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Results for “Innate Immunity Recognition”

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PubMed2003

IL-2-activated CD8+CD44high cells express both adaptive and innate immune system receptors and demonstrate specificity for syngeneic tumor cells.

CD8(+) T cells depend on the alphabeta TCR for Ag recognition and function. However, Ag-activated CD8(+) T cells can also express receptors of the innate immune system. In this study, we examined the expression of NK receptors on a population of CD8(+) T cells expressing high levels of CD44 (CD8(+)CD44(high) cells) from normal mice. These cells are distinct from conventional memory CD8(+) T cells and they proliferate and become activated in response to IL 2 via a CD48/CD2-dependent mechanism. Before activation, they express low or undetectable levels of NK receptors but upon activation with IL-2 they expressed significant levels of activating NK receptors including 2B4 and NKG2D. Interestingly, the IL-2-activated cells demonstrate a preference in the killing of syngeneic tumor cells. This killing of syngeneic tumor cells was greatly enhanced by the expression of the NKG2D ligand Rae-1 on the target cell. In contrast to conventional CD8(+) T cells, IL-2-activated CD8(+)CD44(high) cells express DAP12, an adaptor molecule that is normally expressed in activated NK cells. These observations indicate that activated CD8(+)CD44(high) cells express receptors of both the adaptive and innate immune system and may play a unique role in the surveillance of host cells that have been altered by infection or transformation.

Animals↗

PubMed2003

Detection of peptidoglycans by NOD proteins.

Mechanisms of innate immune defense are based on the recognition of invariant microbial molecular patterns by specific receptors, followed by the activation of signaling pathways and the expression of effector molecules that will defeat the invading microorganism. Two recent reports add to the growing list of these pattern-recognition receptors by showing that the intracellular nucleotide-binding oligomerization domain 1 (NOD1) protein recognizes a diaminopimelate-containing muropeptide, a cell-wall component of Gram-negative bacteria.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Innate recognition of bacteria: engagement of multiple receptors.

Until recently, consensus was that the mechanism of action of the innate immune system was a simplified one. Current research findings in the field of innate recognition of bacteria suggest that it involves complex associations of receptors depending on cell type and bacterial stimuli, CD14, integrins, Toll-like receptors (TLRs), CD55, ion channels, and activation clusters containing heat shock proteins, chemokine receptor 4 and a plethora of other molecules have been shown to serve as key molecules in bacterial recognition. In this article, we review all the advances in the field and discuss the possibility that the repertoire for recognition of pathogens is defined by the combinational engagement of multiple receptors.

Animals↗

PubMed2006

Mannose binding lectin and soluble Toll-like receptor 2 in heart failure following acute myocardial infarction.

BACKGROUND: To determine the relationship between markers of innate immunity and clinical outcomes in patients with heart failure (HF) after acute myocardial infarction (AMI). Atherogenesis and HF is associated with the altered control of inflammation by innate immune defenses that include pattern-recognition molecules such as Toll-like receptors (TLRs) and mannose-binding lectin (MBL). METHODS AND RESULTS: We assessed circulating levels, and relationships with adverse outcomes of MBL and sTLR2 levels in 234 patients with AMI complicated with HF. Blood was sampled at baseline (median 3 days after AMI), 1 month, 1 year, and 2 years. For comparison, we also measured MBL and sTLR2 levels in 20 age- and sex-matched healthy controls. Patients with post-MI HF had markedly decreased serum levels of sTLR2 at baseline that increased during follow-up, but did not reach the concentrations present in healthy controls. In contrast, serum MBL levels were initially normal in patients with post-MI HF, but decreased during follow-up, and MBL levels measured 1 month after the index infarct were inversely associated with a higher incidence of reinfarction. CONCLUSION: These findings suggest that circulating levels of MBL and sTLR2 may reflect different aspects of the innate immune response and further suggest the involvement of innate immunity responses in the pathogenesis of post-MI HF.

Aged↗

PubMed2005

Recognition of human cytomegalovirus by human primary immunoglobulins identifies an innate foundation to an adaptive immune response.

Most primates, including humans, are chronically infected with cospecifically evolved, potentially pathogenic CMV. Abs that bind a 10-aa linear epitope (antigenic determinant 2 site 1) within the extracellular domain of human CMV glycoprotein B neutralize viral infectivity. In this study, we show that genes generated by recombinations involving two well-conserved human germline V elements (IGHV3-30 and IGKV3-11), and IGHJ4, encode primary Ig molecules that bind glycoprotein B at this key epitope. These particular V(H), J(H), and V(kappa) genes enable humans to generate through recombination and N nucleotide addition, a useful frequency of primary Igs that efficiently target this critical site on human CMV and thus confer an innate foundation for a specific adaptive response to this pathogen.

Adaptation, Physiological↗

PubMed2006

Peptidoglycan: a major aetiological factor for psoriasis?

Peptidoglycan (PG), a major cell-wall component of Gram-positive bacteria, has been detected within antigen-presenting cells in various inflammatory conditions, including psoriasis. The additional presence of T-helper 1 cells specific for streptococcal or staphylococcal PG in psoriasis skin lesions implicates PG as an important T-cell stimulator for the disease. PG is a major target for the innate immune system, and associations between genetic polymorphisms of recognition receptors for PG and various auto-inflammatory diseases have been identified. The location of these genes within four linkage sites for psoriasis raises the possibility that an altered innate recognition of PG might contribute to the enhanced T-cell response to the bacterial antigen. These observations suggest that PG is a major aetiological factor for psoriasis and emphasize the importance of PG in bacterial-infection-induced inflammatory disease.

Cell Wall↗

PubMed2006

Myeloid C-type lectins in innate immunity.

C-type lectins expressed on myeloid cells comprise a family of proteins that share a common structural motif, and some act as receptors in pathogen recognition. But just as the presence of leucine-rich repeats alone is not sufficient to define a Toll-like receptor, the characterization of C-type lectin receptors in innate immunity requires the identification of accompanying signaling motifs. Here we focus on the known signaling pathways of myeloid C-type lectins and on their possible functions as autonomous activating or inhibitory receptors involved in innate responses to pathogens or self.

Animals↗

PubMed2001

CD14: a bridge between innate immunity and adaptive IgE responses.

Total IgE levels are known to be under genetic control. Linkage studies have indicated that one or more loci on chromosome 5q may control total IgE, as well as asthma and bronchial hyperresponsiveness to non-specific stimuli. Our group has undertaken a systematic analysis of chromosome 5q, and has recently characterized five single nucleotide polymorphisms at position -1619, -1359, -1145, -809, and -159 in the promoter of the gene encoding CD14, the myeloid pattern recognition receptor that is critical for efficient innate immune responses to lipopolysaccharide and bacterial ligands. Individuals homozygous for the three major CD14 haplotypes found in the Children Respiratory Study population (n = 390) were analyzed for serum levels of total IgE and soluble CD14. A strong inverse correlation was found between these two parameters, i.e. carriers of the -1359T/-1145A/-159C haplotype had the highest levels of IgE, and the lowest levels of sCD14. Conversely, carriers of the -1359G/-1145G/-159T haplotype had the highest levels of sCD14 and the lowest IgE values. Our results suggest that genetic variation in CD14, a key gene of innate immunity, may modulate the effects that exposure to bacterial ligands has on the development of Th2 responses.

Child↗

PubMed2004

Toll-like receptors and microbes take aim at each other.

Toll-like receptors (TLRs) are key components of effective innate immunity. As such, pathogenic microorganisms must evade recognition by TLRs, manipulate the consequences of TLR activation, or contend with the inflammatory consequences of TLR activation. Recent studies have improved our understanding of the various mechanisms by which pathogenic organisms manipulate the TLR recognition system.

Animals↗

PubMed2005

Toll-like receptors in innate immunity.

Functional characterization of Toll-like receptors (TLRs) has established that innate immunity is a skillful system that detects invasion of microbial pathogens. Recognition of microbial components by TLRs initiates signal transduction pathways, which triggers expression of genes. These gene products control innate immune responses and further instruct development of antigen-specific acquired immunity. TLR signaling pathways are finely regulated by TIR domain-containing adaptors, such as MyD88, TIRAP/Mal, TRIF and TRAM. Differential utilization of these TIR domain-containing adaptors provides specificity of individual TLR-mediated signaling pathways. Several mechanisms have been elucidated that negatively control TLR signaling pathways, and thereby prevent overactivation of innate immunity leading to fatal immune disorders. The involvement of TLR-mediated pathways in autoimmune and inflammatory diseases has been proposed. Thus, TLR-mediated activation of innate immunity controls not only host defense against pathogens but also immune disorders.

Animals↗

PubMed2004

Genetic basis of natural variation in D. melanogaster antibacterial immunity.

Many genes involved in Drosophila melanogaster innate immune processes have been identified, but whether naturally occurring polymorphism in these genes leads to variation in immune competence among wild flies has not been tested. We report here substantial variability among wild-derived D. melanogaster in the ability to suppress infection by a Gram-negative entomopathogen, Serratia marcescens. Variability in immune competence was significantly associated with nucleotide polymorphism in 16 innate immunity genes, corresponding primarily to pathogen recognition and intracellular signaling loci, and substantial epistasis was detected between intracellular signaling and antimicrobial peptide genes. Variation in these genes, therefore, seems to drive variability in immunocompetence among wild Drosophila.

Alleles↗

PubMed2005

Toll-like receptors: sentinels of host defence against bacterial infection.

Innate immunity provides a first line of host defence against infection through microbial recognition and killing while simultaneously activating a definitive adaptive immune response. Toll-like receptors (TLRs) are principal mediators of rapid microbial recognition and function mainly by detection of structural patterns that do not exist in the host. TLR2 and TLR4 were the first members of this innate immune receptor family to be strongly implicated in antibacterial host defence. Following the initial description of the mammalian TLR family, susceptibility to infection with numerous human microbial pathogens has been intensively studied using mice with engineered deletions of each of these molecules. While it has become quite clear that TLR activation is necessary for optimal host defence, a comprehensive understanding of the mechanisms by which this family of pattern recognition receptors engages protective immunity, particularly the adaptive response, is still evolving.

Adaptor Proteins, Signal Transducing↗

PubMed2002

ML -- a conserved domain involved in innate immunity and lipid metabolism.

ML (MD-2-related lipid-recognition) is a novel domain identified in MD-1, MD-2, GM2A, Npc2 and multiple proteins of unknown function in plants, animals and fungi. These single-domain proteins were predicted to form a beta-rich fold containing multiple strands, and to mediate diverse biological functions through interacting with specific lipids.

Amino Acid Sequence↗

PubMed2002

Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster.

Recognition of bacterial lipopolysaccharide (LPS) by the innate immune system elicits strong pro-inflammatory responses that can eventually cause a fatal sepsis syndrome in humans. LPS-mediated activation of mammalian cells is believed to involve the interaction of LPS with lipopolysaccharide-binding protein (LBP) in the serum and, subsequently with CD14. Although there is no doubt that CD14 binds LPS, CD14 is not capable of initiating a transmembrane activation signal because it is a glycosylphosphatidylinositol (GPI)-anchored protein. Accumulating evidence has suggested that LPS must interact with a transmembrane receptor(s) that is responsible for signal transduction. Integrins CD11c and/or CD18, Toll-like receptors (TLRs), as well as CD55, have been suggested to serve this function. Recently, we have revealed that a signalling complex of receptors is formed following LPS stimulation, which comprises heat-shock proteins (Hsps) 70 and 90, chemokine receptor 4 (CXCR4) and growth differentiation factor 5 (GDF5). Taking into account the discovery of the TLRs and the LPS-activation cluster, we propose a new model of LPS recognition.

Animals↗

PubMed2003

MHC specificity of iIELs.

Intestinal intra-epithelial lymphocytes (iIELs) are a major lymphocyte population, reside in close proximity to the intestinal lumen and are conserved throughout vertebrate evolution. iIELs consist of several unique T-cell phenotypes and express both non-rearranged innate immune receptors and rearranged adaptive immune receptors. The ligands for the innate immune receptors on iIELs, such as NKG2D (natural killer-cell receptor), often bind to non-classical MHC class I molecules, such as the human MHC class I-related molecules MICA or MICB. These ligands costimulate T-cell receptor (TCR)-mediated signaling. In most cases, the MHC molecules that bind to the TCR are still unknown. However, recent efforts to understand the MHC molecules that are involved in the development of and antigen recognition by iIELs have revealed several important results. Here, we focus systematically on recent developments in innate immunity and in TCR recognition of different subtypes of iIELs by various MHC molecules.

Adaptation, Physiological↗

PubMed2004

CpG-DNA as immune response modifier.

Toll-like receptors (TLRs) have been recognized to play a fundamental role in the recognition of microbial pathogens and the activation of innate immunity. However, it has also turned out that triggering of TLRs with purified compounds or synthetic ligands represents a powerful means to modulate innate as well as adaptive immune responses. Among the substances currently under investigation as immune response modifiers CpG-DNA has gained particular interest. One reason for this is the feasibility to easily synthesize and modify immunostimulatory CpG-containing oligodeoxynucleotides (CpG-ODNs). This review deals with the structural needs of CpG-ODNs. CpG-ODNs are discussed as being composed of distinct building blocks (e.g. sequence strings, backbone modifications) giving rise to a concept of structural modules within CpG-ODNs.

Adjuvants, Immunologic↗

PubMed2006

Role of the innate immune system and host-commensal mutualism.

Host organisms live in intimate contact with indigenous microflora. The interactions between the host and commensal microbiota are highly complex and heterogeneous. A growing body of evidence indicates that commensal symbionts provide many benefits to the host physiology, particularly in the gastrointestinal system. The molecular mechanisms of the mutualistic interactions between the host and commensals are largely unknown but can be due either to bioactivity of the commensals or to the reaction of the host immune system to the commensal-derived products. Recent advances in our understanding of the innate immune system allow re-evaluation of some of the older findings regarding the mechanisms of benefits conferred by microflora. Here we review the examples of the benefits of host-commensal interactions that are due to recognition of commensal microbial products by the host innate immune system.

Animals↗

PubMed2005

Innate immunity and organ transplantation: the potential role of toll-like receptors.

Traditionally, the recognition and tolerance of transplanted grafts has been considered to be within the realm of the adaptive immune system. Innate immunity, on the other hand, as the first line of host defense, plays a role in fighting against invading microorganisms. Recently, with the discovery of the Toll-like receptors (TLRs), the role of innate immune responses in the control of adaptive immunity has become a new area of interest. Emerging evidence suggests that in addition to responding to pathogen-associated molecular patterns of microorganisms, TLRs can be activated by endogenous ligands, expressed by mammalian cells. These 'danger signals' may participate in ischemia-reperfusion related organ damage and subsequently influence function and survival of transplanted grafts. Furthermore, it has been suggested that adaptive immune responses can enhance the acute inflammatory responses controlled by innate immunity in organ transplantation. This review addresses the potential involvement of TLRs in different stages of organ transplantation. Intriguing and controversial findings are presented and discussed in order to stimulate more attention to this emerging and potentially important area of research in organ transplantation.

Animals↗