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Results for “Receptors, Pattern Recognition”

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At least 451 records · Page 25Linked to original sources

PubMed2005

The expression profile of lipopolysaccharide-binding protein, membrane-bound CD14, and toll-like receptors 2 and 4 in chronic periodontitis.

BACKGROUND: This study aimed to investigate the interrelationship of in vivo expression of lipopolysaccharide-binding protein (LBP) and membrane-bound CD14 (mCD14) in human gingival tissues as well as the coexpression of Toll-like receptors (TLR) 2 and 4 in association with periodontal conditions. METHODS: Gingival biopsies were collected from 43 subjects with chronic periodontitis, including periodontal pocket tissues (PoTs) and clinically healthy gingival tissues (HT-Ps), and from 15 periodontally healthy subjects as controls (HT-Cs). The expression of LBP, CD14, TLR 2, and TLR 4 was detected by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: LBP and mCD14 peptides were simultaneously detected in 91% of PoTs, 85% of HT-Ps, and 100% of HT-Cs. LBP and mCD14 mRNAs were simultaneously detected in 55% of PoTs, 55% of HT-Ps, and 75% of HT-Cs. The expression of LBP was confined to the gingival epithelium, whereas mCD14 was observed around the epithelium-connective tissue interface. A positive correlation existed between LBP and mCD14 peptides in both detection expression (r(s) = 0.608; P <0.001) and expression levels (r = 0.304; P <0.05) of these two molecules. In PoTs, TLR 2 was detected in both pocket epithelia and macrophage-like cells in connective tissues, whereas TLR 4 was predominantly detected in connective tissues. In HT-Ps and HT-Cs, a weak expression of TLR 2 was found in gingival epithelia, and no TLR 4 expression was detected. In PoTs, mCD14 was codetected on CD68-labeled macrophages in the underlying connective tissues of pocket epithelium as well as on CD1a-labeled dendritic cells in the pocket epithelium and connective tissues interface. No similar expression profile was detected in HT-Ps and HT-Cs. CONCLUSIONS: This study suggests that the in vivo expression of LBP and mCD14 may be interrelated. Altered cellular expression profiles of mCD14 and TLR 2 and 4 in periodontal pocket tissues imply that these pattern recognition receptors may play a role in periodontal pathogenesis.

Acute-Phase Proteins↗

PubMed2026

Molecular Bases and Genetic Design of Rice Disease Resistance for Optimized Yield and Sustainable Agriculture.

Rice diseases continue to undermine yield stability and threaten the sustainability of rice production. The central challenge is therefore not simply to maximize immune activation, but to identify genetic interventions that remain effective across diverse pathogen races and environmental conditions without imposing excessive penalties on growth or yield. Here, we synthesize the molecular basis of rice immunity from a design-oriented perspective. We first examine cell-surface pattern-recognition receptors and intracellular nucleotide-binding leucine-rich repeat receptors, and then assess the shared signaling hubs and defence outputs that connect pathogen perception to antimicrobial responses. Rather than treating these components as equivalent breeding targets, we compare their translational potential according to resistance spectrum, anticipated durability, tunability, pleiotropic risk, and the strength of field evidence. We further discuss breeding strategies based on receptor engineering, editing of susceptibility genes and cis-regulatory elements, post-translational motif engineering, pathogen-inducible and upstream open reading frame-mediated regulation, resistance-gene stacking and artificial intelligence-assisted prediction. We argue that rational resistance design in rice should move beyond constitutive immune activation toward allele-specific, quantitative, spatially restricted and infection-responsive regulation. Integrating mechanistic insights with precision genome editing, accelerated breeding and responsible deployment offers a practical route to durable, yield-compatible disease resistance while reducing dependence on chemical control.

breeding strategy↗

PubMed2007

Serine/threonine kinase PKR: a sentinel kinase that discriminates a signaling pathway mediated by TLR4 from those mediated by TLR3 and TLR9.

Cells of the innate immune system discriminate between "noninfectious self" and "infectious nonself" via pattern recognition receptors known as Toll-like receptors (TLRs). Though TLRs and the related interleukin 1 receptors share considerable homology in their cytoplasmic domains and adaptor molecules, signaling cascades may substantially differ from one another depending on the adaptor proteins recruited. Here we show that ectopic overexpression of catalytically inactive dominant-negative PKR expression system suppressed NF- kappa B activation mediated by TLR3, TLR9, TNF receptor 1 and 2 (TNF-R 1/2), but not by TLR4. Physiological relevance of the observations described here are discussed.

Animals↗

PubMed2006

PAMP recognition and the plant-pathogen arms race.

Plants have evolved systems analogous to animal innate immunity that recognise pathogen-associated molecular patterns (PAMPs). PAMP detection is an important component of non-host resistance in plants and serves as an early warning system for the presence of potential pathogens. Binding of a PAMP to the appropriate pattern recognition receptor leads to downstream signalling events and, ultimately, to the induction of basal defence systems. To overcome non-host resistance, pathogens have evolved effectors that target specific regulatory components of the basal defence system. In turn, this has led to the evolution in plants of cultivar-specific resistance mediated by R proteins, which guard the targets of effectors against pathogen manipulation; the arms race continues.

Flagellin↗

PubMed2005

Synthesis and proinflammatory properties of muramyl tripeptides containing lysine and diaminopimelic acid moieties.

The unusual amino acid diaminopimelic acid (DAP) was prepared by cross metathesis of appropriately protected vinyl glycine and allyl glycine derivatives. Catalytic hydrogenation of the cross-coupling product resulted in reduction of the double bond and the removal of protecting groups. The resulting compounds were appropriately protected for the polymer-supported and solution-phase synthesis of muramyl tripeptides 2 and 3, which differ in the amidation of the alpha-carboxylic acids of the isoglutamine and DAP moieties. Muramyl dipeptide (1, MDP), the DAP-containing muramyl tripeptide 3, and the lysine-containing muramyl tripeptides 4 and 5 induced TNF-alpha gene expression without TNF-alpha protein production in a human monocytic cell line. The observed block in translation could be removed by co-incubation with LPS, resulting in an apparent synergistic effect. Compound 2 did not induce TNF-alpha gene expression, neither did it exhibit a synergistic effect with LPS; this indicates that amidation of the alpha-carboxylic acids of the isoglutamine and DAP moieties results in a loss of biological activity. It is proposed that amidation of alpha-carboxylic acids is a strategy that may be used by pathogens to avoid detection by the innate immune system. Furthermore, the pattern recognition receptors Nod1 and Nod2 have been implicated in the possible induction of a synergistic effect of muropeptides with LPS.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed2007

Dectin-1 promotes fungicidal activity of human neutrophils.

Human polymorphonuclear leukocytes (PMN) are a first line of defense against fungal infections. PMN express numerous pattern recognition receptors (PRR) that facilitate identification of invading microorganisms and ultimately promote resolution of disease. Dectin-1 (beta-glucan receptor) is a PRR expressed on several cell types and has been studied on monocytes and macrophages. However, the role played by dectin-1 in the recognition and killing of fungi by PMN is unknown. We investigated the ability of dectin-1 to mediate human PMN phagocytosis and fungicidal activity. Dectin-1 was expressed on the surface of PMN from all subjects tested (n=29) and in an intracellular compartment that co-sedimented with azurophilic granules in Percoll density gradients. Soluble beta-glucan and mAb GE2 (anti-dectin-1) inhibited binding and phagocytosis of zymosan by human PMN (e.g., ingestion was inhibited 40.1% by 30 min, p<0.001), and blocked reactive oxygen species production. Notably, soluble beta-glucan and GE2 inhibited phagocytosis and killing of Candida albicans by PMN (inhibition of killing was 54.8% for beta-glucan and 36.2% for GE2, p<0.01). Our results reveal a mechanism whereby PMN dectin-1 plays a key role in the recognition and killing of fungal pathogens by the innate immune system.

Candida albicans↗

PubMedDate not supplied

Viruses as adjuvants for autoimmunity: evidence from Coxsackievirus-induced myocarditis.

Adjuvants historically are considered to stimulate immune responses 'non-specifically'. Recently, a renewed understanding of the critical role of innate immunity in influencing the development of an adaptive immune response has led researchers to a better understanding of 'the adjuvant effect'. Although innate immune cells do not respond to specific antigenic epitopes on pathogens, they do produce restricted responses to particular classes of pathogens via pattern recognition receptors such as Toll-like receptors (TLR). Coxsackievirus infection was found to upregulate TLR4 on mast cells and macrophages immediately following infection. Although both susceptible and resistant mice produce a mixture of Th1 and Th2 cytokines, susceptible mice have increased levels of key proinflammatory cytokines, increased numbers of mast cells, and go on to develop chronic autoimmune heart disease. TLR4 signalling also increases acute myocarditis and proinflammatory cytokines in the heart. Many similarities are described in the pathogenesis of Coxsackievirus and the adjuvant-induced model of myocarditis including upregulation of particular TLRs and cytokines soon after inoculation. Recent findings suggest that mast cell activation by viruses or adjuvants may be important in initiating autoimmune disease.

Adjuvants, Immunologic↗

PubMed2001

Differential response of the murine IL-12 p35 gene to lipopolysaccharide compared with interferon-gamma and CD40 ligation.

Expression of the heterodimeric cytokine interleukin-(IL-)12 is induced by pattern recognition receptors responding to microbial stimuli such as lipopolysaccharide (LPS) and products of the immune system such as interferon-gamma (IFN-gamma) and CD40L. The formation of bioactive IL-12 requires equimolar synthesis of p35 and p40 subunits. However, p35 expression limits the amount of IL-12 formed. Transcription of the gene for the p35 subunit of IL-12 initiates within the first exon, an alternate first exon (exon 1a), or second exon. Here we show that LPS and IFN-gamma/CD40 ligation increase the amount of total p35 mRNA in splenic adherent cells (SAC) to a similar extent. However, the exon 1 transcript was a smaller fraction of total p35 mRNA in IFN-gamma/CD40-stimulated cells than in unstimulated or LPS-stimulated cells. Despite comparable levels of total p35 mRNA, LPS-induced p35 exon 1 transcripts led to significantly more bioactive IL-12 from SAC than IFN-gamma/CD40-induced exon 1a/exon 2 transcripts as measured by ELISA. The data suggest that LPS-inducible p35 synthesis from exon 1 p35 transcripts leads to greater amount of bioactive IL-12 than IFN-gamma/CD40-induced p35 expression from alternate p35 exon 1a/exon 2 transcripts.

Animals↗

PubMed2005

Molecular mimicry: anti-DNA antibodies bind microbial and nonnucleic acid self-antigens.

Although cells of the innate immune response have a variety of pattern recognition receptors that are triggered by blood classes of markers, a critical feature of the adaptive immune response is antigenic specificity. Yet it is becoming increasingly clear that the specificity of lymphocyte receptors admits of some laxity. Cross-reactivity may, in fact, be necessary for lymphocyte survival as antigen receptor signaling maintains cellular viability in the absence of antigen activation. Studies of molecular mimicry have revealed many instances in which antibodies to microbial antigens bind also to self-antigens; in some cases, this cross-reactivity has pathogenic potential. In this chapter, we describe cross-reactivity between two self-antigens, DNA and NMDA receptors, and how antibodies with specificity for DNA in patients with splenic lupus may cause central nervous system damage by virtue of binding also to neuronal receptors. This example serves as a reminder that cross-reactivity may exist among self-antigens as well as between foreign and self-antigens.

Animals↗

PubMed1999

The development of CD4+ T effector cells during the type 2 immune response.

Multiple pathways may be involved in the development of interleukin 4 (IL-4) producing T helper (Th) cells and the associated type 2 immune response. Increasing evidence suggests that the strength of signals delivered to the T cell may favor the development of the type 2 response. In contrast, antigen-presenting cell- (APC) derived stimuli produced following pattern recognition receptor binding during the innate response promotes the development of interferon-gamma (IFN-gamma) producing cells and the associated type 1 immune response. In many cases, the balance between increased signaling strength and the innate response may determine whether the type 2 response develops. T cell receptor (TCR), CD4, and costimulatory molecule interactions may all contribute to signal strength, but the type 2 immune response may be particularly dependent on the availability of coreceptor and costimulatory molecule interactions. B7 ligand interactions are required for the development of the type 2 immune response and interaction of CD28 with either B7-1 or B7-2 can provide sufficient signals for its initiation. In B7-2-deficient mice, the initial type 2 immune response is intact, but the response is not sustained, suggesting that B7-2 is important at later stages of the type 2 immune response. The roles of CD28 and CTLA-4 during the type 2 response remain unclear. The type 2 response to infectious pathogens is pronounced in CD28-/- mice, suggesting that other costimulatory molecule interactions can substitute for CD28 for the development of IL-4 producing T cells and the associated type 2 immune response.

Abatacept↗

PubMed2003

Recognition of bacterial peptidoglycan by the innate immune system.

The innate immune system recognizes microorganisms through a series of pattern recognition receptors that are highly conserved in evolution. Peptidoglycan (PGN) is a unique and essential component of the cell wall of virtually all bacteria and is not present in eukaryotes, and thus is an excellent target for the innate immune system. Indeed, higher eukaryotes, including mammals, have several PGN recognition molecules, including CD14, Toll-like receptor 2, a family of peptidoglycan recognition proteins, Nod1 and Nod2, and PGN-lytic enzymes (lysozyme and amidases). These molecules induce host responses to microorganisms or have direct antimicrobial effects.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Consequence of functional Nod2 and Tlr4 mutations on gene transcription in Crohn's disease patients.

The concept that mutations in germ-line encoded pattern recognition receptors with immune activating functions are associated with an increased incidence in Crohn's disease (CD) is gaining acceptance. Whether these mutations have similar or distinct effects on cellular physiology remains obscure. The incidence of three single nucleotide polymorphisms (SNPs) within the Nod2 gene and one functional SNP within both the Tlr4 and Tlr5 gene in a Dutch cohort of 637 patients with inflammatory bowel disease and 127 controls was investigated. The functional consequence of mutant NOD2 and TLR4 was investigated by comparing gene expression profiles after stimulation of monocyte-derived dendritic cells (DCs) from homozygous TLR4- and NOD2-mutant patients with lipopolysaccharides and peptidoglycan, respectively. We observed that the R702W and 1007fs Nod2 alleles and the A299G Tlr4 alleles were significantly more prevalent in patients with CD as compared to healthy controls or patients with ulcerative colitis. The phenotype of TLR4- and NOD2-mutant DCs is distinct, but a large number of genes are up- or down-regulated concordantly. These data provide a concept for the genetic basis of CD; mutations in innate immunity cause similar effects on gene transcription and finally result in comparable clinical disease presentation.

Adult↗

PubMed2000

Signal transduction induced by immunostimulatory CpG DNA.

The immune recognition of unmethylated CpG motifs appears to be an example of the ability of the immune system to detect molecular patterns which are characteristic of microbes, but are not present in vertebrates. This detection is accomplished by the means of pattern recognition receptors (PRR). Unlike some other examples of PRR, immune recognition of CpG DNA appears to require cell uptake and to be accomplished through an intracellular PRR system. This then results in the activation of mitogen-activated protein kinases, culminating in the phosphorylation of transcription factors and the activation of transcription and translation. The rapid activation of these pathways by CpG DNA leads to the induction of protective immune responses.

Adjuvants, Immunologic↗

PubMed2006

Presence of functional TLR2 and TLR4 on human adipocytes.

In addition to the well-known role of adipose tissue in energy metabolism, it has recently been demonstrated that this tissue can secrete a large array of molecules, including inflammatory cytokines. Furthermore, recent studies suggest that adipose cells can behave as immune cells. Therefore, the aim of this study was to determine the presence of the two most prominent 'pattern recognition receptors' for bacterial and fungal cell wall components, TLR2 and TLR4 on human adipose cells, as well as to assess their functionality. We demonstrated that TLR2 and TLR4 were expressed at relatively high levels (compared to a monocyte cell line) on the surface of human adipose cells. Stimulation of human adipocytes with lipopolysaccharide (LPS), or with lipoteichoic acid (LTA), two specific ligands of TLR4 and TLR2, respectively, induced a strong increase in TNFalpha production. The specificity of the response was demonstrated by the use of anti-TLR4 and anti-TLR2 blocking antibodies, which were able to decrease LPS- or LTA-induced TNFalpha secretion. Thus, it is clear that these receptors are functional in human adipocytes. This study adds weight to the argument that human fat tissue plays a potential role in innate immunity.

Adipocytes↗

PubMed2006

Genetic advances in inflammatory bowel disease.

The translation of basic science advances to tangible benefits in clinical practice remains a fundamental goal of biomedical research. Genetic approaches provide a unique opportunity to enhance bench-to-bedside translational efforts, with inflammatory bowel disease (IBD) being a model genetic disorder in several respects. The association of the NOD2 (CARD15) mutations to Crohn's disease (CD) represents, in complex human disorders, one of the clearest cases of a definitive disease association. The NOD2 gene is located in the IBD1 genetic linkage region on chromosome 16 and functions as an intracellular pattern recognition receptor for components of bacterial peptidoglycan. CD-associated variants within NOD2 have a decreased capacity to appropriately signal with peptidoglycan and provide an important example of gene-environment interactions. Genetic variation in other innate immune receptors, notably Toll-like receptor (TLR)4, has been defined and may also play a role in CD pathogenesis. Replicated CD association in the IBD5 region on chromosome 5q has been reported, and candidate functional polymorphisms within the organic cation transporters OCTN1 (SLC22A4) and OCTN2 (SLC22A5) have been described. Confirmatory studies demonstrating altered OCTN activity and expression in primary human cells stratified on the IBD5 risk haplotype would provide important confirmatory support for disease contribution. A comprehensive understanding of IBD will involve integrating information from animal models, functional human polymorphisms, and expression studies from human IBD tissues. Genes and pathways implicated as contributing to IBD pathogenesis through multiple lines of evidence should be more intensively examined, including the tumor necrosis factor-alpha, MDR1, and peroxisome proliferator-activated receptor (PPAR)gamma pathways. To attain full advantage of new genetic information, novel methods of classifying patients that go beyond phenotypic classifications presently utilized will be required. Genetic data will need to be integrated with novel biomarker development in IBD, including functional, expression (mRNA or protein), or biochemical indicators of physiologic/disease processes and responses to therapies.

Journal Article↗

PubMed2026

Clinical and immunological characterization of a child with a homozygous TBK1 kinase-domain truncation.

TBK1 is a serine-tyrosine kinase protein that transmits signals from pattern recognition receptors to the NF-κB pathway leading to production of Type 1 Interferons. Mutations in this protein have been associated with arthritis, vasculitis, herpes simplex encephalitis and amyotrophic lateral sclerosis. In the current study, we characterized the functional consequences of a TBK1-variant bearing a truncation in exon 4 and 5 in a patient with poly arthritis resembling juvenile idiopathic arthritis and necrotizing encephalitis. The truncation was associated with reduced TBK1 protein abundance and altered phosphorylation. The variant was associated with increased basal/and or Poly-I: C induced IL-6, TNFα, IL-1β and IL-18 and type 1 Interferon ex vivo. Our findings expand the phenotypic spectrum of TBK1 loss-of-function variants and may provide insight into the management of immune dysregulation in affected patients.

Child↗

PubMed2026

A highly prevalent lupus risk haplotype increases IRF7-dependent induction of IFN-α, enhancing antiviral defense and exacerbating autoimmunity.

Genome-wide association studies have identified genetic polymorphisms at 11p15 associated with systemic lupus erythematosus (lupus). Statistical fine mapping prioritizes a highly prevalent coding haplotype within IRF7. Analysis of ancient DNA confirms that this haplotype has persisted at high frequencies in the global population for millennia. The IRF7 risk haplotype is sufficient to increase nuclear localization of IRF7 and transcriptional activity downstream of pattern recognition receptor pathways. This risk haplotype increases IRF7 DNA-binding strength and alters IRF7 DNA sequence specificity, resulting in genotype-dependent increases in interferon-α production in numerous biological systems, including monocytes and airway epithelial cells. CRISPR engineering of the corresponding risk variant in mouse Irf7 results in both enhanced innate control of virus infection and increased autoantibody titers in a model of autoimmunity. Altogether, we establish a persistent and prominent IRF7 haplotype that amplifies IRF7 activity in a manner that has immunological risks and benefits.

ancient DNA↗

PubMed2006

Pathogen recognition and innate immunity.

Microorganisms that invade a vertebrate host are initially recognized by the innate immune system through germline-encoded pattern-recognition receptors (PRRs). Several classes of PRRs, including Toll-like receptors and cytoplasmic receptors, recognize distinct microbial components and directly activate immune cells. Exposure of immune cells to the ligands of these receptors activates intracellular signaling cascades that rapidly induce the expression of a variety of overlapping and unique genes involved in the inflammatory and immune responses. New insights into innate immunity are changing the way we think about pathogenesis and the treatment of infectious diseases, allergy, and autoimmunity.

Adaptation, Physiological↗