Search PubMed⌕ Search

Biomedical subjects

M L Cuzner

Publications and source records attributed to M L Cuzner.

At least 73 records · Page 4Linked to original sources
PubMed1993

Modulation of interferon-gamma-induced major histocompatibility complex class II and Fc receptor expression on isolated microglia by transforming growth factor-beta 1, interleukin-4, noradrenaline and glucocorticoids.

Interleukin-4 (IL-4) enhances Fc receptor (FcR) expression on isolated rat brain microglia and peritoneal macrophages but has little effect on major histocompatibility complex (MHC) class II antigen expression. In contrast transforming growth factor-beta 1 (TGF-beta 1) causes a reduction in expression of MHC class II on macrophages and of FcR on both cell types. Both microglia and peritoneal macrophages demonstrate enhanced expression of FcR and MHC class II on treatment with interferon-gamma (IFN-gamma). The effect of IL-4 or TGF-beta 1 in combination with IFN-gamma, added either sequentially or simultaneously, has been investigated. TGF-beta 1 down-regulates IFN-gamma-induced effects in both microglia and macrophages when present before or during the activation stage. In combination, IL-4 and IFN-gamma can be additive or antagonistic, depending on their concentrations and the sequence in which cells are exposed to the cytokines. Non-cytokine mediators present during stimulation, such as noradrenaline, dexamethasone and corticosterone, are also potent inhibitors of IFN-gamma-induced activation of microglia and macrophages.

Brain↗
PubMed1992

Gamma delta T-cell receptor repertoire in acute multiple sclerosis lesions.

Gamma delta T cells are a distinct lymphocyte population that can exhibit reactivity with heat shock proteins over-expressed at inflammatory sites. As gamma delta T cells may be involved in the central nervous system (CNS) inflammatory process in multiple sclerosis (MS), we examined T-cell populations in MS plaque tissue by quantitative immunohistochemistry and sequence analysis of T-cell antigen receptor (TCR) delta chains. Gamma delta T cells that express the variable (V) gene segments V delta 1, V delta 2, and V gamma 2 (V gamma 9) were found to accumulate in acute, demyelinating MS plaques and appeared to have undergone clonal expansion, most likely because of recognition of a specific CNS ligand. Further, 60-kDa and 90-kDa heat shock proteins (hsp60 and hsp90), which may be target antigens for autoreactive gamma delta T cells, were found to be expressed in normal CNS tissue and overexpressed in acute MS plaques. In acute plaques, hsp60 was found in foamy macrophages, while hsp90 was detected in reactive astrocytes. These results provide evidence for a role of gamma delta T cells in active stages of MS.

Base Sequence↗
PubMed1992

T cell receptor V alpha-V beta repertoire and cytokine gene expression in active multiple sclerosis lesions.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with presumed autoimmune etiology. A recent study has suggested the presence of a restricted T cell receptor (TCR) V alpha repertoire in MS lesions. The presence of such a restricted TCR repertoire at the site of inflammation would have important consequences for the pathogenesis and the ultimate treatment of MS. To further characterize the TCR V alpha and V beta repertoire in MS plaque tissue, we examined a series of 26 histologically well-characterized central nervous system (CNS) tissue specimens from six MS patients as well as samples from five normal postmortem cases and a case of subacute sclerosing panencephalitis. RNA was extracted from frozen sections and cDNAs were amplified by polymerase chain reaction using primers for TCR V alpha (V alpha 1-18) and V beta (V beta 1-19) gene families. This analysis demonstrated a broad TCR V alpha-V beta repertoire in active lesions, while fewer TCR V genes were detected in chronic plaques and control samples. Even though a large number of TCR V alpha and V beta gene segments were present in the majority of active lesions, there were clear differences in the TCR repertoire between plaques from the same case, suggesting that local events influence the TCR repertoire at the level of T cell recruitment or T cell expansion. Examination of cytokine mRNAs demonstrated that IL-1 mRNA was present in the majority of acute and subacute plaques, while IL-2 and IL-4 mRNA were detected in only a few acute lesions. These data demonstrate that the TCR repertoire in MS plaques is polyclonal. However, autoreactive alpha/beta T cells thought to be critical in the initiation of the inflammatory process probably represent a minor fraction of T cells in active MS plaques and may use a limited number of TCR V gene segments for recognition of the autoantigen.

Acute Disease↗
PubMed1992

beta-Adrenergic receptor density and function of peripheral blood mononuclear cells are increased in multiple sclerosis: a regulatory role for cortisol and interleukin-1.

An increased density of beta-adrenergic receptors was demonstrated on peripheral blood mononuclear cells (PBMCs) from patients with progressive or relapsing-remitting multiple sclerosis (MS). The same observation was made in patients with chronic active rheumatoid arthritis, but not in those with myasthenia gravis. The affinity of the receptors was within the normal range in all tested groups of patients and there was a positive correlation between density and function as determined by intracellular cyclic AMP production after stimulation with isoproterenol. A putative link between inflammatory process and the functional upregulation of beta-adrenergic receptors on PBMCs was tested by in vitro studies with the soluble mediators interleukin-1 and hydrocortisone. A functional upregulation of beta-adrenergic receptors was observed when PBMCs from normal control subjects were cultured in the presence of either mediator, whereas the already upregulated receptor density on PBMCs from patients with MS remained unchanged. Whether this represents a recovery mechanism to inflammation in MS or a blunting of homeostatic immunoregulatory mechanisms requires further investigation.

Adult↗
PubMed1992

Monoclonal antibody 14E recognizes an antigen common to human oligodendrocytes, Schwann cells, Bergmann glia, and a subpopulation of reactive glia.

The monoclonal antibody 14E immunocytochemically stains the nuclear membrane of oligodendrocytes but not myelin in tissue sections of adult normal human white matter. The nuclear membranes of Schwann cells in human peripheral nerve and cerebellar Bergmann glia were also visualized with this antibody. In actively demyelinating multiple sclerosis plaques the 14E antibody stained increased numbers of oligodendrocytes and the nuclei, perikarya and cell processes of hypertrophic glia, which were often multinucleate. Scattered small groups of these hypertrophic glia were present in areas of dense astrogliosis in acute plaques. The 14E-positive hypertrophic cells could be either a subpopulation of reactive astrocytes or bipotential glial precursors.

Antibodies, Monoclonal↗
PubMed1992

Up-regulation of beta-adrenoceptors on circulating mononuclear cells after reduction of central sympathetic outflow by clonidine in normal subjects.

Short term regulation of beta-adrenoceptors in peripheral blood mononuclear cells after sympathetic activation has been previously documented in normal individuals but changes after a central reduction in sympathetic activity are not known. We have studied beta-adrenoceptor number and affinity on peripheral blood mononuclear cells in normal subjects, before and after intravenous clonidine, an alpha 2-adrenoceptor agonist which lowers blood pressure predominantly by reducing central nervous system sympathetic outflow. After clonidine there was a decrease in plasma levels of noradrenaline and adrenaline, and an increase in growth hormone. There was up-regulation of beta-adrenergic receptors on peripheral blood mononuclear cells 30 and 60 min after clonidine which was related to the fall in blood pressure, noradrenaline and adrenaline levels and to the increase in growth hormone levels. The affinity of the receptors was decreased. Return to baseline values was observed after 2 h. Intracellular production of cAMP after isoproterenol stimulation demonstrated that the up-regulation was not functional. Our studies indicate short term up-regulation of beta-adrenoceptors in peripheral blood mononuclear cells after clonidine. These observations after a reduction in sympathetic activity may be of importance if they mirror the pattern of redistribution of adrenoceptors, which are present in a wide range of tissues.

Adult↗
PubMed1992

Regulation of Fc receptor and major histocompatibility complex antigen expression on isolated rat microglia by tumour necrosis factor, interleukin-1 and lipopolysaccharide: effects on interferon-gamma induced activation.

Isolated rat brain microglia display enhanced expression of Fc receptors on treatment with interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) and lipopolysaccharide (LPS), whereas major histocompatibility complex (MHC) antigen expression is enhanced only by IFN-gamma. Although TNF and LPS individually have no effect on MHC expression by microglia, they both antagonize IFN-gamma-induced expression. The enhanced expression of Fc receptors observed in the presence of IFN-gamma, TNF or LPS is significantly inhibited by the combination of IFN-gamma with either LPS or TNF. IL-1 alpha has little effect on IFN-gamma-induced MHC or Fc receptor expression by microglia. Peritoneal macrophages behave similarly to microglia, with the notable exception that IL-1 alpha enhances IFN-gamma-induced FcR expression. These observations suggest that the functional activity of microglia during inflammation or demyelination in the central nervous system can be influenced by the changing profile of cytokines present during lesion development.

Animals↗
PubMed1991

Detection of interleukin-1 and interleukin-6 in adult rat brain, following mechanical injury, by in vivo microdialysis: evidence of a role for microglia in cytokine production.

In vivo levels of interleukin-1 (IL-1) and IL-6, present in the interstitial spaces of brain, have been repeatedly monitored up to 7 days after insertion of a microdialysis probe, designed to induce mechanical trauma to the brain. IL-1 is barely detectable immediately after implantation but over a 24-48 h period a 15-fold increase is seen. In contrast IL-6 levels at day 0 are high, increasing slightly (10%) by day 1 but decreasing to 40% by day 2. The temporal pattern of IL-6 recovery in the cerebrospinal fluid was similar to that in the dialysate but the levels were significantly lower and may reflect diffusion from the site of the probe lesion. Cellular sources of these cytokines include macrophages and neutrophils, which have infiltrated the lesion and microglia resident in the brain, which can be identified at the lesion site within 24 h of probe implantation. The astrocytic response to injury, evidenced by increased glial fibrillary acidic protein staining occurs much later, by day 7, and is unlikely to be responsible for IL-1 and IL-6 production found at 24-48 h. Since upon isolation and stimulation of microglia in vitro with lipopolysaccharide IL-1 and IL-6 can be measured in the supernatant, it would appear that they have the capacity to produce cytokines in vivo. Localised synthesis of cytokines at sites of brain injury by microglia would further stimulate microglia in an autocrine manner and also propagate the astrocytic reaction.

Animals↗
PubMed1991

Hypothalamic noradrenergic pathways exert an influence on neuroendocrine and clinical status in experimental autoimmune encephalomyelitis.

The immunomodulatory action of corticosteroids and the ability of central noradrenergic systems to activate the hypothalamic-pituitary-adrenal (HPA) axis led us to investigate the relationship between neuroendocrine status and the clinical course of encephalomyelitis (EAE) following adrenalectomy and depletion of noradrenaline (NA) centrally or peripherally. A significant inverse correlation was found between hypothalamic NA and serum corticosterone (CS) at peak clinical signs of EAE in all the sham groups or when NA was depleted only in the peripheral nervous system. A positive correlation was found between serum CS and disease severity, and in all experimental groups with intact peripheral and/or central noradrenergic pathways a uniformly increased splenic NA content was also observed at peak disease. Administration of 6-OHDA i.p. to neonatal or adult Lewis rats produced a significant depletion of splenic NA alone which resulted in increased disease severity, despite the fact that circulating CS was elevated. Thus the rise in the NA content of lymphoid tissue at peak clinical signs contributes to recovery. A single i.c.v. injection of 6-OHDA into the hypothalamic region resulted in an 80% reduction in NA content, which subsequently modified the clinical severity of EAE. Serum CS levels rose preclinically in the treated group and remained high despite milder clinical disease than that seen in the sham group. The overriding immunoregulatory influence of glucocorticoids is demonstrated by the rapid onset of clinical EAE and morbidity in adrenalectomized animals. However, the strong inverse correlation found between hypothalamic NA and circulating CS indicates that regulation of the HPA axis may ultimately be controlled by central sympathetic pathways.

Adrenal Glands↗
PubMed1991

Histopathology of multiple sclerosis lesions detected by magnetic resonance imaging in unfixed postmortem central nervous system tissue.

Postmortem unfixed whole brains from 17 multiple sclerosis and 6 control cases were examined by magnetic resonance imaging (MRI) using a T2-weighted spin echo sequence and histology to determine the relationship between areas of abnormal MRI signal and underlying pathological change. In group 1, small MRI lesions and correspondingly small plaques, most of which were chronic, were detected histologically in 5 brains. In 4 brains there were more extensive areas of both abnormal signal and histological plaques which were more often active (group 2). However, in a further 5 brains extensive MRI abnormalities were observed when only small periventricular plaques were present histologically (group 3). Lesions in the hindbrain and cerebral grey matter were infrequently observed by MRI. The extensive MRI abnormalities seen in areas in which only small histological plaques were found may be the result of vascular permeability changes in the normal-appearing white matter surrounding plaques.

Autopsy↗
PubMed1990

Splenic noradrenergic and adrenocortical responses during the preclinical and clinical stages of adoptively transferred experimental autoimmune encephalomyelitis (EAE).

When experimental autoimmune encephalomyelitis (EAE) is induced by adoptive transfer of myelin basic protein (MBP)-specific lymphocytes the splenic noradrenergic and adrenocortical responses mirror in most respects those that occur following sensitization with spinal cord and Freund's adjuvant (CFA), despite the absence of the primary immune challenge. An early drop in splenic noradrenaline (NA), observed only when purified protein derivative-primed cells are transferred may reflect a vigorous proliferative response in vitro, not observed with MBP-specific cells. However, serum corticosterone (CS) levels and the density of splenocyte beta-adrenergic receptors were increased in both experimental groups within 3 days of cell inoculation. The stress of clinical signs of EAE resulted in highly significant increases in both splenic NA and plasma CS. Thus adoptively transferred EAE provides a well-delineated model of autoimmune disease for investigating the immunomodulatory role of the neural and endocrine systems.

Adrenal Cortex↗
PubMed1989

Changes in lymphocyte beta-adrenergic receptor density and noradrenaline content of the spleen are early indicators of immune reactivity in acute experimental allergic encephalomyelitis in the Lewis rat.

Neural activity in the spleen in the pre-clinical stage of experimental allergic encephalomyelitis (EAE) mirrored that of animals immunized with complete Freund's adjuvant (CFA) alone. In response to immune challenge the splenic noradrenaline content fell significantly, accompanied by an increase in lymphocyte beta-receptor density. The response of the pituitary-adrenal axis was reflected in increased circulating levels of corticosterone in both experimental groups; this was amplified by the stress of clinical signs leading to a 2-fold increase in animals with EAE. The increased, potentially immunosuppressive concentration of noradrenaline in the spleen during the acute stage may also represent a recovery mechanism and indicate how neuroimmune interactions could influence the relapsing-remitting nature of chronic inflammatory demyelinating disease.

Animals↗
PubMed1989

Fc receptor density, MHC antigen expression and superoxide production are increased in interferon-gamma-treated microglia isolated from adult rat brain.

Treatment of microglia isolated from adult rat brain with interferon-gamma (IFN-gamma) at a concentration of 1 U/ml resulted in enhanced expression of Fc receptors and major histocompatibility complex (MHC) antigens and increased production of superoxide anions. Neonatal microglia and peritoneal macrophages, isolated and cultured in the same manner, displayed functional properties very similar to those of adult microglia, indicating a common origin for different macrophage populations. The Fc binding capacity of microglia was found to be significantly greater than that of peritoneal cells, thus underlining the potential role of microglia in immune-mediated demyelination.

Animals↗
PubMed1988

Characterisation of microglia isolated from adult human and rat brain.

A method has been developed to isolate microglia from adult human and rat brain cell suspensions by rosette formation via Fc receptors. Immunocytochemical characterisation of the cells immediately following isolation and after 7-10 days in vitro with a panel of monoclonal antibodies has demonstrated that microglia from adult brain have the phenotypic characteristics and phagocytic capacity of mononuclear phagocytes, but lack the hydrolytic enzyme, non-specific esterase. The ability to isolate rapidly a purified population of microglia from adult brain provides a means for investigating mechanisms of activation and differentiation of tissue macrophages, which could elucidate their role in inflammation of the central nervous system.

Animals↗
PubMed1988

Monoclonal antibody 14E identifies the oligodendrocyte cell body in normal adult human and rat white matter.

A monoclonal antibody, 14E, which detects immunocytochemically the perikarya of interfascicular oligodendrocytes in sections of normal adult human and rat white matter, was obtained using isolated normal human oligodendrocytes as the immunogen. 14E is an IgM antibody that reacts with a polypeptide of approximate molecular weight 23,000 on immunoblots of the particulate fraction of normal white matter. In sections of active multiple sclerosis plaques and recent infarcts, 14E immunostained the cell bodies and processes of only a small number of hypertrophic glial cells which could be oligodendrocytes undergoing pathological changes or a subpopulation of reactive astrocytes.

Animals↗
PubMed1988

The nature of inflammatory components during demyelination in multiple sclerosis.

Immune reactivity in the central nervous system (CNS) in multiple sclerosis (MS) can be fuelled by activated T lymphocytes sequestered in the brain and those entering systemically. The perivascular cuff of the inflammatory lesion consists predominantly of T cells and macrophages, while the hypercellular interface between normal and degenerating myelin is comprised mainly of macrophages and activated microglia. MHC class II+ cells are abundant in the hypercellular zone and expression of both the polymorphic and invariant chains of the molecule are expressed beyond the plaque edge in the white matter where the staining is restricted largely to microglia. Under carefully controlled staining conditions expression of MHC class II can be demonstrated on microglia in control white matter. Thus the immunological privilege of the CNS does not appear to preclude constitutive expression of MHC antigens or prevent the traffic of activated lymphocytes into the brain parenchyma. However, the antigens priming the immune reaction in the CNS in MS and the role of antibodies in the demyelinating process remain a matter for speculation and the exact mechanisms of demyelination are as yet unresolved.

Animals↗