Biomedical subjects

S Jung

Publications and source records attributed to S Jung.

At least 145 records · Page 8Linked to original sources

PubMed1996

Effector mechanisms in demyelinating neuropathies.

While the cause of the immune-mediated neuropathies (Guillain-Barr-e syndrome, GBS; CIDP; multi-focal motor neuropathy and paraproteinemic neuropathies) remains elusive considerable progress has been made in delineating the effector mechanisms that underlie myelin destruction. In GBS circulating antibodies to glycolipids possibly precipitated by an antecedent Campylobacter jejuni infection can be detected with high frequency. These antibodies may interfere with neuromuscular transmission and eventuate myelin damage by activating the complement system, providing for the generation of chemotactically active split products C3a and C5a, the opsonin C3b, and assembly of the membrane attack complex. Such antibodies may also, via binding to the Fc receptor, target macrophages to the myelin sheath. Corroborative evidence for a crucial pathogenic role of antibody-mediated complement activation is also available for the MAG-associated neuropathies. Macrophages as decisive effector cells of myelin damage may also act by releasing injurious molecules such as oxygen radicals, nitric oxide metabolites, proteases, eicosanoids and cytokines. Demyelinative as well as degenerative actions have been described for the cytokines TNF-alpha and lymphotoxin. Increased understanding of the effector mechanisms underlying demyelination may aid in developing more efficacious treatments for this group of neuropathies.

Autoantibodies↗

PubMed1995

T cell antigenic and neuritogenic activity of recombinant human peripheral myelin P2 protein.

The major neuritogenic protein of peripheral nerve myelin is the P2 protein. Human P2 is a candidate autoantigen in inflammatory demyelinating diseases of the peripheral nervous system. Since human P2 is not readily available, we produced full-length recombinant human P2 protein (rhP2) in Escherichia coli. RhP2 was recognized by neuritogenic rat T cell lines and induced experimental autoimmune neuritis in Lewis rats. Production of rhP2 allowed the generation of human T cell lines reactive to the autologous protein. Studies of human T cell autoreactivity as well as efforts to use hP2 as a tolerogen will be facilitated by the large-scale expression of rhP2.

Amino Acid Sequence↗

PubMed1995

Soluble complement receptor type 1 inhibits experimental autoimmune neuritis in Lewis rats.

Experimental autoimmune neuritis (EAN) in Lewis rats induced by immunization with bovine peripheral nerve myelin in complete Freund's adjuvant is an animal model of the human Guillain-Barré syndrome. In this study myelin-induced EAN was treated with 30 mg/kg per day human soluble complement receptor type 1 (sCR1) beginning on day 8 post immunization (p.i.). Clinical signs of disease were markedly suppressed by application of sCR1 and none of eight treated animals but seven of nine control rats developed paraparesis. Electrophysiologic examination of sciatic nerve function 13 days p.i. revealed faster nerve conduction velocities and significantly higher compound muscle action potentials in sCR1-injected animals. In sections of sciatic nerves acquired 16 days p.i. extended demyelination and axonal degeneration was prevented by treatment with sCR1 in vivo. Our findings underscore the functional importance of complement during inflammatory demyelination in the peripheral nervous system and suggest sCR1 as a potential therapeutic approach in these diseases.

Animals↗

PubMed1995

Costimulation requirement for AP-1 and NF-kappa B transcription factor activation in T cells.

The transcriptional activity of the IL-2 promoter requires T-cell costimulation delivered by the TCR and the auxiliary receptor CD28. Several transcription factors participate in IL-2 promoter activation, among which are AP-1-like factors and NF-kappa B. Protein phosphorylation has an important role in the regulation of these two factors: (1) it induces the transactivating capacity of the AP-1 protein c-Jun; and (2) it is involved in the release of the cytoplasmic inhibitor, I kappa B, from NF-kappa B, allowing translocation of the latter into the nucleus. We have recently shown that both phosphorylation processes require T-cell costimulation. Furthermore, in activated T cells, the kinetics of the two phosphorylation events are essentially similar. According to our results, however, the kinases responsible for the two processes are distinct entities. Whereas TPCK inhibits phosphorylation of I kappa B and, consequently, activation of NF-kappa B, it markedly enhances the activity of JNK, the MAP kinase-related kinase that phosphorylates the transactivation domain of c-Jun. We, therefore, propose the activation scheme presented in FIGURE 3 for T-cell costimulation. Costimulation results in the activation of a signaling pathway that leads to the simultaneous induction of the two transcription factors, AP-1 and NF-kappa B. Integration of the signals generated by TCR and CD28 engagement occurs along this pathway, which then bifurcates to induce I kappa B phosphorylation and NF-kappa B activation on the one hand, and JNK activation and c-Jun phosphorylation on the other. We are currently engaged in defining where the two signals integrate along the AP-1/NF-kappa B pathway.

Antibodies↗

PubMed1995

The catalytic subunit of cAMP-dependent protein kinase from Ascaris suum. The cloning and structure of a novel subtype of protein kinase A.

A complete cDNA clone encoding the catalytic subunit of cAMP-dependent protein kinase of Ascaris suum was constructed from two overlapping partial clones. The encoded sequence of 337 amino acids is 48% identical with the sequence of mouse C alpha subunit. Approximately the same low similarity was found with the sequence of the C subunit from another nematode, Caenorhabditis elegans. The N-terminal 14 amino acids and the myristoylation site of the mammalian protein are not contained in the enzyme from Ascaris. Two cysteines (Cys33 and Cys319) replace a basic residue in the N-terminal region and an acidic amino acid near the C-terminus which are conserved in all known C subunits from other sources. The substitutions provide the possibility of disulfide bridge formation between the N-terminal and C-terminal parts of the protein. There is strong evidence that a single gene encodes cAMP-dependent protein kinase in Ascaris. Modelling of the sequence into the coordinates of the X-ray structure of the mammalian enzyme suggest a high degree of conservation in the three-dimensional structure. However, structural variations occur at the surface of the protein near the catalytic cleft and are likely to account for the variations in substrate specificity previously observed between the purified protein kinase from Ascaris [Thalhofer, H. P., Daum, G., Harris, B. G. & Hofer, H. W. (1988) J. Biol. Chem. 263, 952-957] and the mammalian enzyme.

Amino Acid Sequence↗

PubMed1995

Design and synthesis of 1-heteroaryl-3-(1-benzyl-4-piperidinyl)propan-1-one derivatives as potent, selective acetylcholinesterase inhibitors.

Herein is described the synthesis and structure--activity relationship of a novel series of aromatic and heteroaromatic 3-(1-benzyl-4-piperidinyl)propan-1-one derivatives that display potent and selective inhibition of the enzyme acetylcholinesterase (AChE). 1-(2-Methyl-6-benzothiazolyl)-3-(N-benzyl-4-piperidinyl)propan-1-one hydrochloride, 6d, is one of the most active compounds within this series exhibiting an IC50 for the inhibition of the AChE enzyme equal to 6.8 nM. Compound 6d has shown a dose-dependent elevation of total acetylcholine (ACh) levels in the mouse forebrain with an oral ED50 = 9.8 mg/kg. In addition, in vivo microdialysis experiments in the rat demonstrate that 6d increases extracellular ACh (100% over basal) 1-3 h postdose with an oral ED50 = 4.8 mg/kg.

Animals↗

PubMed1995

Switch transcripts in immunoglobulin class switching.

B cells can exchange gene segments for the constant region of the immunoglobulin heavy chain, altering the class and effector function of the antibodies that they produce. Class switching is directed to distinct classes by cytokines, which induce transcription of the targeted DNA sequences. These transcripts are processed, resulting in spliced "switch" transcripts. Switch recombination can be directed to immunoglobulin G1 (IgG) by the heterologous human metallothionein IIA promoter in mutant mice. Induction of the structurally conserved, spliced switch transcripts is sufficient to target switch recombination to IgG1, whereas transcription alone is not.

Animals↗

PubMed1995

Inhibition of brain macrophage/microglial respiratory chain enzyme activity in experimental autoimmune encephalomyelitis of the Lewis rat.

We measured the activities of five respiratory chain enzymes in brain macrophages/microglial cells from Lewis rats with experimental autoimmune encephalomyelitis (EAE) and found a significant reduction of the activity of nicotinamide adenine dinucleotide-dehydrogenase (NADH-DH), succinate cytochrome c reductase (SCCR) and succinate dehydrogenase (SDH) when compared with age-matched healthy control animals. The inhibition of NADH-DH (complex I) was specific for EAE, while we also found a reduction of SCCR and SDH activities (complex II) in newborn rats and adjuvant-immunised rats. Activities of NADH cytochrome c reductase (NCCR) and cytochrome c oxidase (COX) were not significantly changed. These observations demonstrate an impairment of brain macrophage/microglial respiratory chain function in central nervous system inflammation.

Animals↗

PubMed1995

A mathematical model explaining the molecular weights and distribution of very long chain dicarboxylic acids formed during the adaptive response of Sarcina ventriculi.

A simple mathematical model is presented to explain a recent new discovery of an unusual membrane adaptive response in Sarcina ventriculi. In this response, this organism synthesizes very long chain alpha, omega-dicarboxylic acids ranging from 28 to 36 carbon atoms in length. The distribution of chain lengths of the new fatty acid species is not consistent with de novo synthesis but suggests elaboration from the existing regular-chain fatty acids by a coupling process. Here, we demonstrate, using a mathematical model, that if the molecular weights and relative abundances of regular chain fatty acids are known, the molecular weights and relative abundances of the new, very long chain dicarboxylic fatty acid species can be predicted using a model based on the random, pairwise combination of regular chain species. This combination takes place across the bilayer leaflet to form transmembrane fatty acids. It is proposed that this coupling phenomenon is regulated by the motional dynamics of the membrane.

Cell Membrane↗

PubMed1995

Activated T cells of nonneural specificity open the blood-nerve barrier to circulating antibody.

Recent studies from our laboratory and by other investigators have shown that autoreactive CD4+ cells specific for peripheral nerve P2 protein have a powerful effect on blood-nerve barrier permeability. In this study we injected CD4+ T cells reactive to a nonneural antigen (ovalbumin) systemically and achieved their accumulation in the tibial nerve of Lewis rats by previous intraneural injection of ovalbumin. Selected rats were given systemic demyelinating antibody (antigalactocerebroside) to provide an indicator of changes in the permeability of the blood-nerve barrier, and the animals were monitored by sequential neurophysiological studies and histology. Circulating ovalbumin-specific T cells accumulated at sites of intraneural ovalbumin injection without inducing demyelination in control animals. In rats with circulating galactocerebroside antibodies, local conduction block and demyelination were seen in the region of T-cell accumulation. Electron microscopy demonstrated dissolution of some tight junctions between endothelial cells in areas of T-cell accumulation, and T cells traversing the endothelium between endothelial cells and through their cytoplasm. Endothelial cell damage was evident in these areas. This study demonstrates breakdown of the blood-nerve barrier by activated T cells, even of nonneural specificity, allowing the development of focal conduction block and demyelination in the presence of circulating antimyelin antibodies.

Action Potentials↗

PubMed1995

Suppression of experimental autoimmune encephalomyelitis in Lewis rats by antibodies against CD2.

The immunotherapeutic potential of three anti-rat CD2 monoclonal antibodies (mAb) (OX34, OX54, OX55) and the combination of OX54 with OX55 was tested in Lewis rat experimental autoimmune encephalomyelitis (EAE). In actively induced EAE, a single injection of OX34 2 days before immunization with myelin basic protein (MBP) in complete Freund's adjuvant (CFA) completely prevented or greatly attenuated EAE in all animals. Injection of OX54 acted moderately suppressive while OX55 or OX54/55 did not affect disease severity. Abrogation of EAE by OX34 was not restricted to its application before immunization. Therapeutic administration of all three mAb and the Ab combination from onset of first clinical signs efficiently blocked progression of disease and prevented all animals from developing hind limb paresis. In adoptive transfer EAE induced with in vitro activated cells of an encephalitogenic T helper line, clinical and histological signs were completely prevented by injection of OX34 on the day of cell transfer and 4 days later, underlining the strong impact of anti-CD2 mAb on the effector phase of disease. Immunocytofluorometric analysis of peripheral blood lymphocytes after a single Ab injection demonstrated that all mAb induced a variable degree of transient reduction in T cell numbers and modulation of CD2 antigens. In contrast to the other mAb, OX34 persisted on lymphocytes for at least 11 days, which may explain its unique suppressive effect on EAE after a single injection before immunization. The assumption that prophylactic administration of OX34 also inhibits MBP-induced EAE, due to persistence into the effector phase, was substantiated by the finding that none of the mAb prevented generation of an antigen-specific cellular response in MBP/CFA-immunized animals. Since none of the Ab induced T cell unresponsiveness or inhibited T cell activation by antigen- or Ab-mediated stimulation of the T cell receptor, we suggest that their marked action on the effector phase of EAE may rely on inhibition of T cell infiltration into the central nervous system. The demonstrated efficacy of these anti-CD2 mAb in EAE suggests a potential therapeutic role that may be equal to that of anti-CD4 or anti-T cell receptor Ab.

Animals↗

PubMed1995

Immunolocalization of vgr (BMP-6, DVR-6), a TGF-beta related cytokine, to Schwann cells of the rat peripheral nervous system: expression patterns are not modulated by autoimmune disease.

The transforming growth factors type beta (TGF-beta) have been implicated in regulation of peripheral nervous system inflammation and regeneration. Here we demonstrate expression of a TGF-beta-related bone morphogenetic protein, the vgr (BMP-6, DVR-6) in Schwann cells of the rat peripheral nervous system. The expression of vgr in the peripheral nervous system suggests that this factor and probably other TGF-beta-related bone morphogenetic proteins might participate in Schwann cell function during aspects of peripheral nervous system physiology and pathology. However, we did not observe changes in expression patterns in response to autoimmune inflammation (experimental autoimmune neuritis) of the peripheral nervous system.

Amino Acid Sequence↗

PubMed1995

Administration of nitric oxide synthase inhibitors in experimental autoimmune neuritis and experimental autoimmune encephalomyelitis.

The nitric oxide (NO) synthase pathway is activated during experimental autoimmune inflammation of the central nervous system, and administration of aminoguanidine, an inhibitor of the cytokine-inducible NO synthase (NOS), ameliorated the disease course of autoimmune encephalomyelitis in the SJL mouse. We studied the role of nitric oxide synthase (NOS) in the pathogenesis of experimental autoimmune neuritis (EAN) and experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. NG-L-monomethyl-arginine (L-NMMA), a competitive inhibitor of NOS, partially suppressed T cell line-mediated EAN, but not myelin-induced EAN, myelin basic protein (MBP)-induced EAE, or T cell line-mediated EAE. Aminoguanidine (AG), a selective inhibitor of the cytokine-inducible NOS, enhanced MBP-induced EAE, but had no significant effects on myelin-induced EAN. Two other NOS inhibitors, nitro-arginine methyl-ester and N-nitro arginine, had only little or no effects in EAN and EAE. The administration of NOS inhibitors showed some striking effects in EAN and EAE, but the observed diversity of actions points to a much more complex role of the NO pathway than previously suggested.

Acetates↗

PubMed1995

A new data model for biological classification.

In the domain of biological classification, classifications are performed hierarchically. There are no standard classifications which are unanimously accepted by the community of each domain; many different interacting views of classification exist about the same data, and the discovery of new data results in changes to the existing classification. Even a single individual may change his or her own classification of a particular group. Since multiple classification views interact, they are semantically related. It is difficult to model this kind of dynamically evolving and semantically interacting classification system using traditional data models, which lack the structural flexibility necessary to support dynamic views of hierarchic classifications, and cannot properly capture the history of these complex interactions. We have developed a new data model which is suitable for supporting semantically interacting dynamic views of hierarchic biological classifications. On the basis of our new data model we have developed a prototype database system called HICLAS (HIerarchical CLAssification System); its domain is plant taxonomy. HICLAS is available through the Internet and an X-window interface has been implemented to support queries to classification data.

Classification↗

PubMed1995

Macrophages in T cell line-mediated, demyelinating, and chronic relapsing experimental autoimmune encephalomyelitis in Lewis rats.

About 50% of the mononuclear cells in the perivascular lesions in the central nervous system (CNS) of rats suffering from experimental allergic encephalomyelitis (EAE) are blood-borne macrophages. In this study we investigated the role of these macrophages in different variants of EAE, using a liposome-mediated macrophage depletion technique. Intravenously injected liposomes containing dichloromethylene diphosphonate (Cl2MDP) are ingested by macrophages and cause temporary and selective elimination of these cells. Macrophage depletion during EAE induced by a T cell line specific for myelin basic protein (MBP; T cell-EAE) suppresses development of neurological signs of EAE. T cell-EAE with pronounced demyelination as induced by an additionally injected MoAb directed against myelin oligodendrocyte glycoprotein (MOG) was also significantly ameliorated after macrophage depletion. During chronic relapsing EAE (CR-EAE) the occurrence of relapses was prevented or suppressed, provided that the liposomes were injected before the initiation of a putative relapse. A chronic progressive course of CR-EAE was not modified by Cl2MDP containing liposome treatment. Histologic examination of the CNS of liposome-treated animals confirmed decreased infiltration of macrophages into the parenchyma in the rats with T cell and AD-EAE, whereas T cells were still present.

Animals↗

PubMed1995

In vivo stimulation of I kappa B phosphorylation is not sufficient to activate NF-kappa B.

NF-kappa B is a major inducible transcription factor in many immune and inflammatory reactions. Its activation involves the dissociation of the inhibitory subunit I kappa B from cytoplasmic NF-kappa B/Rel complexes, following which the Rel proteins are translocated to the nucleus, where they bind to DNA and activate transcription. Phosphorylation of I kappa B in cell-free experiments results in its inactivation and release from the Rel complex, but in vivo NF-kappa B activation is associated with I kappa B degradation. In vivo phosphorylation of I kappa B alpha was demonstrated in several recent studies, but its role is unknown. Our study shows that the T-cell activation results in rapid phosphorylation of I kappa B alpha and that this event is a physiological one, dependent on appropriate lymphocyte costimulation. Inducible I kappa B alpha phosphorylation was abolished by several distinct NF-kappa B blocking reagents, suggesting that it plays an essential role in the activation process. However, the in vivo induction of I kappa B alpha phosphorylation did not cause the inhibitory subunit to dissociate from the Rel complex. We identified several protease inhibitors which allow phosphorylation of I kappa B alpha but prevent its degradation upon cell stimulation, presumably through inhibition of the cytoplasmic proteasome. In the presence of these inhibitors, phosphorylated I kappa B alpha remained bound to the Rel complex in the cytoplasm for an extended period of time, whereas NF-kappa B activation was abolished. It appears that activation of NF-kappa B requires degradation of I kappa B alpha while it is a part of the Rel cytoplasmic complex, with inducible phosphorylation of the inhibitory subunit influencing the rate of degradation.

Amino Acid Sequence↗

PubMed1995

How cytokines control immunoglobulin class switching.

B lymphocytes can alter the class of antibody they produce by immunoglobulin class switch recombination. This recombination is targeted by distinct cytokines to particular switch regions. Prior to switch recombination, the same cytokines induce transcription through the targeted switch regions and generate IH "switch" transcripts. To show whether the two events are functionally related, we have replaced the endogenous interleukin-4 (IL-4) dependent promoter of murine I gamma 1 switch transcripts by an heterologous promoter, the human metallothionein IIA (hMT) promoter. Indeed, switch recombination can be targeted to IgG1 by the hMT promoter. In mutant mice, which cannot generate processed switch transcripts, switch recombination cannot be targeted to IgG1 by the hMT promoter. Thus, IL-4 targets switch recombination to IgG1 by induction of processed switch transcripts.

Animals↗

PubMed1995

The effects of thiopentone, etomidate, ketamine and midazolam on several bactericidal functions of polymorphonuclear leucocytes in vitro.

Polymorphonuclear leucocytes (PMNL) are an essential component of the defence system against invading bacteria. There is evidence that some anaesthetics are able to suppress PMNL functions, promoting, perhaps, perioperative infection. We studied the effects of thiopentone, etomidate, ketamine, and midazolam on the generation of bactericidal agents (superoxide anion, hydrogen peroxide, and myeloperoxidase) by PMNL in vitro. Thiopentone inhibited superoxide anion (P < or = 0.01) as well as hydrogen peroxide production (P < or = 0.001). However, there was no statistically significant effect on myeloperoxidase release. Neither etomidate nor ketamine influenced the PMNL functions tested to any extent. Midazolam suppressed superoxide anion generation (P < or = 0.01) but only if a concentration far beyond clinical relevance was used.

Adult↗