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PubMed1991

Class II-restricted T cell responses in Theiler's murine encephalomyelitis virus-induced demyelinating disease. IV. Identification of an immunodominant T cell determinant on the N-terminal end of the VP2 capsid protein in susceptible SJL/J mice.

Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease serves as a relevant animal model of human multiple sclerosis. Myelin damage induced by TMEV infection appears to be immune mediated. Disease susceptibility correlates best with the temporal development of chronic, high levels of TMEV-specific, MHC class II-restricted delayed-type hypersensitivity (DTH) responses. We have proposed a model wherein these responses result in CNS demyelination via a macrophage-mediated terminal nonspecific bystander response. As virus-specific DTH responses appear to be intimately involved in the pathogenicity of CNS demyelination, it is critical to determine the specificity of these responses so that effector T cells specific for potential pathogenic epitopes can be targeted to serve as the focus of specific immunoregulatory processes. In the current study, the capsid protein specificity of the TMEV-susceptible SJL/J and TMEV-resistant C57BL/6 mouse strains was examined. DTH and Tprlf responses in both infected and immunized SJL/J mice were found to be predominantly directed toward the VP2 capsid protein, specifically to an epitope(s) contained within the N-terminal 150 amino acids of VP2. This same epitope was also found to be dominant in priming SJL/J mice for responses to challenge with intact virions. In contrast, the T cell-mediated responses of TMEV-resistant C57BL/6 mice did not show preferential reactivity towards VP2, because all three major capsid proteins (VP1, VP2, and VP3) elicited responses with essentially equal potency. The relationship of the restricted VP2 T cell epitope to predicted neutralizing antibody sites on the VP2 protein is discussed as is the potential use of this epitope for prevention and/or treatment of TMEV-induced demyelinating disease via the induction of epitope-specific tolerance.

Animals↗

PubMed1991

[Nerve conduction abnormalities in chronic inflammatory demyelinating polyneuropathy (CIDP)].

Changes in compound muscle action potentials (CMAPs) were evaluated in 13 cases with CIDP by using inching-stimulation technique. The presence of electrophysiological multifocal lesion distinguished CIDP from hereditary demyelinating neuropathy (HDN). The size of each CIDP lesion was sometimes as small as a few millimeters, showing a decrease in CMAP amplitude proximally. No HDN cases revealed such focal changes. It is thus important to demonstrate small lesions with CMAP changes of demyelination-type in diagnosis of CIDP. Decrease in amplitude of proximally-evoked CMAP is essential but sometimes inadequate to determine partial conduction block, because HDN may show decrease in CMAP amplitude, up to 45%, by elbow stimulation as compare to one by wrist stimulation in our series. In determining partial conduction block a standard two-point stimulation can cause an error, because that threshold is quite high over a demyelinated segment, and that a cross stimulation may occur when high voltage stimulation is applied. Multiple-sites stimulation is the most reliable technique to demonstrate convincing changes in CMAPs over small demyelinating lesions. Revival of blocked motor fibers introduces new units to CMAP. In most cases some increase in CMAP amplitude occur first, because remyelinated fibers are slowly-conducting. Some units with shorter latency occasionally revived first, which suggests a possibility of conduction block without morphological background.

Action Potentials↗

PubMed1990

Immunologic mechanisms in chronic demyelinating diseases of the central and peripheral nervous system.

MS and CIP are inflammatory diseases of the CNS and PNS that are characterized by focal demyelination. Both disorders are thought to involve autoimmune processes. The factors that lead to a chronic inflammatory process have not been completely defined, but the immune system is thought to play a prominent role as has been discussed in this chapter. The role of a persistent or recurrent viral exposure has not been reviewed here but may well be a contributing factor. Since chronic relapsing experimental encephalomyelitis in animal models is a T-cell-mediated disease that pathologically resembles MS, T cells are postulated to be of primary importance in human demyelinating diseases. Oligoclonal T-cell populations can be found in the CSF of MS patients, even though their antigenic specificity is not known. HLA associations (HLA Dw2 and HLA DR2 in MS and HLA Dw3 in chronic inflammatory neuropathy) might relate to the proposed immunopathogenesis, as class II antigens encoded by these loci might serve as restriction elements for T-cell recognition of an autoantigen by encephalitogenic cell populations. Humoral factors are thought to play an important role in the pathogenesis of CIP, as plasma exchange has been shown to be beneficial. Experimental work with an antimyelin glycoprotein monoclonal antibody demonstrates the in vivo demyelinating activity of antibodies as well as the importance of cellular elements in the demyelinating process. Finally, a number of immunoregulatory abnormalities have been demonstrated in MS patients that point to defects in immunoregulation, in particular in the generation of suppression. Decreases in AMLR in active MS might be of importance, as the AMLR is a reaction against self MHC determinants during which suppression is generated. Defects in suppression might allow self-reactive cells to escape regulation and cause inflammatory lesions in the nervous system.

Autoantibodies↗

PubMed1989

Characterization of the inflammatory response in the central nervous system of mice susceptible or resistant to demyelination by Theiler's virus.

Intracerebral inoculation of mice with Theiler's murine encephalomyelitis virus results in an intense inflammatory response of mononuclear leukocytes which infiltrate into the central nervous system. Resistant strains of mice have the ability to clear virus whereas susceptible strains become infected persistently and are associated with chronic demyelination which is proposed to be immune-mediated. In an attempt to better understand the role of the immune response during demyelination, mononuclear leukocytes were isolated from the central nervous system of infected mice and stained by an immunoperoxidase technique with anti-Thy-1.2, anti-L3T4, anti-Lyt-2 and anti-MAC-1 mAb. Infection of susceptible SJL/J mice resulted in a biphasic immune response which peaked on days 7 and 27 post-infection. In contrast, a single peak (day 7) was observed in resistant C57BL/10SNJ mice. The presence of Thy-1.2, L3T4, and MAC-1+ cells was similar between the two strains. However, although the number of Lyt-2+ cells peaked on day 7 in C57BL/10SNJ mice, they were not detected in SJL/J mice until 14 days post-infection and gradually increased in number over the course of infection. To further study the role of T cells in demyelination, serial frozen sections of brain and spinal cord were stained for the presence of Lyt-2 and L3T4+ cells in the lesions of chronically infected SJL/J mice. L3T4+ cells were observed predominantly in perivascular regions while Lyt-2+ cells were observed infiltrating the parenchyma. These results provide further evidence that Lyt-2+ lymphocytes are important in the mechanism of susceptibility/resistance to Theiler's murine encephalomyelitis virus-induced demyelination.

Animals↗

PubMed1989

Role of natural killer cells as immune effectors in encephalitis and demyelination induced by Theiler's virus.

Infection of susceptible mice (SJL) with Theiler's murine encephalitis virus (TMEV) causes a biphasic disease characterized by gray matter inflammation followed by late chronic demyelination. The role of NK cells was studied in this model by using susceptible (SJL) or resistant (C57BL/10) mice. CNS TMEV titer were higher in SJL compared with C57BL/10 mice, correlating with a 50% lower NK cell activity in the SJL than in the C57BL/10 mice. When resistant (C57BL/10) mice were depleted of NK cells using either mAb NK1.1 or polyclonal anti-asialo-GM1, TMEV induced the development of diffuse encephalitis and meningitis early in the postinfection period (days 6 to 11). However, the second phase of TMEV-induced CNS disease (demyelination) was observed only in resistant C57BL/10 mice treated with anti-asialo-GM1. Experiments with beige/beige mice of C57BL/10 background showed a mild degree of gray matter inflammation but no demyelination. In conclusion, NK cells are critical effectors in protecting against TMEV-induced gray matter disease, whereas a different population of either NK1.1- NK cells, or other activated lymphocytes may be critical in resistance/susceptibility to demyelination.

Animals↗

PubMed1987

Theiler's murine encephalomyelitis: a model of demyelination and persistence of virus.

Theiler's murine encephalomyelitis virus (TMEV) causes immune-mediated demyelination in susceptible mice which is similar to human demyelinating disorders such as multiple sclerosis. In addition, the picornavirus persists within the central nervous system throughout the course of the chronic demyelinating disease. This article reviews the neuropathology, virology, immunology, and molecular biology of the model system. We analyze the possible mechanisms by which this virus induces demyelination and persists in the nervous system. Finally, we provide a hypothesis that the specificity of primary white matter destruction in the TMEV model depends on immune-sensitized cells which interact with viral antigen plus major histocompatibility complex (MHC) antigens on the surfaces of oligodendrocytes or myelin sheaths.

Acute Disease↗

PubMed1987

Semliki Forest virus induced, immune mediated demyelination: the effect of irradiation.

Intraperitoneal infection with the avirulent A7(74) strain of the alphavirus Semliki Forest virus (SFV) induces an immune mediated demyelinating encephalomyelitis. The blood and brain virus titres, the serum antibody titres and the histopathological changes in the brains of normal mice and mice immunosuppressed with 5.0 or 8.0 Gy total body irradiation (TBX) were determined. SFV infection of immunosuppressed mice resulted in persistently high blood and brain virus titres, neuronal pycnosis, paralysis and death. No demyelination or central nervous system (CNS) inflammatory response occurred in these immunosuppressed mice despite high and persistent brain virus titres. The CNS inflammatory response and associated demyelination could be restored to infected immunosuppressed mice by adoptive transfer of spleen cells, and these changes were brought forward if the donor spleen cells were from mice previously sensitized to SFV. The results indicate that the immune response following SFV A7(74) infection is both protective and pathogenic, and that the demyelination is immune mediated and does not result from direct viral destruction of oligodendrocytes, or any other direct effect of the virus.

Animals↗

PubMed1988

Demyelination and axonal degeneration in Lewis rat experimental allergic neuritis depend on the myelin dosage.

We describe the clinical and pathologic features of experimental allergic neuritis in Lewis rats inoculated with varying doses of myelin, ranging from 0.5 to 20 mg. The clinical scores were assessed daily. On days 18 and 19 or 28 postimmunization, the rats were perfused with fixative and samples of cervical and lumbar roots and sciatic nerves were processed and embedded in Epon. Tissues were examined by light and electron microscopy and the degree of edema, inflammation, demyelination, and axonal degeneration was assessed quantitatively. We found that the severity of clinical and pathologic experimental allergic neuritis correlated positively with the dose of myelin used for immunization. High dose tolerance was not observed. Demyelination prevailed in nerve roots and increased with higher doses of antigen. Accompanying axonal degeneration was seen only with high doses of myelin. The pathology of sciatic nerves differed. Sciatic nerves of rats immunized with 0.5 and 1 mg of myelin were either normal or showed perivenular lymphocytic infiltrates and demyelination, but nerves from rats with higher immunizing doses of myelin showed increasingly severe axonal degeneration. The axonal degeneration in nerve roots paralleled the degree of inflammation and demyelination and may have been a nonspecific product of the inflammatory reaction. However, the much more severe axonal destruction seen in sciatic nerves with high myelin doses was probably due to other pathogenetic mechanisms.

Animals↗

PubMed1988

Immunoglobulins and complement in demyelination induced in mice by Theiler's virus.

Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) produces chronic demyelination and persistent infection in the central nervous system (CNS) of susceptible SJL mice. This series of experiments examined the contribution of humoral immunity and C to myelin destruction. As in multiple sclerosis, mice persistently infected with TMEV had elevated levels of IgG and oligoclonal bands in the cerebrospinal fluid (CSF). Immunoblot studies revealed that even in animals exhibiting profound demyelination, IgG in the serum and CSF was directed primarily at virus antigen rather than at normal myelin components. Inflammatory cells positive for Ig were distributed mainly around blood vessels, but occasionally they infiltrated the spinal cord parenchyma. Rare examples of myelin sheaths positive for IgG were found by immunoelectron microscopy in spinal cord sections from infected mice; the third component of complement (C3) was commonly found in the walls of CNS blood vessels but not on myelin. Neither serum nor CSF IgG from infected mice bound to myelin sheaths or other CNS components in sections of normal syngeneic spinal cord. There were significantly more demyelinating lesions in infected mice depleted of C components with cobra venom factor. These data do not support a humoral autoimmune basis for the CNS demyelination that occurs in association with persistent TMEV infection. However, the humoral immune response directed at TMEV antigens may either limit virus spread or promote virus persistence.

Animals↗

PubMed1987

A monoclonal antibody against a myelin oligodendrocyte glycoprotein induces relapses and demyelination in central nervous system autoimmune disease.

The factors contributing to chronic relapsing inflammatory disease processes of the central nervous system (CNS) and demyelination are poorly understood. In addition to cellular immune reactions, humoral factors such as antibodies might quantitatively or qualitatively influence the disease process. We therefore investigated the effects of administration of a monoclonal antibody specific for a CNS autoantigen on both acute and chronic experimental autoimmune encephalomyelitis (EAE) in mice and rats. This monoclonal antibody, 8-18C5, specific for a myelin/oligodendrocyte glycoprotein, was observed to accelerate clinical and pathologic changes of CNS autoimmune disease. In SJL mice with chronic relapsing EAE, injection of antibody into animals recovering from an attack induced fatal relapses; in Lewis rats, acute EAE was enhanced and associated with a hyperacute inflammatory response with demyelination, a feature not commonly seen in acute EAE. The demonstration that relapses and demyelination can be induced by administration of a white matter-reactive monoclonal antibody offers new possibilities to study processes resulting in CNS damage during autoimmune disease. Furthermore, these findings support the immunopathogenic potential of antibody to myelin components in inflammatory CNS disease processes and, specifically, in causing demyelination.

Animals↗

PubMed1986

Mechanism of Theiler's virus-induced demyelination in nude mice.

In its natural murine host, infection with Theiler's murine encephalomyelitis virus (TMEV) produces a chronic, progressive demyelinating disease. To help elucidate the role of host immune mechanisms involved in demyelination, we studied TMEV infection in Nude mice. These animals demonstrated rising titers of infectious virus within the central nervous system and failed to produce anti-TMEV antibody. Neurologic signs including the development of severe hind limb paralysis were evident approximately 2 weeks postinfection with most animals succumbing within the first month. Immunoperoxidase studies demonstrated viral antigen in the cytoplasm of neurons and glial cells for the entire period of observation. Plaques of demyelination associated with scanty inflammatory infiltrates were present in the spinal cord by 14 days postinfection. Electron microscopic studies of the involved white matter revealed numerous degenerating glial cells, many of which contained paracrystalline arrays of picornavirus within their cytoplasm. Some of the infected glial cells were identified as oligodendrocytes by demonstrating their myelin-plasma membrane connections. The studies indicate that in Nude mice TMEV causes a lytic infection of oligodendrocytes producing demyelination independent of the T lymphocyte immune system.

Animals↗

PubMed1987

Remyelination in demyelinating diseases of the central nervous system.

It is well accepted that a thorough understanding of pathogenetic mechanisms involved in demyelination and remyelination of the central nervous system (CNS) is fundamental to a better understanding of the etiology and pathogenesis of clinical demyelinating disease. In this review, experimental and clinical models of demyelination are discussed in an attempt to elucidate the mechanism by which they cause breakdown of the myelin sheath and/or damage to the oligodendrocyte. An attempt is made to determine whether mechanisms operating during experimental diseases may be applicable to the human situation. In a similar fashion, the occurrence of remyelination within the CNS in experimental animals and its relationship to the potential for remyelination following not only demyelinating disease but also remyelination following trauma and other destructive lesions are explored. The evidence for meaningful remyelination in the clinical situation is assessed, and the importance of such theoretical factors as the ability of oligodendrocytes to proliferate and migrate is evaluated.

Animals↗

PubMed1985

Effect of macrophage inactivation on the neuropathology of lysolecithin-induced demyelination.

The effect of macrophage inactivation on lysolecithin-induced demyelination was studied. Adult rats were pretreated with a single intraperitoneal dose of 200 mg silica quartz dust, which selectively blocks the activity of circulating monocytes. Surgery was performed the following day and 2 microliters of 1% lysolecithin were injected intraspinally. The animals were perfused with aldehydes at 8 to 60 days postoperatively. Tissues were examined by optical and electron microscopy. The injection of lysolecithin produced a localized demyelinating lesion. Myelin debris in controls was phagocytosed by invading macrophages. Axons within the lesion appeared denuded. At later stages remyelination occurred. When animals were pretreated with silica, the macrophage response was remarkably reduced. The clearance of collapsed myelin was delayed. Accumulation of fluid within the sheaths resulted in tissue oedema and persistent spongiform changes. At 28 and 60 days postoperatively, increased fibrillary astrogliosis was observed but did not appear to interfere with remyelination. The findings of this study suggest that (a) active participation of macrophages is essential for the attainment of demyelination in the lysolecithin model and (b) treatment with silica prevents complete demyelination but has no apparent effect on remyelination.

Animals↗

PubMed1979

Demyelination and remyelination in the rat central nervous system following ethidium bromide injection.

Intracisternal injection of ethidium bromide induced status spongiosus with prominent degenerative changes in oligodendroglia in the subpial regions of the central nervous system of the rat. Chronologic investigation of the lesions has revealed that status spongiosus resulted in myelin degeneration, and by the 6th day postinjection many axons were demyelinated. At this time, numerous debris-filled phagocytic cells were observed among the totally naked axons. Vesicular transformation of myelin was the common degenerative change. Features suggestive of separation of myelin lamellae by phagocytic cells were also observed. In the demyelinated areas, oligodendroglial cells disappeared completely. By the 12th day postinjection, remyelination was apparent and numerous active oligodendroglia appeared in association with thinly myelinated axons. Some central nervous system axons were myelinated by Schwann cells. These patterns of demyelination and remyelination observed in ethidium bromide-treated rats were compared with those observed in other demyelinating conditions of varied etiology such as experimental allergic encephalomyelitis, diphtheria toxin, or lysolecithin injection and cuprizone intoxication.

Animals↗

PubMed1984

Acute and subacute demyelination induced by mouse hepatitis virus strain A59 in C3H mice.

Mouse hepatitis virus (MHV, strain A-59), a coronavirus, induced acute and subacute demyelinating disease in the central nervous system of weanling C3H mice that were reported to be genetically resistant to MHV. Subtle clinical signs developed in greater than 90% of animals 5-7 days after intracerebral inoculation of 25 PFU, and foci of demyelination were detected from 1 to 4 weeks postinoculation (p.i.) by histopathology and immunolabeling with antibody directed against myelin basic protein. Infectious virus could be isolated only during the first 10 days p.i., but viral antigens persisted in the cytoplasm of oligodendrocytes in the demyelinating lesions for up to 4 weeks p.i. Serum antibody titers against MHV-A59 rose by 2 weeks p.i. and persisted at high levels for months. This infection of genetically "resistant" animals by a normally hepatotropic strain of MHV can serve as a highly reproducible model for the study of acute and subacute demyelination by a coronavirus.

Animals↗

PubMed1977

A new model of persistent viral infection with primary demyelination.

Theiler's encephalomyelitis virus (TMEV) in mice represents one of the few existing animal models of virus-induced demyelination and may provide further information about the human disease, Multiple Sclerosis. An inbred strain of mice (SJL/j) employed in the present ultrastructural study, develops a life-long neurologic illness characterized by profound spasticity after intracerebral inoculation of TMEV. Anesthetized animals were sacrificed sequentially by total body perfusion with gluteraldehyde from 7 days to 9 months after infection. An intense mononuclear inflammatory infiltrate appeared in the leptomeninges and white matter of spinal cord by 15 days and persisted for as long as one year. These infiltrates contained numerous plasma cells, and perivascular demyelination could be found in almost every 1 micron section. Vesiculation and stripping of myelin by mononuclear cell processes were seen as mechanisms of myelin break-down. However, virions were not found in cells in grey or white matter and the integrity of oligodendrocytes was maintained. At one year, active demyelination was still seen in areas containing naked and remyelinated axons. The relevance of these ultrastructural findings to postulated mechanisms of virus-induced demyelination will be discussed.

Animals↗

PubMed1981

Serum-induced demyelination: an electrophysiological and histological study.

Serum from rabbits with EAN in the acute phase of the disease has been injected into rat sciatic nerve, and compared to control rabbit serum and serum from patients with demyelinating neuropathy and to normal human control serum. Electrophysiological studies were performed on all rat sciatic nerves so injected, and the nerve was then removed and examined histologically. Control rabbit and human serum and neuropathic human serum, when injected in a 20 microL quantity through a 30 gauge needle, did not produce significant electrophysiological abnormalities. EAN serum, however, produced significant dispersion of the muscle action potential and conduction block. All serum produced some histological evidence of demyelination but that seen with EAN serum was quite profound compared to all other sera. It is concluded that humoral factors are present within animals with EAN which has potent demyelinating potential. We were not able to demonstrate the same effect from patients with demyelinating neuropathy in this test system.

Animals↗

PubMed1982

Immune-mediated demyelination--immunopathological basis for electrophysiological changes.

A focal immune-mediated demyelinating lesion of peripheral nerve was produced by intraneural injection of antiserum to galactocerebroside, a major glycosphingolipid hapten common in CNS and PNS myelin. This model provides an excellent system for correlative studies of physiological and pathological alterations in the processes of demyelination, because the time course of such changes is predictable from animal to animal. Twenty minutes after antiserum injection, Schwann cells showed focal cytoplasmic outpouching and their external mesaxons opened. Between 1 and 8 h after injection "melting," splitting, vesiculation and vacuolation of myelin became increasingly prominent at paranodal regions and Schmidt-Lantermann clefts, with concomitant degenerative changes in Schwann cell cytoplasm. Disruption of myelin in the paranodal region with detachment of the outermost paranodal myelin loops from paranodal axon resulted in an increase in nodal surface area. This seems to be the most critical anatomical alteration responsible for the early changes in propagation of nerve impulses in this antibody-mediated demyelinating lesion. Between 8 h and 3 days axons became demyelinated progressively over several internodes by macrophage phagocytosis. The onset of clinical and saltatory conduction recovery from the lesion corresponded to the appearance of 2-8 myelin lamellae around each remyelinating axon.

Animals↗