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Biomedical subjects

M L Cuzner

Publications and source records attributed to M L Cuzner.

18 recordsLinked to original sources
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

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↗
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↗
PubMed1979

Proteinase inhibitors in cerebrospinal fluid in multiple sclerosis.

Levels of the proteinase inhibitors alpha 2-macroglobulin (alpha 2-m) and alpha 1-antitrypsin (alpha 1-at), and total protein, IgG and transferrin were measured in cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS) and other neurological diseases. All groups except that termed "meningitis" had similar alpha 2-m levels, but alpha 1-at and transferrin were significantly depressed in MS. Total protein levels were normal and IgG levels were elevated in MS. Serum levels of alpha 1-at were normal so the decreases observed in the CSF in MS were not due to impaired systemic production. In view of previous reports that proteinase activity is high in MS plaques and CSF, the inhibitory capacity of alpha 2-m and alpha 1-at in CSF was measured. As any decreases in inhibitory capacity noted in MS were slight, they could only be important in the local environment of a plaque where enzyme levels may be critically high.

Cerebrospinal Fluid Proteins↗
PubMed1978

Proteolytic enzyme activity of blood leukocytes and cerebrospinal fluid in multiple sclerosis.

Upon stimulation by immune complexes, the polymorphonuclear (PMN) blood secretes lysosomal hydrolases, including neutral proteinase, which is concentrated in the PMN cell. Neutral and acid proteinase activity were increased and decreased, respectively, in the circulating white cells of patients with multiple sclerosis during an exacerbation of the disease, but there was no correlation with serum immune complex levels. Neutral proteolytic activity in the cellular fraction of the cerebrospinal fluid was also found to be elevated in acute multiple sclerosis, as monitored by digestion of myelin basic protein.

Antigen-Antibody Complex↗
PubMed1978

Proteolytic activity in CSF.

Proteolytic enzyme activity, present at both acid and neutral pH values, in cerebrospinal fluid, can be measured by a sensitive assay, which monitors the rate of 125I-basic protein breakdown on polyacrylamide gel electrophoresis. CSF cellular neutral proteinase and supernatant acid proteinase are increased in acute multiple sclerosis and in CNS infections.

Acute Disease↗
PubMed1976

Myelin composition in acute and chronic multiple sclerosis in relation to cerebral lysosomal activity.

The neuropathology of 3 cases of acute multiple sclerosis was correlated with biochemical analyses. Astrocytosis was a characteristic feature of the diffuse demyelinating lesions in one case and lymphocytic cuffing characterized the well-defined plaques present in the white matter of the other two cases. No abnormalities were found in the protein or lipid composition of isolated myelin, despite a wide range of recovery. Nevertheless, the gel electrophoretic protein pattern of white matter adjacent to plaque areas showed selective loss of myelin basic protein. Lysosomal acid proteinase and beta-glucuronidase levels were very significantly increased in all white matter samples in which astrocytosis was a major neuropathological feature. Levels were less markedly raised in samples containing discrete active plaques. Enzyme changes were also found in the apparently normal white matter of 2 of the cases. Acid proteinase activity was in the normal range but the activities of beta-glucuronidase and acetylcholine esterase were elevated. The significance of these results in relation to glial cell activity in the early stages of demyelination is discussed.

Adolescent↗
PubMed1976

Neurochemical findings in a perinatal sudanophilic leukodystrophy rich in steryl ester.

Neurochemical and neuropathological studies have been made of a 10-day-old child who suffered from a sudanophilic leukodystrophy. The brain white matter contained abundant sudanophilic material. The patient's grey matter total cholesterol content was 30% higher than whole brain tissue derived from a comparable control. White matter cholesterol content was more than double the control value. Nearly 80% of the white matter cholesterol was esterified. Subcellular fractionation of the white matter resulted in a "floating fraction" rich in cholesteryl ester. The steryl ester fatty acid composition was not typical of control tissue or demyelinating tissue. Patient phospholipid fatty acid composition patterns differed from control, but white matter galactolipid fatty acid composition appeared normal. Cholesteryl ester hydrolase activity appeared normal. Myelin and myelin-like fractions, isolated from diseased and normal brain tissue, were of a primitive developing nature but appeared to be comparable. The findings indicate a neonatal sudanophilic leukodystrophy which doubtless began in prenatal life and which was rich in cholesteryl ester. The aetiology of the leukodystrophy is unknown.

Brain↗
PubMed1975

Leucocyte proteinase activity and acute multiple sclerosis.

Increased leucocyte neutral proteinase activity is associated with an attack of multiple sclerosis. Raised neutral proteinase is found in other diseases with rapid destruction of neural tissues. Increased enzyme activity may be responsible for removing antigenic protein from the blood.

Humans↗