Pathogenetic aspects of demyelinating lesions in chronic relapsing experimental allergic encephalomyelitis: possible interaction of cellular and humoral immune mechanisms.
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Animals↗
Biomedical subjects
H Lassmann
Publications and source records attributed to H Lassmann.
Increased blood-brain barrier permeability in scrapie-infected mice.
The present investigation was designed to study the ultrastructural integrity of the blood-brain barrier (BBB) in the cerebral microvasculature of scrapie-infected mice showing clinical illness. Cerebral microvessels from either IM, VM, or C57BL/6J mice, terminally affected with various strains of scrapie agent showed a focal leakage of horseradish peroxidase (HRP) in all agent-strain and mouse-strain combinations. This leakage was most pronounced in and near the primary site of agent inoculation, but was also observed in microvessels scattered throughout the brain. Cytochemical studies also revealed a redistribution of plasmalemma-bound alkaline phosphatase in the endothelial cells. In control mice, the enzymatic activity was mainly concentrated in the luminal plasmalemma, while in the scrapie-infected mice the activity also appeared in the abluminal side in the majority of microvessels. Our observations are evidence that the BBB of the mouse is altered in some way by the scrapie agent. Such an alteration may have important implications for human disease, since the scrapie agent is related to the group of "slow" viral infections, including kuru and Creutzfeldt-Jakob disease. Scrapie may also serve as an important model for the study of senile dementia of the Alzheimer type (SDAT).
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Comparative neuropathology of chronic experimental allergic encephalomyelitis and multiple sclerosis.
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Animals↗
Antibodies-restricted heterogeneity in serum and cerebrospinal fluid of chronic relapsing experimental allergic encephalomyelitis.
An animal model which might help to study multiple sclerosis has long been sought. With chronic relapsing experimental allergic encephalitis (EAE), the search seems to have brought hope and evidence of comparable pathology whether concerned with clinical or neuropathological results, but no study of the cerebrospinal fluid (CSF) electrophoretic pattern has been made so far. A new sensitive method enables to study the CSF proteins: unconcentrated CSF proteins after agar gel electrophoresis are stained with silver reagents. The silver technique allows to follow the evolution of the inflammatory reaction in chronic relapsing EAE as well as in the acute form of EAE. This technique provides an additional approach to the study of EAE and an argument in favor of chronic relapsing EAE in guinea pigs as a model for multiple sclerosis.
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Fractionation of spinal cord tissue affects its activity to induce chronic relapsing experimental encephalomyelitis.
Chronic relapsing experimental allergic encephalomyelitis (EAE), an animal disease closely resembling multiple sclerosis, was induced in young guinea pigs by sensitization with guinea pig spinal cord tissue together with complete Freund's adjuvant and a high amount of mycobacterium tuberculosis. Sensitization of animals with myelin basic protein leads to an acute form of EAE, but not to a chronic demyelinating disease. The present study was designed to trace the factors of spinal cord tissue responsible for chronic disease and demyelination by using fractionated spinal cord tissue for sensitization. The following preparations were tested for encephalitogenic activity: a) total guinea pig spinal cord homogenized in chloroform/methanol (C/M), b) C/M residue (protein fraction), c) C/M extract (lipid fraction) and d) bovine brain gangliosides. C/M treated spinal cord preparations were less encephalitogenic as compared to untreated spinal cord. The protein fraction showed very little encephalitogenic activity, the histological changes were limited to perivascular inflammation without demyelination. A crude lipid fraction induced some chronic inflammation. Neither the purified lipid fraction nor gangliosides produced any EAE symptoms. The conclusion can be made that protein is necessary for the induction of chronic relapsing EAE, whereas lipid or a protein-lipid complex seems to be responsible for the demyelinating component of this disease.
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Ultrastructural variability of demyelinating lesions in experimental allergic encephalomyelitis and multiple sclerosis.
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Animals↗
Isolated leptomeninges of the spinal cord: an ideal tool to study inflammatory reaction in EAE.
Isolated and stretched leptomeninges have several advantages for the study of basic mechanisms in inflammation of the CNS. They offer a three dimensional view of the vascular tree which has basically the functional characteristics of cerebral vessels (the tight barrier, excluding macromolecules to enter the CNS compartment). The limited, small thickness of the specimen facilitates the performance of histochemical and immunohistochemical methods.
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Relapsing experimental allergic encephalomyelitis induced with isolated myelin and with myelin basic protein plus myelin lipids.
To test the ability of different spinal cord fractions to reproduce the clinicopathological features of relapsing experimental allergic encephalomyelitis (R-EAE), groups of young guinea pigs were inoculated with: (1) spinal cord myelin; (2) delipidated myelin; (3) reconstituted myelin and (4) MBP plus myelin lipids. The four sets of antigens induced acute EAE in most of the animals tested. During an observation period of 18 months, only one clinical relapse was observed in animals sensitized with myelin and with MBP plus myelin lipids. Extensive CNS demyelination was found in relapsing animals injected with myelin. No demyelinated lesions were observed in non-relapsing animals. By contrast, half of the surviving guinea pigs injected with MBP plus myelin lipids had demyelinated lesions, irrespective of whether they relapsed or not. The inability of the spinal cord myelin fractions to fully reproduce the R-EAE model suggest that other non-myelin antigens may be involved in the pathogenesis of multiple relapses.
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Myelin proteins, glycoproteins, and myelin-related enzymes in experimental demyelination of the rabbit optic nerve: sequence of events.
Wallerian degeneration of the rabbit optic nerve was investigated by the technique of retinal ablation which precludes edema, hemorrhage, or macrophage infiltration. After 8 days of degeneration, marked degradation of axons and some myelin abnormalities appeared in the optic nerve, optic chiasma, and optic tract. Myelin lesions were maximal 32 days after retinal destruction. The amount of material stained with a myelin dye decreased drastically between 32 and 90 days after the operation. Biochemical parameters gave the following sequence of events. The concentration of the major periodic acid--Schiff staining glycoproteins was decreased after 2 days, and 6 days later the presence of cholesterol esters was detected in the optic tissue. After 16 days of Wallerian degeneration, the specific activity of 2',3'-cyclic nucleotide 3'-phosphodiesterase not associated with myelin decreased, indicating a possible de-differentiation of oligodendrocytes. Degradation of myelin basic protein became significant at 32 days and the amount of myelin isolated decreased later. The loss of myelin basic protein coincided with a reduction of myelin periodicity as measured in purified fractions by electron microscopy. These results show that secondary myelin destruction in the absence of edema, hemorrhage, or macrophages is a very slow process, and in this situation myelin undergoes a selective and sequential loss of its constituents.
2',3'-Cyclic-Nucleotide Phosphodiesterases↗
Chronic relapsing experimental allergic encephalomyelitis. Immunohistochemical studies.
The immunohistochemical staining of immunoglobulins (Ig), complement (C3), and fibrinogen in chronic relapsing experimental allergic encephalomyelitis lesions showed different staining patterns in the acute vs the chronic stage of the disease. In the acute stage, Ig, C3, and fibrinogen were present in the perivascular tissue of the brain and the spinal cord. In hyperacute-type lesions, the binding of Ig and C3 to the parenchyma was especially pronounced. The chronic stage of the disease was characterized by Ig-containing cells and Ig binding to white matter in actively demyelinating lesions. Linear or granular deposits of immunoglobulin and complement, reminiscent of those described in immune complex disease, were found in the choroid plexus.
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Chronic relapsing experimental allergic encephalomyelitis: effect of age at the time of sensitization on clinical course and pathology.
Experimental allergic encephalomyelitis was induced by sensitization with guinea pig spinal cord in complete Freund's adjuvant with increased content of myobacterium in Hartley guinea pigs between the first and 28th day after birth. The animals either died during acute EAE or showed chronic progressive, chronic relapsing or chronic EAE with delayed onset. In animals immunized between the 1 and 13 day after birth, predominatly ordinary and chronic progressive EAE was noted, whereas animals sensitized between the 14th and 23rd day frequently suffered from hyperacute or chronic relapsing EAE. Immunization on the 24th day led to very high mortality in acute EAE. The relation of the pathohistologic alterations to different types of human inflammatory demyelinative disease is discussed.
Age Factors↗
Chronic relapsing experimental allergic encephalomyelitis: morphological sequence of myelin degradation.
Myelin degradation in chronic relapsing experimental allergic encephalomyelitis was studied using light microscopic histochemistry and electron microscopy. In the earliest stages, a large number of myelin stripping macrophages were found. The Luxol fast blue positive degradation products were then gradually transformed into PAS positive material. No sudanophilic stage of myelin degradation was found in this model. In electron microscopy, the Luxol fast blue positive material was identified as uniformly layered lipid inclusions with a periodicity of 4.0--4.5 nm. During further digestion, this material was transformed into polymorph structured material, consisting of lamellar leaflets with a diameter of 7--10 nm, curved cylindrical profiles and granular osmiophilic material.
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Chronic relapsing experimental allergic encephalomyelitis: clinicopathological comparison with multiple sclerosis.
Clinical and neuropathological observations in chronic, relapsing experimental allergic encephalomyelitis (EAE) are reported and compared with data available for multiple sclerosis (MS). Clinical, relapsing EAE was found in 95 of 119 of the strain 13 and 22 of 57 of the Hartley guinea pigs immunized. Examination of the brains and spinal cords of the guinea pigs showed a high incidence of macroscopically visible, demyelinated plaques. The topographic distribution of lesions resembled a pattern similar to that described in MS. Microscopic features of the lesions consisted of perivenous inflammation, primary demyelination, oligodendrocyte loss, and reactive gliosis. It is concluded that, with the exception of minor differences, the clinical and pathological alterations in chronic, relapsing EAE closely resemble those found in MS.
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Tactile corpuscle-like structures in a case of plexiform neurofibromatosis.
Tactile corpuscle-like structures were identified in a plexiform neurofibroma, which was localized on the right cranial hemisphere os a 16-year-old boy and had necessitated repeated surgery. These structures were studied by light and electron microscopy. The origin of their component cells is, however, still controversial. We believe to have accumulated sufficient evidence for a Schwann cell origin of these cells.
Adolescent↗
Ultrastructural sequence of myelin degradation. I. Wallerian degeneration in the rat optic nerve.
The ultrastructural events in myelin degradation in the rat optic nerve following transection have been studied. Myelin debris was found in cells similar to multipotential glia cells (Vaughn and Peters, 1968) as well as in astrocytes and in few oligodendrocytes. The different types of inclusions found during myelin degradation were described in their quantitative relations. Similarities to inclusions described in adrenoleukodystrophy adn multiple sclerosis are discussed. By comparison of the ultrastructural findings with histochemical and biochemical data available a hypothetical model of myelin degradation is presented. The process starts with the degradation of digestible proteins resulting in uniformly layered lipid inclusions. Lipid degradation leads to the formation of unstructured lipid droplets and crystals. During the late stages of Wallerian degeneration numerous polymorph inclusion typed can be found, probably representing poorly digestible lipids or lipoproteins.
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Ultrastructural sequence of myelin degradation. II. Wallerian degeneration in the rat femoral nerve.
Myelin degradation in Wallerian degeneration of rat femoral nerves has been studied with the electron microscope. In the initial stages, a decrease of myelin periodicity from 115 A to 88 A was noted, followed by the transformation of the myelin structure into uniformly layered lipid inclusions. 10--14 days after nerve section, most of the inclusions found represented unstructured lipid droplets or crystals. In the later stages of degeneration, numerous pleomorphic lamellar inclusions were found, some of them resembling the structure of pi and micron-granules. Lysosomal enzyme activity was found especially in pleomorphic inclusions during the late stages of myelin degradation. Normal myelin sheaths, as well as unstructured lipid droplets and crystals, were devoid of enzyme activity. The results are compared with alterations found in Wallerian degeneration of the central nervous system.
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Chronic relapsing EAE. Time course of neurological symptoms and pathology.
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Animals↗
The relation of nervous elements to intradermal nevi. As electron microscopic study.
Intratumoral nerves of dermal nevi were investigated by electron microscopy in order to elucidate the role of neural elements in the development of these tumors. The following results were obtained: 1. Intratumoral nerves exhibit an increased cellularity, but the number of myelinated fibers is reduced. 2. Nevus cells type B and C are frequently present within nerve fascicles. 3. Unmyelinated axons were found in close relationship to nevus cells. 4. Schwann cells may show proliferations similar to early stages of neurofibroma and can be differentiated from unpigmented tumor cells by their relation to axons only. These findings indicate that identical cell populations are present within the intratumoral nerves and the tumor itself. Therefore, the theory of a neural component in the histogenesis of intradermal nevi is supported.
Adult↗