Extensive Remyelination Research Articles

THE ORIGIN OF REMYELINATING OLIGODENDROCYTES IN ANTISERUM-MEDIATED DEMYELINATIVE OPTIC NEUROPATHY

The origin of the remyelinating oligodendrocyte in a focal antigalactocerebroside-induced demyelinating lesion of the cat optic nerve was studied with detailed correlative electron microscopy and immunocytochemistry using a panel of antigenic markers. Within 10 days of the destruction of all endogenous oligodendrocytes and demyelination of all axons in the lesion, a new population of small glial cells appeared coincident with division of the residual astrocytes and developed a process-bearing axon-embracing morphology. The processes of these small glial cells (SGCs) contained intermediate filaments composed not of glial fibrillary acidic protein but of vimentin and over the ensuing 14 days these cells confirmed their oligodendrocyte destiny by differentiating to lose the intermediate filaments, form myelin and acquire the acquire the typical oligodendrocyte antigenic phenotype. It is suggested that the extensive remyelination of this lesion is sponsored by the new population of SGCs which in turn are generated either by dedifferentiated reactive astrocytes or by as yet unidentified precursor cells.

Donor-derived cells in the central nervous system of twitcher mice after bone marrow transplantation.

The twitcher mouse is an animal model of galactosylceramidase deficiency, comparable to Krabbe's disease, a lysosomal storage disease in humans. As in most lysosomal storage diseases, neurological deterioration is a prominent feature of the disease in these mice. Transplantation of enzymatically normal congenic bone marrow was earlier found to result in prolonged survival and increased levels of galactosylceramidase in the visceral organs of twitcher mice. It is now reported that bone marrow transplantation results in increased galactosylceramidase levels in the central nervous system (CNS). Concomitantly, the levels of psychosine, a highly toxic lipid that progressively accumulates in the CNS of untreated twitcher mice, stabilized at much lower levels in the CNS of treated twitcher mice. Histologically, a gradual disappearance of globoid cells, the histological hallmark of Krabbe's disease, and the appearance of foamy macrophages capable of metabolizing the storage product were seen in the CNS. By immunohistochemical labeling it was demonstrated that these foamy macrophages were of donor origin. The infiltration of enzymatically competent, donor-derived macrophages was accompanied by extensive remyelination in the CNS. It is concluded that after bone marrow transplantation, donor-derived macrophages infiltrate the affected brain tissue and are capable of inducing a partial reversal of the enzyme deficiency.

Extensive oligodendrocyte remyelination following injection of cultured central nervous system cells into demyelinating lesions in adult central nervous system.

Following the injection of central nervous system (CNS) cell cultures, prepared from 1-day-old rats and maintained in vitro for 7 days, into irradiated, demyelinating lesions in the spinal cord of adult isologous animals, extensive remyelination of axons by oligodendrocytes was observed. In addition, astrocytes, within the transplanted cell suspension, established normal relationships with oligodendrocytes, axons and other tissue elements, which led to the establishment of large CNS territories throughout the lesions. Outside these CNS domains, Schwann cells, which are present in the transplanted cell suspension, myelinated groups of axons. These observations indicate that the irradiated, ethidium bromide lesion provides an in vivo environment, devoid of the influences of host glia, in which to examine the interactions of transplanted glial cells with demyelinating axons.

Schwann cell remyelination of CNS axons following injection of cultures of CNS cells into areas of persistent demyelination

The injection of suspensions of central nervous system (CNS) cells, prepared by standard methods from 4-day-old rat brain and maintained in vitro for 10 days, into areas of persistent demyelination in rat spinal cord resulted in extensive remyelination of axons by Schwann cells. As control lesions injected with medium showed no remyelination, the most likely explanation of this finding is that ‘CNS cultures’ contain a small population of Schwann cells which are stimulated to proliferate by the demyelinated axons.

Progressive axonopathy: an inherited neuropathy of boxer dogs. 4. Myelin sheath and Schwann cell changes in the nerve roots.

Changes in the myelin sheath have been studied in the nerve roots of dogs with Progressive axonopathy, an autosomal recessive inherited neuropathy. The earliest changes were attenuation of the sheath at the proximal paranode and adjacent internode, probably in response to the axonal swelling which occurs in this area. Myelin bubbles were frequently observed along internodes. As the disease developed, progressively more fibres demonstrated short internodes of irregular length and thin myelin sheaths suggesting extensive remyelination and remodelling of the sheath. Short lengths of axons devoid of myelin, and occasional macrophages were also encountered. Sheaths of both original and newly formed internodes were highly irregular in outline. Occasional intra-axonal projections of adaxonal Schwann cell cytoplasm were observed, but complex interdigitations were unusual. A moderately electron-dense, granular material accumulated within the myelin sheath, becoming more obvious in the advanced disease. This material of unknown origin and composition was located predominantly at the intraperiod line principally between the adaxonal cytoplasm and the inner major dense line, but also at Schmidt-Lanterman incisures and between paranodal loops. Xenografts of the canine nerves into athymic mice failed to demonstrate any of the myelin sheath changes. The temporal and spatial relationship of the myelin sheath and axonal changes and the failure to reproduce the natural lesion in grafts suggest that Schwann cell alterations probably occur in response to the axonal changes.

Infection and involution of mouse thymus by MHV-4.

Mouse hepatitis virus type-4 (strain JHM) has extensively been studied as a causative agent of virus-induced demyelinating disease in mice and rats (1). Infection of mice with MHV-4 may result in fatal encephalomyelitis, with infection of all central nervous system cell types, or it may pathologically be limited to demyelination (2). There typically is little perivascular inflammation with MHV-4 infection in the mouse, although infiltrating macrophages and demyelination are found (3). Furthermore, MHV-4 demyelination is commonly followed by extensive remyelination (4, 5). This pattern is contrasted to experimental allergic encephalomyelitis (EAE) and Theiler’s mouse encephalomyelitis virus (TMEV)-induced demyelination, with perivascular lymphocytic and macrophage cuffing and infiltration but little remyelination (6). The paucity of infiltrating lymphocytes in MHV-4 infection may reflect viral perturbation of lymphocyte function (7).KeywordsDemyelinating DiseaseExperimental Allergic EncephalomyelitisThymic Epithelial CellMouse Hepatitis VirusPerivascular InflammationThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Neuropathogenicity of a mutant of mouse hepatitis virus, JHM strain, derived from persistently infected DBT cells.

Subacute or chronic neuropathogenicity of a mutant mouse hepatitis virus (MHV), JHMcc, derived from DBT cell cultures persistently infected with MHV-JHM was studied in 4-week-old ICR mice. After intracerebral inoculation with 105 PFU of the virus, 80% of mice survived for 4 weeks, whereas the original MHV-JHM killed in a few days all mice inoculated with the same dose. The JHMcc titer of the brain reached a peak 4 or 5 days after infection and was still 103 PFU/0.2 g 10 days postinoculation. The virus-specific antigen was detected in neurons of the cerebral cortex and the medulla oblongata 4 weeks postinoculation. At an early stage of infection, moderate inflammation was produced in the cerebral cortex, whereas severe demyelination became distinct after degenerative and necrotic changes had subsided. Most of the mice surviving for 4 weeks postinoculation showed extensive demyelination and remyelination. These findings suggest that persistent infection of MHV-JHMcc in vivo may be established and that inflammatogenic effect and demyelination may be caused by different clones of MHV-JHM.

Use of SEPs to localize degeneration in a rare polyneuropathy: studies on polyneuropathy associated with pigmentation, hypertrichosis, edema, and plasma cell dyscrasia.

Peripheral and cental nerve conduction were studied in five patients who had polyneuropathy associated with pigmentation, hypertrichosis, edema, and plasma cell dyscrasia by using the short-latency somatosensory evoked potential (SEP) to electrical stimulation of the median nerve at the wrist. The clavicular component N9 was markedly reduced in amplitude, and its latency was moderately prolonged. The interpeak latency from N9 to the cervical component N13 was significantly prolonged, indicating a conduction delay in the dorsal root. The interpeak latency from N13 to the cortical component N20 was normal, suggesting normal central conduction. These physiological findings were consistent with the pathological findings, which showed degeneration of axons and segmental demyelination and remyelination in the sural nerve and extensive segmental demyelination and remyelination in the dorsal root but normal posterior columns of the spinal cord. SEP is a noninvasive method of localizing the site of axon or myelin disorder in a peripheral neuropathy.

Chronic relapsing experimental autoimmune encephalomyelitis: Treatment with combinations of myelin components promotes clinical and structural recovery

Preliminary results are presented on the treatment of Strain 13 guinea pigs with chronic relapsing experimental autoimmune (allergic) encephalomyelitis (EAE) induced by a single sensitisation with whole spinal cord. Animals were treated at different stages of the disease with injections containing either myelin basic protein (MBP) alone in incomplete Freund's adjuvant (IFA), or MBP in combination with a lipid hapten of myelin, galactocerebroside (GC) in IFA. The rationale for this treatment stemmed from previous work which suggested that MBP was responsible for T cell sensitisation in EAE and that GC was important in producing demyelinating antibodies and that both myelin components were needed in the induction of disease. Although treatment with MBP alone caused some initial stabilisation of the disease process, subsequent relapses occurred in all animals. However, in animals given MBP and GC together, either early or late in the course of the disease, marked clinical improvement has been noted with little or no development of relapses over an observation period of more than one year posttreatment. In addition, evidence of extensive remyelination and oligodendroglial proliferation in CNS lesions has been found in MBP-GC-treated animals suggesting that this therapy might be beneficial for CNS repair and relevant to multiple sclerosis.

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.

Recurrent demyelination in chronic central nervous system infection produced by Theiler's murine encephalomyelitis virus

A morphologic study of demyelination produced by Theiler's encephalomyelitis virus (TMEV) infection in C3H/He mice was performed. Demyelination in this strain of mouse was less intense and had a milder gliomesodermal response than that observed in SJL mice. As early as 80 days after infection numerous remyelinated axons were present in C3H/He mice, and later, extensive remyelination was observed and was mainly by Schwann cells. About one-third of remyelinated plaques showed recurrent demyelinating activity at 200 days. The best evidence of recurrent demyelination was the loss of myelin by axons which had been previously remyelinated by Schwann cells. In addition, acute areas of demyelination were also seen in spinal cords which contained chronic or quiescent plaques. The demonstration of recurrent demyelination in TMEV infection is important for it increases the relevance of this model to multiple sclerosis (MS). In addition TMEV infection of C3H/He mice appears to be an excellent model for further studies of Schwann cell remyelination and recurrent demyelination in the central nervous system (CNS).

RECURRENT BRACHIAL PLEXUS NEUROPATHY

The clinical, electrophysiological and pathological changes in 3 patients with recurrent attacks of non-traumatic brachial plexus neuropathy have been described. Two had recurrent attacks and a dominant family history of similar attacks, together with evidence of lesser degrees of nerve involvement outside the brachial plexus. In one patient the attacks were moderately painful, while in the other there was little or no pain. Only one showed undue slowing of motor nerve conduction during ischaemia, but in both cases the sural nerves had the changes of tomaculous neuropathy, with many sausage-shaped swellings of the myelin sheaths, and extensive segmental demyelination and remyelination. The third patient had two attacks of acute brachial plexus neuropathy which were both extremely painful. The clinical features were compatible with a diagnosis of neuralgic amuotrophy. In the second attack, there was vagus nerve involvement and the sural nerve showed evidence of healed extensive segmental demyelination. The various syndromes presenting with acute non-traumatic brachial plexus neuropathy are reviewed, and a tentative nonsological classification advanced. Most patients fall into the category of acute, painful paralysis with amyotrophy, with no family history and no evidence of lesions outside the brachial plexus. It is suggested that the term "neuralgic amyotrophy" be restricted to this group. Patients with features outside this clinical picture probably suffer from other disease entities presenting with brachial plexus neuropathy. The familial cases constitute one or more aetioliogical subgroups, differing from neuralgic amyotrophy in the frequency of recurrences, the relative freedom from pain in the attacks, the frequency of nerve lesions outside the brachial plexus, and of hypotelorism. Individual attacks of acute brachial plexus neuropathy, however, may be identical in patients with the different diseases, and further pathological and biochemical studies are awaited to aid in nosology.

Remyelination of the superior cerebellar peduncle in old mice following demyelination induced by cuprizone

The superior cerebellar peduncles of adult mice were demyelinated by feeding a diet containing cuprizone for 10 weeks. When mice were taken off this diet the tract underwent complete remyelination similar to that found in younger animals. It was concluded that age was not a factor which limits extensive remyelination in mice, rather that the limiting factor must be the supply of cells capable of repopulating demyelinated areas. Such cells appeared to be available throughout life in the mouse brain.

Demyelination of the superior cerebellar peduncle in the mouse induced by cuprizone

The superior cerebellar peduncles of mice fed a diet containing 0.5% cuprizone since weaning were examined. It was found that this tract was demyelinating after 4 weeks on the diet, a process which was almost complete after 5 weeks. Demyelination followed degeneration of oligodendrocytes. Extensive remyelination did not occur if the animals were kept on the diet. The reproducibility of demyelination was such that quantitative studies on remyelination can be undertaken. The genotype of the mice used in the present experiments was considered to be of importance in the aetiology of the lesion.