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Results for “Receptors, Pattern Recognition”

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PubMedDate not supplied

The potential role of mannan-binding lectin in the clearance of self-components including immune complexes.

Mannan-binding lectin (MBL) is a pattern recognition receptor in the innate immune system. It recognizes certain sugar residues arranged in a pattern that enables MBL to bind with sufficient strength. Such sugar patterns are common on the surface of many microorganisms, and MBL has therefore been considered to be an agent that can discriminate between self and nonself. There is, however, increasing evidence supporting that MBL, like many membrane-bound C-type lectin-like receptors, also helps to dispose of various outworn or abnormal body components. Most self-components are protected with sialic acid or galactose that disrupt the pattern of the sugars that MBL can bind, but MBL may be significantly involved in the elimination of self-components that have lost these protective terminal residues. The role of MBL in the clearance of invading pathogens has previously been thoroughly reviewed. Here, we review some findings that support the notion that MBL may contribute to noninflammatory removal of immune complexes and abnormal cells by the reticuloendothelial system. Defects in this clearance mechanism may cause an accumulation of potentially dangerous self-components, thereby increasing the likelihood of chronic inflammation and autoimmunity.

Animals↗

PubMed2003

Inflammatory response to infectious pulmonary injury.

This review describing the inflammatory response to infectious pulmonary injury is focused on the innate immunity of the distal lung to bacterial pneumonia. The fact that the inflammatory response varies to some extent with the bacterial strain responsible for the infection is emphasised. The key cellular components present in the distal lung are described. The major role of alveolar macrophage is described, inasmuch as it responds to the usual daily challenges of bacteria entering the terminal airways and is capable of initiating an inflammatory reaction if the microbial challenge is either too large or too virulent. Under these conditions, the alveolar macrophages initiate an inflammatory response that recruits large numbers of neutrophils into the alveolar spaces. The strategy of the innate immune response may not be to recognise every possible antigen, but rather to focus on a few, highly conserved structures present in large groups of microorganisms. These structures are referred to as pathogen-associated molecular patterns and the receptors of the innate immune system that evolved to recognise them are called pattern-recognition receptors. The soluble factors in innate defence, such as cytokines, are described, and a last paragraph discusses whether a specific inflammatory response could characterise nosocomial pneumonia.

Cytokines↗

PubMed2005

Phenotypic and functional profiling of human proinflammatory type-1 and anti-inflammatory type-2 macrophages in response to microbial antigens and IFN-gamma- and CD40L-mediated costimulation.

Macrophages (Mphi) comprise a heterogeneous population of cells with various immune and homeostatic functions. Recently, we have described type-1 and type-2 human monocyte-derived Mphi subsets. Although both support outgrowth of intracellular mycobacteria, Mphi-1 secretes interleukin (IL)-23/IL-12 and supports T helper cell type 1 (Th1) responses, whereas Mphi-2 fails to produce IL-23/IL-12, predominantly secretes IL-10, and inhibits Th1 function. Here, we further describe the phenotypic and functional profiles of Mphi-1 and Mphi-2 in response to microbial antigens and interferon-gamma (IFN-gamma) and CD40L as costimulatory T cell back-talk signals. Activated IL-23(+)/IL-12(+) Mphi-1 secreted IL-1beta, IL-18, IL-6, and tumor necrosis factor-alpha (TNF-alpha), as well as IL-8, monocyte chemoattractant protein-1 (MCP-1), IFN-inducible protein 10 (IP-10), Mphi inflammatory protein-1beta (MIP-1beta), regulated on activation, normal T expressed and secreted (RANTES), Mphi-derived chemokine (MDC), and (low levels of) pulmonary and activation-regulated chemokine and thymus and activation-regulated chemokine (TARC), corroborating their proinflammatory function. Regardless of the stimulus, Mphi-2 maintained their IL-10(+) signature cytokine profile and produced no or relatively low levels of IL-12p40, IL-1beta, IL-6, TNF-alpha, MDC, or TARC. It is remarkable that Mphi-2 secreted high levels of IL-8, MCP-1, IP-10, MIP-1beta, and RANTES, suggesting an active role for these cells in regulating cellular immunity and homeostasis. Mphi-1 and Mphi-2 expressed similar levels of Toll-like receptor and dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin as microbial pattern recognition receptors. Mphi-2, unlike Mphi-1 but like other nonclassical Mphi described previously, expressed CD163 and down-modulated human leukocyte antigen and costimulatory molecules specifically upon activation. These findings demonstrate how Mphi-1/Mphi-2 polarization can differentially skew the host response toward pro- or anti-inflammatory immune responses, respectively. This is likely to be relevant for host-pathogen interactions in chronic bacterial infections and provides a model for dissecting pro- and anti-inflammatory cascades.

Antigens, Bacterial↗

PubMed2004

Mannose receptor-targeted vaccines.

Targeting antigens to endocytic receptors on professional antigen-presenting cells (APCs) represents an attractive strategy to enhance the efficacy of vaccines. Such APC-targeted vaccines have an exceptional ability to guide exogenous protein antigens into vesicles that efficiently process the antigen for major histocompatibility complex class I and class II presentation. Efficient targeting not only requires high specificity for the receptor that is abundantly expressed on the surface of APCs, but also the ability to be rapidly internalised and loaded into compartments that contain elements of the antigen-processing machinery. The mannose receptor (MR) and related C-type lectin receptors are particularly designed to sample antigens (self and non-self), much like pattern recognition receptors, to integrate the innate with adaptive immune responses. In fact, a variety of approaches involving delivery of antigens to the MR have demonstrated effective induction of potent cellular and humoral immune responses. Yet, although several lines of evidence in diverse experimental systems attest to the efficacy of targeted vaccine strategies, it is becoming increasingly clear that additional signals, such as those afforded by adjuvants, may be critical to elicit sustained immunity. Therefore, MR-targeted vaccines are likely to be most efficacious in vivo when combined with agents that elicit complementary activation signals. Certainly, a better understanding of the mechanism associated with the induction of immune responses as a result of targeting antigens to the MR, will be important in exploiting MR-targeted vaccines not only for mounting immune defenses against cancer and infectious disease, but also for specific induction of tolerance in the treatment of autoimmune disease.

Animals↗

PubMed2000

CR3: a general purpose adhesion-recognition receptor essential for innate immunity.

CR3 (CD11b/CD18), a beta(2) integrin, has a key role in innate antimicrobial defenses, as evidenced by the leukocyte adhesion (CD18) deficiency syndrome in humans and the CD11b knockout mouse. CR3 is a highly versatile pattern-recognition receptor that activates leukocytes via signaling complexes and actin reorganization, mediates phagocytosis, and promotes leukocyte transmigration.

Animals↗

PubMed2006

Menstrual cycle-dependent changes of Toll-like receptors in endometrium.

BACKGROUND: Rapid innate immune defences against infection usually involve the recognition of invading pathogens by specific pattern recognition receptors recently attributed to the family of Toll-like receptors (TLRs). Reports from our laboratory and others have demonstrated the existence of TLRs 1-6 in the female reproductive tract. However, little has been done to identify TLRs 7-10 in the female reproductive tract, particularly in the uterus. Also little information exists regarding variation in TLRs in the female reproductive tract during the menstrual cycle. METHOD: The distribution of TLR7-10 protein was detected by immunostaining in timed endometrial biopsies from normal women. RT-PCR was used to show the existence of TLR1-10 genes in endometrial tissue and real-time PCR analysis to investigate the relative expression of these genes during the menstrual cycle in normal human endometrium. RESULTS: TLR7-10 proteins were detected in endometrial epithelium and stroma. TLR1-10 genes were expressed in human endometrial tissue, and the mean relative expression of TLR2-6, 9 and 10 genes was significantly higher during the secretory phase compared with other phases of the menstrual cycle. CONCLUSIONS: TLR7-10 localization is not limited to endometrial epithelium but is also present in the stroma of the endometrial tissue. Endometrial TLR2-6, 9 and 10 genes are cyclically expressed during the menstrual cycle.

Adult↗

PubMed2005

Treatment of intravaginal HSV-2 infection in mice: a comparison of CpG oligodeoxynucleotides and resiquimod (R-848).

The mammalian innate immune system recognizes pathogens via a series of pattern-recognition receptors such as the toll-like receptors (TLR) that interact with pathogen-associated molecular patterns (PAMPs) and lead to the rapid activation of innate immune cells. In this study, we compared the efficacy of CpG ODN (a TLR9 agonist) and resiquimod (R-848; a TLR7/8 agonist) for topical immunoprophylaxis or immunotherapy of vaginal herpes simplex virus type 2 (HSV-2) infection in mice. Efficacy against HSV infection was observed with CpG ODN but less so with R-848, even after repeated administrations. Intravaginal (IVAG) administration of CpG ODN resulted in strong local but relatively weak systemic immune activation, as determined by levels of the chemokines IP-10, MIG and I-TAC in vaginal tissue and plasma, respectively. In contrast, IVAG administration of R-848 resulted in high levels of plasma IP-10, similar to those seen after parenteral administration, but overall, weaker or shorter-lived local immune responses than obtained with CpG ODN. These findings suggest that differences in biodistribution and sites of immune activation between CpG ODN and R-848 after IVAG delivery account for differences in efficacy, and demonstrate the need for local mucosal innate activation for protection against HSV-2.

Adjuvants, Immunologic↗

PubMed2004

The role of Toll-like receptors and Nod proteins in bacterial infection.

Our understanding of innate immunity in mammals has greatly expanded following the discovery of the family of membrane-bound receptors, called the Toll-like receptors (TLRs). More recently, the nucleotide-binding oligomerisation domain (Nod) molecules, Nod1 and Nod2, which are cytoplasmic surveillance proteins, have also been shown to be involved in the innate immune response. These two classes of detection molecules, classified as "pattern recognition receptors" (PRRs), detect microbial ligands in order to initiate a defense response to fight infectious disease. These microbial ligands or "pathogen-associated molecular patterns" (PAMPs), detected by TLRs and Nods are often structural components of the microorganism that are not subject to much variation. These include such factors as lipopolysaccharide (LPS) and peptidoglycan from the cell walls of bacteria. In order to understand the role of TLRs and Nod proteins in infectious disease in vivo it is important to define the site of interaction between PRRs and PAMPS. Additionally, the challenge of mice deficient in the various PRRs in natural infection models will help to decipher the contribution of these molecules not only in the innate immune response against pathogen infection but also how these proteins may instruct the adaptive immune response in order to have a tailored immune response against a particular microbe.

Adaptor Proteins, Signal Transducing↗

PubMed1992

Macrophages in Drosophila embryos and L2 cells exhibit scavenger receptor-mediated endocytosis.

Mammalian macrophage scavenger receptors exhibit unusually broad binding specificity and are implicated in atherosclerosis and host defense. Scavenger receptor-like endocytosis was observed in Drosophila melanogaster embryos and in primary embryonic cell cultures. This receptor activity was expressed primarily by macrophages. The Drosophila Schneider L2, but not the Kc, cell line also exhibited a scavenger receptor-mediated endocytic pathway similar to its mammalian counterpart. L2 receptors mediated high-affinity internalization and subsequent temperature- and chloroquine-sensitive degradation of 125I-labeled acetylated low density lipoprotein and displayed characteristic ligand specificity. These findings suggest that scavenger receptors mediate important, well-conserved functions and raise the possibility that they may be pattern recognition receptors that arose early in the evolution of host defense mechanisms. They also establish additional systems for the investigation of endocytosis in Drosophila and scavenger receptor function in disease, host defense, and development.

Animals↗

PubMed2005

The role of gut-associated lymphoid tissues and mucosal defence.

The newborn infant leaves a germ-free intrauterine environment to enter a contaminated extrauterine world and must have adequate intestinal defences to prevent the expression of clinical gastrointestinal disease states. Although the intestinal mucosal immune system is fully developed after a full-term birth, the actual protective function of the gut requires the microbial stimulation of initial bacterial colonization. Breast milk contains prebiotic oligosaccharides, like inulin-type fructans, which are not digested in the small intestine but enter the colon as intact large carbohydrates that are then fermented by the resident bacteria to produce SCFA. The nature of this fermentation and the consequent pH of the intestinal contents dictate proliferation of specific resident bacteria. For example, breast milk-fed infants with prebiotics present in breast milk produce an increased proliferation of bifidobacteria and lactobacilli (probiotics), whereas formula-fed infants produce more enterococci and enterobacteria. Probiotics, stimulated by prebiotic fermentation, are important to the development and sustainment of intestinal defences. For example, probiotics can stimulate the synthesis and secretion of polymeric IgA, the antibody that coats and protects mucosal surfaces against harmful bacterial invasion. In addition, appropriate colonization with probiotics helps to produce a balanced T helper cell response (Th1=Th2=Th3/Tr1) and prevent an imbalance (Th1>Th2 or Th2>Th1) contributing in part to clinical disease (Th2 imbalance contributes to atopic disease and Th1 imbalance contributes to Crohn's disease and Helicobacter pylori-induced gastritis). Furthermore, a series of pattern recognition receptors, toll-like receptors on gut lymphoid and epithelial cells that interact with bacterial molecular patterns (e.g. endotoxin (lipopolysaccharide), flagellin, etc.), help modulate intestinal innate immunity and an appropriate adaptive immune response. Animal and clinical studies have shown that inulin-type fructans will stimulate an increase in probiotics (commensal bacteria) and these bacteria have been shown to modulate the development and persistence of appropriate mucosal immune responses. However, additional studies are needed to show that prebiotics can directly or indirectly stimulate intestinal host defences. If this can be demonstrated, then prebiotics can be used as a dietary supplement to stimulate a balanced and an appropriately effective mucosal immune system in newborns and infants.

Animals↗

PubMed2002

Transcriptional regulation of the human toll-like receptor 2 gene in monocytes and macrophages.

This report investigates the molecular basis for tissue-restricted and regulated expression of the pattern recognition receptor Toll-like receptor (TLR)2 in human monocytes and macrophages. To define the proximal promoter, the full 5'-sequence and transcriptional start sites of TLR2 mRNA were determined. The human TLR2 gene was found to consist of two 5' noncoding exons followed by a third coding exon. Alternative splicing of exon II was detected primarily in human blood monocytes. The proximal promoter, exon I, and part of intron I were found to be located in a CpG island. Although CpG methylation of the proximal human TLR2 promoter in cell lines correlated with TLR2 repression, the promoter was unmethylated in primary cells, indicating that CpG methylation does not contribute to the cell-type specific expression of human TLR2 in normal tissues. The promoter sequence contains putative binding sites for several transcription factors, including Sp1 and Ets family members. Reporter gene analysis revealed a minimal promoter of 220 bp that was found to be regulated by Sp1, Sp3, and possibly PU.1. Interestingly, no sequence homology was detected between human and murine TLR2 promoter regions. In contrast to murine TLR2, expression of human TLR2 in monocytes/macrophages is not induced by the proinflammatory stimuli LPS or macrophage-activating lipopeptide-2, and reporter activity of the promoter was not enhanced by stimuli-induced NF-kappaB activation in THP-1 or MonoMac-6 cells. Our findings provide an initial definition of the human TLR2 promoter and reveal profound differences in the regulation of an important pattern recognition molecule in humans and mice.

Alternative Splicing↗

PubMed2005

NOD2 and toll-like receptors are nonredundant recognition systems of Mycobacterium tuberculosis.

Infection with Mycobacterium tuberculosis is one of the leading causes of death worldwide. Recognition of M. tuberculosis by pattern recognition receptors is crucial for activation of both innate and adaptive immune responses. In the present study, we demonstrate that nucleotide-binding oligomerization domain 2 (NOD2) and Toll-like receptors (TLRs) are two nonredundant recognition mechanisms of M. tuberculosis. CHO cell lines transfected with human TLR2 or TLR4 were responsive to M. tuberculosis. TLR2 knock-out mice displayed more than 50% defective cytokine production after stimulation with mycobacteria, whereas TLR4-defective mice also released 30% less cytokines compared to controls. Similarly, HEK293T cells transfected with NOD2 responded to stimulation with M. tuberculosis. The important role of NOD2 for the recognition of M. tuberculosis was demonstrated in mononuclear cells of individuals homozygous for the 3020insC NOD2 mutation, who showed an 80% defective cytokine response after stimulation with M. tuberculosis. Finally, the mycobacterial TLR2 ligand 19-kDa lipoprotein and the NOD2 ligand muramyl dipeptide synergized for the induction of cytokines, and this synergism was lost in cells defective in either TLR2 or NOD2. Together, these results demonstrate that NOD2 and TLR pathways are nonredundant recognition mechanisms of M. tuberculosis that synergize for the induction of proinflammatory cytokines.

Journal Article↗

PubMed2003

Human cytomegalovirus activates inflammatory cytokine responses via CD14 and Toll-like receptor 2.

Human cytomegalovirus (CMV) is a ubiquitous opportunistic pathogen that causes significant morbidity and mortality in immunocompromised people. An understanding of how CMV induces and circumvents host immunity is of critical importance in efforts to design effective therapeutics. It was recently discovered that mere cell contact by CMV particles leads to profound modulation of cellular gene expression, including induction of inflammatory cytokines and interferon-stimulated genes characteristic of innate immune detection. These findings suggest that a membrane receptor recognizes a CMV envelope protein(s), leading to innate immune activation. Here, we show that the pattern recognition receptors Toll-like receptor 2 (TLR2) and CD14 recognize CMV virions and trigger inflammatory cytokine production. Induction of inflammatory cytokines is mediated via TLR2-dependent activation of NF-kappa B. Since many of the pathological processes associated with CMV disease are facilitated or directly mediated by inflammatory cytokines, identification of the host membrane detection machinery may ultimately lead to improved therapeutics.

Animals↗

PubMed2004

Bacterial colonization and the development of intestinal defences.

In humans, intestinal defences develop during gestation and, at full term, have the capacity to respond in an appropriate manner to infectious agents and foreign antigens. Before an active protective response can occur, however, the gut must first be exposed to colonizing bacteria. Colonization with diverse intestinal microbes is necessary for the development of important gut defenses such as the synthesis and secretion of polymeric immunoglobulin A and the generation of a balanced T helper (Th) cell response. Insights into normal immune physiological development of the gut have been made by studying the germ-free animal and intestinal defenses. These studies have provided insights into the physiology of immune responses. Two important immunological functions are the secretion of polymeric immunoglobulin A to protect the intestinal surface against harmful stimuli and inhibition of the systemic response to commensal bacteria and food proteins (eg, oral tolerance) to prevent chronic inflammation. Neither function exists in the germ-free state, but rapidly develops after conventionalization (colonization) of the germ-free animal. In the present review, the importance of bacterial colonization on the appearance of normal mucosal immune function and to the clinical consequences of inadequate colonization to the development of disease will be discussed. For example, excessive Th2 activity can lead to atopy, whereas Th1 predominance is found in conditions such as Helicobacter pylori gastritis and Crohn's disease. With the eradication of infectious diseases in developed countries in the past three decades, the incidence of atopic and autoimmune diseases has increased. This epidemiological observation has been explained by the 'hygiene hypothesis', which suggests that a reduction in microbial burden by public health measures has contributed to an immunological imbalance in the intestine. A family of pattern recognition receptors (Toll-like receptors) on gut lymphoid and epithelial cells mediates innate immune responses to bacterial molecular patterns and, thereby, orchestrates acquired immunity. As the role of bacterial communication within the gut (bacterial-epithelial cross-talk) is clarified, physicians should be able to modulate gut immune responses, for example, by the use of probiotics.

Antigens, Bacterial↗

PubMed2005

The dynamics of LPS recognition: complex orchestration of multiple receptors.

The molecular mechanisms that have been designed to protect the host from invading pathogens are responsible for sepsis, an often fatal response of the immune system against microbial pathogens. In the past few years, intense research in the field of innate immunity has identified a plethora of pattern recognition receptors that are responsible for bacterial-induced activation. Recognition of bacterial lipopolysaccharide seems to involve a complex orchestration of protein-protein interactions that eventually leads to cellular activation. In this review, we attempt to unravel the dynamic interactions that occur among the different receptors involved and dictate the outcome of the innate immune response.

Animals↗

PubMed2002

Cutting edge: Toll-like receptor (TLR)2- and TLR4-mediated pathogen recognition in resistance to airborne infection with Mycobacterium tuberculosis.

Innate resistance against Mycobacterium tuberculosis is thought to depend critically on engagement of pattern recognition receptors on macrophages. However, the relative contribution of these receptors for containing M. tuberculosis infection has remained unexplored in vivo. To address this issue, we infected mice defective in CD14, TLR2, or TLR4 with M. tuberculosis by aerosol. Following infection with 100 mycobacteria, either mutant strain was as resistant as congenic control mice. Granuloma formation, macrophage activation, and secretion of proinflammatory cytokines in response to low-dose aerosol infection were identical in mutant and control mice. However, high-dose aerosol challenge with 2000 CFU M. tuberculosis revealed TLR2-, but not TLR4-defective mice to be more susceptible than control mice. In conclusion, while TLR2 signaling contributes to innate resistance against M. tuberculosis in borderline situations, its function, and that of CD14 and TLR4, in initiating protective responses against naturally low-dose airborne infection is redundant.

Administration, Inhalation↗

PubMed2005

Characterization of Toll-like receptors in the female reproductive tract in humans.

BACKGROUND: Rapid innate immune defences against infection involve the recognition of invading pathogens by specific pattern recognition receptors recently attributed to the family of Toll-like receptors (TLR). Little is known about the in vivo protein expression or distribution of TLR in the female reproductive tract in humans. It is likely that TLR distribution in the female reproductive tract reflects the immunological tolerance to the commensal organisms in lower parts of the tract (vagina, ectocervix and, partially, endocervix) and the intolerance to commensal microbial flora in the upper tract (the uterus and uterine tubes). METHODS: Using immunohistochemistry techniques, distribution of TLR1-6 was studied in surgical sections from the vagina, ecto- and endocervix, endometrium and uterine tubes, obtained from patients undergoing abdominal hysterectomy for benign gynaecological conditions. RESULTS: TLR1, 2, 3, 5 and 6 were present in the epithelia of different regions of female reproductive tract. However, TLR4 was only present in the endocervix, endometrium and uterine tubes and absent in vagina and ectocervix. In addition, a secretory form of TLR4 seems to be produced by the endocervical glands. CONCLUSION: TLR4 may play an important role in modulation of immunological tolerance in the lower parts of the female reproductive tract, and in host defence against ascending infection.

Adult↗

PubMed2004

Increased Toll-like receptor 4 expression in infants with respiratory syncytial virus bronchiolitis.

The fusion protein of the respiratory syncytial virus (RSV) binds to the pattern recognition receptors, TLR4 and CD14, and initiates innate immunity response to the virus. The aim of the study was to investigate the expression of TLR4 on peripheral blood lymphocytes and monocytes in peripheral blood of infants in both acute and convalescent phase of RSV bronchiolitis (n = 26). In addition, TNF-alpha expression in lipopolysaccharide-stimulated monocytes was also assessed. The results showed TLR4 to be expressed predominantly by monocytes in both sick infants and controls. During the acute phase of infection monocytes up-regulated TLR4 in eight infants, which returned to the levels recorded in controls 4-6 weeks from infection. There was no difference in the percentage of TNF-alpha secreting monocytes. Of the clinical parameters tested, minimal oxygen saturation was found to correlate negatively with this expression in the group of infants with increased TLR4. Additional studies are under way to correlate this finding with the outcome of the immune response to RSV.

Acute Disease↗