Induction of experimental autoimmune encephalomyelitis by CD4+ T cells specific for an astrocyte protein, S100 beta.

S100 beta protein is a calcium binding protein that is not only expressed by astrocytes in the CNS, but also in many other tissues including the eye, thymus, spleen and lymph nodes. Despite this tissue distribution, which was expected to induce a firm state of self-tolerance to S100 beta, the Lewis rat mounts a strong T cell response to this autoantigen. The pathogenicity of this T cell response was demonstrated by the adoptive transfer of S100 beta-specific T cells which induced an inflammatory response in the CNS and eye of naive syngeneic recipients.

Basic mechanisms of brain inflammation.

The mechanisms, how the immune system surveys the nervous tissue and how brain inflammation is regulated are essential questions for therapy of neuroimmunological diseases. The nervous system is continuously patrolled by hematogenous cells, which may pass the blood brain barrier in an activated state. When these cells find their respective target antigen in the CNS compartment, an inflammatory reaction is started through the secretion of proinflammatory cytokines.

Mechanisms of cell death in Alzheimer's disease.

The etiology of Alzheimer's disease (AD) as well as its exact pathogenesis are unknown. Eventhough the deposition of beta A4 and the formation of neurofibrillary tangles represent impressive morphological hallmarks of the disease, several lines of evidence suggest that both lesions are not sufficient as causes of the neurodegenerative process. On the other hand, in vitro studies have shown that beta A4 is neurotoxic and is able to induce apoptotic cell death in neuronal cell cultures.

Patterns of oligodendrocyte pathology in coronavirus-induced subacute demyelinating encephalomyelitis in the Lewis rat.

Intracerebral infection of rats with JHM coronavirus induces a chronic inflammatory demyelinating disease, which in many respects mimicks the pathology of multiple sclerosis. We investigated the patterns of demyelination and oligodendrocyte pathology in this model. In early stages of the disease infection of oligodendrocytes was associated with a downregulation of expression of mRNA for proteolipid protein in the absence of myelin destruction.

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.

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.

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.

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.

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).

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.

APP peptides stimulate lymphocyte proliferation in normals, but not in patients with Alzheimer's disease.

We hypothesized that metabolic products of the Alzheimer beta amyloid precursor protein (APP) might be targets for cells of the immune system. To test this hypothesis, peripheral blood lymphocytes from young and old healthy blood donors and patients with Alzheimer's disease were analysed for their responsiveness upon stimulation with amyloid beta protein as well as with four other synthetic peptides corresponding to parts of the APP sequence. Stimulation of resting blood lymphocytes from young and old healthy blood donors resulted in IL-2 receptor expression and proliferation in both age groups.

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.

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.

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.

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.

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.

Evidence for neuronal apoptosis in pontosubicular neuron necrosis.

Pontosubicular neuron necrosis (PSN) is characterized by acute neuronal death in the subiculum and the pons occurring in a circumscribed perinatal period. The morphological changes in PSN are quite similar to those described during apoptosis, a form of programmed cell death. Morphological re-evaluation of the lesions by light and electron microscopy revealed the typical changes of apoptosis with condensed basophilic nuclei and the formation of apoptotic bodies.

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.

[Perspectives in multiple sclerosis research].

There is little doubt that multiple sclerosis (MS) is an immune mediated disease, yet the exact immunological mechanisms, that are responsible for inflammation and demyelination in this disease are controversial. Recent evidence is summarized here, which suggests that heterogeneous pathogenetic mechanisms may lead to the inflammatory demyelinating plaques in different MS patients. This heterogeneity apparently involves the antigen specificity of the immune response as well as the mechanisms, responsible for the destruction of myelin sheaths.

[Pathogenesis of multiple sclerosis and other neural autoimmune diseases].

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Its pathological hallmark is the demyelinated plaque with reactive glial scarring. Recent neuropathological and immunopathological data suggest a pronounced pathologic heterogeneity of MS plaques.

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.

Changes of extracellular space volume and tortuosity in the spinal cord of Lewis rats with experimental autoimmune encephalomyelitis.

Three diffusion parameters of nervous tissue, extracellular space (ECS) volume fraction (alpha), tortuosity (gamma) and non-specific uptake (k') of tetramethylammonium (TMA+), were studied in the spinal cord of rats during experimental autoimmune encephalomyelitis (EAE). The three parameters were determined in vivo from concentration-time profiles of TMA+ using ion-selective microelectrodes. EAE was induced by injection of guinea-pig myelin basic protein (MBP), which resulted in typical morphological changes in the CNS tissue, namely inflammatory reaction, astrogliosis, blood-brain barrier (BBB) damage and paralysis.

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.

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.