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Biomedical subjects

H Lassmann

Publications and source records attributed to H Lassmann.

At least 127 records · Page 7Linked to original sources
PubMed1997

Experimental autoimmune encephalomyelitis: the antigen specificity of T lymphocytes determines the topography of lesions in the central and peripheral nervous system.

Recent studies on autoimmune encephalomyelitis and neuritis reveal that many different antigens of the central (CNS) and peripheral nervous system may become targets of an encephalitogenic T-cell response. The aim of this study was to determine the influence of T-cell specificity on the pathology of autoimmune-mediated inflammation in the nervous system. Autoimmune encephalomyelitis was induced by the adoptive transfer of CD4+ T-line cells specific for either myelin basic protein, myelin oligodendrocyte glycoprotein (MOG), myelin-associated glycoprotein, S100 beta, or glial fibrillary acidic protein. The severity of the inflammatory response was antigen- and dose-dependent. With the exception of MOG-specific T-line cells, all autoreactive T-cell lines induced inflammation in the CNS and peripheral nervous system. In the myelin-basic-protein-mediated model, the spinal cord was most severely affected with only minor inflammation in the forebrain. In contrast, both MOG- and myelin-associated-glycoprotein-specific T cells induced a far higher density of lesions in the periventricular and cerebellar white matter. S100 beta- and glial-fibrillary-acidic-protein-specific T cells mediated particularly severe inflammation in the gray matter. In addition to these topographic differences, antigen specificity also influenced the extent of both parenchymal inflammation and macrophage activation in the CNS. However, irrespective of the specificity or number of T cells transferred, the major neuropathologic correlate with disease severity was the absolute number of activated macrophages recruited into the CNS parenchyma (r = 0.9; p < 0.0001). This study suggests that differences in lesion distribution in multiple sclerosis patients may reflect differences in the antigen specificity of an encephalitogenic T-cell response.

Amino Acid Sequence↗
PubMed1996

An antisense transgenic strategy to inhibit the myelin oligodendrocyte glycoprotein synthesis.

To understand the function of the myelin oligodendrocyte glycoprotein (MOG), a myelin specific protein of the central nervous system, transgenic mice were produced. The transgene is a fusion gene containing 1.9 kb of murine myelin basic protein promoter, 430 bp of rat MOG cDNA in the reverse orientation and 4.5 kb of human proteolipid protein gene. In spite of high expression of antisense MOG mRNA in the oligodendrocytes, MOG synthesis was not inhibited in transgenic mice. This lack of inhibition of MOG underlines the difficulties encountered with antisense transgenic strategies.

Animals↗
PubMed1996

T-cell-mediated ganglionitis associated with acute sensory neuronopathy.

A 67-year-old man presented with acute painful sensory loss, areflexia, ataxia, urinary retention, and severe constipation and became unable to walk within 2 weeks. He died suddenly 5 weeks after the onset of symptoms. Autopsy revealed widespread inflammation of sensory and autonomic ganglia with immunocytochemical evidence of a CD8+ T cell-mediated cytotoxic attack against ganglion neurons. This observation suggests a novel pathogenetic mechanism of immune-mediated human ganglion cell damage comparable to mechanisms operating in polymyositis.

Acute Disease↗
PubMed1996

Apoptosis of T cells and macrophages in the central nervous system of intact and adrenalectomized Lewis rats during experimental allergic encephalomyelitis.

The adrenocortical response is central to recovery from experimental allergic encephalomyelitis (EAE) in the Lewis rat, as reflected by the increased severity of the disease in adrenalectomized animals. The protection conferred by glucocorticoids is related to the immunosuppressive effects of the steroid, which may include apoptosis of immunocompetent cells. Here we describe T-cell infiltration and apoptosis in spinal cord lesions of intact (INT) and adrenalectomized (ADX) rats during the course of EAE. The normal disease course (peak clinical score 3) was induced following intra-peritoneal transfer of 4 x 10(7) myelin basic protein (MBP)-sensitized spleen lymphocytes to INT rats. Maximum apoptosis of infiltrating T cells (32%) was evident on day 7 and was associated with the expected increase in circulating corticosterone levels and the onset of disease remission. ADX rats, which have no corticosterone response, administered 4 x 10(7) cells displayed rapid and fatal EAE with only minimal signs of T-cell apoptosis (1.9-3.8%). In order to delay the onset and prolong the disease in ADX rats, a lower cell dose was used. In ADX rats injected with 1 x 10(6) cells, disease onset was comparable to INT 4 x 10(7) rats but disease progression was equally rapid and T-cell apoptosis (1.4-8.5%) was similarly low to that seen in ADX rats given the higher dose of cells. Transfer of the lower number of splenocytes (1 x 10(6) cells) to INT rats resulted in only mild EAE (clinical score 0.5-1) which was reflected both in low T cell apoptosis (1.7-16%) and circulating corticosterone levels. In all treatment groups very few apoptotic macrophages were detected ( < 1% of all macrophages) and no differences between groups were apparent. The results suggest that glucocorticoid-mediated T-cell apoptosis, whether initiated directly or indirectly, may contribute to the recovery phase of EAE in Lewis rats.

Adrenalectomy↗
PubMed1996

Histological heterogeneity of neuroradiologically suspected adult low grade gliomas detected by Xenon enhanced computerized tomography (CT).

Xenon-enhanced computerized tomography (XeCT) was performed on 14 consecutive adult patients presenting with seizures showing supratentorial non-enhancing radiologically uniform appearing low grade gliomas on CT/MR images. Pre-operative XeCT patterns were compared with postoperative histological diagnosis, grading and Ki67 proliferation indices (PI). After gross-total, subtotal resection or biopsy, 11 astrocytomas, 2 oligodendrogliomas and 1 oligo-astrocytoma were diagnosed and graded: Grade I: 2 patients (Ki67-PI = 0.5-0.8), Grade I-II: 4 patients (Ki67-PI = 0.3-1.5), Grade II: 3 patients (Ki67-PI = 0.5-3.5), Grade II-III: 4 patients (Ki67-PI = 3.8-6.8) and Grade III: 1 patient (Ki67-PI = 5.2), (Kernohan Classification). Xenon CT studies revealed different flow patterns, correlating with the postoperative histological diagnosis, grading and proliferation indices: A tumour group with well defined, delayed, only minimally enhancing tumour area (5 patients, Grade I, I-II or II), a second group with less well defined low-flow-area borders and inhomogenous, strong enhancement within the tumour (4 patients, Grade II-III, III) and a third group with fast enhancing tumours was identified. The third pattern was exclusively shown in the 2 oligodendrogliomas (Grade I and II-III) and 1 oligo-astrocytoma (Grade II). The preliminary report identifies the Xenon enhance CT as a beneficial pre-operative investigation for patients with radiologically uniform appearing suspected adult supratentorial low-grade gliomas, which may give information about the presence of anaplastic foci or oligodendroglial components.

Adolescent↗
PubMed1996

Correlations between mental state and quantitative neuropathology in the Vienna Longitudinal Study on Dementia.

Quantitative clinicopathological correlation studies are one way to address the question of the relevance of morphological abnormalities in Alzheimer's dementia (AD). This paper summarizes results of the Vienna Longitudinal Study on Dementia obtained during the past few years and presents a critical discussion on the relevance of clinicopathological correlation studies for the pathogenesis of AD. Plotting of psychometric test scores against the numbers of plaques, tangles and neuropil threads in various cortical areas shows that significant correlations are due primarily to very high lesion counts in severely demented patients. These data indicate that neocortical neurofibrillary pathology can be considered an end-stage marker in the pathology of AD. On the other hand, the topographical staging of neuritic Alzheimer changes proposed by Braak and Braak (1991) appears to be a better reflection of the progression of the degenerative process than numerical lesion counts; there is a linear correlation between the Braak stages and Mini-Mental State scores in 122 aged individuals. Significant correlations are further obtained between the severity of dementia and the levels of a number of synaptic proteins including synaptophysin and the chromogranins. Taken together, our data suggest that none of the classical AD lesions, plaques and tangles, play a central role in the pathogenesis of dementia, a fact that is supported by a molecular biological study showing that there is no close relationship between these lesions and the neurons undergoing degeneration in AD. Whereas neuritic pathology is a useful histopathological marker for the diagnosis and staging of AD, the major correlate of cognitive deficits is the loss of corticocortical and subcorticocortical connections reflected by a depletion of synapses. This pathology may be induced by a mismetabolism of the beta-amyloid precursor proteins or their interaction with cytoskeletal proteins related to neuronal degeneration.

Aged↗
PubMed1996

Partial inhibition of AT-EAE by an antibody to ICAM-1: clinico-histological and MRI studies.

The role of quantitative proton magnetic resonance imaging (MRI) for the evaluation of immunopathological lesions in the CNS was studied in adoptively transferred experimental allergic encephalomyelitis (AT-EAE). We utilized a recently established treatment model, inhibition of the cell adhesion molecule ICAM-1 by the monoclonal antibody 1A-29. The animals were scanned on days 3, 5 and 7 after injection of encephalitogenic T-cells, before and after bolus injection of Gd-DTPA by performing T1-measurements to assess the integrity of the blood-brain barrier (BBB). On day 7, immunohistochemistry was performed looking for T-cells, activated macrophages, and albumin staining. There was clinical evidence of partial inhibition of AT-EAE in rats treated with antibodies against ICAM-1. This finding was in line with a significantly reduced number of T-cells in the medulla. However, the number of activated macrophages and the distribution of albumin did not differ from untreated AT-EAE animals. The histological findings are in agreement with the MRI data before and after Gd-DTPA injection which were similar in treated and untreated AT-EAE rats on day 3 and 5. On day 7 after Gd-DTPA injection there was evidence of a delayed breakdown of the BBB in the treated rats. The observation of a dissociation of clinical and MRI findings, especially evidence of Gd-enhancement despite clinical improvement, may be important in the context of interpreting MRI studies in MS patients in treatment trials.

Animals↗
PubMed1996

Patterns of synaptic and nerve cell pathology in Alzheimer's disease.

Recent neuropathological evidence suggests that synapse pathology is the major correlate of cognitive decline in Alzheimer's disease (AD) patients, but also in other dementia syndromes. We suggest that synapse loss in AD-patients mainly reflects neuronal destruction in other iso- and allocortical areas as well as in brain stem nuclei. In addition an impaired compensatory synaptogenesis may contribute to the reduction in synaptic connectivity. The patterns of cell death in AD-brains determined by analysis of DNA-fragmentation in situ revealed significantly higher numbers of dying cells (neurons as well as glia cells) in AD-brains compared to controls. Amyloid deposition as well as neurofibrillary pathology apparently do not induce cell death directly, but may increase the risk of cells to die in response to additional minor metabolic insults. We propose that multiple pathogenetic factors are involved in the reduction of synaptic connectivity in AD-brains, which finally is reflected in the decline of cognitive functions.

Alzheimer Disease↗
PubMed1996

X-irradiation-induced changes in the diffusion parameters of the developing rat brain.

Three diffusion parameters of brain tissue, extracellular space volume fraction (alpha), tortuosity (lambda) and non-specific uptake (kappa') of tetramethylammonium were studied in the somatosensory neocortex and subcortical white matter of the rat during postnatal development (postnatal days 2-21) after X-irradiation at postnatal days 0-1. The diffusion parameters were determined from extracellular concentration-time profiles of tetramethylammonium. The tetramethylammonium concentration was measured in vivo with ion-selective microelectrodes positioned 130-200 microns from an iontophoretic source. X-irradiation with a single dose of 40 Gy resulted in typical early morphological changes in the tissue, namely cell death, DNA fragmentation, extensive neuronal loss, blood-brain barrier damage, activated macrophages, astrogliosis, increase in extracellular fibronectin and concomitant changes in all three diffusion parameters. The changes were observed as early as 48 h post-irradiation (at postnatal days 2-3) and still persisted at postnatal day 21. On the other hand, X-irradiation with a single dose of 20 Gy resulted in relatively light neuronal damage and loss, while blood-brain barrier damage, astrogliosis and changes in diffusion parameters were not significantly different from those found with 40 Gy. It is known that the volume fraction of the extracellular space in the non-irradiated cortex is large in newborn rats and diminishes with age [Lehmenkühler A. et al. (1993) Neuroscience 55, 339-351]. X-irradiation with a single dose of 40 or 20 Gy blocked the normal pattern of volume fraction decrease during postnatal development, and in fact brought about a significant increase. At postnatal days 4-5, alpha increased to 0.49 +/- 0.036 in layer III, 0.51 +/- 0.042 in layer IV, 0.48 +/- 0.02 in layer V, 0.48 +/- 0.028 in layer VI and 0.48 +/- 0.025 in the white matter. The large increase in alpha persisted three weeks after X-irradiation. Tortuosity and non-specific uptake decreased significantly at postnatal days 2-5; at days 8-9 they were not significantly different from those of control animals, while they increased significantly at days 10-21. Less pronounced but significant changes in all three diffusion parameters were also found in areas in the ipsilateral hemisphere adjacent to directly X-irradiated cortex. Compared to the control animals [Lehmenkühler A. et al. (1993) Neuroscience 55, 339-351], a significant decrease of alpha, lambda and kappa' was found in the contralateral hemisphere 48-72 h after X-irradiation. Later, alpha values were not significantly different from those in control animals. The decrease in lambda persisted at postnatal days 4-5. A significant increase in lambda and kappa' was found at postnatal days 18-21. We conclude that X-irradiation of the brain in the early postnatal period, even when it results in only relatively light damage, still produces changes in all three diffusion parameters, particularly a large increase in extracellular space volume fraction in all cortical layers, and in the subcortical white matter. Such changes in extracellular volume fraction of the brain can contribute to impairment of signal transmission, e.g. by diluting ions and neuroactive substances released from cells, and can play an important role in functional deficits, as well as in the impairment of developmental processes. Moreover, the increase in tortuosity (inferred from the decrease in apparent diffusion coefficient) in the X-irradiated cortex, as well as in the contralateral hemisphere, suggests that, even when extracellular volume is large, the diffusion of the substances is substantially hindered.

Animals↗
PubMed1996

Co-localization of secretoneurin immunoreactivity and macrophage infiltration in the lesions of experimental autoimmune encephalomyelitis.

Secretoneurin, a novel neuropeptide, has recently been shown to attract monocytes. In our present study we have tested whether the local presence of secretoneurin within the CNS of the rat may influence the topographical distribution of inflammatory infiltrates in acute T-cell mediated encephalomyelitis. Experimental allergic encephalomyelitis was induced by passive transfer of myelin basic protein-reactive T-lymphocytes and the distribution of T-cells and macrophages was studied at day 3, 4 and 7 after transfer. In the same sections secretoneurin immunoreactivity was visualized by immunohistochemistry. A clustering of macrophages, but not of T-lymphocytes, was seen at sites of secretoneurin immunoreactivity in all stages of experimental autoimmune encephalomyelitis. Our data indicate for the first time that local neuropeptides may play a role in leucocyte recruitment into inflammatory lesions of the CNS.

Animals↗
PubMed1996

Macrophages in multiple sclerosis.

Macrophages are important effector cells involved in the pathogenesis of demyelination in multiple sclerosis (MS). Macrophage differentiation was studied in a series of 158 MS plaques from 43 patients obtained at different stages of the disease. Macrophages were identified by immunocytochemistry using a panel of antibodies recognizing different formalin- and paraffin-resistant macrophage activation antigens. The number of cells stained with each antibody was related to the demyelinating activity of the lesions as detected by the presence of myelin degradation products as well as to the category of MS tissue. Highest numbers of macrophages were observed in actively demyelinating and early remyelinating lesions using immunocytochemistry for the panmacrophage marker Ki-M1P. Lower numbers were encountered in inactive, demyelinated or late remyelinated lesions. The acute stage inflammatory macrophage markers MRP14 and 27E10 were selectively expressed in early and late active lesions, thus allowing the identification of actively demyelinating lesions. The chronic stage inflammatory macrophage marker 25F9, in contrast, showed a continuous expression also in inactive lesions. The different types of MS tissue revealed significant differences in their macrophage response. The most intense macrophage infiltration was seen in acute MS cases whereas lesions of early and late chronic MS showed lower macrophage levels. These findings indicate a differentiated pattern of macrophage activation in MS depending on the stage of the demyelinating activity as well as on the category of MS tissue. Furthermore, these macrophage markers give new parameters for staging the inflammatory and demyelinating activity of MS lesions.

Acute Disease↗
PubMed1996

Accelerated myelinogenesis by dietary lipids in rat brain.

Our previous work showed an early development of behavioral reflexes in rats whose mothers had been fed, during pregnancy and lactation, a lipid fraction extracted from yeast grown on n-alkanes (which contain 50% odd-chain fatty acids) in comparison with controls fed a margarine diet. To clarify whether the observed changes might be linked to an early myelination, we have investigated mRNAs involved in myelin synthesis in the brains of offspring at 5 days of age by northern blot and in situ hybridization. Northern blot analysis showed that proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG) mRNAs were higher in animals on the lipid diet compared with controls. In situ hybridization with probes specific for PLP, myelin basic protein, and MOG mRNA showed significantly higher numbers of positive cells in test animals compared with controls in all brain regions. This study shows an acceleration of myelinogenesis induced by dietary lipids. These data can give a new insight in the therapeutical approaches involved to promote repair in demyelinating diseases.

Alkanes↗
PubMed1996

In vivo MRI and its histological correlates in acute adoptive transfer experimental allergic encephalomyelitis. Quantification of inflammation and oedema.

In vivo proton MRI was carried out on a 7 Tesla system at 2-3 day intervals over 10 days in rats with adoptive transfer experimental allergic encephalomyelitis (AT-EAE), an animal model of some aspects of multiple sclerosis. In order to assess the integrity of the blood-brain barrier (BBB), MRI was performed by acquiring quantitative MR-relaxation time T1 images of the AT-EAE rat brain before and after i.v. injection gadolinium-diethylene triaminepentaacetic acid (Gd-DTPA) using an ultrafast MRI technique. The MRI findings were compared with the immunohistochemical stain of T cells, macrophages and albumin and, in addition, apoptosis of T cells was assessed using in situ nick translation (ISNT). Prior to injection of Gd-DTPA, an increase of T1 times in the brain of the AT-EAE rats was observed, which paralleled the time course of albumin in histological sections. These were MRI findings observed well before the onset of major cellular infiltration and before the onset of clinical signs. After i.v. injection of Gd-DTPA the observed decrease of T1 times paralleled macrophage activation, and less closely T-cell infiltration. Our results provide evidence that using MRI, it is possible to assess quantitatively the breach of the BBB and to distinguish in vivo between two components of the early phase of the lesion, inflammatory infiltrates and vasogenic oedema.

Acute Disease↗
PubMed1996

Antigen presentation by astrocytes primes rat T lymphocytes for apoptotic cell death. A model for T-cell apoptosis in vivo.

In this study we have characterized apoptotic cell death of autoreactive T cells resulting from their interaction with astrocytes and the modulatory effect of steroid hormones. Time kinetics of T-cell activation by interferon (IFN)-gamma-treated astrocytes from neonatal Lewis rats and by professional antigen presenting cells (APCs) from bulk suspensions of thymus or spleen were performed. [3H]Thymidine incorporation of neuritogenic P2- and encephalitogenic myelin basic protein (MBP)-specific T-cell lines declined after 48 h in culture with astrocytes. A similar suppressive effect was observed when T cells were cocultured with thymic APCs and astrocytes. This effect disappeared when astrocytes were separated by a transwell system. After 72 h of culture with astrocytes a mean of 17.5 +/- 12.4% T cells exhibited morphological signs of apoptosis. Apoptosis was identified by light microscopy, and confirmed by electron microscopy, by in situ tailing reaction and by agarose gel electrophoresis. Glucocorticosteroids and oestrogen specifically enhanced T-cell apoptosis within 8 h (69.8 +/- 23.1% and 69 +/- 17.1%, respectively) when added after 72 h to the astrocyte system, but not at earlier time points of T-cell activation or when thymic APCs were used. Glucocorticoid-mediated T-cell apoptosis was inhibited by the steroid-receptor antagonist RU 486. Pregnenolone, lipocortin-1, indomethacin and transforming growth factor-beta did not induce apoptosis in this system. The steroid effect was not associated with CD28, IL-2 receptor, or transferrin-receptor expression, which were equally upregulated on T cells activated by astrocytes or thymic APC as shown by fluorescence activated cell sorting (FACS) analysis. We conclude that astrocytes as CNS-specific APC may render T cells susceptible for induction of apoptotic cell death. Some steroid hormones can markedly enhance this process in vitro and may augment an additional effect of a systemic corticosteroid response in vivo during recovery from autoimmune encephalomyelitis.

Analysis of Variance↗
PubMed1996

Intracerebral targets and immunomodulation of murine Listeria monocytogenes meningoencephalitis.

In humans, infection with Listeria monocytogenes (L. monocytogenes) can severely affect the central nervous system (CNS). In the present study we have employed a murine model of CNS listeriosis to characterize the intracerebral distribution of L. monocytogenes. Following intracerebral application of a low dose of L. monocytogenes (serovar 1/2a, EGD strain) a severe fatal leptomeningitis, ventriculitis, and encephalitis developed. Listeria were detectable both intracellularly in different cell types of the CNS and extracellularly in the cerebrospinal fluid. Ultrastructural analysis revealed macrophages, granulocytes, plexus epithelial cells, ependymal cells, and neurons as target cells. An inflammatory reaction with macrophages and granulocytes developed in the brains of these animals but was not sufficient to prevent the fatal outcome of the disease. However, active immunization of mice prior to an intracerebral challenge infection significantly reduced the mortality. Immunized animals showed an early recruitment of a significant number of CD8+ and, to a lesser degree, CD4+ T cells within 24 hours p.i. as well as a strong activation of microglial cells and macrophages. These findings may provide an interesting model for studies on the pathogenesis of cerebral listeriosis.

Adjuvants, Immunologic↗
PubMed1996

MHC class I-mediated cytotoxicity does not induce apoptosis in muscle fibers nor in inflammatory T cells: studies in patients with polymyositis, dermatomyositis, and inclusion body myositis.

Apoptosis plays a crucial role in natural recovery from T cell-mediated autoimmune disorders of the nervous system. Whether apoptosis also occurs in human inflammatory myopathies is unclear. In this study we examined muscle biopsy specimens from untreated patients with polymyositis (n = 12), dermatomyositis (n = 12), and inclusion body myositis (n = 12) for the presence of apoptosis using morphological criteria and DNA fragmentation by in situ tailing. In all these disorders, only rare T cells exhibited signs of apoptosis by nuclear morphology and in situ labeling techniques. Although Fas-expression was upregulated in a few inflammatory cells, increased apoptosis of the surrounding T cells was not observed. Further, nuclei of degenerating muscle fibers did not show morphological signs of apoptosis and were not labeled by the tailing reaction. We conclude that in the inflammatory myopathies, T cell inflammation is not cleared by apoptosis and affected muscle fibers do not die by apoptosis. The observations are consistent with the non-self-limited nature of these disorders and suggest that, in contrast to the nervous system, the local microenvironment in muscle does not deliver pro-apoptotic stimuli.

Adult↗
PubMed1996

Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis.

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. The hallmark of its pathology is the demyelinated plaque with reactive glial scar formation. However, a detailed analysis of the patterns of demyelination, oligodendroglia cell pathology and the reaction of other tissue components suggests that the pathogenesis of myelin destruction in this disease may be heterogeneous. In this review we present a new classification scheme of lesional activity on the basis of the molecular composition of myelin degradation products in macrophages. When these criteria are used, different patterns of demyelination can be distinguished, including demyelination with relative preservation of oligodendrocytes, myelin destruction with concomitant and complete destruction of oligodendrocytes or primary destruction or disturbance of myelinating cells with secondary demyelination. Furthermore, in some cases a primary selective demyelination may be followed by a secondary oligodendrocyte loss in the established lesions. Finally, some extraordinarily severe conditions may result in destructive lesions with loss of myelin, oligodendrocytes, axons and astrocytes. This heterogeneity of plaque pathology is discussed in the context of recent experimental models of inflammatory demyelination, which show that different immunological pathways may lead to the formation of demyelinated plaques that reveal the diverse structural aspects described above. Our data indicate, that the demyelinated plaques of multiple sclerosis may reflect a common pathological end point of a variety of different immunological mechanisms of myelin destruction in this disease.

Animals↗