Synergism in the pathogenesis of EAE induced by an MBP-specific T-cell line and monoclonal antibodies to galactocerebroside or a myelin oligodendroglial glycoprotein.
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Animals↗
Biomedical subjects
H Lassmann
Publications and source records attributed to H Lassmann.
Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein.
In this study the authors have developed a model with which can be studied directly the influence of circulating anti-myelin antibody on the clinical and pathologic course of inflammatory T-cell-mediated experimental allergic encephalomyelitis (EAE) in the rat. EAE was induced by passive transfer of either myelin basic protein (MBP)-activated spleen cells derived from sensitized donors or long-term-cultured MBP-specific T-cell lines. At the onset of the disease, monoclonal antibodies against a myelin/oligodendrocyte glycoprotein (MOG) were injected intravenously. This antigen is exposed on the surface of central nervous system myelin and oligodendrocytes. Intravenous injection of the antibody in the course of T-cell-mediated transfer EAE augmented the severity and duration of clinical signs and resulted in the formation of large, confluent demyelinated plaques.
Animals↗
Neurofibrillary tangles in Alzheimer's disease and progressive supranuclear palsy: antigenic similarities and differences. Microtubule-associated protein tau antigenicity is prominent in all types of tangles.
The antigenic profile of neurofibrillary tangles (NFT) in Alzheimer's disease (AD), senile dementia of Alzheimer type (SDAT), progressive supranuclear palsy (PSP) and in non-demented aged humans was investigated by light and electron microscopic immunocytochemistry using antisera and monoclonal antibodies to tubulin, microtubule-associated proteins (MAP1, MAP2 and tau), neurofilament proteins and determinants unique to Alzheimer paired helical filaments (PHF). Antibodies to tau proteins labeled NFT in all cases investigated (AD, SDAT, PSP and non-demented aged humans). However, one monoclonal antibody to PHF recognized numerous tangles in AD/SDAT, but only a small minority of the PSP tangles. Antibodies to tubulin, MAP1, MAP2 and neurofilament proteins did not selectively stain NFT. Whereas pretreatment of sections with phosphatase was required for the detection of tangles with Tau-1 monoclonal antibody, digestion of sections with either phosphatase or pronase had no significant effect on the staining pattern obtained with the other antibodies. Our studies show that, as previously described for AD/SDAT, phosphorylated tau polypeptides are also a major antigenic determinant of tangles in PSP, indicating that tangle formation may follow a common pathogenetic pathway in neurofibrillary degenerations. There is, however, at least one epitope in AD/SDAT tangles which seems to be absent on, or at least inaccessible in, the 15-nm straight fibrils of PSP.
Adult↗
Antibody responses in chronic relapsing experimental allergic encephalomyelitis: correlation of serum demyelinating activity with antibody titre to the myelin/oligodendrocyte glycoprotein (MOG).
Antibody responses to the myelin/oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) were determined in the sera of Hartley guinea pigs with chronic relapsing experimental allergic encephalomyelitis (CREAE) using an enzyme-linked immunoassay. The sera were also tested for in vivo demyelinating activity by infusion into the subarachnoid space of normal rats. In contrast to the MBP titres, the anti-MOG antibody titres showed good correlation with the in vivo demyelinating activity of the sera (r = 0.91, P less than 0.001). This result suggests that antibodies directed against MOG may be involved in the pathogenesis of demyelination in CREAE.
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Effect of mannitol treatment on brain neurotransmitter markers in kainic acid-induced epilepsy.
The effect of mannitol treatment on the behavioural, morphological and neurochemical brain damage induced after subcutaneously applied kainic acid (10 mg/kg) was studied in the rat. Mannitol at a dose of 1.5 g/kg was injected intravenously 10 min, 1.5 h and 3 h respectively after kainic acid administration. A protective effect of mannitol was observed only when mannitol was given 1.5 h after kainic acid application, i.e. within the early phase of kainic acid-induced brain oedema development. At this time period, mannitol prevented the development of kainic acid-induced seizures as well as irreversible brain lesions and neurochemical changes, the latter being reduction of noradrenaline levels in amygdala/pyriform cortex measured 3 h, and reduction of glutamate decarboxylase and choline acetyltransferase activities measured 3 days after kainic acid treatment. Similarly loss of glutamate decarboxylase activity in dorsal hippocampus induced by kainic acid was prevented by mannitol treatment. It is concluded that by washing out brain oedema, mannitol treatment may prevent propagation of seizures and brain damage in the kainic acid model of epilepsy.
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Therapy of rat autoimmune disease by a monoclonal antibody specific for T lymphoblasts.
The central role of T lymphocytes in the initiation, regulation and propagation of autoimmune diseases defines them as most suitable targets for selective immunotherapy. The recent advance in culturing human and animal T cell lines allows us to select monoclonal antibodies specific for differentiation antigens expressed by activated T lymphocytes. We selected a monoclonal antibody cytotoxic for a subpopulation of activated rat T cells. In vivo, this antibody effectively blocks immune responses to foreign antigens or autoantigen and prevents development of autoimmune diseases like experimental allergic encephalomyelitis and adjuvant arthritis. Even already established disease can be blocked by a single injection of antibody. Furthermore, this monoclonal antibody can be used to monitor the course of autoimmune disease progression from peripheral blood samples.
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Ultrastructural analysis of rat brain tissue following systemic kainate administration.
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Effects of clonidine on the stimulation-evoked release of 3H-noradrenaline from superfused rat brain slices as a function of the biophase concentration. Temperature dependent widening of extracellular space.
The influence of clonidine on the stimulation-evoked overflow of tritium was studied in brain slices preincubated with 3H-noradrenaline. The slices were prepared from parietal cortex (Cx), nucleus anterior hypothalami (nah) and nucleus tractus solitarii (nts). After preincubation, the tissues were superfused at 23 degrees C or 37 degrees C with a medium containing the noradrenaline uptake inhibitor desipramine. Electrical field stimulation was applied using stimulation frequencies of 0.3-10 Hz. At 23 degrees C/0.3 Hz, clonidine concentration-dependently inhibited the evoked overflow of tritium in all three brain regions. In contrast, at 23 degrees C/3 Hz the inhibitory effect of the drug in the Cx was abolished and a facilitation was observed in the nah and nts. When tested at increasing frequencies of stimulation in the nts at 23 degrees C, clonidine exerted a dual action, characterized by a reduction of electrically evoked responses at frequencies below 1 Hz and a facilitation at frequencies above 1 Hz. At 37 degrees C, clonidine concentration-dependently decreased the evoked overflow in all brain regions studied, this effect being more pronounced at 0.3 Hz than at 3 Hz. The apparent lack of an effect of clonidine on the stimulation-evoked overflow of tritium in the Cx at 23 degrees C/3 Hz was turned to a facilitation when noradrenaline (0.01 mumol/l) was included in the superfusion medium. Conversely, an inhibitory effect of clonidine was seen when the uptake blocker desipramine (as well as noradrenaline) was omitted from the superfusion medium.(ABSTRACT TRUNCATED AT 250 WORDS)
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Ganglioside GM1, a molecular target for immunological and toxic attacks: similarity of neuropathological lesions induced by ganglioside-antiserum and cholera toxin.
Ganglioside-antisera, the ganglioside GM1-ligands, cholera toxin (CT), and CT subunit B, respectively, were injected into the lumbosacral subarachnoid space of normal rats. The cytotoxic effects of the injected compounds on the peripheral and central nervous system were investigated by light and electron microscopy; the severity of CNS lesions was evaluated by quantitation of macrophages containing debris. In contrast to control sera and GM2-antiserum, antisera against a mixture of the major brain gangliosides GM1, GD1a, GD1b, and GT1b (MaBG) or against GM1 induced demyelination in spinal roots and spinal cord, as well as alterations of astroglia. CT induced the same cytotoxic effects as MaBG- and GM1-antisera, whereas CT subunit B was without effect. The ineffectiveness of GM2-antiserum is obviously due to the very low concentration of the specific binding target, GM2, on cell surfaces; that of CT subunit B to the lack of the cytotoxic operator, subunit A. Our results indicate that a similar pattern of neuropathological lesions may be effected by different cytotoxic mechanisms through attachment of the cytotoxic agent onto the cell surface via a common target molecule, and further substantiate the role of GM1-antibodies in the pathogenesis of demyelination.
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Peripheral nervous system lesions in experimental allergic encephalomyelitis. Ultrastructural distribution of T cells and Ia-antigen.
The distribution of T cells and Ia-antigen in peripheral nervous system (PNS) lesions of experimental allergic encephalomyelitis was studied by light- and electron-microscopic immunocytochemical techniques. Sprague Dawley rats, sensitized with guinea pig spinal cord tissue, developed a biphasic disease with acute inflammatory and chronic inflammatory demyelinating lesions in the PNS. In both the acute non-demyelinating and the chronic demyelinating disease inflammatory infiltrates were composed of T cells and Ia-positive monocytes/macrophages. Dependent upon the stage of the disease a variable percentage of T-lymphocytes carried the Ox 8 antigen (suppressor/cytotoxic cells). In demyelinating lesions no evidence for an interaction of T cells with myelin or Schwann cells was observed, thus arguing against a direct T-cell cytotoxicity in demyelination. The whole sequence of myelin destruction and digestion was performed by W3/13-, Ia+ mononuclear cells with ultrastructural features of monocytes/macrophages. In contrast to the acute inflammatory stage of the disease, high titers of anti-myelin antibodies were present in sera of affected animals sampled during the chronic inflammatory demyelinating stage. The sera from the latter animals also showed pronounced in vivo demyelinating activity when transferred into the cerebrospinal fluid (CSF) of normal recipient rats. It is thus suggested that demyelination in this model is induced by a co-operation of cell-mediated and humoral immune mechanisms. We did not find evidence for Ia-antigen expression on local elements of the PNS (Schwann cells, axons, or endothelial cells).
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The distribution of Ia antigen in the lesions of rat acute experimental allergic encephalomyelitis.
Ia antigen, encoded within the major histocompatibility complex, plays an important role in the activation of T lymphocytes. Since experimental allergic encephalitis is an essentially T cell-mediated disease, Ia antigen in the central nervous system (CNS) may be pathogenetically relevant. The occurrence of Ia antigen in the CNS of normal rats and of rats with experimental allergic encephalitis was studied by light and electron microscope immunocytochemistry using the monoclonal anti-Ia antibodies Ox 4 and Ox 6. In normal, unsensitized animals a district population of stellate cells in the meninges and some perivascular mononuclear cells in the nervous tissue carried Ia antigen. In rats with experimental allergic encephalitis a dramatic increase of Ia-positive cells was found. In addition to the positive cells found in normal animals, monocytes, macrophages and many lymphocytes in the meningeal perivascular and parenchymal inflammatory infiltrates as well as "activated microglia" stained for Ia antigen. We did not find evidence for Ia expression on endothelial cells, astrocytes or other components of the CNS in either normal or diseased rats.
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Presence of chromogranin A, B and C in bovine endocrine and nervous tissues: a comparative immunohistochemical study.
Antisera against chromogranin A, B and C were used to study the distribution of these acidic proteins in bovine endocrine and nervous tissues. The three chromogranins occur together in several endocrine organs (adrenal medulla, anterior pituitary, endocrine pancreas) and in sympathetic ganglion cells. In the posterior pituitary, only chromogranin C and in the intermediate lobe only A and C are found. The parathyroid gland contains only A, and enterochromaffin cells are immunoreactive for A and B. Cells of the thyroid gland and some cells of the anterior pituitary apparently do not contain any chromogranins. It is concluded that the three chromogranins are not always stored together and that they are not present in all endocrine cells. This distinct localization of the chromogranins indicates some special, although still undiscovered, function for these proteins.
Adrenal Medulla↗
Recombinant interleukin 2 (IL-2) promotes T cell line-mediated neuroautoimmune disease.
Autoimmunity is dependent on a delicate balance of cellular interactions preventing activation of autoaggressive T cells. Possible side effects of therapeutically injected recombinant interleukins on latent or overt autoimmune disease are uncertain. Using a T cell transfer model of autoimmune central nervous system (CNS) disease, we investigated the in vivo effect of recombinant IL-2. We observed that recombinant IL-2 strongly promotes autoimmune disease.
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Molecular aspects of MAP-1 and MAP-2: microheterogeneity, in vitro localization and distribution in neuronal and nonneuronal cells.
We have studied various aspects of MAP-1 and MAP-2 from neuronal as well as nonneuronal sources. MAP-1 and MAP-2 polymerized from brain were resolved into a number of subcomponents upon electrophoresis on low percentage gels. Based on peptide mappings performed under a variety of different conditions, we conclude that the three major subcomponents of MAP-1 have very similar, though not identical structures. The two major MAP-2 subcomponents might have identical structure, because their peptide maps were hardly distinguishable. The apparent microheterogeneity of high Mr MAPs is not yet understood on a molecular basis. Proteolysis during isolation or a different degree of phosphorylation, however, seems to be an unlikely cause for microheterogeneity. When localized on microtubules polymerized in vitro by electron microscopy, both MAP-1 and MAP-2 polypeptides apparently form helical arrays on the polymer's surface with periodicities of 100 nm. In the presence of taxol, MAPs form irregular and bulky extensions. Both MAPs are found to be widespread in neuronal as well as nonneuronal cells. MAP-1- and MAP-2-related polypeptides, together with other high Mr proteins, such as plectin, were associated with microtubules polymerized by taxol from extracts of a nonneuronal cultured cell line. MAP-2 from cultured cells was found to be extremely sensitive to proteolysis, in particular in the presence of free Ca-ions. MAP-1 and MAP-2 generally were found associated with typical microtubule structures such as interphase and spindle microtubules and primary cilia. A differential distribution of MAP-1 and MAP-2 was clearly evident in neural tissues, where MAP-2 was restricted to cell bodies and dendrites, whereas MAP-1 was present also in axons. Moreover, a differential distribution of MAPs and tubulin was observed in de-and regenerating peripheral nerve, and in a few occasions, also with nonneuronal cells. A quite unexpected result was the identification of a protein in the extracellular matrix of cultured fibroblast cells, which has antigenic determinants in common with MAP-1 and MAP-2 from brain. As a whole, the data presented support a concept in which a family of structurally homologous, though not identical, high Mr polypeptides constitute the crosslinking elements between microtubules and various other cellular components. The structural diversity of these polypeptides might play a role in the development and dynamic changes in the cytoskeletal architecture.
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Kainic acid-induced seizures: dose-relationship of behavioural, neurochemical and histopathological changes.
Behavioural, neurochemical and histopathological changes induced by systemic injection of kainic acid were investigated at various doses of the neurotoxin (3, 6 and 10 mg/kg s.c.). There was a positive correlation between the dose of kainic acid and the extent of both the acute neurochemical changes 3 h after the injection (increases of 3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid levels and a decrease in noradrenaline levels in all brain regions investigated), the acute histopathological changes (shrinkage and condensation of nerve cells and brain oedema in the entire forebrain) and the extent of behavioural alterations (immobility, 'wet dog shakes' and limbic seizures). However, the slope of the dose-response curves was very steep. Late and irreversible alterations included losses of the enzyme markers glutamic acid decarboxylase and choline acetyltransferase and, histopathologically, incomplete parenchymal necrosis and haemorrhages. These changes, however, were restricted to a few brain regions, the most important being the hippocampus, amygdala, entorhinal and pyriform cortex, and olfactory bulb, and they were seen only in animals which had undergone severe convulsions. It is suggested that the irreversible brain lesions in this animal model of limbic (temporal lobe) epilepsy are not solely induced by a direct action of kainic acid, but may be caused--at least in part--by additional, secondary pathogenetic mechanisms.
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Immunocytochemical study of myelin-associated glycoprotein (MAG), basic protein (BP), and glial fibrillary acidic protein (GFAP) in chronic relapsing experimental allergic encephalomyelitis (EAE).
Chronic relapsing experimental allergic encephalomyelitis (EAE) lesions that resemble those seen in multiple sclerosis (MS) were produced in young Hartley and strain 13 guinea pigs (Lassmann and Wisniewski 1979). To study distributions of myelin-associated glycoprotein (MAG), myelin basic protein (MBP), and glial fibrillary acidic protein (GFAP) in these lesions, paraffin and semithin epon sections of CNS from eight of these guinea pigs were immuno-stained with antisera to these proteins according to the peroxidase-antiperoxidase (PAP) method. In lesions with active myelin sheath breakdown, changes in anti-MAG and anti-BP immunoreactivity corresponded closely. Abnormal and/or decreased anti-MAG staining did not extend beyond margins of lesions into surrounding areas containing myelin sheaths stained normally by anti-BP and by histological stains for myelin. GFAP-stained astrocyte processes were more numerous and much larger in more chronic lesions. Anti-MAG and anti-BP both stained regenerating myelin sheaths which were very numerous in both paraffin and epon sections. In the latter, anti-MAG also stained some myelin-forming oligodendroglia. The results are additional evidence suggesting that in chronic relapsing EAE, myelin sheaths are the primary target. Oligodendroglia appear to be relatively unaffected and remyelinate most of the demyelinated axons.
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Immunological studies on the distribution of chromogranin A and B in endocrine and nervous tissues.
Bovine chromaffin granules contain two major families of acidic proteins, chromogranins A and B. The occurrence of these proteins in endocrine and nervous tissue was investigated by immunoblotting (one- and two-dimensional), and by immunohistochemistry. Immunoblotting revealed that in anterior hypophysis and in splenic nerve from ox, immunologically crossreacting proteins are present which in two-dimensional electrophoresis migrate to the same position as adrenal chromogranins A and B. Smaller proteins derived from chromogranin B by endogenous proteolysis were much less prominent in these tissues when compared with adrenal medulla. Immunohistochemistry performed in rat and bovine tissues established that chromogranin B is present in all cells of the adrenal medulla. It is also found in the anterior hypophysis, the endocrine pancreas, in enterochromaffin and in sympathetic ganglion cells, but e.g. is absent from posterior hypophysis and exocrine tissues. It is concluded that chromogranins A and B have a widespread distribution in endocrine and nervous tissue. Proteolytic processing of chromogranin B in the storage organelles of hypophysis and splenic nerves is apparently slower than that in chromaffin granules. The widespread distribution of the chromogranins resembling that of neuropeptides is a clear indication for some special, yet to be discovered, function.
Adrenal Medulla↗
Pathogenetic aspects of multiple sclerosis and experimental models of inflammatory demyelination.
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Animals↗