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Results for “Receptors, Pattern Recognition”

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PubMed2005

Stimulation of toll-like receptor 2 with bleomycin results in cellular activation and secretion of pro-inflammatory cytokines and chemokines.

The clinical use of bleomycin results in systemic and pulmonary inflammatory syndromes that are mediated by the production of cytokines and chemokines. In this study, we demonstrate that cell activation is initiated upon the recognition of bleomycin as a pathogen-associated molecular pattern by toll-like receptor (TLR) 2. The THP1 human monocytic cell line, which constitutively expresses high levels of TLR2, secretes interleukin (IL)-1beta, IL-8, and tumor necrosis factor (TNF)-alpha during bleomycin exposure. The TLR2-dependent nature of cell activation and cytokine secretion is supported by (1) the inability of TLR2-deficient human embryonic kidney (HEK) 293 cells to exhibit nuclear factor-kappa B (NF-kappaB) activation and secrete IL-8 in response to bleomycin; (2) the acquired ability of HEK293 to exhibit NF-kappaB activation and secrete IL-8 upon experimental expression of TLR2; and (3) the inhibition of cell activation in TLR2-expressing HEK293 and THP1 by anti-TLR2 monoclonal antibody. Collectively, these observations identify TLR2 activation as a critical event that triggers NF-kappaB activation and secretion of cytokines and chemokines during bleomycin exposure. Our in vitro findings could serve as a molecular mechanism underlying the pro-inflammatory toxicity associated with bleomycin. Whether bleomycin engages with other cellular receptors that results in activation of alternate signaling pathways and whether the TLR2-agonist activity of bleomycin contribute to its anti-neoplastic property deserve further study.

Antimetabolites, Antineoplastic↗

PubMed2002

Intracellular vs extracellular recognition of pathogens--common concepts in mammals and flies.

There are common themes in innate immune defense systems across the animal and plant kingdoms. Pathogen recognition is commonly based on the identification of microbial molecular patterns by defined receptors and the subsequent activation of signaling pathways that initiate a defense response to fend off the invading microorganism. The existence of mammalian Toll-like receptors (TLRs) and the recent identification of two mammalian nucleotide-binding site leucine-rich repeat (NBS-LRR) proteins (NOD1 and NOD2) as intracellular sensors of bacterial products bring new insights into the possibility of extracellular versus intracellular pathogen recognition and signal transduction depending on the nature of the infection. The homology between TLRs and the Toll system in Drosophila suggests that conserved defense mechanisms are likely to be shared by diverse organisms.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Automated alignment and pattern recognition of single-molecule force spectroscopy data.

Recently, direct measurements of forces stabilizing single proteins or individual receptor-ligand bonds became possible with ultra-sensitive force probe methods like the atomic force microscope (AFM). In force spectroscopy experiments using AFM, a single molecule or receptor-ligand pair is tethered between the tip of a micromachined cantilever and a supporting surface. While the molecule is stretched, forces are measured by the deflection of the cantilever and plotted against extension, yielding a force spectrum characteristic for each biomolecular system. In order to obtain statistically relevant results, several hundred to thousand single-molecule experiments have to be performed, each resulting in a unique force spectrum. We developed software and algorithms to analyse large numbers of force spectra. Our algorithms include the fitting polymer extension models to force peaks as well as the automatic alignment of spectra. The aligned spectra allowed recognition of patterns of peaks across different spectra. We demonstrate the capabilities of our software by analysing force spectra that were recorded by unfolding single transmembrane proteins such as bacteriorhodopsin and NhaA. Different unfolding pathways were detected by classifying peak patterns. Deviant spectra, e.g. those with no attachment or erratic peaks, can be easily identified. The software is based on the programming language C++, the GNU Scientific Library (GSL), the software WaveMetrics IGOR Pro and available open-source at http://bioinformatics.org/fskit/.

Algorithms↗

PubMed2005

Evolutionary dynamics of hepatitis C virus envelope genes during chronic infection.

Hepatitis C virus (HCV) envelope glycoproteins E1 and E2 are important targets for the host immune response. The genes encoding these proteins exhibit a high degree of variability that gives rise to differing phenotypic traits, including alterations in receptor-binding affinity and immune recognition and escape. In order to elucidate patterns of adaptive evolution during chronic infection, a panel of full-length E1E2 clones was generated from sequential serum samples obtained from four chronically infected individuals. By using likelihood-based methods for phylogenetic inference, the evolutionary dynamics of circulating HCV quasispecies populations were assessed and a site-by-site analysis of the d(N)/d(S) ratio was performed, to identify specific codons undergoing diversifying positive selection. HCV phylogenies, coupled with the number and distribution of selected sites, differed markedly between patients, highlighting that HCV evolution during chronic infection is a patient-specific phenomenon. This analysis shows that purifying selection is the major force acting on HCV populations in chronic infection. Whilst no significant evidence for positive selection was observed in E1, a number of sites under positive selection were identified within the ectodomain of the E2 protein. All of these sites were located in regions hypothesized to be exposed to the selective environment of the host, including a number of functionally defined domains that have been reported to be involved in immune evasion and receptor binding. Dated-tip methods for estimation of underlying HCV mutation rates were also applied to the data, enabling prediction of the most recent common ancestor for each patient's quasispecies.

Amino Acid Sequence↗

PubMed2005

[Toll-like receptor].

Toll-like receptors (TLRs) have been revealed to recognize specific patterns of microbial components. Recognition of microbial components by TLRs initiates signal transduction pathways, triggering expression of genes, which products control innate immune responses and further instruct development of antigen-specific acquired immunity. TIR domain-containing adaptors, such as MyD88, TIRAP, TRIF, and TRAM, play pivotal roles in TLR signaling pathways. Differential utilization of these TIR domain-containing adaptors provides specificity of individual TLR-mediated signaling pathways. TLR-mediated activation of innate immunity, when in excess, leads to immune disorders such as inflammatory bowel diseases. Therefore, several mechanisms that negatively control TLR signaling pathways and thereby prevent overactivation of innate immunity have been elucidated. Nuclear IkappaB proteins, such as Bcl-3 and IkappaBNS, have been revealed to be responsible for this process, by differentially inhibiting TLR-dependent cytokine production.

Animals↗

PubMed1996

Normal T cells express two T cell antigen receptor populations, one of which is linked to the cytoskeleton via zeta chain and displays a unique activation-dependent phosphorylation pattern.

The TCR couples antigen recognition and the transmission of activation signals. We report the expression of two TCR populations on the surface of T lymphocytes, one of which is linked to the cytoskeleton via the zeta chain. We also demonstrate that assembly of the CD3 subunits with cytoskeleton-associated zeta is necessary for their maximal localization to the cytoskeleton. The potential significance of these two receptor forms is underscored by differences observed in non-activated T cells; while detergent-soluble phosphorylated zeta appears as a 21-kDa protein, phosphorylated cytoskeleton-associated zeta appears as a 16-kDa form. This dichotomous phosphorylation pattern is rigidly maintained following activation, although each of the receptor populations undergoes different activation-dependent modifications: 1) levels of soluble phosphorylated 21-kDa zeta are enhanced, while phosphorylated 16-kDa cytoskeleton-associated zeta exhibits little change; 2) soluble non-phosphorylated 16-kDa zeta translocates to the cytoskeleton; 3) activation-dependent ubiquitinated zeta forms localize to both fractions, albeit with different kinetics. We also show that the protein tyrosine kinase Lck undergoes activation-dependent modifications and translocates to the cytoskeleton. The phosphorylation profiles of the dichotomous TCR populations in both non-activated and activated lymphocytes suggest that each population could regulate distinct cellular functions, possibly by select intermolecular associations.

Animals↗

PubMed2003

Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway.

Innate immunity is an evolutionarily ancient system that provides organisms with immediately available defense mechanisms through recognition of pathogen-associated molecular patterns. We show that in the CNS, specific activation of innate immunity through a Toll-like receptor 4 (TLR4)-dependent pathway leads to neurodegeneration. We identify microglia as the major lipopolysaccharide (LPS)-responsive cell in the CNS. TLR4 activation leads to extensive neuronal death in vitro that depends on the presence of microglia. LPS leads to dramatic neuronal loss in cultures prepared from wild-type mice but does not induce neuronal injury in CNS cultures derived from tlr4 mutant mice. In an in vivo model of neurodegeneration, stimulating the innate immune response with LPS converts a subthreshold hypoxic-ischemic insult from no discernable neuronal injury to severe axonal and neuronal loss. In contrast, animals bearing a loss-of-function mutation in the tlr4 gene are resistant to neuronal injury in the same model. The present study demonstrates a mechanistic link among innate immunity, TLRs, and neurodegeneration.

Animals↗

PubMed2007

A gene family of putative immune recognition molecules in the hydroid Hydractinia.

Animal taxa display a wide array of immune-type receptors that differ in their specificities, diversity, and mode of evolution. These molecules ensure effective recognition of potential pathogens for subsequent neutralization and clearance. We have characterized a family of putative immune recognition molecules in the colonial hydroid Hydractinia symbiolongicarpus. A complementary DNA fragment with high similarity to the sea urchin L: -rhamnose-binding lectin was isolated and used to screen 9.5 genome equivalents of a H. symbiolongicarpus bacterial artificial chromosome library. One of the resulting 19 positive clones was sequenced and revealed the presence of a 5,111-bp gene organized in 13 exons and 12 introns. The gene was predicted to encode a 726-amino acid secreted modular protein composed of a signal peptide, an anonymous serine-rich domain, eight thrombospondin type 1 repeats, and a L: -rhamnose-binding lectin domain. The molecule was thus termed Rhamnospondin (Rsp). Southern hybridization and sequence analyses indicated the presence of a second Rsp gene. The cDNA from both Rsp genes was sequenced in 18 individuals, revealing high levels of genetic polymorphism. Nucleotide substitutions were distributed throughout the molecule and showed a significantly higher number of synonymous substitutions per synonymous sites than its nonsynonymous counterparts. Whole-mount in situ hybridization and semi-quantitative reverse transcription polymerase chain reaction of microorganism-challenged colonies indicated that Rsp molecules were specifically and constitutively expressed in the hypostome of gastrozooids' mouth. Thus, the combination of (1) comparative analysis on domain composition and function, (2) polymorphism, and (3) expression patterns, suggest that Rsp genes encode a family of putative immune recognition receptors, which may act by binding microorganisms invading the colony through the polyp's mouth.

Amino Acid Sequence↗

PubMed2006

Host defenses against Staphylococcus aureus infection require recognition of bacterial lipoproteins.

Toll-like receptors and other immune-signaling pathways play important roles as sensors of bacterial pattern molecules, such as peptidoglycan, lipoprotein, or teichoic acid, triggering innate host immune responses that prevent infection. Immune recognition of multiple bacterial products has been viewed as a safeguard against stealth infections; however, this hypothesis has never been tested for Staphylococcus aureus, a frequent human pathogen. By generating mutations that block the diacylglycerol modification of lipoprotein precursors, we show here that S. aureus variants lacking lipoproteins escape immune recognition and cause lethal infections with disseminated abscess formation, failing to elicit an adequate host response. Thus, lipoproteins appear to play distinct, nonredundant roles in pathogen recognition and host innate defense mechanisms against S. aureus infections.

Animals↗

PubMed2004

Expression of Toll-like receptors on human platelets.

INTRODUCTION: Platelets play a crucial role in arterial thrombosis, which is the main cause of acute coronary syndrome. Some mycobacteriums, such as Chlamydia pneumoniae, were associated with progression of atherosclerosis and they are interacted with Toll-like receptors (TLRs), which have been defined as pathogen-associated molecular pattern recognition molecules in innate immunity. In the present study, we examined whether human platelets express TLRs. MATERIALS AND METHODS: Human platelets were obtained from healthy volunteers and the mRNA and protein level of TLRs on platelets and Meg-01 cells, megakaryoblastic cell line, were investigated. RESULTS: Reverse transcription-polymerase chain reaction (RT-PCR) demonstrated that TLR1 and TLR6 mRNA were expressed in platelets and Meg-01 cells. Furthermore, interferon-gamma up-regulated their mRNA levels in dose and time dependent manners after stimuli. Both TLR1 and TLR6 proteins in platelets were detected by Western blotting, and their expression of platelets was more than that of Meg-01 cells. Flow cytometry analysis revealed the expression of TLR1 and TLR6 on the cell surface of Meg-01 cells. Furthermore, immunohistochemical analysis using human coronary thrombi obtained from patients with acute coronary syndrome confirmed the expression of TLR1 and TLR6 on platelets. CONCLUSION: In summary, we demonstrated that human platelets and Meg-01 cells expressed a family of TLRs for the first time, and our findings indicated that platelets might recognize antigens directly via TLRs. Our findings suggest a possibility that platelets have the ability to recognize the antigens via TLRs and that there are mechanistic relations between infectious inflammation and atherosclerotic vascular diseases.

Biomarkers↗

PubMed1998

Glycoconjugate expression and cartilage development of the cranial skeleton.

Only few detailed investigations have focused on the glycobiology of cranial development. The functional elements in most inductive and morphogenetic processes are not individual cells, but rather collectives of interacting populations and extracellular matrix components that give rise to specific tissues and organs. Experimental evidence strongly suggests that sugar chains not only confer morphological characteristics. Complex carbohydrate molecules and their corresponding receptors are involved in recognition processes decoding biological information during cranial morphogenesis. The distribution patterns of glycoconjugates are highly dynamic and show a clear correlation with characteristic structural modifications. However, due to the intricate interactions in vivo the definitive physiological impact of these observations has to be established in further studies. In this review, the spatial and temporal patterns of lectin-reactive epitopes and selected receptor types are presented and discussed with regard to their potential importance to physiological craniogenesis.

Animals↗

PubMed2004

Distinct secreted Frizzled receptor protein 1 staining pattern in patients with hyperplastic polyposis coli syndrome.

CONTEXT: Patients with hyperplastic polyposis coli syndrome are thought to harbor precursor lesions of a proposed hyperplasia-carcinoma pathway in colorectal cancer, but morphologic recognition of such lesions remains difficult. Hypermethylation of the secreted Frizzled receptor protein 1 gene on chromosome 8p12 is one of the earliest molecular alterations in colorectal carcinogenesis, potentially disrupting the Wnt signaling cascade of cellular growth control. OBJECTIVE: To determine if hyperplastic polyps from patients with hyperplastic polyposis coli syndrome show a distinct immunohistochemical expression pattern for mismatch repair proteins and secreted Frizzled receptor protein 1 compared to their sporadic counterparts. DESIGN: Immunohistochemical studies (secreted Frizzled receptor protein 1, 3 mismatch repair proteins, and p53) were performed on 23 hyperplastic polyps, 6 synchronous colon cancers, and normal colonic mucosa from 6 patients with hyperplastic polyposis coli syndrome and were compared with studies of sporadic hyperplastic polyps obtained from 13 matched control subjects. RESULTS: The staining pattern for the mismatch repair proteins MLH-1, MSH-2, and MSH-6 did not differ between sporadic and syndromic hyperplastic polyps. In contrast, 52% of syndromic hyperplastic polyps showed a reproducible and distinct staining pattern for secreted Frizzled receptor protein 1 that was not seen in control specimens and that was associated with larger polyp size (P =.002) and location in the proximal colon (P =.01). CONCLUSIONS: Some hyperplastic polyps from patients with hyperplastic polyposis coli syndrome show a secreted Frizzled receptor protein 1 immunophenotype that could indicate alterations of cellular growth control. These findings may help identify precursor lesions in the proposed hyperplasia-carcinoma pathway of colorectal carcinogenesis.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartments.

Recognition by innate immune cells of the pathogen associated molecular patterns (PAMP) lipopolysaccharide (LPS) from Gram-negative bacteria and bacterial CpG-DNA depends on Toll-like receptor4 (TLR4) and TLR9, respectively. To define differences in the response to these distinct PAMP we compared a key intracellular event, namely recruitment of myeloid differentiation marker 88 (MyD88) to the respective PAMP-initiated TLR signaling. Using MyD88-GFP fusion protein expressing macrophages we demonstrate that LPS and CpG-DNA trigger signaling from two different cellular locations: theformer at the cell membrane and the latter at the lysosomal compartment. While LPS does not require endocytosis to functionally associate with the membrane expressed TLR4/MD2 complex, internalization and endosomal maturation is conditional for CpG-DNA to activate TLR9. In support of these data TLR9 is not localized at the cell surface, but intracellularily. These data stress the need to characterize individual TLR at the very beginning of signal initiation in order to understand their diverse biological functions.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Clonal analysis of NK cell development from bone marrow progenitors in vitro: orderly acquisition of receptor gene expression.

In the mouse, two families of MHC class I-specific receptors, namely Ly49 and CD94/NKG2, have been identified on NK cells. Individual NK cells can express several Ly49 molecules as well as members of the CD94/NKG2 family. The expression of multiple receptors with different specificities for MHC class I is thus thought to generate NK cells with diverse recognition patterns. To delineate the mechanism by which NK cells begin to express different patterns of Ly49 and CD94/NKG2 molecules, we developed a clonal assay in which NK1.1(-), IL-2/ IL-15 receptor beta+ NK precursors generated by culture of multipotential Lin(-), c-kit+ progenitors in IL-7, stem cell factor and flt3 ligand are induced to differentiate into NK1.1+ , Ly49+ NK cells. Examination of the clonal populations thus generated revealed heterogeneity in the pattern of Ly49 and CD94/NKG2 gene expression. In addition, a distinct kinetic pattern of expression was observed. CD94, NKG2A, NKG2C and Ly49B were expressed first followed by Ly49G, then Ly49C and I and finally, Ly49A, D, E and F. The data suggest a stochastic but ordered acquisition of class I receptors on NK cells in which developing NK cells become capable of expressing distinct receptors at different times but show no absolute prerequisite to express the receptors that are acquired early in NK development for the expression of those that are acquired later.

Animals↗

PubMed2006

Expansion of toll-like receptor 9-expressing B cells in active systemic lupus erythematosus: implications for the induction and maintenance of the autoimmune process.

OBJECTIVE: Toll-like receptors (TLRs) are pattern-associated receptors in innate immunity that may be involved in the recognition of self antigens and the production of pathogenic autoantibodies. This study was undertaken to examine the expression and function of various TLRs in subpopulations of peripheral blood mononuclear cells (PBMCs) of patients with systemic lupus erythematosus (SLE). METHODS: The expression of TLRs in PBMCs from 50 SLE patients with active disease (SLE Disease Activity Index [SLEDAI] score >or=8; n = 26) or inactive disease (SLEDAI score <8; n = 24) and 20 healthy controls was studied by flow cytometry. TLR expression was assessed on various subpopulations of PBMCs (TLR-2 and TLR-4 by membrane staining; TLR-3 and TLR-9 by intracellular staining). TLR function was accessed by stimulating PBMCs with specific ligands. RESULTS: The proportion of B cells and monocytes expressing TLR-9 was higher among patients with active SLE (mean +/- SD 49.5 +/- 24.4% and 30.7 +/- 24.1%, respectively) than among patients with inactive disease (22.8 +/- 19.6% and 14.3 +/- 8.4%, respectively; P = 0.02 and P = 0.03). Among B cells, the proportion of plasma cells and memory B cells expressing TLR-9 was increased in patients with active SLE. Increased percentages of TLR-9-expressing B cells correlated with the presence of anti-double-stranded DNA antibodies (P = 0.007). Treatment with serum from patients with active disease increased the percentage of TLR-9-expressing plasma cells in serum from healthy controls. Enhanced induction of HLA-DR after TLR-9 stimulation was documented in B cells from patients with active disease. CONCLUSION: In patients with active SLE, the proportion of peripheral blood memory B cells and plasma cells expressing TLR-9 is increased. Endogenous nucleic acids released during apoptotic cell death may stimulate B cells via TLR-9 and contribute to SLE pathogenesis.

Adult↗

PubMed2004

CpG motifs are efficient adjuvants for DNA cancer vaccines.

DNA vaccines can induce impressive specific cellular immune response (IR) when taking advantage of their recognition as pathogen-associated molecular patterns (PAMP) through Toll-like receptors (TLR) expressed on/in cells of the innate immune system. Among the many types of PAMP, immunostimulatory DNA, so-called CpG motifs, was shown to interact specifically with TLR9, which is expressed in plasmacytoid dendritic cells (pDC), a key regulatory cell for the activation of innate and adaptive IR. We now report that CpG motifs, when introduced into the backbone, are a useful adjuvant for plasmid-based DNA (pDNA) vaccines to induce melanoma antigen-specific protective T cell responses in the Cloudman M3/DBA/2 model. The CpG-enriched pDNA vaccine induced protection against subsequent challenge with melanoma cells at significantly higher levels than its parental unmodified vector. Preferential induction of an antigen-specific, protective T cell response could be demonstrated by (i) induction of antigen-dependent tumor cell protection, (ii) complete loss of protection by in vivo CD4+/CD8+T cell- but not NK cell-depletion, and (iii) the detection of antigen-specific T cell responses but not of relevant NK cell activity in vitro. These results demonstrate that employing PAMP in pDNA vaccines improves the induction of protective, antigen-specific, T cell-mediated IR.

Adjuvants, Immunologic↗

PubMedDate not supplied

Strategic targets of essential host-pathogen interactions.

This review summarizes the present concepts regarding the biological processes that mediate intrinsic and innate host defense against microbial invasion of the lung. Innate immunity is the first line of defense of the higher organisms towards invading pathogens. It accomplishes a wide variety of activities including recognition and effector functions. The innate responses use phagocytic cells (macrophages, monocytes, and neutrophils), cells that release inflammatory mediators (basophils, mast cells, and eosinophils), and natural killer cells. The molecular component of innate responses includes complement, acute-phase proteins, and cytokines. Recognition of pathogen-associated molecular patterns is mediated by the pathogen receptors of the innate immune system, among these molecules toll-like receptors have emerged as fundamental components in the innate immune responses to infection, and a link between innate and adaptive immunity. Additional protection comes from polypeptide mediators of the innate host defense, such as the defensins and other antibiotic peptides. In view of the considerable burden in terms of mortality and morbidity that severe infections still pose worldwide, a better understanding of the biological basis of host-pathogen interactions opens stimulating future treatment perspectives.

Animals↗

PubMed2005

Rheumatic fever: how S. pyogenes-primed peripheral T cells trigger heart valve lesions.

The pathogenesis of rheumatic fever (RF) is related to autoimmune humoral and cellular responses against human tissues triggered by Streptococcus pyogenes. CD4(+) T cells are the ultimate effectors of chronic heart lesions in rheumatic heart disease (RHD). Heart-infiltrating CD4(+) T cell clones are able to recognize heart tissue and streptococcal antigens by molecular mimicry. The streptococcal M5(81-103) region, an immunodominant region, was recognized by both intralesional and peripheral T cell clones (62% and 38%, respectively). Peripheral T lymphocytes from Brazilian patients with severe RHD preferentially recognized the M5(81-96) peptide, in the context of HLA-DR7(+) and DR53(+) molecules. HLA-DR7 seems to be related to the development of multiple valvular lesions in RHD patients from different countries. In addition, the fact that peripheral and intralesional T cells recognized the M5(81-103) region points to this region as one of the streptococcal triggers of autoimmune reactions in RHD. T cell repertoire analysis from peripheral and intralesional T cell lines derived from RHD patients showed several oligoclonal expansions of BV families. Major expansions were found in the heart lesions, suggesting that such T cell populations preferentially migrate from the periphery to the heart. Some cross-reactive intralesional T cell clones displayed the same T cell receptor (TCR) BVBJ and CDR3 sequences, showing a degenerate pattern of antigen recognition. Heart tissue-infiltrating cells from myocardium and valvular tissue produced TNF-alpha, IFN-gamma, IL-10, and IL-4, whereas few cells from valvular tissue produced IL-4, showing that the lack of regulation in the valves could be responsible for the permanent and progressive valvular lesions.

Antigens, Bacterial↗