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PubMed2006

Lack of Toll-like receptor 4 and 2 polymorphisms in Korean patients with bacteremia.

Toll-like receptors (TLRs) are pattern-recognition receptors that are important in innate immune responses to bacterial infection. The purpose of this study is to describe the prevalence of TLRs genetic variations in the bacteremic patients in Korea. A total of 154 patients with bacteremia and 179 healthy volunteers were included. The Asp299Gly and Thr399Ile allele of the TLR4 gene and Arg753Gln and Arg677Trp allele of the TLR2 gene were tested by PCR-RFLP. The DNA sequences were determined to confirm the PCR-RFLP results. Contrary to the expectation, no genetic polymorphisms were detected in both groups of this study, suggesting that it is very rare in Korean.

Bacteremia↗

PubMed2005

A distal regulatory region is required for constitutive and IFN-beta-induced expression of murine TLR9 gene.

TLR9 is critical for the recognition of unmethylated CpG DNA in innate immunity. Accumulating evidence suggests distinct patterns of TLR9 expression in various types of cells. However, the molecular mechanism of TLR9 expression has received little attention. In the present study, we demonstrate that transcription of murine TLR9 is induced by IFN-beta in peritoneal macrophages and a murine macrophage cell line RAW264.7. TLR9 is regulated through two cis-acting regions, a distal regulatory region (DRR) and a proximal promoter region (PPR), which are separated by approximately 2.3 kbp of DNA. Two IFN-stimulated response element/IFN regulatory factor-element (ISRE/IRF-E) sites, ISRE/IRF-E1 and ISRE/IRF-E2, at the DRR and one AP-1 site at the PPR are required for constitutive expression of TLR9, while only the ISRE/IRF-E1 motif is essential for IFN-beta induction. In vivo genomic footprint assays revealed constitutive factor occupancy at the DRR and the PPR and an IFN-beta-induced occupancy only at the DRR. IRF-2 constitutively binds to the two ISRE/IRF-E sites at the DRR, while IRF-1 and STAT1 are induced to bind to the two ISRE/IRF-E sites and the ISRE/IRF-E1, respectively, only after IFN-beta treatment. AP-1 subunits, c-Jun and c-Fos, were responsible for the constitutive occupancy at the proximal region. Induction of TLR9 by IFN-beta was absent in STAT1-/- macrophages, while the level of TLR9 induction was decreased in IRF-1-/- cells. This study illustrates the crucial roles for AP-1, IRF-1, IRF-2, and STAT1 in the regulation of murine TLR9 expression.

Amino Acid Sequence↗

PubMed2006

Listeria monocytogenes activated p38 MAPK and induced IL-8 secretion in a nucleotide-binding oligomerization domain 1-dependent manner in endothelial cells.

Nucleotide-binding oligomerization domain (Nod) proteins serve as intracellular pattern recognition molecules recognizing peptidoglycans. To further examine intracellular immune recognition, we used Listeria monocytogenes as an organism particularly amenable for studying innate immunity to intracellular pathogens. In contrast to wild-type L. monocytogenes, the nonpathogenic Listeria innocua, or L. monocytogenes mutants lacking internalin B or listeriolysin O, poorly invaded host cells and escaped into host cell cytoplasm, respectively, and were therefore used as controls. In this study, we show that only the invasive wild-type L. monocytogenes, but not the listeriolysin O- or internalin B-negative L. monocytogenes mutants or L. innocua, substantially induced IL-8 production in HUVEC. RNA interference and Nod1-overexpression experiments demonstrated that Nod1 is critically involved in chemokine secretion and NF-kappaB activation initiated by L. monocytogenes in human endothelial cells. Moreover, we show for the first time that Nod1 mediated activation of p38 MAPK signaling induced by L. monocytogenes. Finally, L. monocytogenes- and Nod1-induced IL-8 production was blocked by a specific p38 inhibitor. In conclusion, L. monocytogenes induced a Nod1-dependent activation of p38 MAPK signaling and NF-kappaB which resulted in IL-8 production in endothelial cells. Thus, Nod1 is an important component of a cytoplasmic surveillance pathway.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Emerging evidence that molecules expressed by mammalian tissue grafts are recognized by the innate immune system.

The innate immune system existed prior to the emergence of adaptive immunity in sharks and higher vertebrates. Homologues of many mammalian innate immune-system elements such as the toll-like receptors exist in species as distant as Drosophila. Selective pressure has led to the development of highly conserved, soluble, and cell-surface receptors that recognize functionally essential molecules shared by microbial pathogens. It is thought that molecular patterns that exquisitely distinguish pathogenic cells from mammalian cells are recognized. Therefore, it would seem unlikely that innate immune-system elements should recognize mammalian tissues. However, there is increasing evidence to suggest that this is the case and that innate immunity promotes rejection of transplanted mammalian tissues, particularly those from other species (xenografts). Evidence for innate recognition of mammalian grafts, the nature of this recognition, and the bi-directional interactions between innate and adaptive immunity that contribute to graft rejection are discussed in this review, with the emphasis on nonvascular xenografts.

Animals↗

PubMed2006

Structure of tracheal cytotoxin in complex with a heterodimeric pattern-recognition receptor.

Tracheal cytotoxin (TCT), a naturally occurring fragment of Gram-negative peptidoglycan, is a potent elicitor of innate immune responses in Drosophila. It induces the heterodimerization of its recognition receptors, the peptidoglycan recognition proteins (PGRPs) LCa and LCx, which activates the immune deficiency pathway. The crystal structure at 2.1 angstrom resolution of TCT in complex with the ectodomains of PGRP-LCa and PGRP-LCx shows that TCT is bound to and presented by the LCx ectodomain for recognition by the LCa ectodomain; the latter lacks a canonical peptidoglycan-docking groove conserved in other PGRPs. The interface, revealed in atomic detail, between TCT and the receptor complex highlights the importance of the anhydro-containing disaccharide in bridging the two ectodomains together and the critical role of diaminopimelic acid as the specificity determinant for PGRP interaction.

Amino Acid Sequence↗

PubMed2004

Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation.

BACKGROUND AND AIMS: Recent evidence suggests that toll-like receptors (TLRs) recognize certain viruses. We reported that hepatitis C virus (HCV) core and nonstructural 3 (NS3) proteins activate inflammatory pathways in monocytes. The aim of this study was to investigate the role of TLRs in innate immune cell activation by core and NS3 proteins. METHODS: Human monocytes, human embryonic kidney cells transfected with TLR2, and peritoneal macrophages from TLR2, MyD88 knockout, and wild-type mice were studied to determine intracellular signaling and proinflammatory cytokine induction by HCV proteins. RESULTS: HCV core and NS3 proteins triggered inflammatory cell activation via the pattern recognition receptor TLR2 and failed to activate macrophages from TLR2 or MyD88-deficient mice. HCV core and NS3 induced interleukin (IL)-1 receptor-associated kinase (IRAK) activity, phosphorylation of p38, extracellular regulated (ERK), and c-jun N-terminal (JNK) kinases and induced AP-1 activation. Activation of nuclear factor-kappaB by core and NS3 was associated with increased IkappaBalpha phosphorylation. TLR2-mediated cell activation was dependent on the conformation of core and NS3 proteins and required sequences in the regions of aa 2-122 in core and aa 1450-1643 in NS3. Although cellular uptake of core and NS3 proteins was independent of TLR2 expression, cell activation required TLR2. HCV core protein and TLR2 showed intracellular colocalization. The hyper-elevated TNF-alpha induction by TLR2 ligands in monocytes of HCV-infected patients was not due to increased TLR2 expression. CONCLUSIONS: HCV core and NS3 proteins trigger inflammatory pathways via TLR2 that may affect viral recognition and contribute to activation of the innate immune system.

Animals↗

PubMed2005

Toll-like receptor expression in the human nasopharyngeal tonsil (adenoid) and palantine tonsils: a preliminary report.

OBJECTIVE: The Waldeyer's ring, comprised of the nasopharyngeal tonsil (adenoid), the paired tubal tonsils, the paired palantine tonsils, and the lingual tonsil, is arranged in a circular orientation around the wall of the throat. This orientation allows direct contact between the tissues of the Waldeyer's ring and inhaled or ingested material, which may contain potential antigenic substances. Previous studies involving the tissues of the Waldeyer's ring have been focused on the adaptive immune system, with little consideration toward the innate immune system. Since studies have demonstrated that the adenoids and tonsils are capable of producing proinflammatory cytokines, we postulate that toll-like receptors (TLRs), which recognize components of pathogenic organisms, may be involved in the immune response in these tissues. TLRs are innate pattern recognition receptors, which produce proinflammatory cytokines and chemokines upon ligation. In this pilot study, we address expression of TLRs, which are vital components of the innate immune system, in adenoid and tonsil tissue. METHODS: To determine whether TLRs are expressed in the human adenoid and palantine tonsils, we utilized endpoint RT-PCR and real time RT-PCR. Endpoint PCR was performed on all tissue obtained from adenotonsillectomy patients. Real time RT-PCR was performed only on adenoid tissue. RESULTS: All of the ten TLRs examined are expressed in the adenoid and tonsil tissue with varying band intensities. TLR3, TLR7, TLR8, and TLR9 expression is highly variable between patients. CONCLUSIONS: TLRs are expressed in human adenoid and tonsil tissue, and may play a vital role in the immunological outcomes of these tissues.

Adenoids↗

PubMed2000

Negative selection of B lymphocytes: a novel role for innate immunity.

Evidence has accumulated that strongly supports a role for innate immunity in B-cell tolerance. Specific recognition proteins, such as natural antibody and collectins, are present in serum that identify highly conserved self-antigens such as nuclear proteins and activate the classical pathway of complement. The direct localization of these types of antigens to the lymphoid compartment in a complement-receptor-dependent manner provides a mechanism to deal with immature, self-reactive B cells developing daily in the bone marrow. Since it would be disadvantageous for the organism to maintain self-reactive B cells, which cross-react with microbial antigens, the innate immune system provides an efficient pathway for their removal or silencing. A possible outcome of a breakdown in this pathway, as found in individuals bearing natural deficiencies in complement C1q or C4, is autoimmunity such as systemic lupus erythematosus.

Animals↗

PubMed2005

Pentraxins as a key component of innate immunity.

Pentraxins are a complex superfamily of multifunctional molecules characterized by a multimeric structure. C-reactive protein and pentraxin 3 (PTX3) are prototypic molecules of the short and long pentraxin family, respectively. PTX3 is conserved in evolution and produced by innate immune cells. Evidence suggests that PTX3 acts as a non-redundant component of the humoral arm of innate immunity, downstream of, and complementary to, cellular recognition, as well as a tuner of inflammation.

Animals↗

PubMed2002

Molecular basis of non-self recognition by the horseshoe crab tachylectins.

The self/non-self discrimination by innate immunity through simple ligands universally expressed both on pathogens and hosts, such as monosaccharides and acetyl group, depends on the density or clustering patterns of the ligands. The specific recognition by the horseshoe crab tachylectins with a propeller-like fold or a propeller-like oligomeric arrangement is reinforced by the short distance between the individual binding sites that interact with pathogen-associated molecular patterns (PAMPs). There is virtually no conformational change in the main or side chains of tachylectins upon binding with the ligands. This low structural flexibility of the propeller structures must be very important for specific interaction with PAMPs. Mammalian lectins, such as mannose-binding lectin and ficolins, trigger complement activation through the lectin pathway in the form of opsonins. However, tachylectins have no effector collagenous domains and no lectin-associated serine proteases found in the mammalian lectins. Furthermore, no complement-like proteins have been found in horseshoe crabs, except for alpha(2)-macroglobulin. The mystery of the molecular mechanism of the scavenging pathway of pathogens in horseshoe crabs remains to be solved.

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↗

PubMed2002

Pulmonary innate immune proteins and receptors that interact with gram-positive bacterial ligands.

The two major gram-positive bacterial (GPB) ligands are peptidoglycan (PGN) and lipoteichoic acid (LTA). These polymeric LTA and highly organized PGN contain repeating carbohydrate moieties, which are potential targets for pattern recognition molecules. The major pattern recognition proteins and receptors, which bind GPB, either have a lectin, PGN recognition, collagen or leucine-rich repeat (LRR) domain. The soluble innate immune proteins (IIPs) that bind to PGN and LTA include pulmonary collectins surfactant-associated proteins (SP-) A and D, lectin-like pentraxins C-reactive protein (CRP) and serum amyloid P component (SAP), and sCD14. Membrane-anchored lectin or lectin-like group members include macrophage mannose receptor (MR), complement receptor 3 (CR3, or Mac-1, or integrin CD11b/CD18), scavenger receptor A (SRCL-1), lectin-like oxidized LDL receptor 1 (LOX-1), and GPI-anchored CD14. Although Toll-like receptor (TLR) 2 and 4, and CD14 contain extracellular LRR domains, only TLRs have a cytoplasmic domain for signal transduction. Three of the four recently discovered human PGN recognition proteins (PGRP) have a transmembrane domain, and hence, considered as true receptors for GPB. Since lysozyme is the only known pulmonary enzyme that can lyse bacterial cell wall PGN, other innate immune molecules appear to be responsible for signalling and enhancing the clearance of GPB infection from the lung. Interestingly, pulmonary collectins bind not only to GPB ligands but also to the receptors, CD14 and TLR, and antigen processing cells such as dentritic cells. These complex interactions appear to play major roles in linking innate and adaptive immunity, and maintaining a pathogen-free lung with minimal, or no inflammation.

Animals↗

PubMed2003

Intestinal epithelial toll-like receptors: to protect. And serve?

The innate immune system uses a series of pattern recognition receptors to detect the presence of pathogens thus allowing for rapid host defense responses to invading microbes. A key component of such receptors are the "toll-like receptors" (TLRs), which recognize a panel of microbial molecules that tend to be somewhat invariant, at least in select regions, thus permitting a relatively small number of receptors to recognize a large number of different microbes. Accordingly, this panel of TLRs bears little ability to distinguish between commensal and pathogenic microbes as such organisms generally bear far more structural similarities than differences between them. For the professional phagocytic cells classically considered to be the primary mediators of innate immunity such distinction between commensal and pathogenic microbes is not particularly important since any microbe that breaches the outer host defensive barriers to reach these phagocytes, whether doing so by a pathogen-specific or opportunistic mechanism, is likely potentially hazardous to its host. However, epithelial cells that line mucosal surfaces, thus being on the front line of host defense, also play an active role in innate immunity particularly by secreting chemokines and other immune mediators in response to pathogenic microbes. Epithelial cells have been reported to express several TLRs suggesting these receptors play a role in intestinal epithelial innate immune signaling pathways. However, since some mucosal surfaces such as the intestinal epithelium are normally densely colonized by a wide variety of microbes, the ability to distinguish the occasional pathogen from the sea of commensals presents an important challenge. This minireview considers the current findings regarding TLR expression in the intestinal epithelium and the role these receptors might serve in host defense.

Animals↗

PubMed2003

Hepatitis C virus core and nonstructural protein 3 proteins induce pro- and anti-inflammatory cytokines and inhibit dendritic cell differentiation.

Antiviral immunity requires recognition of viral pathogens and activation of cytotoxic and Th cells by innate immune cells. In this study, we demonstrate that hepatitis C virus (HCV) core and nonstructural protein 3 (NS3), but not envelope 2 proteins (E2), activate monocytes and myeloid dendritic cells (DCs) and partially reproduce abnormalities found in chronic HCV infection. HCV core or NS3 (not E2) triggered inflammatory cytokine mRNA and TNF-alpha production in monocytes. Degradation of I-kappa B alpha suggested involvement of NF-kappa B activation. HCV core and NS3 induced production of the anti-inflammatory cytokine, IL-10. Both monocyte TNF-alpha and IL-10 levels were higher upon HCV core and NS3 protein stimulation in HCV-infected patients than in normals. HCV core and NS3 (not E2) inhibited differentiation and allostimulatory capacity of immature DCs similar to defects in HCV infection. This was associated with elevated IL-10 and decreased IL-2 levels during T cell proliferation. Increased IL-10 was produced by HCV patients' DCs and by core- or NS3-treated normal DCs, while IL-12 was decreased only in HCV DCs. Addition of anti-IL-10 Ab, not IL-12, ameliorated T cell proliferation with HCV core- or NS3-treated DCs. Reduced allostimulatory capacity in HCV core- and NS3-treated immature DCs, but not in DCs of HCV patients, was reversed by LPS maturation, suggesting more complex DC defects in vivo than those mediated by core or NS3 proteins. Our results reveal that HCV core and NS3 proteins activate monocytes and inhibit DC differentiation in the absence of the intact virus and mediate some of the immunoinhibitory effects of HCV via IL-10 induction.

Adult↗

PubMed2004

The complement system in regulation of adaptive immunity.

The serum complement system, which represents a chief component of innate immunity, not only participates in inflammation but also acts to enhance the adaptive immune response. Specific activation of complement via innate recognition proteins or secreted antibody releases cleavage products that interact with a wide range of cell surface receptors found on myeloid, lymphoid and stromal cells. This intricate interaction among complement activation products and cell surface receptors provides a basis for the regulation of both B and T cell responses. This review highlights fundamental events, explaining how complement links innate and adaptive immunity as well as describing more recent studies on how this large family of proteins functions locally in peripheral lymph nodes to enhance B and T cell responses.

Adaptation, Physiological↗

PubMed2006

When T cells recognize a pattern, they might cause trouble.

The mechanisms of self and non-self discrimination by T cells remain a fascinating topic for immunologists. How the immune system achieves protection of the host against an ever-changing realm of pathogens using a rather limited repertoire of T-cell receptors and at the same time avoids inflicting damage against its own tissues is equally puzzling. Although a better understanding of these questions has come from studies of the extent of cross reactivity of T-cell clones specific for foreign or self antigens, and also from examination of the different antigen avidities by which they recognize either type of antigen, many details are still lacking. Recently, there has been investigation into how T cells of the adaptive immune system can recognize functional protein domains or amino acid patterns. This type of T-cell reactivity is reminiscent of the pattern recognition that is firmly established as an important function of innate immune receptors such as Toll-like receptors. Many functional protein domains are conserved in evolution and are shared by a wide spectrum of pathogens, as well as by proteins of animals and humans. Hence, pattern recognition by adaptive immune cells might represent an efficient mechanism for host protection by the above-mentioned limited number of T-cell receptors. However, the fact that such functional domains occur so frequently in nature also implies that pattern recognition by T cells might cause autoimmunity, and recent data support this hypothesis.

Amino Acids↗

PubMed2005

The cytosolic pattern-recognition receptor Nod2 and inflammatory granulomatous disorders.

Pattern-recognition receptors are a first line of defense against invading pathogens. Recent advances in the understanding of innate immunity have revealed a novel family of cytosolic pattern-recognition receptors called Nods, which contain an amino-terminal effector-binding domain, a centrally located nucleotide-binding oligomerization domain (NOD) and a carboxy-terminal ligand recognition domain. Hereditary mutations of Nods have been reported in patients with certain inflammatory diseases; for example, Nod2 mutations are associated with the inflammatory granulomatous disorders, Crohn's disease and Blau syndrome. Missense mutations of Nod2 are also associated with early-onset sarcoidosis, a rare but sporadic disease. Because Nod2 is predominantly expressed in monocytes and recognizes a component of bacterial peptidoglycan, analysis of its function may help in understanding the role of the immune system in granuloma formation.

Arthritis↗

PubMed2003

Molecular insights on the cerebral innate immune system.

All species need an immediate reply to the microbial pathogens that is part of an effective immune response and is essential for the survival of most organisms. This reply is known as the innate immune response and is characterized by the de novo production of mediators that either kill the microbes directly or activate phagocytic cells to ingest and kill them. The innate immune response can be driven through specific recognition systems, the best example being an interaction between the endotoxin lipopolysaccharide (LPS) and its receptors CD14 and Toll-like receptor 4 (TLR4). For a long time, the brain was considered to be a privileged organ from an immunological point of view, owing to its inability to mount an immune response and process antigens. Although this is partly true, the CNS shows a well-organized innate immune reaction in response to systemic bacterial infection and cerebral injury. The CD14 and TLR4 receptors are constitutively expressed in the circumventricular organs (CVOs), choroid plexus and leptomeninges. Circulating LPS is able to cause a rapid transcriptional activation of genes encoding CD14 and TLR2, as well as a wide variety of pro-inflammatory molecules in CVOs. A delayed response to LPS takes place in cells located at boundaries of the CVOs and in microglia across the CNS. Therefore, without having direct access to the brain parenchyma, pathogens have the ability to trigger an innate immune reaction throughout cerebral tissue. This review presents evidence supporting the existence of such a system in the brain, which is finely regulated at the transcription level. Transient activation of this system is not harmful toward neuronal elements.

Animals↗