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Biomedical subjects

E Palmer

Publications and source records attributed to E Palmer.

At least 19 recordsLinked to original sources
PubMed1992

Divergent viral superantigens delete V beta 5+ T lymphocytes.

Several murine superantigens in association with class II major histocompatibility complex proteins have been shown to cause the deletion of T cells based on the expression of particular beta-chain variable region (V beta) gene segments. We have previously shown that mice expressing the Etc-1 superantigen, encoded by an open reading frame within the 3' long terminal repeat of the endogenous mouse mammary tumor provirus (Mtv), Mtv-9, delete T cells expressing either V beta 5 or V beta 11 gene segments. Comparison of several Mtv 3' long terminal repeat open reading frame sequences has indicated that the carboxyl terminus likely encodes the V beta specificity of these proteins. Our analysis of C57BL/6 x DBA/2 recombinant inbred strains of mouse revealed three Mtv-9-negative strains that nevertheless have a low frequency of V beta 5-expressing T cells. Here we demonstrate that a second endogenous superantigen, responsible for the deletion of V beta 5-bearing T cells, is encoded by a gene mapping to Mtv-6 on chromosome 16. Surprisingly, the carboxyl-terminal sequences of the Mtv-6 and -9 superantigens are extremely divergent, in spite of the fact that they both mediate the deletion of V beta 5+ lymphocytes.

Amino Acid Sequence↗
PubMed1992

Mls-1-like superantigen in the MA/MyJ mouse is encoded by a new mammary tumor provirus that is distinct from Mtv-7.

Mls-1 is an endogenous superantigen that leads to in vivo deletion and in vitro stimulation of T cell receptor (TCR) V beta 6-, 7-, 8.1-, and 9-expressing cells. The MA/MyJ mouse deletes the identical set of TCR from its mature T cell repertoire; however, it does not contain Mtv-7, the murine mammary tumor provirus (MMTV), whose sag gene encodes Mls-1. Interestingly, the superantigen activity of this mouse strain segregates with a new mammary tumor provirus, Mtv-43, not seen in other inbred strains. The predicted amino acid sequence of the sag gene of Mtv-43 was compared with that of Mtv-7. Strikingly, the COOH terminus of the two molecules is very similar, while all other MMTV-encoded superantigens differ 100% in this segment.

Aging↗
PubMed1992

Ipsilateral fast corticospinal pathways do not account for recovery in stroke.

We tested the hypothesis that in adult humans, recovery from stroke results from the emergence of ipsilateral, fast-conducting corticospinal pathways. In 10 patients recovering from stroke, the unaffected hemisphere was stimulated with an electromagnet and changes in the firing probability of single biceps motor units were used to derive postsynaptic potentials in single biceps motoneurons. Stimuli sufficient to excite the neurons of the fast-conducting corticospinal pathway (as shown by short-latency facilitation of contralateral biceps motoneurons) did not produce short-latency depolarization of ipsilateral biceps motoneurons. The hypothesis is therefore not supported.

Action Potentials↗
PubMed1992

Preferential positive selection of V alpha 2+ CD8+ T cells in mouse strains expressing both H-2k and T cell receptor V alpha a haplotypes: determination with a V alpha 2-specific monoclonal antibody.

A monoclonal antibody, B20.1, was generated by fusing spleen cells from a Lou rat immunized with a soluble alpha/beta T cell receptor (TcR; V alpha 2/V beta 2) to mouse myeloma cells. Analysis of a panel of V alpha 2 mRNA-expressing T cell lines, hybridomas and transfectants revealed that the B20.1 antibody was specific for murine TcR V alpha 2 chains. The V alpha 2+ T cell population was examined in various inbred strains by two-color immunofluorescence using B20.1 and CD4- and CD8-specific antibodies with the following results: (a) the B20.1 antibody detected most members of the TcR V alpha 2 subfamily in the four TcR V alpha haplotypes tested; (b) in most strains examined, TcR V alpha 2 expression was biased to the CD4 subset (7.4%-17.4% V alpha 2+ T cells) as compared to the CD8 compartment (3.8%-13.3%); (c) TcR V alpha 2 expression was not influenced by Mls gene products and (d) increased positive selection of V alpha 2+ CD8+ T cells by H-2k major histocompatibility complex molecules occurred in all murine strains tested of the TcR V alpha a, but not in those bearing the TcR V alpha b haplotype.

Animals↗
PubMed1992

The transcortical nature of the late reflex responses in human small hand muscle to digital nerve stimulation.

The hypothesis that long-latency reflex activity in human small hand muscles in response to stimulation of digital nerves involves a transcortical pathway was tested by combining digital nerve stimulation and magnetic stimulation over the motor cortex in 12 studies on nine normal subjects. Postsynaptic events in human single first dorsal interosseous (FDI) motoneurones were derived from changes in the firing probability of voluntarily activated single motor units. Electromagnetic stimulation over the contralateral motor cortex resulted in a short-latency, brief facilitation of FDI motor units considered to be due to the activation of "fast" corticospinal neurones making monosynaptic projections to motoneurones. Stimulation of the digital nerves of the index finger produced a period of reduced firing probability (I1), a period of increased firing probability (E2) and a further period of reduced firing probability (I2) in FDI motor units. When the two stimuli were given separately and then together, timed so that the magnetic stimulus occurred at the predicted transit time of the E2 through the cortex, the facilitation of FDI motoneurones by the combined stimulation was often less than the algebraic sum of the facilitations from each stimulus alone. Thus, in contrast to the results of similar studies on the late response to muscle stretch, there is no confirmation that the E2 from digital nerve stimulation is due to a transcortical reflex.

Adult↗
PubMed1992

GR94839, a kappa-opioid agonist with limited access to the central nervous system, has antinociceptive activity.

1. The pharmacological profile of GR94839, a kappa-opioid agonist with limited access to the central nervous system, has been investigated. Its antinociceptive activity has been compared with that of GR103545, a centrally-penetrating kappa-agonist and ICI204448, the previously described peripherally-selective kappa-agonist. 2. GR94839 was a potent agonist in the rabbit vas deferens in vitro assay for kappa-opioid receptors (IC50: 1.4 +/- 0.3 nM; n = 6), but had limited activity at mu- or delta-opioid receptors. 3. In the mouse abdominal constriction test, GR94839 was 238 fold more potent when given i.c.v. (ED50: 0.008 (0.004-0.029) mg kg-1; n = 18) than when s.c. (ED50: 1.9 (0.7-3.1) mg kg-1; n = 30). In comparison, GR103545 was equipotent when given i.c.v. or s.c. 4. After intravenous administration, the maximum plasma to brain concentration-ratio attained by GR94839 was 18 compared with 2 for GR85571, a structurally-related kappa-agonist that is centrally-penetrating. 5. GR94839 inhibited the 2nd phase of the rat formalin response at doses 7 fold lower than those required to inhibit the 1st phase (ED50 vs 1st phase: 10.2 (6.7-17.1) mg kg-1, s.c.; ED50 vs 2nd phase: 1.4 (1.0-1.8) mg kg-1, s.c.; n = 18). GR103545 was equipotent against the two phases. 6. Intraplantar administration of the opioid antagonists, norbinaltorphimine (100 micrograms) or naltrexone (1 microgram), reversed the antinociceptive effect of systemic GR94839 (3 mg kg-1, s.c.) against the 2nd phase of the formalin response and intraplantar injection of GR94839 (30-100 micrograms) selectively inhibited the 2nd phase.7. GR94839 and IC1204448 reversed the hyperalgesia in the zymosan-inflamed rat paw at doses (ED50 GR94839: 2.0 (1.1-3.2) mg kg-', s.c.; ED50 IC1204448: 1.2 (0.8-1.7) mg kg-', s.c.), lower than those required to raise the noxious pressure threshold in the non-inflamed paw (EDSO GR94839: 16.4 (8.6-46.7) mg kg', s.c.; ED50 IC1204448: 68.0 (22.1-32000) mg kg', s.c.). GR103545 raised the noxious presure threshold in the inflamed and non-inflamed paws at the same doses.8. GR94839 was sedative in the rat rotarod test (ED50: 35 (12-245) mg kg-', s.c.) at doses higher than those required to inhibit the 2nd phase of the formalin response or reverse hyperalgesia in the zymosan-inflamed rat paw. The doses were comparable to those that inhibited the 1st phase of the formalin response and raised the noxious pressure threshold in the non-inflamed paw.9. The results suggest that GR94839 is a selective kappa-agonist which has antinociceptive activity against inflammatory pain at doses that produce limited central effects. These antinociceptive effects are probably mediated at peripheral opioid receptors.

Analgesics↗
PubMed1992

Corticospinal projections to upper limb motoneurones in humans.

1. Magnetic stimulation was applied over the motor cortex in forty-five normal human subjects and peristimulus time histograms (PSTHs) of the discharges of single motor units were used to record changes in the firing probability of individual spinal motoneurones of contralateral upper limb muscles. Recordings were obtained from 153 motor units from fourteen upper limb muscles. 2. For the majority of motor units the initial effect was a short latency facilitation. The estimated central conduction velocities and the rise times of the underlying excitatory postsynaptic potentials (EPSPs) were compatible with monosynaptic facilitation by a fast corticospinal pathway. In some motor units the initial effect was a short latency inhibition. Other units showed no statistically significant changes in firing probability. The proportion of the tested motor units in each of these categories depended on the muscle. All of the sampled units of first dorsal interosseous (1DI) showed short latency facilitation, as did the majority of units in the forearm and the biceps brachii. More than half of the sampled motor units of triceps brachii and deltoid showed either no effect or were inhibited. 3. To compare the net short latency actions of the neurones activated by magnetic stimulation on various motoneurone pools, the magnitude of the short latency facilitation or inhibition in a given motor unit was normalized to the magnitude of the short latency facilitation in the 1DI motor unit of the same subject at the same stimulus intensity, and these data were pooled for a number of subjects. 4. 1DI motoneurones received strong net facilitation (estimated mean EPSP amplitude 2.9 +/- 0.2 mV), the motoneurones of forearm muscles and biceps brachii received weaker net facilitation and triceps brachii and deltoid received no net effect. 5. It is concluded that the short latency corticospinal projections to upper limb motoneurones in humans have a distinct pattern which is similar to that in other primates.

Adult↗
PubMed1992

Evidence that a long latency stretch reflex in humans is transcortical.

1. The hypothesis that the long latency reflex response to muscle stretch in humans uses a transcortical pathway was tested by looking for convergence onto cortical neurones in eleven normal subjects. 2. Postsynaptic events in single flexor pollicis longus (FPL) motoneurones were derived from changes in the firing probability of individual FPL motor units. 3. Extension of the terminal phalynx of the thumb resulted in both short latency and long latency facilitations of individual FPL motoneurones. These were not reproduced by electrical stimulation of afferents in the terminal phalynx. Magnetic stimulation over the contralateral motor cortex produced strong, short latency facilitation of FPL motoneurones. 4. When the facilitation produced by stimulation over the cortex was superimposed on the long latency facilitation produced by extension of the thumb, the facilitation produced by both stimuli was greater than the sum of the individual facilitations produced by either stimulus given alone. This was not the case when the superimposition occurred on the short latency response to stretch. 5. We conclude that afferent systems excited by the stretch of FPL converge onto cortical neurones which are known to facilitate motoneurones. Thus the cortex is likely to contribute to the long latency stretch reflex in humans.

Adult↗
PubMed1991

An immune response defect due to low levels of class II cell surface expression. Analysis of antigen presentation and positive selection.

The effects of quantitative differences in class II cell surface expression have been difficult to address in intact animals. This study uses several lines of H-2s/s mice carrying an A beta k transgene that differ significantly in terms of class II cell surface expression. Due to inefficient chain pairing, mice carrying 60 to 65 copies of this transgene express only low levels of A alpha s/A beta k on the cell surface, and cell surface expression of the endogenous A alpha s/A beta s complex (and total Ia) is severely reduced (to 7-15% control levels). The significant decrease in class II cell surface expression in the thymic cortex of these mice did not affect the frequency of peripheral T cells expressing at least 10 distinct TCR V beta chains. However, T cell proliferative responses to the A alpha s/A beta s-restricted peptide MBP 89-101 were abrogated in high copy number A beta k mice. Experiments using bone marrow chimeras demonstrated that both inefficient Ag presentation and failure to positively select appropriate T cells contributed to this lack of response. Inefficient Ag presentation was clearly the dominant defect, and the density of class II cell surface expression required for positive selection appeared to be quite low.

Animals↗
PubMed1991

Activation of the metabotropic glutamate receptor attenuates N-methyl-D-aspartate neurotoxicity in cortical cultures.

Excitatory amino acid receptor-mediated neurotoxicity (excitotoxicity) has been proposed to contribute to neuronal loss in a wide variety of neurodegenerative conditions. Although considerable evidence has accumulated implicating N-methyl-D-aspartate (NMDA), kainate, and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in the processes of excitotoxicity, relatively little research has focused on the ability of other neurotransmitter systems to influence excitotoxic neuronal injury. In the present study, we examined the effects of trans-1-aminocyclopentyl-1,3-dicarboylic acid (ACPD), a selective agonist for the metabotropic glutamate, or ACPD, receptor, and carbachol, an agonist at the acetylcholine receptor, on neuronal degeneration produced by brief exposure to NMDA in murine cortical cultures. Since excitotoxic neuronal injury is probably caused by increases in intracellular Ca2+ concentrations, the two transmitter agonists were of particular interest as both have been shown to mobilize intracellular calcium stores. Contrary to what might be expected, ACPD and, to a lesser degree, carbachol attenuated NMDA neurotoxicity. The neuroprotective effect of ACPD, but not of carbachol, was dependent upon the developmental state of cultures; in older cultures (greater than or equal to 18 days in vitro), the protective effect decreased. The neuroprotection by ACPD may be, in part, mediated by protein kinases, since protection is partially reversed by the protein kinase antagonists H-7 and HA-1004. These data suggest that concomitant activation of the ACPD receptor may serve as a protective mechanism against neurotoxicity that could be produced by brief intense NMDA receptor activation during normal or abnormal brain function.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Endogenous superantigen expression is controlled by mouse mammary tumor proviral loci.

Superantigens are defined by their ability to stimulate T cells based predominantly on their V beta expression and ability to delete T cells in the thymus when expressed endogenously. We show here that the expression of one endogenous superantigen, Etc-1, is controlled by the expression of the open reading frame region of the 3' long terminal repeat of the mouse mammary tumor proviral gene, Mtv-9. We show that Mtv-8 controls a superantigen with similar specificity, and that both Mtv-8 and Mtv-9 stimulate some V beta 17+ T cells. A third provirus, Mtv-6, controls a superantigen with specificity for V beta 3. Data presented raise the possibility that endogenous superantigens may compete for class II molecules in a single B cell.

Animals↗
PubMed1991

Physiologic expression of two superantigens in the BDF1 mouse.

The majority of endogenous superantigens in the mouse (including the Mls loci) is encoded by mouse mammary tumor proviruses (Mtv) carried in the germline. To understand the differences between the highly stimulatory viral superantigens such as Mls-1a (encoded by Mtv-7), which have biologic activity in vivo and in vitro, and the poorly stimulatory viral superantigens such as Etc-1 (encoded by Mtv-9), which are active only in vivo, the physiologic expression of each Ag was studied in the Mtv-7+ (Mls-1a+), Mtv-9+ (Etc-1+) C57BL/6 x DBA/2 F1 (BDF1) mouse. Using the T cell hybridomas, 1BVB11.40 (anti Etc-1) and 18bbm.19 (anti Mls-1a), we found that similar to Mls-1a, B cells from the spleen and from the thymus present the Etc-1 superantigen, whereas macrophages and dendritic cells do not. Small, resting B cells present the Mls-1a and Etc-1 superantigens poorly; however, the same cells treated with LPS or IL-4 are at least eightfold more efficient in the presentation of these gene products. Furthermore, the effects of LPS and IL-4 are synergistic, but this synergy is not fully explained by the enhancement of I-A and I-E expression. The depletion of IgM+ B cells from neonatal BDF1 mice prevents the clonal deletion of V beta 5+ and 11+ (Etc-1-reactive) cells but not the deletion of V beta 6+ and 8.1+ (Mls-1a reactive) T cells. Despite the persistence of Mls-1a-mediated clonal deletion in B cell-depleted BDF1 mice, these results taken together, argue that the highly stimulatory Mls-1a gene product and the weakly stimulatory Etc-1 gene product are expressed on similar cell types and that their presentation is regulated in a similar way by agents active with B lymphocytes. It is argued that the differences between the highly stimulatory and weakly stimulatory superantigens reflect differences in avidity between the relevant V beta domain and its class II MHC protein/superantigenic ligand.

Animals↗
PubMed1991

Predominant T cell receptor gene elements in TNP-specific cytotoxic T cells.

H-2b class I-restricted, TNP-specific CTL clones were obtained by limiting dilution cloning of either short term polyclonal CTL lines or spleen cells of TNP-immunized mice directly ex vivo. Sequence analyses of mRNA coding for TCR alpha- and beta-chains of 11 clones derived from CTL lines from individual C57BL/6 mice revealed that all of them expressed unique but clearly nonrandom receptor structures. Five alpha-chains (45%) employed V alpha 10 gene elements, and four of those (36%) were associated with J beta 2.6-expressing beta-chains. The alpha-chains from these four TCR, moreover, contained an acidic amino acid in position 93 of their N or J region-determined sequences. Clones isolated directly from spleen cells carried these types of receptors at lower frequency, 27% V alpha 10 and 19% J beta 2.6, indicating that bulk in vitro cultivation on Ag leads to selection for these particular receptors. However, even in TNP-specific CTL cloned directly ex vivo, V alpha 10 usage was increased about fivefold over that in Ag-independently activated T cells in H-2b mice (4 to 5%). The selection for V alpha 10/J beta 2.6-expressing cells was obtained repeatedly in other TNP-specific CTL lines from C57BL/6 mice but not in FITC-specific CTL from the same strain or in TNP-specific CTL lines from B10.BR (H-2k) or B10.D2 (H-2d) mice. We conclude from this (a) that the selection for V alpha 10/J beta 2.6+ T cells is driven by the complementarity of these receptors to a combination of TNP and MHC epitopes and (b) that predominant receptor structures reflect the existence of a surprisingly limited number of "T cell-relevant" hapten determinants on the surface of covalently TNP-modified cells.

Amino Acid Sequence↗
PubMed1991

A metabotropic glutamate receptor agonist does not mediate neuronal degeneration in cortical culture.

In light of the evidence that calcium plays a critical role in excitotoxic neuronal death, it has been speculated that the metabotropic glutamate receptor may also contribute to excitotoxic damage through the mobilization of Ca2+ from intracellular stores. In the present study we examined this possibility by studying the neurotoxicity of trans-1-amino-cyclopentyl-1,3-dicarboxylate (trans-ACPD), a selective agonist of the metabotropic glutamate receptor. Exposure of cortical neurons to 100 microM trans-ACPD substantially increased phosphoinositide hydrolysis and intraneuronal free calcium in the presence of CPP and CNQX. Despite the presence of functional metabotropic receptors on cultured neurons, however, exposure of cultures to as high as 1 mM trans-ACPD for 24 h failed to produce any morphological or chemical signs of neuronal damage. Furthermore, trans-ACPD did not potentiate submaximal neurotoxicity produced by other non-N-methyl-D-aspartate (NMDA) agonists, kainate and D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid (AMPA).

Animals↗