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PubMed1983

Ross River virus--induced demyelination: II. Ultrastructural studies.

Focal central nervous system demyelination is a prominent feature of Ross River virus encephalitis in mice. The present ultrastructural study shows that oligodendrocytes are a primary site of viral replication. The earliest myelin disruption occurs in association with an inflammatory infiltrate composed primarily of polymorphonuclear leukocytes, which are later replaced by macrophages. Viral particles are found in oligodendrocytes, selected neuronal populations, macrophages, and polymorphonuclear leukocytes through the end of the first week of infection as macrophages remove myelin from normal-appearing axons. Between the second and third weeks of infection, axons within foci of demyelination partially remyelinate with central myelin. Schwann cells are not found within regions of central remyelination. Cyclophosphamide treatment does not prevent or delay demyelination or remyelination. Results of this and previous studies strongly suggest that Ross River virus--induced demyelination is not immune mediated but rather the direct result of viral infection of oligodendrocytes.

Animals↗
PubMed1986

Remyelination follows antibody-induced central nervous system demyelination.

Remyelination after anti-galactocerebroside-induced demyelination in the guinea pig optic nerve was evident 17 days after the onset of demyelination. The tempo of remyelination was uniform for large- and small-diameter axons and progressed, with compaction and thickening of myelin sheaths. Demyelinated axons were found interspersed among remyelinated fibers and were consistently separated from oligodendrocytes by astrocytic processes. These findings indicate that central nervous system remyelination may occur after in vivo antibody-induced demyelination, but that new myelin formation may be limited by mechanical interference from astrocytic processes.

Animals↗
PubMed1987

Multifocal CNS demyelination following peripheral inoculation with herpes simplex virus type 1.

The peripheral inoculation of herpes simplex virus type 1 (HSV 1) in experimental animals induces central nervous system (CNS) demyelinating lesions, but the potential relevance of this model to multiple sclerosis is lessened by the unifocal nature of the lesion. In this study, inbred strains of mice were selected on the basis of varying resistance to mortality following lip inoculation with virus. A spectrum of CNS pathology was observed, ranging from focal collections of inflammatory cells at the trigeminal root entry zone in resistant strains (C57BL/6J), to unifocal demyelinating lesions in moderately resistant strains (BALB/cByJ), to multifocal demyelinating lesions throughout the brain in susceptible strains (A/J). Findings from viral titration studies of the CNS support a direct cytolytic effect of virus in the development of demyelinating lesions at the trigeminal root entry zone but cannot exclude an immune-mediated component. Furthermore, 50% tissue-culture-infective doses, immunofluorescence, and electron microscopic studies of primary cultures of oligodendrocytes, derived from the three strains of adult mice, identify differences in resistance to HSV 1 infection in vitro, suggesting that differences at this level may also contribute to the pathological appearance. Multifocal lesions in A/J mice were first observed when the infectious virus could no longer be isolated from the CNS and may be the result of an immune-mediated process "triggered" by the acute CNS infection in susceptible strains of mice.

Animals↗
PubMed1987

Search for antibodies to galactocerebroside in the serum and cerebrospinal fluid in human demyelinating disorders.

To determine if galactocerebroside (GalC) is a target antigen in the human demyelinating disorders multiple sclerosis, Guillain-Barré syndrome, and chronic demyelinating inflammatory polyneuropathy, we examined the serum and cerebrospinal fluid from patients with these disorders and from control subjects using four assay systems. In none of these assays could we detect significant differences in anti-GalC antibody titer between patients with demyelinating diseases and normal subjects or patients with other neurological disorders. Our data suggest that there is no humoral immune response to GalC in human demyelinating disorders.

Antibodies↗
PubMed1990

Macrophage responses in inflammatory demyelinating neuropathies.

Macrophages are prominent participants in inflammatory demyelinating neuropathies. To provide a different means of evaluating macrophage behavior, we used immunostaining of teased nerve fibers and endoneurial blood vessels. We assessed the frequency with which macrophages were seen in inflammatory demyelinating neuropathies, their relationship to normal and demyelinating fibers, and their expression of major histocompatibility Class II markers (Ia antigen). In 6 patients with chronic inflammatory neuropathy and 1 with Guillain-Barré syndrome, we found regularly that macrophages were adherent to teased blood vessels. Cells presumed to be entering the nerve were elongated, often with a polarized appearance suggesting motility, and were Ia-positive. After entry into nerve, the Ia-positive macrophages were adherent to both normal and demyelinating fibers. They often retained their Ia positivity after penetrating into the nerve fiber and removing myelin. Foamy macrophages, judged to be postphagocytic, were Ia-negative. The foamy macrophages found adhering to blood vessels were presumed to be leaving the nerve. This pattern of entry as Ia-positive prephagocytic cells and evolution to Ia-negative foamy macrophages was compared with other experimental and human neuropathies.

Demyelinating Diseases↗
PubMed1991

Early loss of astrocytes in herpes simplex virus-induced central nervous system demyelination.

Immunohistochemistry was used to study herpes simplex virus type 1-induced central nervous system demyelination in the trigeminal root entry zone of mice inoculated with herpes simplex virus type 1 by the corneal route. There was no change in peripheral nervous system myelin as shown by immunostaining for P0 glycoprotein. Double immunoperoxidase staining for herpes simplex virus type 1 antigens and glial fibrillary acidic protein showed that most of the infected cells were astrocytes. Glial fibrillary acidic protein immunostaining was completely lost in the inferior medial portion of the trigeminal root entry zone at 6 days after herpes simplex virus type 1 inoculation, a time when central nervous system myelin was preserved as indicated by immunostaining for myelin basic protein. The pattern of glial fibrillary acidic protein staining did not change and herpes simplex virus type 1 antigens were no longer detected after day 8. There was a progressive loss of myelin basic protein staining within the area unstained by glial fibrillary acidic protein antisera on days 8 to 14. This pattern of astrocyte loss before central nervous system demyelination is strikingly different from the reactive astrocytosis seen in other demyelinating lesions, such as acute experimental allergic encephalomyelitis, progressive multifocal leukoencephalopathy, or acute multiple sclerosis. Herpes simplex virus type 1 infection in mice provides an unusual model of acute central nervous system demyelination preceded by a loss of astrocytes.

Animals↗
PubMed1994

The virology of demyelinating diseases.

Infectious agents have been postulated as causes of multiple sclerosis for over a century. The possible role of a virus or viruses is supported by data that (1) a childhood exposure is involved and "viral" infections may precipitate exacerbations of disease, (2) experimental infections in animals and natural infections in humans can cause diseases with long incubation periods, remitting and relapsing courses, and demyelination, and (3) patients with multiple sclerosis have abnormal immune responses to viruses. The pathogenesis of three human demyelinating diseases of known viral etiology is discussed. In progressive multifocal leukoencephalopathy, a papovavirus selectively infects oligodendrocytes and causes focal areas of demyelination. In postmeasles encephalomyelitis, the virus is lymphotrophic and disrupts immune regulation that can result in an autoimmune perivenular demyelinating illness without evidence of infection of the central nervous system. In human immunodeficiency virus-encephalopathy and myelopathy virus is present in macrophages and microglia and the myelin abnormalities apparently are caused by soluble factors such as viral proteins, cytokines, or neurotoxins. These findings may have implications on how, when, and where to seek viruses in multiple sclerosis.

Animals↗
PubMed1995

Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy: immune mechanisms and update on current therapies.

The relation between Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy is discussed. Most likely they represent parts of a continuum, arbitrarily separated by their time course. Within the concept of chronic inflammatory demyelinating polyneuropathy the presence of a monoclonal gammopathy of undetermined significance is discussed. The pathogenesis of inflammatory demyelinating polyneuropathies has not been elucidated yet, but involvement of the immune system has been firmly established. Preceding infections, especially with Campylobacter jejuni, and the analysis of antiganglioside antibodies lend new support to the hypothesis of molecular mimicry between epitopes on infectious agents and peripheral nerve constituents as one of the mechanisms in Guillain-Barré syndrome. In the future, a further classification of individual patients based on clinical, epidemiological, electrophysiological, pathological, microbiological, and immunological criteria may give a basis for more individualized treatment strategies. In Guillain-Barré syndrome the efficacy of high-dose intravenous immune globulin treatment was established after earlier positive findings with plasma exchange; immune globulins are easier to administer and may be superior. Even with these treatments it should be anticipated that one fourth of patients after immune globulin treatment and one third of patients after plasma exchange will show further deterioration in the first 2 weeks after onset of treatment. Despite this, just one treatment course usually is indicated in the individual patient, and no valid arguments were found to switch to the other treatment modality. In chronic inflammatory demyelinating polyneuropathy, prednisone, plasma exchange, and immune globulins are effective in a proportion of patients. The last two are equally effective. Patients may respond to one of these if a previous treatment failed, and here switching therapy may be effective due to the chronic course of the disease. Complexity and costs make plasma exchange the last choice. Whether prednisone or immune globulin is the first choice depends on the speed of recovery and the estimation of long-term loss of quality of life due to side effects of prednisone versus the costs of immune globulins. The mechanism of immune globulins in inflammatory polyneuropathies is discussed. There is evidence that idiotypic-antiidiotypic interaction may play a role, but several other mechanisms also may be involved.

Adult↗
PubMed2004

Acute demyelination disrupts the molecular organization of peripheral nervous system nodes.

Intraneurally injected lysolecithin causes both segmental and paranodal demyelination. In demyelinated internodes, axonal components of nodes fragment and disappear, glial and axonal paranodal and juxtaparanodal proteins no longer cluster, and axonal Kv1.1/Kv1.2 K+ channels move from the juxtaparanodal region to appose the remaining heminodes. In paranodal demyelination, a gap separates two distinct heminodes, each of which contains the molecular components of normal nodes; paranodal and juxtaparanodal proteins are properly localized. As in normal nodes, widened nodal regions contain little or no band 4.1B. Lysolecithin also causes "unwinding" of paranodes: The spiral of Schwann cell membrane moves away from the paranodes, but the glial and axonal components of septate-like junctions remain colocalized. Thus, acute demyelination has distinct effects on the molecular organization of the nodal, paranodal, and juxtaparanodal region, reflecting altered axon-Schwann cell interactions.

Acute Disease↗
PubMed1997

Increased severity of experimental autoimmune encephalomyelitis, chronic macrophage/microglial reactivity, and demyelination in transgenic mice producing tumor necrosis factor-alpha in the central nervous system.

Tumor necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine implicated in a number of autoimmune diseases. Apoptotic cell death is induced by TNF-alpha in vitro, and has been suggested as one cause of autoimmune pathology, including autoimmune demyelinating diseases where oligodendrocytes are a target of immune attack. TNF-alpha also regulates macrophage activity which could contribute to autoimmune inflammation. We have expressed TNF-alpha at disease-equivalent levels in the central nervous system of transgenic mice, using a myelin basic protein (MBP) promoter. These mice were normal and showed no spontaneous pathology, but they developed experimental autoimmune encephalomyelitis (EAE) with greater severity than nontransgenic controls when immunized with MBP in adjuvant. Unlike nontransgenic controls, EAE then progressed to a nonabating demyelinating disease. Macrophage/microglial reactivity was evident in demyelinating lesions in spinal cord, but T cells were not detected during chronic disease. The participation of TNF-alpha in the demyelinating process is thus more probably due to the perpetuation of macrophage/microglial activation than to direct cytotoxicity of myelin or oligodendroglia.

Animals↗
PubMed2002

Human antibodies accelerate the rate of remyelination following lysolecithin-induced demyelination in mice.

Immunoglobulin-based therapies are becoming increasingly common for the treatment of neurologic and autoimmune diseases in humans. In this study, we demonstrate that systemic administration of either polyclonal human immunoglobulins or specific human monoclonal antibodies can accelerate the rate of CNS remyelination following toxin-induced demyelination. Injection of lysolecithin directly into the spinal cord results in focal demyelinated lesions. In contrast to other murine models of demyelinating disease, the mechanism of demyelination following lysolecithin injection is independent of immune system activation, and chronic inflammation at the site of the lesion is minimal. Administration of polyclonal human IgM (pHIgM) or a serum-derived human monoclonal antibody (sHIgM22) resulted in approximately a twofold increase in remyelinating axons when compared to animals treated with saline or with antibodies that do not promote repair. Both pHIgM and sHIgM22 show strong binding to CNS white matter and oligodendrocytes, while antibodies that did not accelerate remyelination do not. This differential staining pattern suggests that enhanced remyelination may result from direct stimulation of oligodendrocyte remyelination by binding to surface receptors on oligodendrocytes or glial progenitor cells. We propose the use of human polyclonal IgM or specific human monoclonal IgM antibodies as potential therapies to enhance myelin repair following CNS injury and disease.

Animals↗
PubMed2004

CD44 overexpression by oligodendrocytes: a novel mouse model of inflammation-independent demyelination and dysmyelination.

The CD44 transmembrane glycoprotein family has been implicated in cell-cell adhesion and cell signaling in response to components of the extracellular matrix but its role in the nervous system is not understood. CD44 proteins are elevated in Schwann cells and oligodendrocytes following nervous system insults, in inflammatory demyelinating lesions, and in tumors. Here, we tested the hypothesis that elevated CD44 expression influences Schwann cell and oligodendrocyte functions by generating transgenic mice that express CD44 under the control of the 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) promoter. These mice failed to develop peripheral nerve or CNS tumors. However, they did develop severe tremors that were associated with CNS dysmyelination and progressive demyelination. Loss of CNS myelin was not due to alterations in early oligodendrocyte precursor differentiation, proliferation, or survival. Myelination in the PNS appeared normal. In no instance was there any evidence of an inflammatory response that could account for the loss of CNS myelin. These findings suggest that CNPase-CD44 mice are a novel model for noninflammatory progressive demyelinating disease and support a potential role for CD44 proteins expressed by glial cells in promoting demyelination.

Animals↗
PubMed2001

Plasma exchange for severe attacks of inflammatory demyelinating diseases of the central nervous system.

Plasma exchange has not been widely accepted as a treatment for multiple sclerosis. However, several uncontrolled studies have suggested that patients with severe attacks of MS and other inflammatory demyelinating disease may improve rapidly after plasma exchange treatment. We recently completed a randomized, sham-controlled, crossover clinical trial of plasma exchange in 22 patients with idiopathic inflammatory demyelinating diseases of the central nervous system. Twelve had MS and ten had other inflammatory demyelinating disease syndromes. Forty-two percent of patients experienced moderate or greater recovery over 2 weeks of active treatment administered every other day while only 6% of patients experienced similar improvement while receiving sham treatment. Three patients who failed the sham treatment subsequently improved rapidly after crossover to active treatment; no patient who failed active treatment improved after crossover to sham. This study illustrates the importance of designing randomized clinical trials based on the treatment regimen and patient population studied in the uncontrolled reports that suggested treatment efficacy. Plasma exchange should be considered for patients with idiopathic inflammatory demyelinating disease syndromes when they have failed corticosteroid therapy.

Demyelinating Autoimmune Diseases, CNS↗
PubMed1990

Comparison of demyelination and neural degeneration in spiral and Scarpa's ganglia of C57BL/6 mice.

Spiral and Scarpa's (vestibular) ganglia of female C57BL/6 mice, ranging in age from 1.5 to 32 months, were examined by light and electron microscopy. The spiral ganglia of C57BL/6 mice undergo sweeping neuronal losses. Based on cytological characteristics that repeat themselves in both young and old mice, we divided perikaryal demyelination and degeneration of spiral ganglia into four arbitary stages: 1) incipient demyelination, myelin sheaths begin to loosen and unravel; 2) contact, the partially demyelinated perikarya abut as the extracellular matrix disappear; 3) clumping, clusters of naked perikarya clump together, cytoplasmic processes surround the exterior of the clump; and 4) resorption, the clumps gradually disintegrate, leaving at completion large, fluid-filled spaces and few cellular remnants. In Scarpa's ganglia, a small number of neurons demyelinate and clump, but none degenerate or undergo resorption.

Animals↗
PubMed1995

Spontaneous and induced remyelination in multiple sclerosis and the Theiler's virus model of central nervous system demyelination.

Remyelination in the central nervous system, originally thought to occur rarely, if ever, is now an established phenomena in multiple sclerosis patients. However, the extent of myelin repair is incomplete and limited. Experimental models of central nervous system demyelination provide an opportunity to study the cellular and molecular events involved in remyelination. These models may provide some clue to why remyelination in multiple sclerosis is incomplete as well as suggest potential methods to stimulate central nervous system repair. In this review we examine the morphological aspects of central nervous system remyelination and discuss both spontaneous and induced remyelination in multiple sclerosis and experimental models of central nervous system demyelination. We give special emphasis to the Theiler's virus model of central nervous system demyelination and its usefulness to identify therapeutic agents to promote remyelination. The role of immunoglobulins in promoting remyelination in both the Theiler's model system and in multiple sclerosis is discussed. Finally, we examine the potential physiological role of demyelination and remyelination and its relationship with clinical manifestations of central nervous system disease.

Animals↗
PubMed2002

Growth factor treatment promotes mobilization of young but not aged adult subventricular zone precursors in response to demyelination.

Precursor cells of the adult mouse subventricular zone (SVZ) are mobilized and recruited by a lysolecithin (LPC)-induced demyelination of the corpus callosum. Because age decreases the proliferation of the SVZ neural precursors as well as the potential for myelin repair of the adult central nervous system, we have compared the ability of young and aged adult neural precursors to respond to LPC-induced demyelination. With age, the SVZ cells lost their capacity to proliferate and to be recruited by the lesion. Whereas a single injection of fibroblast growth factor-2 or transforming growth factor-alpha stimulated the proliferation of SVZ and rostral migratory stream precursors in both groups of animals after demyelination, they favored recruitment at the lesion in young mice but not in aged ones. In vitro experiments using neurospheres derived from young and aged animals indicated that both populations have the same migratory performances. Our in vivo data thus suggest that aged neural precursors may loose their intrinsic capacities to respond to demyelination-induced signals. Alternatively, their function may be altered by modification of the aged extracellular environment.

Age Factors↗
PubMed1993

Demyelination in a transgenic mouse: a model for multiple sclerosis.

A transgenic mouse containing 70 copies (ND4) of the transgene encoding DM20, a myelin proteolipid protein, appeared clinically normal up to 3 months of age. By 8-10 months, it showed tremors, unsteady gait, and died shortly thereafter. We concluded that the clinical symptoms correlated with demyelination based on the following criteria: 1) at 10 months of age only 17% of the amount of myelin obtained from normal mice was isolated from the ND4 mice; 2) astrogliosis, a prominent feature of demyelinating disease was minimal at 3 months of age but prominent by 10 months; 3) at the electron microscopic level disrupted myelin was seen at 8 months of age in the ND4 mice and ingested myelin debris was found in astrocytes; 4) lymphocytic infiltration in association with endothelial cells was observed routinely in the ND4 mice; 5) sections through optic nerves showed denuded and thinly myelinated axons in the 8 month old ND4 mice. Although the mechanism by which demyelination takes place is not fully understood, measurements of the amounts of PLP suggest it is down-regulated by the large amount of DM20. Since DM20 is a major proteolipid in the young but a minor one in the adult, the persistence of high levels in the adult results in improperly assembled myelin which is prone to disruption. Therefore demyelination in the ND4 mouse appears to result from the persistence of immature myelin into the adult.

Animals↗
PubMed2002

Dejerine-Sottas disease and hereditary demyelinating polyneuropathy of infancy.

Dejerine-Sottas disease (DSD) was originally described as a hypertrophic polyneuropathy characterized by onset in infancy or early childhood in patients born to unaffected parents. The clinical features included distal sensory changes with ataxia; pes cavus, at times with kyphoscoliosis; motor deficit and atrophy predominating in the distal lower limbs and progressing toward the proximal limbs following a length-dependent pattern; palpable nerve hypertrophy; and Argyll-Robertson pupils. The morphological hallmark was the extensive nerve and root hypertrophy associated with demyelination-remyelination of surviving, originally myelinated axons and profuse Schwann-cell proliferation forming onion bulbs. Wide variations in clinical manifestations of chronic demyelinating polyneuropathies of early onset in children born to unaffected parents have now been reported, with only some of the characteristics required in the original study, and at least seven genes encoding the myelin proteins P0, PMP22, the transcriptional factor EGR2, and others have been implicated. Thus, DSD is now a component of the hereditary demyelinating polyneuropathies of infancy that also include subsets of the recently individualized CMT4 neuropathies. The presumed recessive transmission of patients with DSD should be confirmed by molecular genetic analysis, which is still negative in a significant proportion of patients. The nerve biopsy can be useful in patients in whom genealogical or DNA abnormalities in favor of a genetic disorder are missing, because in a few patients with a progressive or relapsing course the diagnosis of early-onset chronic inflammatory demyelinating polyneuropathy must be considered.

Axons↗