Paper alert. Immunology.
A selection of interesting papers that were published in the two months before our press date in major journals most likely to report significant results in immunology.
Allergy and Immunology↗
Biomedical subjects
T Elliott
Publications and source records attributed to T Elliott.
The quantity of naturally processed peptides stably bound by HLA-A*0201 is significantly reduced in the absence of tapasin.
Tapasin plays a critical role in promoting peptide binding by major histocompatibility complex (MHC) class I molecules in the endoplasmic reticulum. In its absence, cell surface expression of most allotypes is significantly reduced. Two exceptions are HLA-A*0201 and HLA-B*2705. In this study, the repertoire of peptides bound endogenously by these allotypes in the absence of tapasin was examined and stability of the HLA class I/peptide complexes assessed. Similar quantities of peptides were recovered from B*2705 complexes expressed in the absence and presence of tapasin and the composition of the peptide pools were not radically different. However, the stability of B*2705 molecules expressed at the surface of tapasin-deficient cells was found to be reduced which suggests there are subtle changes to the peptide repertoire. The impact of the absence of tapasin was more dramatic for A*0201. Although equivalent levels of cell surface A*0201 are expressed in the presence and absence of tapasin, very little A*0201 glycoprotein was recovered from tapasin-deficient cells suggesting the complexes readily dissociate. Consistent with reduced stability, A*0201 complexes were found to be rapidly lost from the surface of tapasin-deficient cells. Analysis of the small quantity of endogenously bound peptides recovered from A*0201 expressed in the absence of tapasin revealed a complex mixture typical of A*0201 molecules expressed in normal cells. Therefore these molecules are unable to exploit the alternative supply of TAP-independent A*0201-binding peptides present in the endoplasmic reticulum. Loading of A*0201 with peptides from both TAP-dependent and TAP-independent sources is significantly compromised without tapasin.
Antigens, Surface↗
N(G)-monomethyl-L-arginine alters insulin-mediated calf blood flow but not glucose disposal in the elderly.
It has been proposed that an important component of glucose disposal is insulin-mediated vasodilation via a nitric oxide (NO)-dependent mechanism. Normal aging is characterized by a resistance to insulin-mediated glucose disposal and deficient endothelial NO production. Impairment of insulin-mediated vasodilation could contribute to this insulin resistance. We tested the hypothesis that the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) would decrease insulin-mediated calf vasodilation and whole-body glucose disposal in young subjects but would have little or no effect in the elderly. Experiments were performed on healthy young (n = 10) and old (n = 10) subjects on 2 study days. Insulin was infused for 4 hours at 40 mU/m(2)/min (young) and 34 mU/m(2)/min (old) during both studies, and L-NMMA (0.1 mg/kg/min) was coinfused during the last 2 hours of insulin on one of these sessions. Calf blood flow was measured by venous occlusion plethysmography, and calf vascular conductance was derived from calf blood flow and mean arterial blood pressure (MABP). L-NMMA increased whole-body insulin-mediated glucose uptake (IMGU) in young subjects (from 11.22 +/- 0.08 to 12.22 +/- 0.87 mg/kg/min, P <.05) but decreased calf blood flow (from 6.53 +/- 0.62 to 5.49 +/- 0.43 mL/100 mL/min, P <.05). In contrast, L-NMMA had no effect on IMGU in elderly subjects (control v L-NMMA, 7.58 +/- 0.46 v 7.86 +/- 0.37 mg/kg/min, P = nonsignificant) but increased calf blood flow (from 3.65 +/- 0.36 to 4.50 +/- 0.32 mL/100 mL/min, P <.01). L-NMMA decreased calf vascular conductance in young subjects (from 0.083 +/- 0.008 to 0.064 +/- 0.005 mL/100 mL/min/mm Hg, P <.05) but not in the elderly (control v L-NMMA, 0.038 +/- 0.004 v 0.040 +/- 0.002 mL/100 mL/min/mm Hg), consistent with the concept that skeletal muscle endothelial NO production is reduced with age. We therefore conclude that (1) L-NMMA has different or opposite actions on calf blood flow and IMGU in both age groups, indicating that the effect of insulin on skeletal muscle blood flow is independent of its influence on glucose disposal in young and old, and (2) skeletal muscle NO production decreases with age.
Adult↗
IFN-beta mediates coordinate expression of antigen-processing genes in RSV-infected pulmonary epithelial cells.
Major histocompatibility complex (MHC) class I-restricted cytotoxic T lymphocytes (CTLs) clear respiratory tract infections caused by the pneumovirus respiratory syncytial virus (RSV) and also mediate vaccine-induced pulmonary injury. Herein we examined the mechanism for RSV-induced MHC class I presentation. Like infectious viruses, conditioned medium from RSV-infected cells (RSV-CM) induces naive cells to coordinately express a gene cluster encoding the transporter associated with antigen presentation 1 (TAP1) and low molecular mass protein (LMP) 2 and LMP7. Neutralization of RSV-CM with antibodies to interferon (IFN)-beta largely blocked TAP1/LMP2/LMP7 expression, whereas anti-interleukin-1 antibodies were without effect, and recombinant IFN-beta increased TAP1/LMP2/LMP7 expression to levels produced by RSV-CM. LMP2, LMP7, and TAP1 expression were required for MHC class I upregulation because the irreversible proteasome inhibitor lactacystin or transfection with a competitive TAP1 inhibitor blocked inducible class I expression. We conclude that RSV infection coordinately increases MHC class I expression and proteasome activity through the paracrine action of IFN-beta to induce expression of the TAP1/LMP2/LMP7 locus, an event that may be important in the initiation of CTL-mediated lung injury.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Staff members' prediction of consequences for their work in residential settings.
Staff members supporting people with mental retardation in residential care were given scenarios describing tasks they might carry out and asked what would happen if they did, or failed to do, them (i.e., who would notice, what would their reaction be). Only a minority reported strong, certain consequences for anything they did from residents, families, or external professionals. Although a majority reported consequences from managers or coworkers, a large minority did not. The tasks for which most staff members reported consequences were administration, followed by enabling residents. Results suggest that staff members who give priority to administration may be responding to the contingencies established by their managers and that a shift in priorities may be required to improve staff members' interactions with clients.
Adult↗
Antibiotic prophylaxis for full-face laser resurfacing: is it necessary?
OBJECTIVE: To evaluate the need for antibiotic prophylaxis when performing full-face laser resurfacing. METHOD: Prospective study of 31 patients undergoing full-face laser resurfacing, 17 with and 14 without antibiotic prophylaxis. OBSERVATION: Four of 14 patients without antibiotic prophylaxis had microbiologic and clinical evidence of infection. None of the 17 patients with antibiotic prophylaxis had clinical infection. Early treatment prevented adverse sequelae in the 4 patients who developed infection. CONCLUSION: Antibiotic prophylaxis against Staphylococcus aureus is useful but not essential, because meticulous wound care and close clinical monitoring of patients daily with routine bacterial swabs can detect infection early.
Antibiotic Prophylaxis↗
Intravascular catheter-related sepsis--novel methods of prevention.
Intravascular catheter-related sepsis continues to cause a significant degree of morbidity and mortality, and accounts for the majority of staphylococcal bacteraemias and septicaemias in hospitalised patients. Methods designed to prevent these infections include those directed at aseptic techniques involving the patient and improvements in catheter design. More recently catheters which are either coated or have incorporated into their polymers antimicrobial agents have been developed. The antimicrobial agents have included both antimicrobials which are used to treat infections as well as antiseptics. The antimicrobial catheters currently available appear to only give protection for relatively short periods of time (approximately 14 days). The use of these antimicrobial catheters needs to be restricted to the situation where infection rates and the risk to the patient of sepsis are relatively high. Further novel approaches for the prevention of these infections include the combination of low voltage electric current together with antimicrobials; these await clinical evaluation.
Anti-Infective Agents, Local↗
Identification of novel Tapasin polymorphisms and linkage disequilibrium to MHC class I alleles.
Tapasin is a Mr 48,000 glycoprotein and has a specialized role in MHC class I-restricted antigen presentation. It is encoded by a gene which maps centromeric to the MHC class II region of human Chromosome 6 within 200 kb of HLA-DP. There is variable dependence upon tapasin for MHC class I expression among different MHC class I alleles. HLA-B*4402 and to a lesser extent HLA-A1 and B8 are tapasin dependent, whereas HLA-B27, A2 and to a lesser extent B7 and A3 are tapasin independent. We investigated whether tapasin is polymorphic and whether these Tapasin alleles are in linkage with any MHC class I alleles. We identified three new mutations within intron 4, which are in a particular linkage with the previously described exon 4 (G16003C) dimorphism. The intronic mutations are G16146T, G16232A, and T16317A (numbering according to cosmid clone F0811; GenBank accession number Z97184). The allele frequency of Tapasin*01 (G16003) was 0.47 and Tapasin*02 (C16003) was 0.53 in this UK population. Four of the eight possible intronic haplotypes were identified and their cis linkage with the tapasin dimorphism ascertained. Tapasin*01 was associated with all the identified haplotypes, while Tapasin*02 was only associated with the wild-type intronic sequence (GGT). There was no significant linkage (P>0.01) of the Tapasin dimorphism or new Tapasin alleles to any of the MHC class I A, B, or C alleles studied or to the extended A1 B8 DR3 haplotype.
Adult↗
Poor correspondence between predicted and experimental binding of peptides to class I MHC molecules.
Naturally processed peptides presented by class I major histocompatibility complex (MHC) molecules display a characteristic allele specific motif of two or more essential amino acid side chains, the so-called peptide anchor residues, in the context of an 8-10 amino acid long peptide. Knowledge of the peptide binding motif of individual class I MHC molecules permits the selection of potential peptide antigens from proteins of infectious organisms that could induce protective T-cell-mediated immunity. Several methods have been developed for the prediction of potential class I MHC binding peptides. One is based on a simple scanning for the presence of primary peptide anchor residues in the sequence of interest. A more sophisticated technology is the utilization of predictive computer algorithms. Here, we have analyzed the experimental binding of 84 peptides selected on the basis of the presence of peptide binding motifs for individual class I MHC molecules. The actual binding was compared with the results obtained when analyzing the same peptides by two well-known, publicly available computer algorithms. We conclude that there is no strong correlation between actual and predicted binding when using predictive computer algorithms. Furthermore, we found a high number of false-negatives when using a predictive algorithm compared to simple scanning for the presence of primary anchor residues. We conclude that the peptide binding assay remains an important step in the identification of cytotoxic T lymphocyte (CTL) epitopes which can not be substituted by predictive algorithms.
Algorithms↗
Lectin purified human class I MHC-derived peptides: evidence for presentation of glycopeptides in vivo.
Previously, using synthetic glycopeptides carrying a natural cytosolic type of monosaccharide O-beta-linked N-acetylglucosamine (GlcNAc) glycosylation of serine residues, we have shown that glycopeptides act as suitable substrates for TAP-mediated transport into the endoplasmic reticulum (ER), and that they bind efficiently to class I major histocompatibility complex (MHC) molecules and can elicit glycopeptide-specific cytotoxic T-lymphocyte (CTL) responses in mice. Recently, we have reported that peptides presented by human class I MHC molecules in vivo encompass a small but significant amount of peptides which seem to be carrying O-beta-linked monosaccharide GlcNAc. In the present report we provide further evidence that glycosylated peptides are indeed presented by class I MHC molecules in vivo. Thus, peptides derived from HLA-A*0201 were purified by wheat germ agglutinin (WGA) lectin affinity chromatography as previously described. Subsequently, the peptides contained in the WGA-eluate were subjected to sequence analysis by Edman degradation. It was found that the peptides derived from HLA-A*0201 which had been retained by the O-GlcNAc-binding lectin WGA did indeed carry a HLA-A*0201 binding motif. Furthermore, using an enzymatic labeling procedure we present evidence that the HLA-A*0201-derived peptides which bind to the WGA lectin are glycosylated with terminal GlcNAc residues. Together, these data provide further evidence for the natural presentation by human class I MHC of glycopeptides carrying terminal O-GlcNAc residues in vivo.
Acetylglucosamine↗
Significance of GAD positivity in elderly patients with diabetes.
Explore the source record for details and available documents.
Adult↗
A novel serological test for the laboratory diagnosis of central venous catheter-associated sepsis.
Explore the source record for details and available documents.
Antibodies, Bacterial↗
Sexuality and genetic identity in the Agaricus section Arvenses.
Twelve wild collections and one commercial strain were used to characterize breeding systems and to develop molecular identities in the Arvenses section of the genus Agaricus, which includes the "horse mushroom" A. arvensis. Two morphotypes were identified based on macro- and micromorphological features. However, not all collections could be delimited by conventional taxonomic characters. Sequencing of the small subunit intergenic spacer (ITS) region (368 to 370 bp) of the rRNA genes clearly resolved the 13 collections into two clusters consistent with the identified morphotypes. Single-spore progenies and mating type testers were established and used to test intra- and interstock compatibility. The two compatibility groups identified were consistent with ITS clusters. Compatibility group I stocks readily interbred within the constraints of a unifactorial heterothallic system with a multiallelic mating type factor. Compatibility group II had a more restricted breeding pattern, and interactions were difficult to predict on the basis of mating type. Morphological data, ITS sequences, and the ability to interbreed suggest that these collections are part of a complex of interrelated species. Single-spore, homokaryotic isolates from both compatibility groups were able to fruit in compost culture, and two of the collections may represent natural homokaryotic fruiting. We conclude that species from the section Arvenses have versatile unifactorial heterothallic life cycles that permit both interbreeding and homokaryotic fruiting.
Agaricus↗
Phosphorylated peptides can be transported by TAP molecules, presented by class I MHC molecules, and recognized by phosphopeptide-specific CTL.
CTL recognize short peptide fragments presented by class I MHC molecules. In this study, we examined the effect of phosphorylation on TAP transport, binding to class I MHC molecules, and recognition by CTL of peptide fragments from known phosphorylated oncogene proteins or virus phosphoproteins. We show that phosphopeptides can be efficiently transported from the cytosol to the endoplasmic reticulum by the TAP. Furthermore, we show that phosphorylation can have a neutral, negative, or even a positive effect on peptide binding to class I MHC. Finally, we have generated phosphopeptide-specific CTL that discriminate between the phosphorylated and the nonphosphorylated versions of the peptide. We conclude that phosphopeptide-specific CTL responses are likely to constitute a subset of the class I MHC-restricted CTL repertoire in vivo.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Beta-lactam-dependent coagulase-negative staphylococcus associated with urinary-tract infection.
Beta-lactam-dependent Staphylococcus saprophyticus was isolated from midstream urine from a patient treated with repeated courses of amoxycillin for recurrent urinary-tract infection.
Aged↗
A neurotrophic model of the development of the retinogeniculocortical pathway induced by spontaneous retinal waves.
The development of the retinogeniculate pathway or the geniculocortical pathway, or both, occurs either before birth or before eye opening in many species. It is widely believed that spontaneous retinal activity could drive the segregation of afferents into eye-specific laminae or columns and the refinement of initially diffuse receptive fields and the emergence of orderly, retinotopic organization. We show that a recent computational model that generates a phenomenologically accurate representation of spontaneous retinal activity can indeed drive afferent segregation and, more particularly, topographic and receptive field refinement in the retinogeniculocortical system. We use a model of anatomical synaptic plasticity based on recent data suggesting that afferents might compete for limited amounts of retrograde neurotrophic factors (NTFs). We find that afferent segregation and receptive field formation are disrupted in the presence of exogenous NTFs. We thus predict that infusion of NTFs into the lateral geniculate nucleus should disrupt normal development and that the infusion of such factors into the striate cortex should disrupt receptive field refinement in addition to the well known disruption of ocular dominance column (ODC) formation. To demonstrate that the capacity of our model of plasticity to drive normal development is not restricted just to spontaneous retinal activity, we also use a coarse representation of visually evoked activity in some simulations. We find that such simulations can exhibit the formation of ODCs followed by their disappearance, reminiscent of the New World marmoset. A decrease in interocular correlations stabilizes these ODCs. Thus we predict that divergent strabismus should render marmoset ODCs stable into adulthood.
Animals↗
Presentation of cytosolic glycosylated peptides by human class I major histocompatibility complex molecules in vivo.
Antigens presented by class I major histocompatibility complex (MHC) molecules for recognition by cytotoxic T lymphocytes consist of 8-10-amino-acid-long cytosolic peptides. It is not known whether posttranslationally modified peptides are also presented by class I MHC molecules in vivo. Many different posttranslational modifications occur on cytoplasmic proteins, including a cytosolic O-beta-linked glycosylation of serine and threonine residues with N-acetylglucosamine (GlcNAc). Using synthetic glycopeptides carrying the monosaccharide O-beta-GlcNAc substitution on serine residues, we have shown that glycopeptides bind efficiently to class I MHC molecules and elicit a glycopeptide-specific cytotoxic T lymphocyte response in mice. In this study, we provide evidence that peptides presented by human class I MHC molecules in vivo encompass a small, significant amount of glycopeptides, constituting up to 0.1% of total peptide. Furthermore, we find that carbohydrate structures present on glycopeptides isolated from class I MHC molecules are dominated by the cytosolic O-beta-GlcNAc substitution, and synthetic peptides carrying this substitution are efficiently transported by TAP (transporter associated with antigen presentation) into the endoplasmic reticulum. Thus, in addition to unmodified peptides, posttranslationally modified cytosolic peptides carrying O-beta-linked GlcNAc can be presented by class I MHC molecules to the immune system.
ATP-Binding Cassette Transporters↗