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M E Bruce

Publications and source records attributed to M E Bruce.

At least 19 recordsLinked to original sources
PubMed2003

Comparison of the neuropathological characteristics of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) in mice.

Bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) belong to a group of diseases called the transmissible spongiform encephalopathies (TSEs). Transmission studies in inbred mice (strain typing) provided overwhelming evidence that vCJD arose from BSE. In this study, we compare the patterns of neuropathology in a panel of three inbred mouse strains (RIII, C57BL and VM) and one cross (C57BL x VM) infected with either vCJD or BSE. For each mouse strain, patterns of abnormal prion protein (PrPres) deposition, astrocytosis and vacuolation were similar in the vCJD- and BSE-challenged mice. Prion protein (PrP)-positive plaques were prominent in the VM and C57BL x VM mice in addition to diffuse PrPres accumulation, whereas only diffuse PrPres labelling was observed in the RIII and C57BL mice. The hippocampus was targeted in all mouse strains, as was the cochlear nucleus in the medulla, both showing consistent severe vacuolation and heavy PrPres deposition. Although the targeting of PrPres was similar in the BSE- and vCJD-infected brains, the amount and intensity of PrPres observed in the brains treated with formic acid during fixation was reduced considerably. The distribution of astrocytosis was similar to the targeting of PrPres deposition in the brain, although some differences were observed in the hippocampi of mice challenged with vCJD. We conclude that there are no significant differences in the targeting of neuropathological changes observed in the BSE- and vCJD-infected mice, consistent with the previous evidence of a link between BSE and vCJD.

Animals↗
PubMed2001

Detection of variant Creutzfeldt-Jakob disease infectivity in extraneural tissues.

Abnormal accumulations of prion protein (PrP) can be detected in the spleen, lymph nodes, and tonsils of patients with variant Creutzfeldt-Jakob disease (vCJD). Therefore, it has been assumed, but not shown, that these tissues harbour infectivity, which in turn presents the potential for iatrogenic spread through surgery. Here, we show and measure levels of infectivity in spleen and tonsil from two patients with vCJD, by bioassay in intracerebrally inoculated RIII mice. Similar bioassays failed to detect infectivity in buffy coat and plasma.

Animals↗
PubMed2001

Scrapie strains maintain biological phenotypes on propagation in a cell line in culture.

Bovine spongiform encephalopathy (BSE) and its human equivalent, variant Creutzfeldt-Jakob disease (vCJD), are caused by the same strain of infectious agent, which is similar to, but distinct from, >20 strains of their sheep scrapie homologue. A better understanding of the molecular strain determinants could be obtained from cells in monoculture than from whole animal studies where different cell targeting is commonly a strain-related feature. Although a few cell types can be infected with different strains, the phenotypes of the emergent strains have not been studied. We have cured the scrapie-infected, clonal SMB cell line with pentosan sulfate, stably re-infected it with a different strain of scrapie and shown that biological properties and prion protein profiles characteristic of each original strain are propagated faithfully in this single non-neuronal cell type. These findings attest to the fact that scrapie strain determinants are stable and host-independent in isolated cells.

Animals↗
PubMed2001

Temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays onset of scrapie.

Following peripheral exposure to transmissible spongiform encephalopathies (TSEs), infectivity usually accumulates in lymphoid tissues before neuroinvasion. The host prion protein (PrPc) is critical for TSE agent replication and accumulates as an abnormal, detergent insoluble, relatively proteinase-resistant isoform (PrPSc) in diseased tissues. Early PrPSc accumulation takes place on follicular dendritic cells (FDCs) within germinal centers in lymphoid tissues of patients with variant Creutzfeldt-Jakob disease (vCJD), sheep with natural scrapie or rodents following experimental peripheral infection with scrapie. In mouse scrapie models, the absence of FDCs blocks scrapie replication and PrPSc accumulation in the spleen, and neuroinvasion is significantly impaired. The mechanisms by which the TSE agent initially localizes to lymphoid follicles and interacts with FDCs are unknown. Antigens are trapped and retained on the surface of FDCs through interactions between complement and cellular complement receptors. Here we show that in mice, both temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays the onset of disease following peripheral infection, and reduces the early accumulation of PrPSc in the spleen. Thus, in the early stages of infection, C3 and perhaps C1q contribute to the localization of TSE infectivity in lymphoid tissue and may be therapeutic targets.

Animals↗
PubMed2000

Detection of PrP in extraneural tissues.

Transmissible spongiform encephalopathies (TSEs) or "prion diseases" are a group of unconventional fatal diseases. TSEs are characterised by the accumulation of a modified form of the normal host glycoprotein, PrP (PrP(c)). In the course of infection PrP(c) is converted to an abnormally protease resistant form, PrP(Sc). The exact nature of the infectious agent responsible for these diseases remains controversial. While there is compelling evidence that TSE agents contain an informational molecule, possibly a nucleic acid, some believe that the infectious agent or "prion" is solely composed of PrP(Sc). Nevertheless, PrP is required for TSE pathogenesis, as mice devoid of the PrP gene (PrP(-/-)) remain healthy when challenged with TSE isolates and are unable to replicate infectivity within the central nervous system (CNS) or in other tissues. In recent years immunocytochemistry has been used to pinpoint which cells are associated with abnormal accumulations of PrP, providing important information on the cellular targeting of TSE infection. In uninfected and scrapie-infected mice, PrP protein is found in the CNS and in extraneural tissues such as spleen and lymph nodes. In the peripheral lymphoid system, PrP is associated with follicular dendritic cells that are known to be important for replication of infectivity for at least one TSE strain. This review will focus on current methods for the immunocytochemical detection of PrP in murine extraneural tissues, mainly lymphoid tissues, and will discuss recent findings on the role of the peripheral lymphoid system in TSE pathogenesis.

Animals↗
PubMed2000

Sites of prion protein accumulation in scrapie-infected mouse spleen revealed by immuno-electron microscopy.

Prion protein (PrP) from the brains of animals with transmissible spongiform encephalopathies is partially protease resistant (PrP(res)) compared with fully sensitive PrP (PrP(sen)) from uninfected brains. In most experimental models, PrP(res) is a reliable indicator of infectivity. Light microscopic studies have suggested that both PrP(sen) and disease-specific accumulations of PrP are associated with follicular dendritic cells (FDCs). Using immunogold electron microscopy, this study has demonstrated disease-specific accumulation of PrP in the spleens of C57 BL mice, 70 days after intracerebral infection with the ME7 strain of scrapie and at the terminal stage of disease at 170 days. At both stages, tingible body macrophages contained PrP within lysosomes and PrP was also detected at the plasmalemma of FDCs. In the light zone of follicles of terminally diseased mice, all FDC dendrites were arranged in the form of highly reactive or hyperplastic labyrinthine glomerular complexes, within which PrP was consistently seen between FDC processes in association with abundant electron dense material, interpreted as antigen-antibody complexes. Within some glomeruli, fibrillar forms of PrP consistent with amyloid were seen. At 70 days after challenge, large or hyperplastic labyrinthine complexes were rare and invariably labelled for PrP. However, sparse PrP labelling was also seen on simple FDC processes at this stage. The ubiquitous accumulation of extracellular PrP in complex glomerular dendrites of FDCs in spleens from terminally affected mice, contrasted with simple FDC profiles, sparse PrP and limited electron dense deposits in all but a few FDCs of 70-day post-infected mice. This suggests that FDCs continually release PrP from the cell surface, where it is associated with trapped antigen-antibody complexes and dendritic extension. It is likely that tingible body macrophages acquire PrP following phagocytosis of PrP within iccosomes or from the extracellular space around FDC dendrites. These studies would not support an intracellular phase of PrP accumulation in FDCs but show that PrP is produced in excess by scrapie-infected cells from where it is released into the extracellular space. We suggest that PrP(sen) is involved in dendritic extension or in the process of antibody-antigen trapping, perhaps as part of the binding mechanism for antigen-antibody complexes. Reproduced with the permission of Her Majesty's Stationery Office. Published by John Wiley & Sons, Ltd.

Animals↗
PubMed2000

Follicular dendritic cells in scrapie pathogenesis.

Scrapie pathogenesis was studied in chimaeric mice that carried the prion protein (PrP) gene only in particular cells of the immune system. These mice were produced by grafting bone marrow from PrP expressing donors into PrP deficient recipients and vice versa. As follicular dendritic cells are not replaced significantly from the bone marrow in adult mice, this procedure resulted in a mismatch in PrP genotype between these cells and bone marrow derived cells such as lymphocytes. Using these models we obtained strong evidence that follicular dendritic cells produced high levels of the normal form of PrP in uninfected mice. Furthermore, the replication of a mouse-passaged scrapie strain in the spleen depended only on the presence of PrP expressing follicular dendritic cells. PrP expression by lymphocytes or other bone marrow derived cells had no influence on replication in spleen or on neuroinvasion in these models. These results indicate that the follicular dendritic cell is a potential target for prophylactic or therapeutic intervention in transmissible spongiform encephalopathies.

Animals↗
PubMed2000

Follicular dendritic cells in TSE pathogenesis.

The pathogenesis of transmissible spongiform encephalopathies (TSEs) often includes a replication phase in lymphoid tissues before infection spreads to the central nervous system. Recent studies show that the follicular dendritic cells of the germinal centres are critical for this replication. These cells are therefore potential targets for therapy or prophylaxis in natural TSEs, such as variant Creutzfeldt-Jakob disease.

Animals↗
PubMed2000

Tumor necrosis factor alpha-deficient, but not interleukin-6-deficient, mice resist peripheral infection with scrapie.

In most peripheral infections of rodents and sheep with scrapie, infectivity is found first in lymphoid tissues and later in the central nervous system (CNS). Cells within the germinal centers (GCs) of the spleen and lymph nodes are important sites of extraneural replication, from which infection is likely to spread to the CNS along peripheral nerves. Here, using immunodeficient mice, we investigate the identity of the cells in the spleen that are important for disease propagation. Despite possessing functional T and B lymphocytes, tumor necrosis factor alpha-deficient (TNF-alpha(-/-)) mice lack GCs and follicular dendritic cell (FDC) networks in lymphoid tissues. In contrast, lymphoid tissues of interleukin-6-deficient (IL-6(-/-)) mice possess FDC networks but have impaired GCs. When the CNSs of TNF-alpha(-/-), IL-6(-/-), and wild-type mice were directly challenged with the ME7 scrapie strain, 100% of the mice were susceptible, developing disease after closely similar incubation periods. However, when challenged peripherally (intraperitoneally), most TNF-alpha(-/-) mice failed to develop scrapie up to 503 days postinjection. All wild-type and IL-6(-/-) mice succumbed to disease approximately 300 days after the peripheral challenge. High levels of scrapie infection and the disease-specific isomer of the prion protein, PrP(Sc), were detectable in spleens from challenged wild-type and IL-6(-/-) mice but not from TNF-alpha(-/-) mice. Histopathological analysis of spleen tissue demonstrated heavy PrP accumulations in direct association with FDCs in challenged wild-type and IL-6(-/-) mice. No PrP(Sc) accumulation was detected in spleens from TNF-alpha(-/-) mice. We conclude that, for the ME7 scrapie strain, mature FDCs are critical for replication in lymphoid tissues and that in their absence, neuroinvasion following peripheral challenge is impaired.

Animals↗
PubMed1999

Scrapie replication in lymphoid tissues depends on prion protein-expressing follicular dendritic cells.

The immune system is central in the pathogenesis of scrapie and other transmissible spongiform encephalopathies (TSEs) or 'prion' diseases. After infecting by peripheral (intraperitoneal or oral) routes, most TSE agents replicate in spleen and lymph nodes before neuroinvasion. Characterization of the cells supporting replication in these tissues is essential to understanding early pathogenesis and may indicate potential targets for therapy, for example, in 'new variant' Creutzfeldt-Jakob disease. The host 'prion' protein (PrP) is required for TSE agent replication and accumulates in modified forms in infected tissues. Abnormal PrP is detected readily on follicular dendritic cells (FDCs) in lymphoid tissues of patients with 'new variant' Creutzfeldt-Jakob disease, sheep with natural scrapie and mice experimentally infected with scrapie. The normal protein is present on FDCs in uninfected mice and, at lower levels, on lymphocytes. Studies using severe combined immunodeficiency (SCID) mice, with and without bone marrow (BM) grafts, have indicated involvement of FDCs and/or lymphocytes in scrapie pathogenesis. To clarify the separate roles of FDCs and lymphocytes, we produced chimeric mice with a mismatch in PrP status between FDCs and other cells of the immune system, by grafting bone marrow from PrP-deficient knockout mice into PrP-expressing mice and vice versa. Using these chimeric models, we obtained strong evidence that FDCs themselves produce PrP and that replication of a mouse-passaged scrapie strain in spleen depends on PrP-expressing FDCs rather than on lymphocytes or other bone marrow-derived cells.

Animals↗
PubMed1999

Molecular analysis of ovine prion protein identifies similarities between BSE and an experimental isolate of natural scrapie, CH1641.

New variant Creutzfeldt-Jakob disease (vCJD) and bovine spongiform encephalopathy (BSE) are caused by the same strain of pathogen and, as sheep can develop experimental BSE, this has raised concern that humans may be at risk from eating mutton if BSE has naturally transmitted to sheep. Biochemical typing of abnormal prion proteins (PrPsc) has been suggested to detect BSE in sheep. Although this approach is ingenuous, we can now report biochemical evidence of strain variation in contemporary and archival brain tissue from cases of experimental BSE or experimental and natural scrapie in sheep. Interestingly, we found at least one isolate of natural scrapie (CH 1641) with a very similar, but not identical, PrPsc profile to BSE but which differs from BSE in its transmission characteristics to mice.

Animals↗
PubMed1998

Determination of the frequency and distribution of vascular and parenchymal amyloid with polyclonal and N-terminal-specific PrP antibodies in scrapie-affected sheep and mice.

Brains from 17 histopathologically confirmed cases of scrapie, five of which had congophilic vascular amyloid, were stained immunohistochemically for prion protein (PrP) using a polyclonal antibody. Two clinically suspect but pathologically unconfirmed cases of natural sheep scrapie and the brains of four mice infected with the 111A murine scrapie strain were also examined. Selected sections containing amyloid were stained with each of two peptide antibodies which recognise the N-terminal amino acid residues which are lost following protease digestion of the disease-specific isoform of PrP. The mice infected with the 111A murine scrapie strain had large numbers of hypermature plaques. All the amyloid plaques from both natural sheep scrapie brains and experimental murine brains were heavily immunostained by the polyclonal and both peptide antibodies. In addition, disease-specific accumulations of PrP were detected in endothelial cells or in the intima of blood vessels of the cerebral cortex of sheep scrapie brains. The affected blood vessels were located in areas which otherwise lacked typical scrapie pathology. Vascular accumulations of PrP were also found in leptomeningeal and choroid plexus blood vessels. Vascular amyloid was found mainly in the neocortex. Vascular amyloid and disease-specific parenchymal accumulations of PrP were found in two sheep which showed clinical signs of scrapie but lacked its typical vacuolar pathology. These results show that the mature amyloid of scrapie is composed of, or contains a substantial proportion of, whole length PrP protein. Thus truncation of PrP is not essential for the aggregation of PrP into amyloid. The vascular amyloid of natural sheep scrapie originates from the accumulation and release of PrP from endothelial cells presumably following systemic scrapie infection. The topography of vascular amyloid distribution in Great Britain differs from that reported in the Netherlands. As amyloid deposition in mice is largely controlled by the strain of the infecting agent it is possible that the strain of the agent may influence vascular amyloid deposition.

Amyloid↗
PubMed1998

Heparan sulfate proteoglycan is associated with amyloid plaques and neuroanatomically targeted PrP pathology throughout the incubation period of scrapie-infected mice.

Heparan sulfate proteoglycan (HSPG) has been found to be associated with amyloid deposits in a number of diseases including the cerebral amyloid plaques of Alzheimer's disease and the transmissible spongiform encephalopathies (TSEs). The role of HSPG in amyloid formation and the neurodegenerative pathology of these diseases have not been established. We have addressed these questions using a scrapie mouse model which exhibits both amyloid and nonamyloid deposition of abnormal PrP protein, the protein marker of TSE infection. The distribution of HSPG was examined throughout the course of the disease in the brains of experimentally infected mice and compared with the distribution of abnormal PrP. Abnormally high levels of HSPG were associated with most types of PrP pathology including all plaque types and diffuse neuroanatomically targeted forms. Scrapie-associated HSPG was present from 70 days after infection, the earliest time-point examined, in the same target areas as abnormal PrP. The association with amyloid plaques may indicate that HSPG is involved in amyloid plaque formation and/or persistence but involvement with early diffuse forms of PrP suggests a more fundamental role in scrapie pathogenesis.

Alleles↗
PubMed1998

Treating tuberculosis: the essential role of social work.

The resurgence of tuberculosis gives cause for alarm. Compliance with an effective medication regimen leads to cure; yet, many patients fail to comply. This paper discusses factors affecting compliance and the essential role of social work, from an ecological perspective, when intervening to increase compliance. The authors relate comments made by patients at the only hospital originally and still serving as a TB sanatorium in relation to literature on compliance. Changes at the hospital include the development of a social work department which uses the ecological perspective in working with patients whose histories include non-compliance, as well as alcoholism, homelessness, loneliness, joblessness, and AIDS. The content of interviews with patients reveal and identify problems for future research.

Florida↗