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H Lassmann

Publications and source records attributed to H Lassmann.

At least 19 recordsLinked to original sources
PubMed1992

Interferon-gamma potentiates antibody-mediated demyelination in vivo.

The pathogenetic events leading to demyelination in experimental allergic encephalomyelitis and in human multiple sclerosis are still unclear. The involvement of anti-myelin antibodies and activated macrophages as effector cells has been postulated. We investigated the synergistic action of the monoclonal antibody 8-18C5 against myelin/oligodendrocyte glycoprotein and recombinant interferon-gamma on demyelination after simultaneous injection into the subarachnoid space of Sprague-Dawley rats. After combined injection of anti-myelin/oligodendrocyte glycoprotein antibody and interferon-gamma, electrophysiological and morphological evidence for demyelination was found. Cervical somatosensory evoked potentials and cervical short-latency somatosensory evoked potentials were significantly delayed, and the demyelinated area in the spinal cord was significantly enlarged when compared to control rats injected with either compound alone. Injection of either an irrelevant antibody and interferon-gamma or of peritoneal macrophages without anti-myelin/oligodendrocyte glycoprotein antibody and interferon-gamma did not induce demyelination. Our data suggest that the deleterious effect of interferon-gamma on multiple sclerosis may be not only due to its effect on antigen presentation but also due to potentiation of demyelination.

Animals↗
PubMed1992

Cell adhesion molecules of the immunoglobulin supergene family as tissue-specific autoantigens: induction of experimental allergic neuritis (EAN) by P0 protein-specific T cell lines.

The P0 glycoprotein is a homophilic cell adhesion molecule of the immunoglobulin supergene family which is responsible for maintaining the structure of compact internodal myelin in the peripheral nervous system (PNS). Utilizing a panel of synthetic P0 peptides two distinct T cell epitopes have been identified that can induce T cell-mediated experimental autoimmune neuritis (EAN) in the Lewis rat. One T cell epitope (amino acid residues 56-71), is located within the extracellular, immunoglobulin-like domain of P0, while the other disease-inducing T cell epitope (residues 180-199) is located within the proteins cytoplasmic carboxyterminal domain. The adoptive transfer of 10(6) CD4+ T line cells specific for either of these peptide antigens induced EAN in syngeneic recipients. However, while the pathogenic response induced by both peptide-specific T cell lines was identical, their epitopes differ markedly in their immunologic properties in vivo. In particular while the response to peptide p180-199 was immunodominant in animals immunized with either purified P0 protein or the native membrane-bound P0 protein in autologous rat peripheral nerve myelin, no response to peptide p56-71 was detected, indicating that this epitope is cryptic. This study provides the first experimental evidence that the immunoglobulin-like domains of members of the immunoglobulin supergene family can function as target autoantigens in T cell-mediated autoimmune disease.

Amino Acid Sequence↗
PubMed1992

Expression of leucocyte adhesion molecules at the human blood-brain barrier (BBB).

The expression of leucocyte adhesion molecules was studied on cerebral endothelia by immunocytochemistry. In peritumoral "normal" brain tissue we found low endothelial expression of ICAM1, LFA3, CD44, and CD9, whereas VLA1 was present on vessels in high incidence and density. LFA1, CD2, and CR3 were found on intraluminal and parenchymal leucocytes, but were absent on brain vessels. In brain tumors and inflammatory brain lesions, we observed an up-regulation of endothelial ICAM1 and LFA3 expression, whereas other adhesion molecules on endothelial cells remained unchanged. Within the brain parenchyma, ICAM1 and LFA3 were found on astrocytes and tumor cells; on the contrary, LFA1 was expressed on microglial cells similar to CR3. CD44 and CD9 showed a diffuse neuropil expression in normal and tumoral tissue, whereas VLA1 was not expressed on any parenchymal cells. Our data show that multiple different adhesion molecules are present on blood-brain barrier endothelium (BBB) under normal conditions and some adhesion molecules are up-regulated in brain tumors and under inflammatory conditions. The presence of adhesion molecules in the vessel walls as well as on parenchymal cells like astrocytes and microglia may guide inflammatory cells into and through the brain in the course of immune surveillance and inflammation.

Antibodies, Monoclonal↗
PubMed1992

In situ hybridization with digoxigenin-labeled probes: sensitive and reliable detection method applied to myelinating rat brain.

A method for in situ hybridization of digoxigenin-labeled cDNA and cRNA probes to myelin protein mRNA is described. This technique has dual advantages of high structural resolution and high sensitivity and avoids problems associated with handling of radioactive materials. Furthermore, it can be readily combined in double labeling with immunocytochemical protein detection. We have used this technique to detect and locate mRNA for myelin basic protein (MBP), proteolipid protein (PLP), 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and myelin-associated glycoprotein (MAG) in oligodendrocytes of 7-day-old and adult rat brains. PLP and MAG mRNA were restricted to the perinuclear cytoplasm, whereas MBP and CNPase mRNA was additionally present in peripheral oligodendrocyte processes.

Animals↗
PubMed1992

Synaptic pathology in Alzheimer's disease: immunological data for markers of synaptic and large dense-core vesicles.

We have analysed several markers for small synaptic vesicles (synaptin-synaptophysin, p65 and SV2) and large dense-core vesicles (chromogranin A, secretogranin II/chromogranin C) in the brains of patients with Alzheimer's disease, and normal controls by immunoblotting and immunohistochemistry. In comparison to age-matched controls the levels of all three synaptic vesicle markers were decreased in temporal cortex of Alzheimer patients. On the other hand, the levels of chromogranin A were increased, and those of secretogranin II lowered. This resulted in a significant increase of the ratios of chromogranin A to synaptophysin, p65 or SV2 and of that for chromogranin A to secretogranin II. These increases were significantly correlated to clinical severity of dementia and extent of neuropathological changes. By immunohistochemistry a high percentage of senile plaques was found to contain chromogranin A-reactive dystrophic neurites, whereas synaptophysin reactivity within plaques was rare. These results indicate that the number of synaptic vesicles is lowered in Alzheimer's disease, and that one component of large dense-core vesicles, i.e. chromogranin A, is elevated. We, thus, suggest that in Alzheimer's brain distinct changes occur for both types of synaptic organelles.

Aged↗
PubMed1992

Bone marrow-derived elements in the central nervous system: an immunohistochemical and ultrastructural survey of rat chimeras.

This report defines the bone marrow-derived elements found in the central nervous system of adult rat radiation chimeras. Four cell types were identified which bore the major histocompatibility (MHC) class I molecules of the donor rat strain thereby indicating a marrow origin. They were: meningeal macrophages, perivascular "microglial" cells, lymphocytes and rare cells with parenchymal microglial morphology. These cells were examined by immunohistochemical methods at the light microscopic and ultrastructural levels. Extended descriptions of the perivascular marrow-derived elements and the parenchymal microglial cells are presented. These latter two cell types, which exist in humans, have a significant role in neuroimmune processes and most probably function as the antigen-presenting cells in the central nervous system of mammals.

Animals↗
PubMed1991

Nucleocapsid or spike protein-specific CD4+ T lymphocytes protect against coronavirus-induced encephalomyelitis in the absence of CD8+ T cells.

To investigate the antiviral CD4+ T cell response in coronavirus MHV-JHM-induced encephalomyelitis, spleen and thymic lymphocytes from diseased rats were stimulated in culture with virus Ag, expanded and tested for their specificity to viral proteins and nucleocapsid (N) and spike (S) proteins that had been expressed in bacteria. A strong T cell response specific for N was measurable during acute disease, whereas S-specific T cells were only detectable in rats with a later onset of disease. CD4+ T cell lines with specificity for virus and either N or S protein were established and their influence on the course of a mouse hepatitis virus-JHM infection was investigated. All lines were of the CD4+ phenotype. Both N and S protein-specific CD4+ T cells conferred protection to infected Lewis rats and reduced the amount of infectious virus in the central nervous system. After transfer of CD4+ T cells and challenge with virus, an increase in the antiviral IgM response occurred, but neutralizing antibodies were not detectable during the period of virus clearance. Previous CD8+ cell depletion did not abrogate protection mediated by CD4+ T cell line transfer.

Animals↗
PubMed1991

Progressive encephalopathy and myopathy in transgenic mice expressing human foamy virus genes.

Transgenic mice carrying the bel region of human foamy retrovirus (HFV) under transcriptional control of its own long terminal repeat expressed the transgene in their central nervous systems and in smooth and striated muscle tissues. The animals developed a progressive degenerative disease of the central nervous system and of the striated muscle. Because expression of the transgene was closely correlated with the appearance of structural damage and inflammatory reactions were scanty, the disease is likely to be caused directly by the HFV proteins. These unexpected findings call for a reevaluation of the pathogenic potential of HFV in humans.

Animals↗
PubMed1991

Immunohistochemical localization of the alpha 1, alpha 2 and alpha 3 subunit of the GABAA receptor in the rat brain.

The immunohistochemical distribution of the alpha 1, alpha 2 and alpha 3 subunit of the gamma-aminobutyric acid-A (GABAA) receptor was investigated in the rat brain using affinity-purified antibodies against unique parts of the amino acid sequence of the respective subunits. The distribution of the 3 subunits differed markedly from each other indicating heterogeneity of the GABAA-receptor composition in different brain regions and at various receptive compartments (dendrites or somata) of neuronal cells.

Animals↗
PubMed1991

Microglial cells are a component of the perivascular glia limitans.

The ultrastructural relation between microglial cells and cerebral blood vessels was studied in rat brains by immune electron microscopy using antibodies against the common leukocyte antigen (Ox1), the complement receptor 3 (Ox42), and against class I and class II histocompatibility antigens (MHC antigens; Ox3, Ox6, Ox18, and I1-69). Microglial cell processes were found incorporated between the astrocytic foot processes of the glia limitans in 4-13% of cerebral microvessels. After intravenous injection of gamma-interferon, either alone or in combination with tumor necrosis factor, these microglial cell processes expressed classes I and II MHC antigens. Studies in (Lewis X DA)F1-DA bone marrow chimeras demonstrated that these cell processes belonged to resident microglia. This study suggests that microglial cells may play an important role in antigen recognition at the blood-brain barrier.

Animals↗
PubMed1991

Cytoskeleton pathology in Alzheimer's disease and related disorders.

The reported findings suggest that ubiquitination of pathological proteinaceous intracytoplasmic inclusions is not at all specific of AD. On the contrary it appears to be a general biochemical marker for disorders in the degradation of a variety of cytoskeletal and other cytoplasmic proteins. The pattern of affected cytoskeletal components is not specific of AD/SDAT tangles. Tau definitely is present also in PSP tangles and possibly in Pick bodies but not in Lewy bodies. Therefore it has to be considered that the intracytoplasmic accumulation of cytoskeletal protein/ubiquitin complexes in itself is a rather unspecific cellular reaction pattern, possibly a secondary reaction to cell injury of many types, especially, however, of neuronal aging. Nevertheless, the manifestation of NFT in an excessive quantity, intensity, and dynamics with severe concomitant lesions as in AD/SDAT undoubtedly is a true pathological and in this sense a disease-specific change.

Alzheimer Disease↗
PubMed1991

Chronic relapsing experimental allergic neuritis induced by repeated transfer of P2-protein reactive T cell lines.

Chronic relapsing experimental allergic neuritis (crEAN) was induced by repeated transfers of P2-protein reactive T lymphocyte lines. Clinically, each intravenous transfer of P2-reactive T cells induced a relapse of the disease with weight loss and flaccid paresis of the hindlimbs followed by recovery. After multiple transfers, recovery from disease was incomplete, leading to increasing neurological deficit during the remissions. The pathology of the lesions during exacerbations was characterized by massive inflammation in the peripheral nervous system, associated with extensive endoneurial oedema, nerve fibre destruction and wallerian degeneration. Selective primary demyelination and remyelination was found in the minority of affected nerve fibres. No onion bulbs were present in chronic lesions. In the central nervous system partial degeneration of the posterior columns reflected the extent of wallerian degeneration in the peripheral nerves and spinal roots. In addition, during stages of active disease some T lymphocytes and upregulation of Ia antigen expression were found in the spinal cord.

Animals↗
PubMed1991

Antibody-mediated demyelination in experimental allergic encephalomyelitis is independent of complement membrane attack complex formation.

The effects of decomplementation by cobra venom factor (CVF) on the pathogenesis of inflammation and demyelination in experimental allergic encephalomyelitis (EAE) and acute antibody-mediated demyelinating EAE (ADEAE) have been quantified histologically and immunocytochemically. In rats immunized with 50 micrograms of myelin basic protein in Freund's complete adjuvant containing 100 micrograms heat-killed Mycobacterium tuberculosis H37Ra, clinical signs of EAE were completely suppressed by two injections of CVF given 9 and 12 days post-immunization. Suppression of clinical disease was associated with a dramatic reduction in peri-vascular inflammation in the CNS, although immunohistochemical staining identified small numbers of infiltrating T cells and macrophages. In contrast, CVF treatment had no significant effect on the clinical severity of ADEAE and although C9 deposition within the CNS was virtually abolished, there was no statistically significant decrease in the extent of demyelination or inflammation. These observations indicate that in the absence of complement components C3 and C5 an antibody-dependent cell-mediated cytotoxic response plays an important role in the pathogenesis of antibody-mediated demyelination. The major role of the complement cascade in EAE appears to be the generation of pro-inflammatory factors that enhance the inflammatory response within the CNS in animals facing a mild encephalitogenic challenge.

Animals↗
PubMed1991

Coronavirus induced primary demyelination: indications for the involvement of a humoral immune response.

Coronavirus MHV-JHM infection of rodents can result in demyelinating encephalomyelitis. We analysed histological changes induced by coronavirus MHV-JHM infection in Lewis rats. Besides an acute disease (AE), chronic panencephalitis (CPE) and subacute demyelinating encephalomyelitis (SDE) were induced. These disease types were differentiated by the incubation period, the localization of lesions, the type of tissue damage and distribution of virus antigen. In AE and CPE, virus antigen was detected in neurons, astrocytes and oligodendrocytes, whereas in SDE neurons lacked virus antigen. Viral nucleocapsid protein (N) was present in the cytoplasm and the spike protein (S) was displayed on the surface of infected neural cells. However, expression of S protein relative to N protein was severely impaired in SDE lesions. Quantitative analysis of infiltrating inflammatory cells revealed that the number of macrophages and T cells were similar in lesions of AE, CPE and SDE. In contrast to that, SDE lesions contained a significantly higher number of IgG + B cells and plasma cells. In addition active demyelinating SDE lesions displayed an enhanced IgG content and deposits of complement C9. These results indicate that virus induced primary demyelination could be a consequence of antibody mediated cytotoxicity. Furthermore, a reduction in the number of cells producing spike protein in the chronic forms of the disease indicates down-regulation of this protein, possibly mediated by anti-S antibodies.

Animals↗
PubMed1991

Expression of adhesion molecules and histocompatibility antigens at the blood-brain barrier.

The migration of inflammatory cells through the blood-brain barrier in health and disease involves complex interactions between hematogenous cells, endothelial cells, the basement membrane and the perivascular glia limitans. Recent evidence is presented, suggesting that part of these interactions involve antigen independent mechanisms, mediated by cellular adhesion molecules. The accessibility of endothelial adhesion molecules in the intact blood-brain barrier is lower compared to vessels in other organs. This may account for the low traffic of hematogenous cells through the normal blood-brain barrier. However, in inflammatory conditions the expression of endothelial adhesion molecules is upregulated, which may lead to recruitment of inflammatory cells into the lesions. Antigen specific activation of T-cells at the blood-brain barrier apparently takes place mainly at perivascular monocytes and microglia cells. In severe inflammatory lesions, however, astrocytes may be additionally involved in antigen presentation.

Animals↗
PubMed1991

[Alzheimer dementia. A clinical long-term study with quantitative neuropathology].

Alzheimer's disease causes about 80% of dementias in old age. The pathological hallmarks of Alzheimer's disease are senile plaques (SP) and neurofibrillary tangles (NFT), which to a lesser degree can also be found in the brains of mentally intact elderly. The question whether SP or NFT or any other process are primarily correlated to severity of dementia can only be answered in prospective longitudinal clinical and neuropsychological studies with quantitative neuropathological investigation. We report the correlations between mini-mental-state scores and lesion counts in 3 isocortical and 3 hippocampal areas in a consecutive series of 19 Alzheimer's patients studied prospectively in the Vienna Longitudinal Study on Dementia. Lesion counts increased at very late stages of dementia and were rather low in mild to moderate severity of dementia. Mildly demented patients with very slow progression of dementia also had rather high lesion counts. Neurofibrillary changes in NFT and neuritic plaques were correlated with severity of dementia, but diffuse plaques, i.e. SP without neuritic degeneration, were not at all correlated with severity of dementia. We speculate that NFT and SP do not represent the primary process which leads to dementia.

Aged↗