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Biomedical subjects

A Shaw

Publications and source records attributed to A Shaw.

At least 19 recordsLinked to original sources
PubMed1992

High levels of IL-2 alter signal transduction in cloned IL-4-producing CD4 T cells.

Cloned CD4 T cells of the Th2 type make IL-4 and related cytokines upon receptor cross-linking, whereas cloned CD4 T cells of the Th1 type make IL-2, IFN-gamma, and TNF-beta. These two types of CD4 T cell are also reported to use distinct mechanisms of signal transduction. It has been reported that Th1 cells flux Ca2+ upon receptor cross-linking, whereas Th2 cells do not. We have noted that when cloned Th2 cells are exposed to high levels (20 U/ml) of IL-2, they show an altered phenotype. Such cells are much more sensitive to activation by certain antireceptor antibodies, they flux calcium upon receptor ligation without additional cross-linking with anti-Ig antibodies, and they make much larger amounts of IL-4. In addition, the organization of their TCR is altered, with increased levels of the TCR-eta chain and an increase in the extent of association of CD4 with CD3 and CD45, changes similar to those found in Th1 cells. These results suggest that there is no fundamental difference in the signal transduction apparatus of Th1 and Th2 cells; rather, the IL-2 made by Th1 cells may create similar phenotypic changes in these cells and thus create the impression of altered signal transduction mechanisms. These results do show that exposure to high levels of IL-2 can profoundly affect signal transduction in T cells. Furthermore, we found that the Ca2+ signal caused by CD3 antibodies seemed to differ in character from that caused by TCR antibodies suggesting that the use of CD3 antibodies is not always a good model for activation through the TCR.

Biological Assay↗
PubMed1992

Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins.

Advanced glycosylation end products of proteins (AGEs) are nonenzymatically glycosylated proteins which accumulate in vascular tissue in aging and at an accelerated rate in diabetes. A approximately 35-kDa polypeptide with a unique NH2-terminal sequence has been isolated from bovine lung and found to be present on the surface of endothelial cells where it mediates the binding of AGEs (receptor for advanced glycosylation end product or RAGE). Using an oligonucleotide probe based on the amino-terminal sequence of RAGE, an apparently full-length cDNA of 1.5 kilobases was isolated from a bovine lung cDNA library. This cDNA encoded a 394 amino acid mature protein comprised of the following putative domains: an extracellular domain of 332 amino acids, a single hydrophobic membrane spanning domain of 19 amino acids, and a carboxyl-terminal domain of 43 amino acids. A partial clone encoding the human counterpart of RAGE, isolated from a human lung library, was found to be approximately 90% homologous to the bovine molecule. Based on computer analysis of the amino acid sequence of RAGE and comparison with databases, RAGE is a new member of the immunoglobulin superfamily of cell surface molecules and shares significant homology with MUC 18, NCAM, and the cytoplasmic domain of CD20. Expression of the RAGE cDNA in 293 cells allowed them to bind 125I-AGE-albumin in a saturable and dose-dependent manner (Kd approximately 100 nM), blocked by antibody to RAGE. Western blots of 293 cells transfected with RAGE cDNA probed with anti-RAGE IgG demonstrated expression of immunoreactive protein compared to its absence in mock-transfected cells. These results suggest that RAGE functions as a cell surface receptor for AGEs, which could potentially mediate cellular effects of this class of glycosylated proteins.

Albumins↗
PubMed1992

Physical association of CD4 with the T cell receptor.

The coreceptor hypothesis postulates that physical association of CD4 with the TCR is required for effective signaling for T cell activation. A variety of studies has suggested that the coreceptor function of CD4 allows responses to 10- to 100-fold lower levels of peptide:self MHC class II ligand. We test the hypothesis of CD4 physical association with the TCR in two different ways. First, we use a panel of soluble antibodies directed at different TCR epitopes to activate a cloned T cell line, and show that activation by antibodies directed at a particular TCR epitope can be inhibited by anti-CD4 antibodies binding to a certain CD4 epitope. These effects establish that the interaction of CD4 and the TCR occurs in a specific orientation. Second, we use the same system to provide evidence that the physical association of CD4 with the TCR is required for effective tyrosine phosphorylation of the TCR zeta-chain subunit, presumably reflecting delivery of p56lck (lck) to the TCR. Only anti-TCR antibodies that induce physical association of CD4 with the TCR as monitored by cocapping can induce efficient tyrosine-phosphorylation of the TCR zeta-chain, unless second antibodies are used to force CD4 and the TCR to associate. Furthermore, the phosphorylation of the TCR zeta-chain exactly parallesl physical association in time and drug sensitivity. We conclude from these studies that stimuli that drive physical association of CD4 and the TCR strongly favor T cell activation, supporting the coreceptor hypothesis of CD4 function.

Animals↗
PubMed1992

Extensive CD4 cross-linking inhibits T cell activation by anti-receptor antibody but not by antigen.

Anti-CD4 mAbs have been shown to inhibit T cell activation in a variety of ways. We have tested a panel of IgG and IgM anti-CD4 mAbs for their effects on the activation of a cloned T cell line by antigen presented by syngeneic accessory cells, by soluble anti-T cell receptor antibodies, and by mitogenic lectins. Both IgM and IgG mAbs to CD4 inhibit responses to mitogenic lectins. However, IgM, but not IgG, anti-CD4 antibodies inhibit T cell activation by mAbs specific for the TCR. This inhibitory activity appears to be due to the signaling effects of IgM mAbs, as cross-linked IgG antibodies mimic the behavior of the IgM anti-CD4 antibodies. Inhibition of T cell activation correlates with the ability of IgM and of cross-linked IgG anti-CD4 antibodies to induce tyrosine phosphorylation of the CD4-associated tyrosine kinase p56lck and an unknown substrate, pp32. Surprisingly, we find that the IgM anti-CD4 mAbs tested had no effect on the specific antigen recognition, despite their potent inhibitory effects on the other responses of the same cloned T cell line. These results suggest that multivalent CD4 interactions with ligands such as MHC class II molecules are inhibitory of T cell activation, but that this inhibition can be reversed when CD4 and the TCR bind the same ligand. We discuss the possible implications for positive intrathymic selection of these findings on signaling through CD4.

Animals↗
PubMed1979

Ganglioneuroma, heterochromia iridis, and Horner's syndrome.

A child with mediastinal and supraclavicular ganglioneuroma, heterochromia iridis, and Horner's syndrome is described. The authors postulate that the thoracic neoplasm originated as a congenital neuroblastoma with metastasis to the supraclavicular lymph nodes and subsequent benign transformation, and that the ocular abnormalities resulted from sympathetic ganglion injury by the tumor in infancy. This seems to be the first published report of such ocular abnormalities associated with mediastinal ganglioneuroma.

Child↗
PubMed1979

A perspective for pediatric surgeons: chronic idiopathic intestinal pseudoobstruction.

Chronic idiopathic intestinal pseudoobstruction (CIIP) is a disorder of alimentary tract motility with onset of symptoms in adolescence or young adulthood, characterized by recurring attacks of abdominal pain, distention, vomiting, and constipation often leading to malnutrition and death. Starting with an adolescent patient, treated for a succession of life-threatening attacks of pseudoobstruction, the authors have identified CIIP in four generations of a Virginia family. Studies show characteristic dilation and diminished motility of the esophagus and intestine. Surgery's role in CIIP is palliative, and operation should only be offered when medical measures have failed to control symptoms.

Adolescent↗