Organ-specific regulation of innate immunity.
Immune responses to microbial challenge in various tissues are not the same. Organ-specific immune responses are adapted to maintain organ physiology.
Bacterial Infections↗
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Results for “Receptors, Pattern Recognition”
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The development of an automated method for analyzing communication rate in augmentative and alternative communication.
A significant barrier to evidence-based practice in Augmentative and Alternative Communication (AAC) is the lack of validated performance measures that can be used by speech-language pathologists and rehabilitation engineers to evaluate the communication and device use of AAC consumers. Recently an effort has been made to develop automated data-logging techniques to facilitate the transcription and analysis of the AAC speaker's device use. A major source of error for the automated measurement of communication rate is the presence of excessive Inter-Selection Intervals (ISIs) (i.e., pause times), for which no communicative activity is occurring. The goal of this study was to develop an automated technique to filter out extreme ISIs, while preserving true communication rate performance. AAC data log files were obtained from seven individuals participating in a 1-month field trial of an AAC technology. Two temporal filtering techniques (arbitrary and individual) were compared for their ability to eliminate excessive ISIs. Results indicated that use of an individualized temporal filter was more sensitive to performance variability than use of an arbitrary temporal filter. Further, the individualized temporal filter elevated the participants' communication rate (measured by words per minute) by a factor of 1.8 to 34.5 greater than that of the unfiltered communication rate estimate. In addition, the first AAC communication rate performance estimates taken from the field are presented. Implications for further research and the valid use of automated data logging and analysis are discussed.
Activities of Daily Living↗
Autoantibodies make a U-turn: the toll hypothesis for autoantibody specificity.
Like the immune response itself, our efforts to understand the "rules" for self-nonself discrimination are constantly evolving. The discovery of pattern recognition receptors-the Toll-like receptor (TLR) family in particular-shifted the emphasis of self-nonself recognition from lymphocytes functioning in the adaptive immune system to antigen-presenting cells (APCs) functioning in the innate immune system. Two new articles, one in a recent issue (1) and one in this issue (see Vollmer et al. [2] on p. 1575), demonstrate that antigen-antibody complexes containing RNAs activate B lymphocytes and dendritic cells (DCs) through interaction with TLR7 and/or TLR8. From these and other papers, one begins to see how specific types of autoantigens-by virtue of their capacity to act as TLR ligands-favor autoantibody production. This is known as the Toll hypothesis.
Animals↗
Surfactant protein D in human lung diseases.
The lung is continuously exposed to inhaled pollutants, microbes and allergens. Therefore, the pulmonary immune system has to defend against harmful pathogens, while an inappropriate inflammatory response to harmless particles must be avoided. In the bronchoalveolar space this critical balance is maintained by innate immune proteins, termed surfactant proteins. Among these, surfactant protein D (SP-D) plays a central role in the pulmonary host defence and the modulation of allergic responses. Several human lung diseases are characterized by decreased levels of bronchoalveolar SP-D. Thus, recombinant SP-D has been proposed as a therapeutical option for cystic fibrosis, neonatal lung disease and smoking-induced emphysema. Furthermore, SP-D serum levels can be used as disease activity markers for interstitial lung diseases. This review illustrates the emerging role of SP-D translated from in vitro studies to human lung diseases.
Animals↗
Activation of plasmacytoid dendritic cells.
Four years after the discovery of mouse plasmacytoid dendritic cells (pDC), pDC are still very much an 'enigmatic' cell type. It is clear that pDC are potent producers of type I IFN in response to viral, bacterial and even mammalian nucleotides. The role that they play in vivo before and after activation is still under scrutiny. This review concentrates on the pathways to activation of pDC, examining the activating ligands, receptors and signalling molecules that are known to be involved, and the relevance of these activation pathways to human disease.
Animals↗
Functional genomics of innate host defense molecules in normal human monocytes in response to Aspergillus fumigatus.
Aspergillus fumigatus induces the release of innate immune-related molecules from phagocytic cells early in the course of infection. Little is known, however, about the complex expression profiles of the multiple genes involved in this response. We therefore investigated the kinetics of early gene expression in human monocytes (HMCs) infected with conidia of A. fumigatus using DNA microarray analysis. Total RNA from HMCs at 0, 2, 4, and 6 h was extracted, linearly amplified, hybridized onto Affymetrix HG133 Plus 2.0 gene chips, and analyzed with an Affymetrix scanner. Changes in gene expression were calculated as a ratio of those expressed by infected versus control HMCs. Aspergillus fumigatus induced differential regulation of expression in 1,827 genes (P < 0.05). Genes encoding cytokines and chemokines involved in host defense against A. fumigatus, including interleukin-1beta (IL-1beta), IL-8, CXCL2, CCL4, CCL3, and CCL20, as well as the opsonin long pentraxin 3, were up-regulated during the first 2 to 6 h, coinciding with an increase in phagocytosis. Simultaneously, genes encoding CD14, ficolin1, and MARCO were down-regulated, and genes encoding IL-10 and matrix metalloproteinase 1 were up-regulated. Up-regulation of the genes encoding heat shock proteins 40 and 110 and connexins 26 and 30 may point to novel molecules whose role in the pathogenesis of aspergillosis has not been previously reported. Verification of the transcriptional profiling was obtained for selected genes by reverse transcription-PCR and enzyme immunoassay. Thus, A. fumigatus conidia induced a coordinated expression of genes important in host defense and immunomodulation.
Aspergillosis↗
Role of surfactant protein D (SP-D) in innate immunity in the gastric mucosa: evidence of interaction with Helicobacter pylori lipopolysaccharide.
Surfactant protein D (SP-D) is a collagenous glycoprotein, a collectin, which functions as a pathogen-associated molecular pattern (PAMP) recognition receptor in the innate immune response. Although originally identified in the lung as a component of surfactant, SP-D also occurs in the gastric mucosa at the luminal surface and within gastric pits of mucus-secreting cells. Infection with the gastroduodenal pathogen Helicobacter pylori up-regulates expression of SP-D in human patients with gastritis, and its influence on colonization has been demonstrated in a Helicobacter SP-D-deficient (SP-D(-/-)) mouse model. SP-D binds and agglutinates H. pylori cells in a lectin-specific manner, and has been shown to bind H. pylori lipopolysaccharide. Furthermore, evidence indicates that H. pylori varies LPS O-chain structure to evade SP-D binding which is speculated aids persistence of this chronic infection.
Gastric Mucosa↗
[Humoral and cellular responses in innate immunity].
The immune system is divided into innate and adaptive immunity. Either immunity consists of humoral and cellular responses, and immunity is maximized when both responses coordinately function. Adaptive immunity has been intensively studied, while it was only recently that we gained some understanding of innate immunity. In particular, cellular responses in innate immunity have been poorly understood compared with humoral responses. In addition, the mechanisms and roles of innate immune responses could be distinct between the organisms that possess both innate and adaptive immunity and those possessing only innate immunity. On the other hand, invading pathogenic microbes employ various strategies to inhibit the host immune system for their survival. I here summarize what needs to be known to gain a deeper understanding of the innate immune response. The readers are suggested to refer to the accompanying articles for more detailed description.
Animals↗
The use of protoplasts to study innate immune responses.
The use of plant protoplast transient expression system has facilitated the discovery and dissection of many signal transduction pathways in response to hormones, metabolites, and stresses. Recently, Arabidopsis protoplasts also have been used successfully to study plant innate immune responses triggered by pathogen-derived elicitors. Here, we describe the detailed protocols for studying innate immune responses, including cell death and early defense gene regulation activated by two types of elicitors, pathogen-associated molecular patterns and bacterial type III effectors in Arabidopsis protoplasts. This cell-based system simplifies the complex pathogen-plant interactions to pure individual signals and synchronized cell-autonomous responses. The application of this novel approach provides high temporal and spatial resolution to enhance our understanding of the distinct and overlapping signaling events in pathogen-associated molecular pattern- and bacterial type III effector-activated immune responses at the molecular and cellular level.
Arabidopsis↗
Host defence against disseminated Candida albicans infection and implications for antifungal immunotherapy.
The different manifestations of Candida albicans infection are dictated by an underlying defect in the immune response of the host. Protective immunity to disseminated candidiasis, the manifestation of C. albicans infection discussed in this review, has traditionally been ascribed to innate immunity with emphasis on the role of granulocytes. Lately, however, immunological studies have learned that host defence against disseminated candidiasis is based on a complex interplay between innate and cell-mediated immunity. Despite the availability of new antifungal agents, mortality associated with disseminated C. albicans infection remains high. Immunotherapy that augments host defence is an important strategic option in the battle against disseminated candidiasis. Here, the authors review the chronological events in the pathogenesis of disseminated candidiasis that aid in predicting the impact of existing immunotherapy and the development of future immunomodulating strategies.
Adjuvants, Immunologic↗
Mechanism of alpha-melanotropin action.
A structure-function study of alpha-melanotropin has shown that this tridecapeptide consists of two message sequences, (-Glu)-His-Phe-Arg-Trp- and -Gly-Lys-Pro-Val-NH2, and a potentiator sequence, Ac.Ser-Tyr-Ser-Met-(Glu-), when acting on its melanophore receptors. The key elements of the message, -Phe-Arg- and -Lys-Pro-, do not correspond exactly to those responsible for eliciting the effect in other tissues. It appears that alpha-MSH contains more information than would be necessary to interact with only one complementary receptor site; therefore, the topography of the hormone exposed to the binding site may be different on contact with the receptors of different target cells. To further investigate this aspect, new methods for the isolation and characterization of functional receptors must be developed. We are investigating the use of chemically well-defined, biologically active, covalent hormone-macromolecule complexes for this purpose. Another approach utilizes model receptors with a recognition pattern similar to that of the biological receptor, as described in this communication for certain highly specific antibodies.
Amino Acid Sequence↗
[Vasopressin, oxytocin and angiotensin receptors in mammals].
The synthesis of new radiolabelled compounds and the evolution of the techniques designed to study the hormonal receptors allow a better understanding of their properties. Three types of vasopressin receptors have been described: the V1a receptor of liver and blood vessels, the V1b receptor of hypophysis and the V2 receptor of kidney. Such a classification was based on two criteria: The structure of the binding site and the nature of the second messenger produced. The V2 receptor coupled positively to adenylate cyclase regulates the water reabsorption via the increase of intracellular cyclic AMP. The V1a and V1b receptors involved in glycogenolysis, contraction and probably neurotransmission mobilize intracellular calcium via a positive coupling to phospholipase C. These two receptors exhibit different recognition patterns for vasopressin analogues. In mammals, the oxytocin receptors are mainly involved in myometrial contraction and lactation. Their characterization are generally difficult since they also interact with vasopressin and are sometimes colocated with vasopressin receptors. As for V1 receptor, they are coupled to phospholipase C and mobilized intracellular calcium. The receptors of angiotensin II regulate the blood pressure by different mechanisms. They are coupled to at least two transduction mechanisms (positive coupling to phospholipase C and negative coupling to adenylate cyclase). Electrophysiological data seems to indicate that such receptor may also control a calcium channel. Yet different molecules (cAMP, calcium, inositol phosphates, diacyl-glycerol) trigger the hormonal effect of angiotensin II inside the cell.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Direct binding and functional transfer of NK cell inhibitory receptors reveal novel patterns of HLA-C allotype recognition.
Cytotoxicity of human NK cells is under negative control of killer cell Ig-like receptors (KIR) specific for HLA class I. To determine the specificity of five KIR containing two Ig domains (KIR2D), direct binding of soluble recombinant KIR2D to a panel of HLA class I transfectants was assayed. One soluble KIR2D, derived from an inhibitory receptor with a long cytoplasmic tail (KIR2DL1), bound to HLA-C allotypes containing asparagine 77 and lysine 80 in the heavy chain, as expected, since these allotypes inhibit lysis by NK cells expressing KIR2DL1. Surprisingly, another KIR2D (KIR2DL2), which inhibits NK lysis of cells expressing HLA-C molecules with serine 77 and asparagine 80, bound to HLA-C allotypes carrying either amino acid motif. Expression of the KIR2DL receptors in NK cells using recombinant vaccinia viruses confirmed these patterns of recognition, and identified KIR2DL3 as another KIR reacting with both groups of HLA-C allotypes. Mutagenesis of amino acid 44 in KIR2DL1 and KIR2DL2 suggested this residue controls the affinity of KIR for the 77/80 motif of HLA-C molecules. Two other soluble KIR2D, derived from noninhibitory receptors with short cytoplasmic tails (KIR2DS), did not bind to any of the HLA class I allotypes tested. One of these receptors (KIR2DS2) is closely related in sequence to KIR2DL2. Substitution of tyrosine 45 with the phenylalanine conserved in other KIR was sufficient to permit specific binding of KIR2DS2 to HLA-C. These results show that KIR2DL receptors are specific for HLA-C, but that recognition of HLA-C allotypes appears more permissive than indicated by previous functional experiments.
Alleles↗
Differential receptor arrays and assays for solution-based molecular recognition.
Nature has inspired an emergent supramolecular field of synthetic receptor arrays and assays for the pattern-based recognition of various bioanalytes and metal species. The synthetic receptors are not necessarily selective for a particular analyte, but the combined signal response from the array is diagnostic for the analyte. This tutorial review describes recent work in the literature for this emerging supramolecular field and details basic array and assay design principles. We review the analytes targeted, signaling types used, and pattern recognition. Developing specific receptors for the solution-based analysis of complex analytes and mixtures is a daunting task. A solution to this difficult task has been inspired by nature's use of arrays of receptors in the senses of taste and smell. An emerging field within supramolecular chemistry is the use of synthetic and readily available receptors in array formats for the detection of analytes in solution. Each receptor in a differential array does not necessarily have selectivity for a particular analyte, but the combined fingerprint response can be extracted as a diagnostic pattern visually, or using chemometric tools. This new genre of molecular recognition is advancing rapidly with several groups developing novel array platforms and receptors.
Adenosine Triphosphate↗
Electrostatic components of drug-receptor recognition. II. The DNA-binding antibiotic actinomycin.
The semiempirical molecular orbital method PCILO has been used to study the electronic charge distribution and conformation of the antibiotic actinomycin. Molecular electrostatic potential fields have been constructed in three-dimensional space round the molecule and displayed stereoscopically together with contour maps in the orthogonal planes relative to that of the chromophore. It was found that the drug has a considerable dipole moment and that the electrostatic fields can be separated into two large regions; an area of positive potential surrounds the chromophore and one of negative potential is directed away from the peptide rings. In this and the preceding paper these observations are discussed with respect to drug-receptor recognition phenomena. Pattern-matching of complementary electrostatic fields between the drug and polynucleotide receptor can be discerned.
Chemical Phenomena↗
Toll-like receptors: cellular signal transducers for exogenous molecular patterns causing immune responses.
Innate immunity initiates protection of the host organism against invasion and subsequent multiplication of microbes by specific recognition. Germ line-encoded receptors have been identified for microbial products such as mannan, lipopeptide, peptidoglycan (PGN), lipoteichoic acid (LTA), lipopolysaccharide (LPS), and CpG-DNA. The Drosophila Toll protein has been shown to be involved in innate immune response of the adult fruitfly. Members of the family of Toll-like receptors (TLRs) in vertebrates have been implicated as pattern recognition receptors (PRRs). Ten TLRs are known and six of these have been demonstrated to mediate cellular activation by distinct microbial products. TLR4 has been implicated as activator of adaptive immunity, and analysis of systemic LPS responses in mice led to the identification of LPS-resistant strains instrumental in its identification as a transmembrane LPS signal transducer. Structural similarities between TLRs and receptor molecules involved in immune responses such as CD14 and the IL-1 receptors (IL-1Rs), as well as functional analysis qualified TLR2 as candidate receptor for LPS and other microbial products. Targeted disruption of the TLR9 gene in mice led to identification of TLR9 as CpG-DNA signal transducer. Involvement of TLR5 in cell activation by bacterial flagellin has been demonstrated. Further understanding of recognition and cellular signaling activated through the ancient host defense system represented by Toll will eventually lead to means for its therapeutic modulation.
Amino Acid Sequence↗
MyD88-dependent responses involving toll-like receptor 2 are important for protection and clearance of Legionella pneumophila in a mouse model of Legionnaires' disease.
Legionella pneumophila is a gram-negative facultative intracellular parasite of macrophages. Although L. pneumophila is the causative agent of a severe pneumonia known as Legionnaires' disease, it is likely that most infections caused by this organism are cleared by the host innate immune system. It is predicted that host pattern recognition proteins belonging to the Toll-like receptor (TLR) family are involved in the protective innate immune responses. We examined the role of TLR-mediated responses in L. pneumophila detection and clearance using genetically altered mouse hosts in which the macrophages are permissive for L. pneumophila intracellular replication. Our data demonstrate that cytokine production by bone marrow-derived macrophages (BMMs) in response to L. pneumophila infection requires the TLR adapter protein MyD88 and is reduced in the absence of TLR2 but not in the absence of TLR4. Bacterial growth ex vivo in BMMs from MyD88-deficient mice was not enhanced compared to bacterial growth ex vivo in BMMs from heterozygous littermate controls. Wild-type mice were able to clear L. pneumophila from the lung, whereas respiratory infection of MyD88-deficient mice caused death that resulted from robust bacterial replication and dissemination. In contrast to an infection with virulent L. pneumophila, MyD88-deficient mice were able to clear infections with L. pneumophila dotA mutants, indicating that MyD88-independent responses in the lung are sufficient to clear bacteria that are unable to replicate intracellularly. In vivo growth of L. pneumophila was enhanced in the lungs of TLR2-deficient mice, which resulted in a delay in bacterial clearance. No significant differences were observed in the growth and clearance of L. pneumophila in the lungs of TLR4-deficient mice and heterozygous littermate control mice. Our data indicate that MyD88 is crucial for eliciting a protective innate immune response against virulent L. pneumophila and that TLR2 is one of the pattern recognition receptors involved in initiating this MyD88-dependent response.
Adaptor Proteins, Signal Transducing↗
Toll-like receptors-2, -3 and -4 expression patterns on human colon and their regulation by mucosal-associated bacteria.
The colonic epithelium provides an interface between the host and micro-organisms colonising the gastrointestinal tract. Molecular recognition of bacteria is facilitated through Toll-like receptors (TLR). The colonic epithelium expresses relatively high levels of mRNA for TLR3 and less for TLR2 and -4. Little is known of the expression patterns and mode of induction of expression for these pattern recognition receptors in human colon. The aim of this study was to investigate their localization in the gut and induction of expression in epithelial cell lines by mucosal bacteria. TLR2 and -4 were expressed only in crypt epithelial cells, expression was lost as the cells matured and moved towards the gut lumen. In contrast, TLR3 was only produced in mature epithelial cells. HT29 and CACO-2 had different levels of expression for TLR1-4. Co-culture of HT29 cells with different mucosal isolates showed that they were highly responsive to bacterial challenge, with up-regulation of mRNA for TLR1-4. In contrast, CACO-2 cells were refractive to bacterial challenge, showing little difference in mRNA levels. TLR3 was induced in HT29 only by Gram-positive commensals with up-regulation of both mRNA and protein and an enhancement of the antiviral immune response. This pattern of expression allows induction of responsiveness to bacteria only by the crypt epithelium so that tolerance to commensal organisms can be maintained. In contrast, mature columnar epithelium is able to respond to viral pathogens, which are not part of the normal gut commensal microbiota.
Bacteroides fragilis↗