern blotting, in situ hybridization, and immunocytochemistry to examine temporal alterations in Schwann cell gene expression related to demyelination and remyelination. Tellurium-induced demyelination is associated with downregulation of myelin protein expression and a corresponding upregulation of NGF receptor (NGF-R) and glial fibrillary acidic protein (GFAP) expression. Steady-state mRNA levels (expressed on a "per nerve" basis) for P0, the major myelin protein, were decreased by about 50% after 5 d of tellurium exposure, while levels of mRNA for NGF-R and GFAP were markedly increased (about 15-fold). In situ hybridization of teased fibers suggested that the increase in steady-state mRNA levels for NGF-R was primarily associated with demyelinated internodes and not with adjacent unaffected internodes. Although P0 message was almost totally absent from demyelinating internodes, it was also reduced in normal-appearing internodes as well. This suggests that limiting the supply of a required membrane component (cholesterol) may lead to partial downregulation of myelin gene expression in all myelinating Schwann cells. In partially demyelinated internodes, NGF-R and GFAP immunofluorescence appeared largely confined to the demyelinated regions. This suggests specific targeting of these proteins to local areas of the Schwann cell where there is myelin loss. These results demonstrate that demyelination is associated with reversion of the affected Schwann cells to a precursor cell phenotype. Because axons remain intact, our results suggest that these changes in Schwann cell gene expression do not require input from a degenerating axon, but instead may depend on whether concerted synthesis of myelin is occurring.

Animals↗
PubMed1972

A computer simulation of conduction in demyelinated nerve fibres.

1. The theoretical effects of demyelination on conduction of a propagated impulse have been examined in a computer simulated myelinated nerve fibre. Demyelination was simulated by increasing the capacitance and conductance of the myelin sheath of individual internodes or parts of internodes.2. Internodal conduction time increased as myelin thickness was decreased. The increase in internodal conduction time became more precipitous as the myelin became thinner. Propagation continued past a single demyelinated internode until myelin thickness was uniformly reduced to less than 2.7% of normal myelin thickness.3. Paranodal demyelination was more effective in slowing impulse conduction than was uniform demyelination of an entire internode with an equivalent rise in overall internodal capacitance and conductance.4. The effects on conduction of demyelination of two adjacent internodes or of two internodes separated by a normal internode were more than the sum of the effects of demyelination of each internode individually.5. Propagation across a severely demyelinated internode was blocked with an increase in internal sodium concentration which had a trivial effect on conduction in a normal fibre.6. Propagation across a severely demyelinated internode was blocked with increased temperature at a temperature at which propagation proceeds normally across normal internodes.7. The similarity between the findings of the computer simulations and the experimental findings in demyelinated fibres is discussed.

Action Potentials↗
PubMed2000

Areas of demyelination do not attract significant numbers of schwann cells transplanted into normal white matter.

If Schwann cell transplantation is to be used as a therapy for demyelinating disease, it is important to know if the number of transplanted cells and their transplantation site affects the extent of remyelination. Primary Schwann cell cultures were obtained from neonatal rat sciatic nerve, purified, and expanded using bovine pituitary extract and forskolin. Areas of persistent demyelination were created in the dorsal funiculus of the thoracolumbar spinal cord of rats by injecting ethidium bromide into white matter exposed to 40 Gy of X-irradiation, and a high and low number of Schwann cells were transplanted, into either the area of demyelination or the dorsal funiculus cranial to the area of demyelination. Animals were perfused 4 weeks after transplantation. After injection of 4 x 10(4) cells into the area of demyelination, the area of Schwann cell remyelination was 0.88 +/- 0.16 mm(2), while following the injection of 3 x 10(3) cells it was significantly smaller, 0.29 +/- 0.09 mm(2). After implantation of Schwann cells 1-3 mm (mean 2.5 mm) cranial to the area of demyelination, only one of the eight animals (a high-dose animal) showed extensive Schwann cell remyelination. In this animal, the cells were transplanted within 1 mm of the area of demyelination, well within the length of tissue over which cells are passively spread by the injection procedure (1-3 mm). Our results show that significant numbers of transplanted Schwann cells are not attracted through normal tissue to areas of demyelination and when transplanted into areas of demyelination the extent of myelination is related to the number of Schwann cells transplanted.

Animals↗
PubMed1984

DA strain of Theiler's murine encephalomyelitis virus induces demyelination in nude mice.

DA strain of Theiler's murine encephalomyelitis virus produces a chronic, progressive demyelinating disease in mice that resembles multiple sclerosis. An immunopathological mechanism for demyelination has been postulated, because there is a brisk immune response with low virus titers at the time of demyelination and because immunosuppression lessens the degree of demyelination. We inoculated Nude mice with DA virus to clarify the role of immune-mediated demyelination. Animals became paralyzed 3 weeks to 2 months after inoculation, usually dying within a week of appearance of signs. Demyelinated foci were present in the spinal cords, with evidence of degenerating myelin around intact axons as well as completely demyelinated, naked axons. Occasional macrophages were present, but none was seen actively stripping intact myelin lamellae. These results suggest that DA virus lytic infection, without a contribution from the T lymphocyte immune system, is sufficient to produce demyelination. It is likely that DA virus demyelination has varying mechanisms that may be active at different times.

Animals↗
PubMed1991

In vitro demyelination by serum antibody from patients with Guillain-Barré syndrome requires terminal complement complexes.

Serum from 7 patients who had acute-phase Guillain-Barré syndrome with high anti-peripheral nerve myelin antibody activity (54 to 210 units/ml) was compared with serum from 3 patients in the recovery phase (0 to 17 units/ml) and serum from 7 disease control subjects (0 to 24 units/ml) and 7 normal control subjects (0 to 7 units/ml) for its ability to demyelinate rodent dorsal root ganglion cultures. The demyelinating capacity of each serum was quantitated by counting the percent of damaged internodal segments in each of four cultures. All sera from patients in the acute phase GBS caused 50 to 78% demyelination, in contrast with 6 to 19% by the sera from all 3 patients in the recovery phase and all other control subjects. The degree of demyelination correlated with anti-peripheral nerve myelin antibody activity of the sera and demyelination was complement-dependent. Further, cultures were treated with an immunoglobulin M (IgM) fraction of an acute-phase Guillain-Barré syndrome plasma plus normal human serum depleted of complement component C7. Only those cultures treated with IgM and C7-depleted human serum reconstituted with purified C7 resulted in 50.8% demyelination, which was significantly greater than the 14.2 to 16.2% demyelination observed in the presence of heat-inactivated, C7-depleted human serum plus purified C7 or in the absence of C7 or antibody. In summary, our work suggests that anti-peripheral nerve myelin antibody in Guillain-Barré syndrome mediated complement dependent-demyelination of rodent dorsal root ganglion cultures. Further, this in vitro demyelination required generation of activation complexes of the terminal complement cascade.

Acute Disease↗