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Results for “Receptors, Pattern Recognition”

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PubMed2004

A Toll-like receptor in horseshoe crabs.

Non-self-recognition of invading microbes relies on the pattern-recognition of pathogen-associated molecular patterns (PAMPs) derived from microbial cell-wall components. Insects and mammals conserve a signaling pathway of the innate immune system through cell-surface receptors called Tolls and Toll-like receptors (TLRs). Bacterial lipopolysaccharides (LPSs) are an important trigger of the horseshoe crab's innate immunity to infectious microorganisms. Horseshoe crabs' granular hemocytes respond specifically to LPS stimulation, inducing the secretion of various defense molecules from the granular hemocytes. Here, we show a cDNA which we named tToll, coding for a TLR identified from hemocytes of the horseshoe crab Tachypleus tridentatus. tToll is most closely related to Drosophila Toll in both domain architecture and overall length. Human TLRs have been suggested to contain numerous PAMP-binding insertions located in the leucine-rich repeats (LRRs) of their ectodomains. However, the LRRs of tToll contained no obvious PAMP-binding insertions. Furthermore, tToll was non-specifically expressed in horseshoe crab tissues. These observations suggest that tToll does not function as an LPS receptor on granular hemocytes.

Amino Acid Sequence↗

PubMed1996

Differential effects of D2- and D4-blocking neuroleptics on the procedural learning of schizophrenic patients.

OBJECTIVE: To illustrate the differential effects of D2- and D4-blocking neuroleptics on the procedural learning of patients with schizophrenia. METHOD: Twenty-nine schizophrenic patients were divided into 3 groups according to their pharmacological treatment: 1) drug naive, 2) haloperidol, and 3) clozapine. They were all assessed on clinical and procedural measures, the latter being the mirror drawing task. RESULTS: All groups showed progressive learning over the successive trials, and drug-naive patients performed better than the other groups. Patients in the haloperidol group showed many fluctuations over trials, suggesting difficulty in the progressive automation of the task. Such fluctuations did not occur in the clozapine group, but performances per se were worse than in the other groups during the learning trials. Automation of the task occurred at the same point (second block of trials) for all groups. CONCLUSION: These results suggest that D2- and D4-blocking neuroleptics do not similarly affect striatal dependent procedural learning in schizophrenia.

Adult↗

PubMed2005

Mannose receptor expression specifically reveals perivascular macrophages in normal, injured, and diseased mouse brain.

Perivascular macrophages are believed to have a significant role in inflammation in the central nervous system (CNS). They express a number of different receptors that point toward functions in both innate immunity, through pathogen-associated molecular pattern recognition, phagocytosis, and cytokine responsiveness, and acquired immunity, through antigen presentation and co-stimulation. We are interested in the receptors that are differentially expressed by perivascular macrophages and microglia in both the normal CNS as well as in neuroinflammation and neurodegeneration. In this article we report the use of a well-characterized monoclonal antibody, 5D3, to localize the expression of the mannose receptor to perivascular macrophages in the normal CNS and in various models of brain pathology. Mannose receptor expression was limited to perivascular, meningeal, and choroid plexus macrophages in normal, inflamed, injured, and diseased CNS. In particular, activated microglia and invading hematogenous leukocytes were mannose receptor negative while expressing the F4/80 antigen, macrosialin (CD68), FcRII (CD32), scavenger receptor (CD204), and CR3 (CD11b/CD18). Since the perivascular macrophages expressing the mannose receptor are known to be the only constitutively phagocytic cells in the normal CNS, we injected clodronate-loaded liposomes intracerebroventricularly in control mice to deplete these cells. In these mice, there was no detectable mannose receptor expression in perivascular spaces after immunocytochemistry with the 5D3 monoclonal antibody. This finding underlines the value of the monoclonal antibody 5D3 as a tool to study murine perivascular macrophages selectively. Mannose receptor expression by macrophages located at blood-brain (perivascular), brain-cerebrospinal fluid (CSF) (meningeal), and CSF-blood (choroid plexus) interfaces supports a functional role of these cells in responding to external stimuli such as infection.

Animals↗

PubMed2005

Structure of the ectodomain of Drosophila peptidoglycan-recognition protein LCa suggests a molecular mechanism for pattern recognition.

The peptidoglycan-recognition protein LCa (PGRP-LCa) is a transmembrane receptor required for activation of the Drosophila immune deficiency pathway by monomeric Gram-negative peptidoglycan. We have determined the crystal structure of the ectodomain of PGRP-LCa at 2.5-A resolution and found two unique helical insertions in the LCa ectodomain that disrupt an otherwise L-shaped peptidoglycan-docking groove present in all other known PGRP structures. The deficient binding of PGRP-LCa to monomeric peptidoglycan was confirmed by biochemical pull-down assays. Recognition of monomeric peptidoglycan involves both PGRP-LCa and -LCx. We showed that association of the LCa and LCx ectodomains in vitro depends on monomeric peptidoglycan. The presence of a defective peptidoglycan-docking groove, while preserving a unique role in mediating monomeric peptidoglycan induction of immune response, suggests that PGRP-LCa recognizes the exposed structural features of a monomeric muropeptide when the latter is bound to and presented by the ectodomain of PGRP-LCx. Such features include N-acetyl glucosamine and the anhydro bond in the glycan of the muropeptide, which have been demonstrated to be critical for immune stimulatory activity.

Animals↗

PubMed2005

Wistar rats show episodic-like memory for unique experiences.

Human episodic memory refers to the recollection of an unique past experience in terms of its details, its locale, and temporal occurrence. Episodic memory, even in principle, has been difficult to demonstrate in non-verbal mammals. Previously, we provided evidence that mice are able to form an integrated memory for "what," "where," and "when" aspects of single experiences by combining different versions of the novelty-preference paradigm, i.e., object recognition memory, the memory for locations in which objects were explored, and the temporal order memory for objects presented at distinct time points. In the present series of experiments we evaluated whether this paradigm, with minor modifications, also works with rats. We found that rats spent more time exploring an "old familiar" object relative to a "recent familiar" object, suggesting that they recognized objects previously explored during separate trials and remembered their order of presentation. Concurrently, the rats responded differentially to spatial object displacement dependent on whether an "old familiar" or "recent familiar" object was shifted to a location, where it was not encountered previously. These results provide strong evidence that the rats established an integrated memory for "what," "where," and "when." We also found that acute stress impaired the animal's performance in the episodic-like memory task, which, however, could be partially reversed by the N-Methyl-D-aspartate-receptors agonist D-cycloserine.

Animals↗

PubMed2005

Quadratic regression analysis for gene discovery and pattern recognition for non-cyclic short time-course microarray experiments.

BACKGROUND: Cluster analyses are used to analyze microarray time-course data for gene discovery and pattern recognition. However, in general, these methods do not take advantage of the fact that time is a continuous variable, and existing clustering methods often group biologically unrelated genes together. RESULTS: We propose a quadratic regression method for identification of differentially expressed genes and classification of genes based on their temporal expression profiles for non-cyclic short time-course microarray data. This method treats time as a continuous variable, therefore preserves actual time information. We applied this method to a microarray time-course study of gene expression at short time intervals following deafferentation of olfactory receptor neurons. Nine regression patterns have been identified and shown to fit gene expression profiles better than k-means clusters. EASE analysis identified over-represented functional groups in each regression pattern and each k-means cluster, which further demonstrated that the regression method provided more biologically meaningful classifications of gene expression profiles than the k-means clustering method. Comparison with Peddada et al.'s order-restricted inference method showed that our method provides a different perspective on the temporal gene profiles. Reliability study indicates that regression patterns have the highest reliabilities. CONCLUSION: Our results demonstrate that the proposed quadratic regression method improves gene discovery and pattern recognition for non-cyclic short time-course microarray data. With a freely accessible Excel macro, investigators can readily apply this method to their microarray data.

Algorithms↗

PubMed2004

Toll-like receptor 2-dependent bacterial sensing does not occur via peptidoglycan recognition.

Toll-like receptor 2 (TLR2) has been shown to recognize several classes of pathogen-associated molecular patterns including peptidoglycan (PG). However, studies linking PG with TLR2 recognition have relied mainly on the use of commercial Staphylococcus aureus PG and have not addressed TLR2 recognition of other PG types. Using highly purified PGs from eight bacteria (Escherichia coli, Pseudomonas aeruginosa, Yersinia pseudotuberculosis, Helicobacter pylori, Bacillus subtilis, Listeria monocytogenes, Streptococcus pneumoniae and S. aureus), we show that these PGs are not sensed through TLR2, TLR2/1 or TLR2/6. PG sensing is lost after removal of lipoproteins or lipoteichoic acids (LTAs) from Gram-negative and Gram-positive cell walls, respectively. Accordingly, purified LTAs are sensed synergistically through TLR2/1. Finally, we show that elicited peritoneal murine macrophages do not produce tumour necrosis factor-alpha or interleukin-6 in response to purified PGs, suggesting that PG detection is more likely to occur intracellularly (through Nod1/Nod2) rather than from the extracellular compartment.

Animals↗

PubMed2004

Antigenic drift in the ligand domain of Plasmodium vivax duffy binding protein confers resistance to inhibitory antibodies.

Interaction of the Duffy binding protein (DBP) with its erythrocyte receptor is critical for maintaining Plasmodium vivax blood-stage infections, making DBP an appealing vaccine candidate. The cysteine-rich region II is the ligand domain of DBP and a target of vaccine development. Interestingly, most of the allelic diversity observed in DBP is due to the high rate of nonsynonymous polymorphisms in this critical domain for receptor recognition. Similar to the hypervariability in influenza hemagglutinin, this pattern of polymorphisms in the DBP ligand domain suggests that this variation is a mechanism to evade antibody neutralization. To evaluate the role that dbp allelic diversity plays in strain-specific immunity, we examined the ability of an anti-Sal1 DBP serum to inhibit the erythrocyte-binding function of variant dbp alleles expressed on COS cells. We observed that the PNG-7.18 allele was significantly less sensitive to immune inhibition of its erythrocyte-binding activity than were the Sal1 and PNG-27.16 alleles. This result suggested that the unique polymorphisms of resistant PNG-7.18 were part of a protective epitope on the DBP ligand. To confirm this, Sal1 was converted to the refractory phenotype by introduction of 3 polymorphisms unique to PNG-7.18, via site-directed mutagenesis. The results of the present study indicate that linked polymorphisms have an additive, synergistic effect on DBP antigenic character.

Alleles↗

PubMed2004

Protein kinase C epsilon: a new target to control inflammation and immune-mediated disorders.

Recent advances in understanding the molecular basis for mammalian host immune responses to microbial invasion suggest that the first line of defense against microbes is the recognition of pathogen-associated molecular patterns by a set of germline-encoded receptors: the Toll-like receptors (TLRs). TLRs have been identified as being part of a large family of pathogen-recognition receptors that play a decisive role in the induction of both innate and adaptive immunity. Indeed, activation of T lymphocytes depends on their interaction with dendritic cells previously stimulated by TLR agonists such as bacterial lipopolysaccharide (LPS), a TLR-4 ligand. A novel PKC epsilon (epsilon) was recently found to be a critical component of TLR-4 signaling pathway and thereby to play a key role in macrophage and dendritic cell (DC) activation in response to LPS. Thus, controlling the kinase activity of PKC epsilon might represent an efficient strategy to prevent or treat certain inflammatory disorders of microbial origin.

Animals↗

PubMed2004

Differential expression of Toll-like receptor (TLR)-2 and TLR-4 on monocytes in human sepsis.

Toll-like receptors (TLRs) are a recently described family of immune receptors involved in the recognition of pathogen-associated molecular patterns (PAMPs). The central role of TLR-2 and TLR-4 in microbial responses suggests they may be implicated in the pathogenesis of human sepsis. We hypothesized that the incidence and outcome of sepsis would be influenced by the expression of TLR-2 and TLR-4 on monocytes. We have examined the expression of TLR-2 and TLR-4 mRNA and protein and their response to pro- and anti-inflammatory agents on monocytes from subjects in the intensive therapy unit (ITU) with and without Gram-negative, Gram-positive or polymicrobial sepsis. We compared these data to ITU and healthy control subjects. TLR-2 mRNA was significantly up-regulated on monocytes from subjects with both Gram-positive and Gram-negative sepsis. Similarly, we detected increased levels of TLR-2 protein on the surface of monocytes from sepsis subjects relative to ITU controls. TLR-4 mRNA was increased in Gram-positive subjects; however, there was no corresponding increase in TLR-4 protein. Although TLR-4 mRNA expression in healthy control monocytes could be modulated in vitro by culture with lipopolysaccharide or interleukin-10, this was not observed in monocytes obtained from sepsis and ITU control subjects, suggesting that septic and ITU control milieus may alter the immunoregulation of TLR-4 mRNA expression on monocytes. TLR-2 mRNA was not modulated in culture by any stimulus in any group. We suggest that expression and regulatory response of monocyte TLR-2, and to a lesser extent TLR-4 may be abnormal in human sepsis.

Adult↗

PubMed1990

The specificity of the binding of platelet activating factor (PAF) to anti-PAF antibodies.

Quantitative hapten inhibition experiments employing sheep anti-PAF antibodies and selected PAF analogues were undertaken with the aim of defining the antigenic determinant structures complementary to the antibody combining sites. The most important fine structural features for inhibition of antibody to PAF were shown to be an acetyl group at position 2 of the phospholipid glycerol backbone and an ether group at position 1. Of the naturally occurring compounds, C16- and C18:1-PAF proved to be the most potent inhibitors and more active than C18-PAF while phospholipids with a propionyl, butyryl or hexanoyl group at position 2 showed either weak or no inhibitory activity. The 1-acyl, thioether and deoxy analogues proved inactive. Variations in the polar head group of PAF were found to be less critical with, for example, the dimethyl and ethanolamine derivatives retaining some activity. This antibody recognition pattern is very similar to that of the PAF receptor, although the antibodies appear to have a more specific requirement for an acyl linkage at position 2.

Animals↗

PubMed1985

Composition, removal and metabolic fate of chylomicrons derived from diabetic rats.

Tri[14C]acylglycerol-labelled chylomicrons, obtained from cannulated mesenteric lymph of streptozotocin-diabetic donor rats, when intravenously injected into non-diabetic recipient rats, disappeared from the circulation at a significantly slower rate than similarly prepared tri[14C]acylglycerol chylomicrons from non-diabetic donor rats (t1/2, 5.6 +/- 0.7 vs. 3.2 +/- 0.5 min-1, P less than 0.02). The appearance of labelled lipolysis products among plasma lipids (free fatty acid, cholesterol ester and phospholipid fractions) was delayed, indicating decreased availability for lipolysis of the chylomicron-borne triacylglycerol of diabetic origin. Tissue distribution of triacylglycerol, 15 min after the injection of chylomicrons to recipient rats, disclosed a 4-5-fold increase in uptake by muscles (heart and diaphragm) in relation to adipose tissues (epididymal and perirenal sites), in the case of chylomicrons of diabetic derivation. Since a large share of the chylomicron triacylglycerol was taken up by the liver, this tissue was perfused with chylomicron 'remnants' prepared by partial in vitro lipolysis with purified lipoprotein lipase. The 'remnants' of diabetic derivation were taken up by the liver at a 2-3-fold slower rate than those of non-diabetic origin. Chylomicrons derived from diabetic rats were found to be similar in size but markedly depleted of E apolipoproteins as determined by SDS-polyacrylamide gel electrophoresis, isoelectric focussing and a specific immunoassay. Decreases were also seen in A-I apolipoproteins by immunoassay and isoelectric focussing. Chylomicron 'remnants' were also markedly apolipoprotein E-deficient. In vitro incubation of the 'diabetic remnants' with high-density lipoproteins raised their apolipoprotein E content approx. 3-fold and considerably increased their hepatic uptake. Injection of intact chylomicrons preincubated with high-density lipoproteins likewise increased their in vivo removal rate toward the range of that of 'non-diabetic' chylomicrons. We conclude that diabetes-induced changes in the apolipoprotein composition of the chylomicrons and chylomicron remnants play an important role in their removal from the circulation. It appears that their recognition pattern is altered, reducing their ability to interact with receptor sites in the peripheral tissues and the liver, respectively.

Animals↗

PubMed2003

TLR-induced negative regulatory circuits: role of suppressor of cytokine signaling (SOCS) proteins in innate immunity.

Recognition of pathogen-associated molecular pattern (PAMP) by PAMP receptors of innate immune cells leads to activation and initiation of innate and adaptive immune responses. While the initial steps have been elucidated recently, the mechanisms how innate immune responses are controlled and regulated are only poorly understood. Suppressor of cytokine signaling (SOCS) proteins seem to play an important role in this process. It has been recognized that SOCS proteins not only regulate JAK/STAT-dependent cytokine signaling pathways but are also induced by TLR stimuli and in addition might also regulate TLR signaling.

Animals↗

PubMed2002

Correlation of a dynamic model for immunological synapse formation with effector functions: two pathways to synapse formation.

During antigen recognition by T cells different receptors and ligands form a pattern in the intercellular junction called the immunological synapse, which might be involved in T-cell activation. Recently, a synapse assembly model has been proposed, which enables the calculation of the propensity for synapse assembly driven by membrane-constrained protein binding interactions. We bring together model predictions of mature synapse assembly with data on the dependence of T-cell responses on T-cell receptor (TCR)-MHC-peptide (pMHC) binding kinetics. Predictions of mature synapse assembly, based on TCR-pMHC binding kinetics, correlate well with observed cytokine responses by T cells bearing the relevant TCR but not with cytotoxic T lymphocyte-mediated killing. We discuss the suggested different role for the synapse in pre- and post-nuclear activation events in T cells. The view of immunological synapse assembly given here emphasizes the importance of both the on and off rates for the TCR-pMHC interaction and in this context recent data on a positive role for analogs of self-peptides in synapse assembly is considered.

Animals↗

PubMedDate not supplied

A new subunit of the human T-cell antigen receptor complex.

The T-cell antigen receptor binds antigen in association with a cell surface molecule encoded by the major histocompatibility complex (MHC). MHC restricted recognition of antigen by this receptor leads to the complex pattern of programmed gene expression that characterizes T-cell activation. The eventual understanding of human T-cell function will require the complete elucidation of the structure of the human T-cell antigen receptor. On human T cells, clonally determined, disulphide-linked alpha and beta chains of the receptor are non-covalently and stoichiometrically associated with three additional polypeptides known as the T3 complex. These receptor subunits are glycoproteins of relative molecular mass (Mr) 25,000 (25K) and 20K (gamma and delta) and a non-glycosylated 20K protein (epsilon). Our studies of murine T cells show that the mouse T-cell antigen receptor consists of at least seven distinct polypeptide chains. In addition to clonotypic alpha and beta chains, the murine complex consists of glycoproteins of 26K and 21K and endoglycosaminidase F (endo F)-insensitive polypeptides of 25K, 21K and 16K. The latter, which we have termed zeta (zeta), exists as a homodimer within the complex. The 26K component (gp26) has been shown to be the murine analogue of the human delta chain. Other cross species homologies remain to be established, however none of the described human receptor components appear similar to the murine zeta polypeptide. We report here the use of an antiserum raised against the murine zeta subunit to identify a previously unrecognized component of the human T-cell antigen receptor. This human protein is T-cell specific and biochemically similar to the murine zeta polypeptide.

Animals↗

PubMed2005

Lentiviral vectors and antiretroviral intrinsic immunity.

Multicellular organisms have evolved under relentless attacks from pathogens, and as a consequence have spiked their genomes with numerous genes that serve to thwart these threats, notably through the building of the innate and adaptive arms of the immune system. The innate immune system is by far the most ancient, being found as widely as in plants and Drosophila, while adaptive immunity arose with the emergence of cartilaginous fishes. Innate immunity enters rapidly into the game during the course of an infection and generally involves the recognition by specific cellular receptors of common pathogen-associated patterns to elicit broad defensive responses, mediated in humans by interferons, macrophages, and natural killer cells, amongst others. When innate immunity fails to eradicate the infection quickly, adaptive immune responses enter into play, to generate exquisitely specific defenses to virtually any pathogen, thanks to a quasi-infinite repertoire of nonself receptors and effectors. A specific form of innate immunity, coined "intrinsic immunity," completes this protection by providing a constant, always-on, line of defense, generally through intracellular obstacles to the replication of pathogens. This component of the immune system has gained much attention as it was discovered that it is a cornerstone of the resistance of mammals against retroviruses. One of these newly discovered intracellular molecular weapons, the APOBEC family of proteins, is active against several classes of retroelements. We present here the current state of knowledge on this rapidly evolving field and discuss implications for gene therapy.

APOBEC-3G Deaminase↗

PubMed2005

Inhibition of Toll Like Receptor immune responses by microbial pathogens.

Toll Like Receptors (TLRs) are pathogen recognition receptors (PRRs) that respond to specific pathogen associated molecular patterns (PAMPs) during microbial invasion. After TLR stimulation a series of cellular responses initiate an inflammatory response and influence specific adaptive immunity that ultimately destroy the pathogen. But the immune response is not always able to control the infection. Pathogens have developed mechanisms to overcome and evade distinct arms of vertebrate immunity. Many of these strategies have been extensively described, but with the recent discovery of TLRs additional means to manipulate the innate immune response are currently being studied. Pathogens generally inhibit TLR mediated immunity by either blocking signals that stimulate further host defense mechanisms or by down-regulating their expression. These inhibitory mechanisms have been mainly elucidated in bacterial systems, whereas in other microorganisms they remain to be identified. Here the strategies that pathogenic microbes use to subvert TLR mediated immune responses are reviewed.

Bacterial Infections↗

PubMed1985

Neuropeptides and their receptors: a psychosomatic network.

A major conceptual shift in neuroscience has been wrought by the realization that brain function is modulated by numerous chemicals in addition to classical neurotransmitters. Many of these informational substances are neuropeptides, originally studied in other contexts as hormones, "gut peptides," or growth factors. Their number presently exceeds 50 and most, if not all, alter behavior and mood states, although only endogenous analogs of psychoactive drugs like morphine, Valium, and phencyclidine have been well appreciated in this context. We now realize that their signal specificity resides in receptors (distinct classes of recognition molecules), rather than the close juxtaposition occurring at classical synapses. Rather precise brain distribution patterns for many neuropeptide receptors have been determined. A number of brain loci, many within emotion-mediating brain areas, are enriched with many types of neuropeptide receptors suggesting a convergence of information at these "nodes." Additionally, neuropeptide receptors occur on mobile cells of the immune system; monocytes can chemotax to numerous neuropeptides via processes shown by structure-activity analysis to be mediated by distinct receptors indistinguishable from those found in brain. Neuropeptides and their receptors thus join the brain, glands, and immune system in a network of communication between brain and body, probably representing the biochemical substrate of emotion.

Animals↗