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Results for “Receptors, Pattern Recognition”

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At least 73 records · Page 4Linked to original sources

PubMed2000

Innate recognition of bacteria in human milk is mediated by a milk-derived highly expressed pattern recognition receptor, soluble CD14.

Little is known about innate immunity to bacteria after birth in the hitherto sterile fetal intestine. Breast-feeding has long been associated with a lower incidence of gastrointestinal infections and inflammatory and allergic diseases. We found in human breast milk a 48-kD polypeptide, which we confirmed by mass spectrometry and sequencing to be a soluble form of the bacterial pattern recognition receptor CD14 (sCD14). Milk sCD14 (m-sCD14) concentrations were up to 20-fold higher than serum sCD14 from nonpregnant, pregnant, or lactating women. In contrast, lipopolysaccharide (LPS)-binding protein was at very low levels. Mammary epithelial cells produced 48-kD sCD14. m-sCD14 mediated activation by LPS and whole bacteria of CD14 negative cells, including intestinal epithelial cells, resulting in release of innate immune response molecules. m-sCD14 was undetectable in the infant formulas and commercial (cows') milk tested, although it was present in bovine colostrum. These findings indicate a sentinel role for sCD14 in human milk during bacterial colonization of the gut, and suggest that m-sCD14 may be involved in modulating local innate and adaptive immune responses, thus controlling homeostasis in the neonatal intestine.

Amino Acid Sequence↗

PubMed2006

Functional expression of NOD2, a novel pattern recognition receptor for bacterial motifs, in primary murine astrocytes.

There is growing appreciation that resident brain cells can initiate and/or regulate inflammation after trauma or infection in the central nervous system (CNS). Recent studies from our laboratory have begun to shed light on the mechanisms by which astrocytes perceive bacterial challenges by demonstrating the functional expression of Toll-like receptors (TLR) in this cell type. In the present study, we demonstrate that astrocytes also express members of the novel nucleotide-binding oligomerization domain (NOD) family of proteins that can serve as cytosolic pattern recognition receptors. We show that isolated cultures of murine astrocytes constitutively express robust levels of NOD2, a molecule that can recognize a minimal peptidoglycan motif. Expression of NOD2 is significantly upregulated after exposure to two disparate and clinically relevant bacterial pathogens of the CNS, Borrelia burgdorferi and Neisseria meningitidis. Similarly, NOD2 protein expression is elevated after exposure to specific bacterial ligands for TLRs. Importantly, we show that astrocytes express Rip2 kinase, an essential downstream effector molecule for NOD-mediated cell responses, and demonstrate that this expression is upregulated after bacterial challenge. Furthermore, we confirm the functional nature of NOD2 in astrocytes by demonstrating that a specific ligand for this receptor induces significant inflammatory cytokine production and augments immune responses induced by TLR ligation. Taken together, the present demonstration that astrocytes express functional NOD2 proteins may represent a potentially important mechanism by which this glial cell type initiates either protective host responses within the brain or the progression of damaging CNS inflammation.

Animals↗

PubMed2005

Peptide mapping of bacterial fimbrial epitopes interacting with pattern recognition receptors.

The fimbriae of the oral pathogen Porphyromonas gingivalis induce Toll-like receptor 2 (TLR2)-dependent macrophage activation upon their recognition by CD14 and the beta(2) integrin CD11b/CD18. To map functional epitopes of fimbriae that interact with these pattern recognition receptors (PRRs), we examined 20 synthetic peptides covering the entire length of the 41-kDa fimbrillin subunit. Using direct or competitive inhibition assays for receptor binding or cell activation, the CD14 binding activity of fimbriae was localized to residues 69-90 and was essential for TLR2-dependent cytokine induction. The CD11b/CD18 binding activity of fimbriae was localized to two neighboring epitopes defined by residues 166-185 and 206-225. Unlike epitope 69-90 that constitutively bound CD14, the CD11b/CD18 binding activity of epitopes 166-185 and 206-225 was inducible by integrin activators. The CD11b/CD18 binding activity played a contributory role to TLR2-dependent induction of tumor necrosis factor-alpha by fimbriae but was involved in specific down-regulation of interleukin-12. Cell activation by a combination of fimbrillin peptides corresponding to the CD14 and CD11b/CD18 binding activities resulted in higher tumor necrosis factor-alpha responses than would be expected from a simply additive effect, attributable to CD14-dependent inside-out signaling leading to enhanced binding interactions with CD11b/CD18. These data suggest that P. gingivalis fimbriae display a modular structure that interacts through discrete epitopes and in a regulated mode with distinct PRRs, which in turn differentially modulate the state of cell activation. Elucidation of pathogen interactions with PRRs at the molecular level may glean insight into host defense mechanisms as well as into microbial strategies that subvert innate immunity.

Amino Acid Sequence↗

PubMed2004

Single-base oligodeoxyguanosine-binding proteins on nonspecific cytotoxic cells: identification of a new class of pattern-recognition receptors.

The present study was designed to identify a possible new class of pathogen-recognition proteins that bind single-base oligodeoxynucleotide (ODN) ligands. Binding by the teleost natural killer cell equivalent [referred to as nonspecific cytotoxic cells (NCC)] was compared with mammalian cells (mouse RAW264.7 cells and human THP-1 cells). The ODN analysed were composed of 20-mers of guanosine (dG20), adenosine (dA20), thymidine (dT20) or cytosine (dC20). Binding studies first determined the 50% saturation levels for NCC (1.25 microg/ml), RAW264.7 (0.2 microg/ml) and THP-1 (0.8 microg/ml). Binding by dG20 to all the three cell types was saturable. Ligand blots of NCC membrane lysates with biotinylated dG20 revealed two different major molecular weight species (16-18 and 29 kDa) of binding proteins. The 29-kDa protein was identified with the help of Western blot analysis using a polyclonal antibody specific to an NCC antimicrobial protein (ncamp-1). The membrane expression of the 29-kDa ncamp-1 was determined by the binding of surface-biotinylated NCC membrane proteins with digoxigenin dG20 followed by immunoprecipitation using anti-digoxigenin agarose beads. The 29 and 14-18 kDa NCC membrane proteins were cross-reactive using Western blot examination with a polyclonal anti-histone 1 antibody. Function studies revealed that dG20 activated a twofold upregulation of membrane binding by homologous dG20-biotin. dG20 also stimulated NCC-increased membrane expression of NCC receptor protein 1. Additional experiments were performed to determine the DNase sensitivity of the different ODN. dG20 appeared to be more resistant to DNase treatment, compared to dC20, dA20 and dT20. The single-base ODN-binding proteins may represent a new class of pattern-recognition receptors that are involved in innate anti-bacterial resistance mediated by NCC.

Animals↗

PubMed2004

Immulectin-2, a pattern recognition receptor that stimulates hemocyte encapsulation and melanization in the tobacco hornworm, Manduca sexta.

In insects, encapsulation followed by melanization is a major defense mechanism against metazoan parasites. However, insects must recognize and differentiate nonself before they mount an immune response. Recognition of pathogens in insects is accomplished by a set of pattern recognition receptors (PRRs). Binding of PRRs to pathogens is linked to a variety of immune responses including phagocytosis, nodule formation, encapsulation, and prophenoloxidase activation. So far, little is known about how recognition of pathogens by PRRs triggers different immune responses. In this article, we report that immulectin-2, a C-type lectin, enhances encapsulation and melanization processes in the tobacco hornworm, Manduca sexta. Coating of agarose beads with recombinant carboxyl-terminal carbohydrate-recognition domain (CRD2-II) of immulectin-2 enhanced encapsulation of the beads in vitro by hemocytes and melanization of the beads in vivo in M. sexta larvae. Recombinant CRD2-II also directly bound to granular cells and oenocytoids, but not to plasmatocytes or spherule cells. Immulectin-2 in hemolymph of M. sexta larvae bound to the surface of a nematode, Caenorhabditis elegans, and recombinant CRD2-II directly bound to C. elegans and a human filarial nematode, Brugia malayi. Binding of CRD2-II to C. elegans enhanced melanization of the nematode in vivo. Our results suggest that binding of immulectin-2 to the surface of parasites can trigger encapsulation and melanization responses in M. sexta.

Animals↗

PubMed2002

Human vascular endothelial cells express pattern recognition receptors for fungal glucans which stimulates nuclear factor kappaB activation and interleukin 8 production. Winner of the Best Paper Award from the Gold Medal Forum.

Fungal cell wall glucans nonspecifically stimulate various aspects of innate immunity via interaction with membrane receptors on macrophages, neutrophils, and natural killer cells. We investigated the binding of water-soluble glucans in primary cultures of normal human coronary or dermal vascular endothelial cells (VECs). Membranes from VECs exhibited saturable binding. Competition studies demonstrated the presence of at least two glucan binding sites on VECs. Glucan phosphate competed for all binding sites with a KD of 3.7 microM for coronary VECs and 11 microM for dermal VECs, respectively. Laminarin, a low molecular weight glucan, competed for 47 to 51 per cent of binding (KD = 2.8-2.9 microM), indicating the presence of at least two binding sites. Glucan (1 microg/mL) stimulated VEC nuclear factor kappaB nuclear binding activity and Interleukin 8 expression--but not that of vascular endothelial growth factor--in a time-dependent manner. This is the first report of pattern recognition receptors for glucan on human VECs. It also provides the first evidence that glucans can directly modulate the functional activity of VECs by stimulating cytokine gene. These results provide new insights into the mechanisms by which the host recognizes and responds to fungal cell wall products and suggests that the response to glucans may not be confined to leukocytes.

Antigens, Fungal↗

PubMed2001

Normal human fibroblasts express pattern recognition receptors for fungal (1-->3)-beta-D-glucans.

Fungal cell wall glucans nonspecifically stimulate various aspects of innate immunity. Glucans are thought to mediate their effects via interaction with membrane receptors on macrophages, neutrophils, and NK cells. There have been no reports of glucan receptors on nonimmune cells. We investigated the binding of a water-soluble glucan in primary cultures of normal human dermal fibroblasts (NHDF). Membranes from NHDF exhibited saturable binding with an apparent dissociation constant (K(D)) of 8.9 +/- 1.9 microg of protein per ml and a maximum binding of 100 +/- 8 resonance units. Competition studies demonstrated the presence of at least two glucan binding sites on NHDF. Glucan phosphate competed for all binding sites, with a K(D) of 5.6 microM (95% confidence interval [CI], 3.0 to 11 microM), while laminarin competed for 69% +/- 6% of binding sites, with a K(D) of 3.7 microM (95% CI, 1.9 to 7.3 microM). Glucan (1 microg/ml) stimulated fibroblast NF-kappaB nuclear binding activity and interleukin 6 (IL-6) gene expression in a time-dependent manner. NF-kappaB was activated at 4, 8, and 12 h, while IL-6 mRNA levels were increased by 48% at 8 h. This is the first report of pattern recognition receptors for glucan on human fibroblasts and the first demonstration of glucan binding sites on cells other than leukocytes. It also provides the first evidence that glucans can directly modulate the functional activity of NHDF. These results provide new insights into the mechanisms by which the host recognizes and responds to fungal (1-->3)-beta-D-glucans and suggests that the response to glucans may not be confined to cells of the immune system.

Binding Sites↗

PubMed2002

Overexpression of a pattern-recognition receptor, peptidoglycan-recognition protein-LE, activates imd/relish-mediated antibacterial defense and the prophenoloxidase cascade in Drosophila larvae.

In Drosophila, microbial infection activates an antimicrobial defense system involving the activation of proteolytic cascades in the hemolymph and intracellular signaling pathways, the immune deficiency (imd) and Toll pathways, in immune-responsive tissues. The mechanisms for microbial recognition are largely unknown. We report that, in larvae, the imd-mediated antibacterial defense is activated by peptidoglycan-recognition protein (PGRP)-LE, a PGRP-family member in Drosophila. Consistent with this, PGRP-LE binds to the diaminopimelic acid-type peptidoglycan, a cell-wall component of the bacteria capable of activating the imd pathway, but not to the lysine-type peptidoglycan. Moreover, PGRP-LE activates the prophenoloxidase cascade, a proteolytic cascade in the hemolymph. Therefore, PGRP-LE acts as a pattern-recognition receptor to the diaminopimelic acid-type peptidoglycan and activates both the proteolytic cascade and intracellular signaling in Drosophila immunity.

Animals↗

PubMed2002

Pattern recognition receptors: doubling up for the innate immune response.

Antigen presenting cells (macrophages and dendritic cells) express pattern recognition molecules that are thought to recognize foreign ligands during early phases of the immune response. The best known of these are probably the Toll-like receptors, but a number of other receptors are also involved. Several of these recognize endogenous as well as exogenous ligands, suggesting that they play a dual role in normal tissue function and host defense.

Animals↗

PubMed1998

Point mutations in the beta chain CDR3 can alter the T cell receptor recognition pattern on an MHC class I/peptide complex over a broad interface area.

To study how the T cell receptor interacts with its cognate ligand, the MHC/peptide complex, we used site directed mutagenesis to generate single point mutants that alter amino acids in the CDR3beta loop of a H-2Kb restricted TCR (N30.7) specific for an immunodominant peptide N52-N59 (VSV8) derived from the vesicular stomatitis virus nucleocapsid. The effect of each mutation on antigen recognition was analyzed using wild type H-2Kb and VSV8 peptide, as well as H-2Kb and VSV8 variants carrying single replacements at residues known to be exposed to the TCR. These analyses revealed that point mutations at some positions in the CDR3beta loop abrogated recognition entirely, while mutations at other CDR3beta positions caused an altered pattern of antigen recognition over a broad area on the MHC/peptide surface. This area included the N-terminus of the peptide, as well as residues of the MHC alpha1 and alpha2 helices flanking this region. Assuming that the N30 TCR docks on the MHC/peptide with an orientation similar to that recently observed in two different TCR-MHC/peptide crystal structures, our findings would suggest that single amino acid alterations within CDR3beta can affect the interaction of the TCR with an MHC surface region distal from the predicted CDR3beta-Kb/VSV8 interface. Such unique recognition capabilities are generated with minimal alterations in the CDR3 loops of the TCR. These observations suggest the hypothesis that extensive changes in the recognition pattern due to small perturbations in the CDR3 structure appears to be a structural strategy for generating a highly diversified TCR repertoire with specificity for a wide variety of antigens.

Amino Acid Sequence↗

PubMed2004

A serine protease zymogen functions as a pattern-recognition receptor for lipopolysaccharides.

Bacterial lipopolysaccharide (LPS)-induced exocytosis of granular hemocytes is a key component of the horseshoe crab's innate immunity to infectious microorganisms; stimulation by LPS induces the secretion of various defense molecules from the granular hemocytes. Using a previously uncharacterized assay for exocytosis, we clearly show that hemocytes respond only to LPS and not to other pathogen-associated molecular patterns, such as beta-1,3-glucans and peptidoglycans. Furthermore, we show that a granular protein called factor C, an LPS-recognizing serine protease zymogen that initiates the hemolymph coagulation cascade, also exists on the hemocyte surface as a biosensor for LPS. Our data demonstrate that the proteolytic activity of factor C is both necessary and sufficient to trigger exocytosis through a heterotrimeric GTP-binding protein-mediating signaling pathway. Exocytosis of hemocytes was not induced by thrombin, but it was induced by hexapeptides corresponding to the tethered ligands of protease-activated G protein-coupled receptors (PARs). This finding suggested the presence of a PAR-like receptor on the hemocyte surface. We conclude that the serine protease zymogen on the hemocyte surface functions as a pattern-recognition protein for LPS.

Enzyme-Linked Immunosorbent Assay↗

PubMed2002

Binding of hemolin to bacterial lipopolysaccharide and lipoteichoic acid. An immunoglobulin superfamily member from insects as a pattern-recognition receptor.

Hemolin, a plasma protein from lepidopteran insects, is composed of four immunoglobulin domains. Its synthesis is induced by microbial challenge. We investigated the biological functions of hemolin in Manduca sexta. It was found to bind to the surface of bacteria and yeast, and caused these micro-organisms to aggregate. Hemolin was demonstrated to bind to lipopolysaccharide (LPS) from Gram-negative bacteria and to lipoteichoic acid from Gram-positive bacteria. Binding of hemolin to smooth-type forms of LPS was competed for efficiently by lipoteichoic acid and by rough mutant (Ra and Rc) forms of LPS, which differ in polysaccharide length. Binding of hemolin to LPS was partially inhibited by calcium and phosphate. Hemolin bound to the lipid A component of LPS, and this binding was completely blocked by free phosphate. Our results suggest that hemolin has two binding sites for LPS, one that interacts with the phosphate groups of lipid A and one that interacts with the O-specific antigen and the outer-core carbohydrates of LPS. The binding properties of M. sexta hemolin suggest that it functions as a pattern-recognition protein with broad specificity in the defense against micro-organisms.

Animals↗

PubMed2003

Dual activation of the Drosophila toll pathway by two pattern recognition receptors.

The Toll-dependent defense against Gram-positive bacterial infections in Drosophila is mediated through the peptidoglycan recognition protein SA (PGRP-SA). A mutation termed osiris disrupts the Gram-negative binding protein 1 (GNBP1) gene and leads to compromised survival of mutant flies after Gram-positive infections, but not after fungal or Gram-negative bacterial challenge. Our results demonstrate that GNBP1 and PGRP-SA can jointly activate the Toll pathway. The potential for a combination of distinct proteins to mediate detection of infectious nonself in the fly will refine the concept of pattern recognition in insects.

Animals↗

PubMed2003

Pattern recognition receptors and differentiation antigens define murine myeloid cell heterogeneity ex vivo.

Recruitment of myeloid cells during inflammatory reactions plays an important role in the propagation and resolution of inflammation. However, the identification and characterization of these cells in mice has been hampered by cellular heterogeneity at the functional and phenotypic level. We have defined criteria for the rapid flow-cytometric identification of monocytes (M(o)), macrophages (MPhi), neutrophils (N(eu)) and eosinophils (E(os)) in murine tissues using novel and established myeloid markers. These criteria were applied to the study of naive mice and mice with experimentally induced inflammation, both local and systemic, and also to a murine model of tumor progression. We show that the murine 7/4 antigen and the beta-glucan receptor, Dectin-1, are particularly useful for the sub-division of myeloid cells into individual populations, even when inflammatory conditions modulate their surface expression. Furthermore, 7/4 expression allows distinction between M(o) recently recruited to a site and the resident cells already present. These studies highlight the heterogeneity of the murine M(o)/MPhi-lineage, define an extended phenotype for murine myeloid cells and greatly facilitate the ex vivo characterization of these cells during very different models of inflammation.

Animals↗

PubMed1994

CD14 is a pattern recognition receptor.

Septic shock caused by a diverse group of bacterial pathogens is a serious human disease. Recognition of bacterial envelope constituents is one mechanism used by mammalian cells to initiate responses leading to bacterial killing or, unfortunately, responses that also cause fatal septic shock. Here we show that CD14 plays a key role in initiating cell activation by a group of bacterial envelope components from Gram-negative and Gram-positive microorganisms, as well as mycobacteria. We propose that CD14 is a receptor used by mammalian cells to recognize and signal responses to a diverse array of bacterial constituents. This finding defines the molecular basis for innate microbial immunity; implicit in these findings are new possibilities for therapeutics.

Animals↗

PubMed2004

Selective induction of pentraxin 3, a soluble innate immune pattern recognition receptor, in infectious episodes in patients with haematological malignancy.

Pentraxins are a superfamily of conserved proteins induced in response to microbial and inflammatory stimuli. Members of this family include C-reactive protein (CRP) and serum amyloid P component, collectively known as the classical short pentraxins, and the more recently discovered pentraxin 3 (PTX3), a member of the closely related subfamily of the long pentraxins. PTX3 has been shown to be produced in response to microbial infections, and highly elevated levels were reported in patients with sepsis. In this study, PTX3 levels were evaluated in sera of a group of patients with haematological malignancy. Our findings indicate that serum PTX3 was elevated in only 1/11 afebrile episodes, despite evidence of mucositis (median 1.39), in 10/10 episodes of blood stream or target organ infections (median 7.2) but, surprisingly, was normal in 5/5 episodes of invasive aspergillosis (median 1.39). The data suggest that serum PTX3 levels are elevated selectively in response to infection. These disparate responses require further study.

C-Reactive Protein↗

PubMed2006

Suppression of pattern-recognition receptor TLR4 sensing does not alter lung responses to pneumovirus infection.

Toll-like receptors (TLR) are an important component in the innate immune response to a wide variety of pathogens. Recently, a series of studies has addressed the hypothesis that TLR4 also participates in the host innate response against respiratory syncytial virus (RSV), the leading cause of lower respiratory tract infections in infants and young children. In most of the studies available, RSV, which is not a natural pathogen of mice, has been systematically used in mouse models of human bronchiolitis, with conflicting results. Pneumonia virus of mice (PVM), a member of the pneumovirus genus, shares many similarities with RSV. The serological and structural relationships that exist between them suggest that the immune response to these viruses may be similar in their respective natural hosts. To determine the role of TLR4 in host defense against PVM, TLR4-competent and TLR4-deficient mice were intranasally infected with PVM. Variation of body weight, pulmonary function values, histopathology, and pulmonary viral loads were analyzed. None of the investigated clinical, functional, histological and virological parameters was different between strains, which demonstrates that the sensitivity of the mouse to its natural pneumovirus infection is independent of the presence or absence of TLR4 sensing.

Animals↗

PubMed2003

Pentraxin 3, a non-redundant soluble pattern recognition receptor involved in innate immunity.

Pentraxin 3 (PTX3) is the first long pentraxin identified. Long pentraxins consist of a C-terminal pentraxin domain, which has sequence similarity to C-reactive protein (CRP) and serum amyloid P (SAP) component (the classic short pentraxins), and of an unrelated N-terminal portion. PTX3 is made by diverse cell types, most prominently endothelial cells, macrophages and dendritic cells, in response to primary inflammatory signals (e.g. interleukin-1 (IL-1), tumour necrosis factor (TNF), lipopolysaccharide (LPS)). It binds diverse ligands, including microbial moieties, C1q and apoptotic cells. Evidence suggests that PTX3 plays a role in the regulation of innate resistance to pathogens, inflammatory reactions, possibly clearance of self-components and female fertility.

Animals↗