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Results for “Receptors, Pattern Recognition”

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PubMed2006

Dendritic cell immunoreceptors: C-type lectin receptors for pattern-recognition and signaling on antigen-presenting cells.

C-type lectin receptors are equipped on phagocytes for antigen capturing. Some of them seem to have a major role in cellular activation, rather than antigen internalization. The dendritic cell (DC) immunoreceptor (DCIR) and DC-associated C-type lectin (dectin)-1 have been identified as prototypic DC-associated C-type lectin receptors, characterized by their signaling mechanisms through distinct intracellular motifs; the former contains the immunoreceptor tyrosine-based inhibitory motif (ITIM), to act as an inhibitory receptor, whereas the latter works as an activating receptor via its immunoreceptor tyrosine-based activation motif (ITAM). Genes of both receptors are localized very close to the natural killer (NK) gene complex (NKC), in which genes of lectin-type activating and inhibitory NK cell receptors are clustered. Recently, the gene of the DC immunoactivating receptor (DCAR) has been identified next to the DCIR gene, and this acts as a putative activating pair of DCIR through association with an ITAM-bearing Fc receptor (FcR) gamma chain. On the other hand, the gene of an ITIM-bearing myeloid inhibitory C-type lectin-like receptor (MICL) has been found close to the dectin-1 gene. The genes of other homologous DC-associated C-type lectin receptors, dectin-2 and blood DC antigen (BDCA)-2, form a cluster with those of DCIR and DCAR, while the dectin-1 gene cluster contains lectin-like oxidized low-density lipoprotein receptor (LOX)-1, C-type lectin-like receptor (CLEC)-1 and 2, as well as MICL. Although no ligand of DCIR has yet been identified, dectin-1 recognizes fungal beta-glucan and its critical role in the biological effects of beta-glucan has been vigorously investigated. In this review, the characteristic features of these DCIR and dectin-1 family lectins, including the signaling mechanisms, ligand recognition and regulation of cellular functions, are summarized and the term "DC immunoreceptors" is applied to a distinct set of signaling pattern-recognition receptors described here.

Antigen-Presenting Cells↗

PubMed2001

Extracellular Toll-like receptor 2 region containing Ser40-Ile64 but not Cys30-Ser39 is critical for the recognition of Staphylococcus aureus peptidoglycan.

Toll-like receptor 2 (TLR2) and CD14 function as pattern recognition receptors for bacterial peptidoglycan (PGN). TLRs and CD14 possess repeats of the leucine-rich motif. To address the role of the extracellular domain of TLR2 in PGN signaling, we constructed CD14/TLR2 chimeras, in which residues 1-356 or 1-323 of CD14 were substituted for the extracellular domain of TLR2, and five deletion mutants of TLR2, in which the progressively longer regions of extracellular TLR2 regions were deleted. PGN induced NF-kappaB activation in HEK293 cells expressing TLR2 but not in cells expressing CD14/TLR2 chimeras. The cells transfected with a deletion mutant TLR2(DeltaCys30-Ile64) as well as TLR2(DeltaCys30-Asp160) and TLR2(DeltaCys30-Asp305) failed to respond to PGN, indicating the importance of the TLR2 region Cys(30)-Ile(64). Although TLR2(DeltaCys30-Ser39) conferred cell responsiveness to PGN, the cells expressing TLR2(DeltaSer40-Ile64) failed to induce NF-kappaB activation. In addition, NF-kappaB activity elicited by PGN was significantly attenuated in the presence of synthetic peptide corresponding to the TLR2 region Ser(40)-Ile(64). From these results, we conclude that; 1) CD14 cannot functionally replace the extracellular domain of TLR2 in PGN signaling; 2) the TLR2 region Cys(30)-Ser(39) is not required for PGN recognition; 3) the TLR2 region containing Ser(40)-Ile(64) is critical for PGN recognition.

Amino Acid Sequence↗

PubMed2006

Toll-like receptors in ocular immunity and the immunopathogenesis of inflammatory eye disease.

Microbial agents have an important role in the pathogenesis of various inflammatory eye diseases, such as uveitis and keratitis. Microbial infections of the eye such as microbial keratitis, ocular onchocerciasis, bacterial endophthalmitis, viral retinitis, and other infectious uveitis are unfortunately common. In addition, microbial agents have been implicated in the pathogenesis of "non-infectious" immune mediated diseases such as HLA-B27 associated acute anterior uveitis. Toll-like receptors (TLR) are a family of pattern recognition receptors that initiates rapid host innate immune response to microbial components known as pathogen associated molecular patterns, which are unique to a given class of microbes, such as lipopolysaccharide of Gram negative bacteria. Recent in vitro and in vivo studies have demonstrated the expression and function of TLRs in the eye, with significant implications for better understanding of ocular immunity and the pathogenesis of inflammatory eye diseases affecting the cornea, uvea, and retina.

Eye↗

PubMed2001

Surface characteristics of foreign targets that elicit an encapsulation response by the moth Pseudoplusia includens.

Hemocytes from the moth Pseudoplusia includens encapsulate a variety of biotic and abiotic targets. Prior studies indicated that granular cells are usually the first hemocyte type to attach to foreign targets. Thereafter, large numbers of plasmatocytes attach to the target and form a capsule. To identify surface features that induce an encapsulation response, chromatography beads that differed in matrix composition, charge, and functional groups were tested using in vitro and in vivo bioassays. We first conducted in vitro assays using hemocytes with no plasma components present. These experiments indicated that bead types having sulfonic, diethylaminoethyl, and quaternary amine functional groups were encapsulated significantly more often than beads with other functional groups. Charge also significantly affected encapsulation with positively charged beads being encapsulated more often than negatively charged or neutral beads. In vitro assays using purified populations of hemocytes confirmed that these targets were recognized as foreign by granular cells, and that plasmatocytes only formed capsules after granular cells attached to the target. Bead types that were encapsulated under these in vitro conditions were always rapidly encapsulated when injected into P. includens larvae. However, some bead types, like CM-Sephadex, not encapsulated in vitro were encapsulated in vivo if left in the insect hemocoel for a longer period of time (ca. 24 h). Purified plasmatocytes encapsulated these beads in vitro if they were preincubated in plasma. Basic characterization studies suggest these humoral recognition molecules are proteins or small peptides. Comparative studies with other species of noctuid moths also indicated that encapsulation of some bead types differed significantly among species. Collectively, these results reveal that P. includens recognizes some targets as foreign by pattern recognition receptors on granular cells, whereas others are recognized by pattern recognition molecules in plasma. The binding affinities of these recognition molecules also appear to differ among closely related species of Lepidoptera.

Journal Article↗

PubMed2002

Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation.

BACKGROUND: Innate immune reactions against bacteria and viruses have been implicated in the pathogenesis of atherosclerosis. To explore the molecular mechanism by which microbe recognition occurs in the artery wall, we characterized the expression of toll-like receptors (TLRs), a family of pathogen pattern recognition receptors, in atherosclerotic lesions. METHODS AND RESULTS: Semiquantitative polymerase chain reaction and immunohistochemical analysis demonstrated that of 9 TLRs, the expression of TLR1, TLR2, and TLR4 was markedly enhanced in human atherosclerotic plaques. A considerable proportion of TLR-expressing cells were also activated, as shown by the nuclear translocation of nuclear factor-kappaB. CONCLUSION: Our findings illustrate a repertoire of TLRs associated with inflammatory activation in human atherosclerotic lesions, and they encourage further exploration of innate immunity in the pathogenesis of atherosclerosis.

Antigens, CD↗

PubMed2002

CD14 expression by activated parenchymal microglia/macrophages and infiltrating monocytes following human traumatic brain injury.

The immune response in the central nervous system (CNS) is under tight control of regulatory mechanisms, resulting in the establishment of immune privilege. CNS injury induces an acute inflammatory reaction, composed mainly of invading leukocytes and activated microglial cells/macrophages. The generation of this robust immune response requires binding of receptors such as CD14, a pattern recognition receptor of the immune system. CD14, a surface molecule of monocytic cells, is up-regulated after monocyte stimulation and is involved in cellular activation. To examine CD14 expression in human brain lesions we investigated sections of brains obtained at autopsy from 25 cases following closed traumatic brain injury (TBI) and 5 control brains by immunohistochemistry. Detection of CD14 in controls demonstrated constitutive expression by perivascular cells, but not in parenchymal microglial cells, equivalent to known expression pattern of ED2 in rats. Following TBI, numbers of CD14(+) cells in perivascular spaces and in the brain parenchyma increased in parallel within 1-2 days, both at the lesion and in adjacent perilesional areas. The number of CD14(+) cells in perivascular spaces and in the brain parenchyma reached maximum levels within 4-8 days and remained elevated until weeks after trauma. In contrast to activated parenchymal microglia/macrophages, resting parenchymal microglial cells lacked CD14. Thus, early CD14 expression constitutes an essential part of the acute inflammatory CNS response following trauma.

Adolescent↗

PubMed2004

Self- and nonself-recognition by C-type lectins on dendritic cells.

Dendritic cells (DCs) are highly efficient antigen-presenting cells (APCs) that collect antigen in body tissues and transport them to draining lymph nodes. Antigenic peptides are loaded onto major histocompatibility complex (MHC) molecules for presentation to naive T cells, resulting in the induction of cellular and humoral immune responses. DCs take up antigen through phagocytosis, pinocytosis, and endocytosis via different groups of receptor families, such as Fc receptors for antigen-antibody complexes, C-type lectin receptors (CLRs) for glycoproteins, and pattern recognition receptors, such as Toll-like receptors (TLRs), for microbial antigens. Uptake of antigen by CLRs leads to presentation of antigens on MHC class I and II molecules. DCs are well equipped to distinguish between self- and nonself-antigens by the variable expression of cell-surface receptors such as CLRs and TLRs. In the steady state, DCs are not immunologically quiescent but use their antigen-handling capacities to maintain peripheral tolerance. DCs are continuously sampling and presenting self- and harmless environmental proteins to silence immune activation. Uptake of self-components in the intestine and airways are good examples of sites where continuous presentation of self- and foreign antigens occurs without immune activation. In contrast, efficient antigen-specific immune activation occurs upon encounter of DCs with nonself-pathogens. Recognition of pathogens by DCs triggers specific receptors such as TLRs that result in DC maturation and subsequently immune activation. Here we discuss the concept that cross talk between TLRs and CLRs, differentially expressed by subsets of DCs, accounts for the different pathways to peripheral tolerance, such as deletion and suppression, and immune activation.

Animals↗

PubMed2005

Regulation of Streptococcus pneumoniae distribution by Toll-like receptor 2 in vivo.

The phagocyte pattern recognition receptor Toll-like receptor 2 (TLR2) and the multi-receptor adaptor MyD88 contribute to the reduction of bacterial load in infections with intra- and extra-cellular Gram-positive bacteria. Their mechanism of antibacterial action is mostly unresolved but evident in vivo by an increased pathogen burden in infected TLR2-/- and MyD88-/- compared to C57BL/6 wild type (wt) mice. We had previously observed higher bacterial numbers in brains of TLR2-/- than of wt mice with meningitis. Here we study bacteria-phagocyte interaction by comparing S. pneumoniae distribution and localization in wt and TLR2-/- brain by confocal microscopy using a green fluorescent protein-transformed encapsulated S. pneumoniae (C5017). Colony-forming units were similarly distributed in TLR2-/- and wt mice and exclusively localized in meninges and ventricles. Bacteria were more abundant in ventricles, in and around TLR2-/- than wt GLT1v+ plexus choroideus epithelial cells. S. pneumoniae were also found in and around Gr-1+ granulocytes, but never in F4/80+ macrophages, Iba1+ microglia, GFAP+ astrocytes, Meca-31+ endothelial cells or Neun+ neurons of either mouse strain. The results indicate that TLR2 does not change bacterial distribution, but may contribute to antibacterial defense by modulating S. pneumoniae adherence and uptake in plexus epithelia.

Animals↗

PubMed2003

Strategic compartmentalization of Toll-like receptor 4 in the mouse gut.

Pattern recognition receptors (PRRs), which include the Toll-like receptors (TLRs), are involved in the innate immune response to infection. TLR4 is a model for the TLR family and is the main LPS receptor. We wanted to determine the expression of TLR4 and compare it with that of TLR2 and CD14 along the gastrointestinal mucosa of normal and colitic BALB/c mice. Colitis was induced with 2.5% dextran sodium sulfate (DSS). Mucosa from seven segments of the digestive tract (stomach, small intestine in three parts, and colon in three parts) was isolated by two different methods. Mucosal TLR4, CD14, TLR2, MyD88, and IL-1beta mRNA were semiquantified by Northern blotting. TLR4 protein was determined by Western blotting. TLR4/MD-2 complex and CD14 were evaluated by immunohistochemistry. PRR genes were constitutively expressed and were especially stronger in colon. TLR4 and CD14 mRNA were increased in the distal colon, but TLR2 mRNA was expressed more strongly in the proximal colon, and MyD88 had a uniform expression throughout the gut. Accordingly, TLR4 and CD14 protein levels were higher in the distal colon. TLR4/MD-2 and CD14 were localized at crypt bottom epithelial cells. TLR4/MD2, but not CD14, was found in mucosal mononuclear cells. Finally, DSS-induced inflammation was localized in the distal colon. All genes studied were up-regulated during DSS-induced inflammation, but the normal colon-stressed gut distribution was preserved. Our findings demonstrate that TLR4, CD14, and TLR2 are expressed in a compartmentalized manner in the mouse gut and provide novel information about the in vivo localization of PRRs.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Toll-like receptors in central nervous system glial inflammation and homeostasis.

Toll-like receptors (TLRs) are a family of pattern-recognition receptors expressed on cells of the innate immune system that allow for the recognition of conserved structural motifs on a wide array of pathogens, referred to as pathogen-associated molecular patterns, as well as some endogenous molecules. The recent emergence of studies examining TLRs in the central nervous system (CNS) indicates that these receptors not only play a role in innate immunity in response to infectious diseases but may also participate in CNS autoimmunity, neurodegeneration, and tissue injury. This review summarizes the experimental evidence demonstrating a role for TLRs in the context of CNS inflammation in both infectious and noninfectious conditions.

Animals↗

PubMed2004

Toll-like receptor gene family and TIR-domain adapters in Danio rerio.

The toll-like family of receptors (TLR) is an ancient pattern recognition receptor family, conserved from insects to mammals. We have identified in zebrafish (Danio rerio) 19 putative TLR variants, the orthologs of mammalian TLR2-5, 7-9, a fish specific receptor type group and three putative splice variants. One receptor is very close to mammalian TLR1, 6 and 10 and seems to be their common ancestor. However, in contrast to the pufferfish, Fugu rubripes, we found two receptors homologous to TLR4, showing that lack of TLR4 is not general for fish. In addition, we identified two members close to mammalian TLR8 and five members close to FuguTLR21 and goldfish TLR, a TLR group which now has only been found in fish. By RT-PCR we showed that all TLR are widely expressed in adult tissues, but also at different stages of development. All these TLRs contain very conserved toll/interleukin-1 receptor (TIR) domains able to interact with TIR-domain of adapter molecules. We demonstrate here that TIR-domain containing adapters MyD88 and SARM are present in zebrafish, showing that TLR adapter molecules are highly conserved in evolution.

Amino Acid Sequence↗

PubMed2004

Toll-like receptors and acquired immunity.

Toll-like receptors are a family of pattern recognition receptors (PRRs) that evolved to detect microbial infection. These receptors recognize conserved molecular products derived from different classes of microorganisms, including Gram-positive and -negative bacteria, fungi, protozoa and viruses. Following recognition of ligands TLRs initiate signaling events that result in acute innate responses. In addition, TLRs are responsible for initiation of adaptive immune responses against pathogen-derived antigens primarily through triggering dendritic cell activation. Control of adaptive immunity by TLRs is a complex phenomenon and much needs to be understood about how different TLRs tailor the outcome of adaptive immune responses to the advantage of the host. Although TLRs have evolved to induce protective immune responses, under some circumstances, activation of these receptors may lead to autoimmune diseases.

Animals↗

PubMed2002

Roles of toll-like receptors in natural interferon-producing cells as sensors in immune surveillance.

Natural IFN-alpha/beta producing cells (IPCs) play a central role in innate immunity against microbial infections. In primary immune responses, toll-like receptors (TLRs), as major pattern-recognition receptors, are essential for IPCs as well as other antigen presenting cell (APC) subsets to recognize microbes. IPCs unequivocally express TLR7 and TLR9, and can respond to the respective ligand to produce IFN-alpha/beta and to rapidly differentiate into dendritic cells (DCs). Thereby, IPCs can not only activate innate immune system but also provoke T cell responses. Thus, IPCs link innate and adaptive immunity through TLR system. In addition, recent work has revealed the regulatory system of DC subsets in response to microbial invasion. In this context, by the different but complementary expression profile of TLRs, IPCs together with myeloid APC subsets constitute a rational system of immune surveillance that can cover a wide variety of pathogens and enlarge immune adjuvant effects.

Antigen-Presenting Cells↗

PubMed2003

Toll-like receptor 4 and atherogenesis.

Toll-like receptor 4 (TLR4) is a pattern recognition receptor involved in the innate immune response to various microorganisms and other exogenous and endogenous stress factors. Recently, evidence emerged that important inflammatory processes implicit in human atherogenesis are mediated in part via the TLR4/nuclear factor-kappaB pathway. Polymorphisms of TLR4, which attenuate receptor signalling, enhance the risk of acute severe infections but may have opposite effects on atherogenesis. The aim of this review is to critically discuss current experimental and epidemiological evidence for a role of TLR4 in atherogenesis and to highlight the main controversies and perspectives in this emerging field of vascular biology.

Animals↗

PubMed2001

Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens.

Toll-like receptors (TLRs) are ancient microbial pattern recognition receptors highly conserved from Drosophila to humans. To investigate if subsets of human dendritic cell precursors (pre-DC), including monocytes (pre-DC1), plasmacytoid DC precursors (pre-DC2), and CD11c(+) immature DCs (imDCs) are developed to recognize different microbes or microbial antigens, we studied their TLR expression and responses to microbial antigens. We demonstrate that whereas monocytes preferentially express TLR 1, 2, 4, 5, and 8, plasmacytoid pre-DC strongly express TLR 7 and 9. In accordance with these TLR expression profiles, monocytes respond to the known microbial ligands for TLR2 (peptidoglycan [PGN], lipoteichoic acid) and TLR4 (lipopolysaccharide), by producing tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. In contrast, plasmacytoid pre-DCs only respond to the microbial TLR9-ligand, CpG-ODNs (oligodeoxynucleotides [ODNs] containing unmethylated CpG motifs), by producing IFN-alpha. CD11c(+) imDCs preferentially express TLR 1, 2, and 3 and respond to TLR 2-ligand PGN by producing large amounts of TNF-alpha, and to viral double-stranded RNA-like molecule poly I:C, by producing IFN-alpha and IL-12. The expression of distinct sets of TLRs and the corresponding difference in reactivity to microbial molecules among subsets of pre-DCs and imDCs support the concept that they have developed through distinct evolutionary pathways to recognize different microbial antigens.

Biomarkers↗

PubMed2004

Increased expression of toll-like receptor 2 on monocytes in HIV infection: possible roles in inflammation and viral replication.

BACKGROUND: Toll-like receptors (TLRs) are key pattern-recognition receptors of the innate immune system, but their role in human immunodeficiency virus (HIV) infection is largely unknown. METHODS: In the present study, we examined the expression of TLR2 and TLR4 on monocytes from 48 HIV-infected patients and 21 healthy control subjects by flow cytometry. RESULTS: We found that freshly isolated monocytes from HIV-infected patients displayed enhanced expression of TLR2 but not TLR4, that TLR2 expression on the surface of monocytes was significantly increased upon stimulation of HIV type 1 envelope protein gp120, and that TLR2 stimulation in HIV-infected patients induced increased viral replication and TNF- alpha response. CONCLUSION: Our findings suggest potential roles for TLR2 in chronic immune activation and viral replication in HIV infection.

Adult↗

PubMed2005

Toll-like receptor 2 modulates the proinflammatory milieu in Staphylococcus aureus-induced brain abscess.

Toll-like receptor 2 (TLR2) is a pattern recognition receptor (PRR) that plays an important role in innate immune recognition of conserved structural motifs on a wide array of pathogens, including Staphylococcus aureus. To ascertain the functional significance of TLR2 in the context of central nervous system (CNS) parenchymal infection, we evaluated the pathogenesis of S. aureus-induced experimental brain abscess in TLR2 knockout (KO) and wild-type (WT) mice. The expression of several proinflammatory mediators, including inducible nitric oxide synthase, tumor necrosis factor alpha, and macrophage inflammatory protein-2, was significantly attenuated in brain abscesses of TLR2 KO mice compared to WT mice during the acute phase of infection. Conversely, interleukin-17 (IL-17), a cytokine produced by activated and memory T cells, was significantly elevated in lesions of TLR2 KO mice, suggesting an association between innate and adaptive immunity in brain abscess. Despite these differences, brain abscess severity in TLR2 KO and WT animals was similar, with comparable mortality rates, bacterial titers, and blood-brain barrier permeability, implying a role for alternative PRRs. Expression of the phagocytic PRRs macrophage scavenger receptor type AI/AII and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) was increased in brain abscesses of both TLR2 KO and WT mice compared to uninfected animals. However, LOX-1 induction in brain abscesses of TLR2 KO mice was significantly attenuated compared to WT animals, revealing that the TLR2-dependent signal(s) influence LOX-1 expression. Collectively, these findings reveal the complex nature of gram-positive bacterial recognition in the CNS which occurs, in part, through engagement of TLR2 and highlight the importance of receptor redundancy for S. aureus detection in the CNS.

Animals↗

PubMed2006

The evolution of adaptive immunity.

Approximately 500 mya two types of recombinatorial adaptive immune systems appeared in vertebrates. Jawed vertebrates generate a diverse repertoire of B and T cell antigen receptors through the rearrangement of immunoglobulin V, D, and J gene fragments, whereas jawless fish assemble their variable lymphocyte receptors through recombinatorial usage of leucine-rich repeat (LRR) modular units. Invariant germ line-encoded, LRR-containing proteins are pivotal mediators of microbial recognition throughout the plant and animal kingdoms. Whereas the genomes of plants and deuterostome and chordate invertebrates harbor large arsenals of recognition receptors primarily encoding LRR-containing proteins, relatively few innate pattern recognition receptors suffice for survival of pathogen-infected nematodes, insects, and vertebrates. The appearance of a lymphocyte-based recombinatorial system of anticipatory immunity in the vertebrates may have been driven by a need to facilitate developmental and morphological plasticity in addition to the advantage conferred by the ability to recognize a larger portion of the antigenic world.

Adaptation, Physiological↗