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Results for “Immunity, Innate”

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PubMed2005

Infection of human endothelial cells with Staphylococcus aureus induces transcription of genes encoding an innate immunity response.

Staphylococcus aureus is a gram-positive bacterium frequently isolated from patients with bloodstream infections. Endothelial cells (EC) play an important role in host defence against bacteria, and recent reports have shown that infection of EC with S. aureus induces expression of cytokines and cell surface receptors involved in activating the innate immune response. The ability of S. aureus to invade nonphagocytic cells, including EC, has been documented. However, the knowledge of the role of EC in pathogenesis of S. aureus infection is still limited. In this study, we investigate the gene-expression program in human EC initiated by internalized S. aureus, using microarray analysis. We found 156 genes that were differentially regulated at least threefold, using arrays representing 14,239 genes. Many of the upregulated genes code for proteins involved in innate immunity, such as cytokines, chemokines and cell adhesion proteins. Other upregulated genes encode proteins involved in antigen presentation, cell signalling and metabolism. Furthermore, intracellular bacteria survived for days without inducing EC death.

Cell Adhesion Molecules↗

PubMed2005

Links between the innate immune system and sleep.

Sleep is a fundamental physiologic process with unknown functions. It is divided into 2 distinct states: non-rapid-eye-movement sleep and rapid-eye-movement sleep. After acute infection with nonneurotropic agents, there are stereotypic changes in non-rapid-eye-movement sleep, particularly increased time spent in slow-wave sleep, and often a reduction of time spent in rapid-eye-movement sleep. It is now recognized that both infection-associated sleep and spontaneous sleep are regulated, in part, by immune mediators called cytokines. This review provides brief tutorials on the elements of the innate immune system that detect infection, how sleep is characterized in the laboratory, issues regarding the interpretation of sleep effects on immune function, the interaction of sleep with circadian rhythms and stress, and some of the microbial products, cytokines, and neuropeptides associated with sleep regulation. We also summarize our current understanding of the role of sleep in host defense and asthma exacerbation.

Acute-Phase Reaction↗

PubMed2005

The involvement of the macrophage mannose receptor in the innate immune response to infection with parasite Trichinella spiralis.

The macrophage mannose receptor (MR) is a pattern recognition receptor of the innate immune system that binds to microbial structures bearing mannose, fucose and N-acetylglucosamine on their surface. The MR can mediate endocytosis and phagocytosis, as well as activation of macrophages and antigen presentation. Since Trichinella spiralis antigens are rich in oligomannose residues, we investigated whether a mannose-recognizing receptor, such as the MR, participated in the host-parasite interaction. The results show that the MR (either on the surface of macrophages or in the purified form) recognizes and binds components of T. spiralis muscle larvae. The presence of parasites provoked activation of peritoneal macrophages, which was indicated by down-regulation of MR expression, and the stimulation of NO secretion. In vitro stimulation of macrophages with T. spiralis components resulted in increased NO and IL-6 production. However, while the MR was partially involved in stimulation of NO production, it did not mediate IL-6 secretion.

Animals↗

PubMed2006

The innate immune system 'puzzle'.

Detecting pathogen invasion and regulating homeostatic processes are two essential functions of myriad non-Toll-like innate immune proteins.

Animals↗

PubMed2004

Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and gammadelta T cells.

Few studies have demonstrated that innate lymphocytes play a major role in preventing spontaneous tumor formation. We evaluated the development of spontaneous tumors in mice lacking beta-2 microglobulin (beta2m; and thus MHC class I, CD1d, and CD16) and/or perforin, since these tumor cells would be expected to activate innate effector cells. Approximately half the cohort of perforin gene-targeted mice succumbed to spontaneous disseminated B cell lymphomas and in mice that also lacked beta2m, the lymphomas developed earlier (by more than 100 d) and with greater incidence (84%). B cell lymphomas from perforin/beta2m gene-targeted mice effectively primed cell-mediated cytotoxicity and perforin, but not IFN-gamma, IL-12, or IL-18, was absolutely essential for tumor rejection. Activated NK1.1+ and gammadeltaTCR+ T cells were abundant at the tumor site, and transplanted tumors were strongly rejected by either, or both, of these cell types. Blockade of a number of different known costimulatory pathways failed to prevent tumor rejection. These results reflect a critical role for NK cells and gammadeltaTCR+ T cells in innate immune surveillance of B cell lymphomas, mediated by as yet undetermined pathway(s) of tumor recognition.

Animals↗

PubMed2006

Mannose-binding lectin in innate immunity: past, present and future.

The human collectin, mannose-binding lectin (MBL), is an important protein of the humoral innate immune system. With multiple carbohydrate-recognition domains, it is able to bind to sugar groups displayed on the surfaces of a wide range of microorganisms and thereby provide first-line defence. Importantly, it also activates the complement system through a distinctive third pathway, independent of both antibody and the C1 complex. Three single point mutations in exon 1 of the expressed human MBL-2 gene appear to impair the generation of functional oligomers. Such deficiencies of functional protein are common in certain populations, e.g. in sub-Saharan Africa, but virtually absent in others, e.g. indigenous Australians. MBL disease association studies have been a fruitful area of research and implicate a role for MBL in infective, inflammatory and autoimmune disease processes. Overall, there appears to be a genetic balance in which individuals generally benefit from high levels of the protein. However, in certain situations, reduced levels of circulating MBL may be beneficial to the host and this may explain the persistence of the deleterious gene polymorphisms in many population groups.

Complement C1↗

PubMed2004

A regulatory role for complement in innate immunity and autoimmunity.

The complement system comprises a strong defense against various pathogens and is a major component of our innate immune system. While earlier studies have established a crucial role of complement in recognition, opsonization and enhanced phagocytosis of microorganisms by professional phagocytes such as polymorphonuclear leukocytes and macrophages, recent studies delineate an additional role of complement in initiation and maintenance of the acquired immune response. In addition, it seems that opsonization of apoptotic cells by complement may lead to polarization of the response of professional antigen-presenting cells to a more inflammatory or tolerogenic response. The present review summarizes these different contributions of complement to the shaping of the immune balance.

Autoimmunity↗

PubMed2002

Systemic inflammation and innate immune response in patients with previous anterior uveitis.

AIM: To determine the presence of systemic inflammation and innate immune responsiveness of patients with a history of acute anterior uveitis but no signs of ocular inflammation at the time of recruitment. METHODS: Tumour necrosis factor alpha (TNF-alpha) production in response to bacterial lipopolysaccharide (LPS) was studied using whole blood culture assay; levels of TNF-alpha in culture supernatants, and soluble interleukin 2 receptor (sIL-2R) in serum were determined by chemiluminescent immunoassay (Immulite); monocyte surface expression of CD11b, CD14, and CD16 and the proportion of monocyte subsets CD14(bright)CD16(-) and CD14(dim)CD16(+) were studied with three colour whole blood flow cytometry; and serum C reactive protein (CRP) levels were determined using immunonephelometric high sensitivity CRP assay. RESULTS: The CRP level (median, interquartile range) was significantly higher in 56 patients with previous uveitis than in 37 controls (1.59 (0.63 to 3.47) microg/ml v 0.81 (0.32 to 2.09) microg/ml; p=0.008). The TNF-alpha concentration of the culture media per 10(5) monocytes was significantly higher in the patient group than in the control group in the presence of LPS 10 ng/ml (1473 (1193 to 2024) pg/ml v 1320 (935 to 1555) pg/ml; p=0.012) and LPS 1000 ng/ml (3280 (2709 to 4418) pg/ml v 2910 (2313 to 3358) pg/ml; p=0.011). The background TNF-alpha release into the culture media was low in both groups. CD14 expression of CD14(bright)CD16(-) monocytes, defined as antibody binding capacity (ABC), was similar for the patients and controls (22,839 (21,038 to 26,020) ABC v 21,657 (19,854 to 25,646) ABC). CONCLUSIONS: Patients with previous acute anterior uveitis show high innate immune responsiveness that may play a part in the development of ocular inflammation.

Adult↗

PubMed2004

Self-reactivity in thymic double-positive cells commits cells to a CD8 alpha alpha lineage with characteristics of innate immune cells.

Thymocytes displaying self-reactive T cell receptors usually undergo negative selection in the thymus. Here we demonstrate that agonist peptides can promote positive selection of immature double-positive thymocytes into distinct lineages, varying with the agonist concentration and the animal's age. Microarray gene expression analyses showed broad transcriptional alterations in a set of transcripts associated with the innate immune system, as well as silencing of CD8 beta expression. The resulting CD8 alpha alpha T cells showed a rapid effector cytokine response. Hence, T cells displaying self-reactive receptors can have the gene expression profile and phenotypic characteristics of innate immune cells.

Animals↗

PubMed2004

Antimicrobial activity of innate immune molecules against Streptococcus pneumoniae, Moraxella catarrhalis and nontypeable Haemophilus influenzae.

BACKGROUND: Despite its direct connection to the nasopharynx which harbors otitis media pathogens as part of its normal flora, the middle ear cavity is kept free of these bacteria by as yet unknown mechanisms. Respiratory mucosal epithelia, including those of the middle ear and eustachian tube, secrete antimicrobial effectors including lysozyme, lactoferrin and beta defensins-1 and -2. To elucidate the role of these innate immune molecules in the normal defense and maintenance of sterility of respiratory mucosa such as that of the middle ear, we assessed their effect on the respiratory pathogens nontypeable Haemophilus influenzae (NTHi) 12, Moraxella catarrhalis 035E, and Streptococcus pneumoniae 3, and 6B. METHODS: Two assay methods, the radial assay and the liquid broth assay, were employed for testing the antimicrobial activity of the molecules. This was done in order to minimize the possibility that the observed effects were artifacts of any single assay system employed. Also, transmission electron microscopy (TEM) was employed to evaluate the effect of antimicrobial innate immune molecules on OM pathogens. For the statistical analysis of the data, Student's t-test was performed. RESULTS: Results of the radial diffusion assay showed that beta defensin-2 was active against all four OM pathogens tested, while treatment with beta defensin-1 appeared to only affect M. catarrhalis. The radial assay results also showed that lysozyme was quite effective against S. pneumoniae 3 and 6B and was partially bacteriostatic/bactericidal against M. catarrhalis. Lysozyme however, appeared not to affect the growth of NTHi. Thus, lysozyme seems to have a more pronounced impact on the growth of the Gram-positive S. pneumoniae as compared to that of Gram-negative pathogens. Lactoferrin on the other hand, enhanced the growth of the bacteria tested. The results of the radial assays were confirmed using liquid broth assays for antimicrobial activity, and showed that lysozyme and beta defensin-2 could act synergistically against S. pneumoniae 6B. Moreover, in the liquid broth assay, beta defensin-1 showed a modest inhibitory effect on the growth of S. pneumoniae 6B. As assessed by ultrastructural analysis, lysozyme and beta defensin-2, and to a much lesser extent, beta defensin-1, appeared to be able to cause damage to the bacterial membranes. CONCLUSIONS: Here we report that lysozyme and the beta defensins can inhibit the growth of clinical isolates of otitis media pathogens - namely NTHi strain 12, S. pneumoniae strains 3 and 6B and M. catarrhalis strain 035E - and cause ultrastructural damage to these pathogens. Moreover, we demonstrate that lysozyme and beta defensin-2 can act synergistically against S. pneumoniae. These findings are consistent with the concept that secreted antimicrobial peptides and other components of innate immunity constitute the first line of defense protecting host mucosal surfaces, including the tubotympanal (eustachian tube and middle ear cavity) mucosa, against pathogens.

Anti-Infective Agents↗

PubMed2006

Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: role of the innate immune response in Celiac disease.

Recent studies have demonstrated the importance of TLR signaling in intestinal homeostasis. Celiac disease (CD) is an autoimmune enteropathy triggered in susceptible individuals by the ingestion of gliadin-containing grains. In this study, we sought to test the hypothesis that gliadin initiates this response by stimulating the innate immune response to increase intestinal permeability and by up-regulating macrophage proinflammatory gene expression and cytokine production. To this end, intestinal permeability and the release of zonulin (an endogenous mediator of gut permeability) in vitro, as well as proinflammatory gene expression and cytokine release by primary murine macrophage cultures, were measured. Gliadin and its peptide derivatives, 33-mer and p31-43, were found to be potent inducers of both a zonulin-dependent increase in intestinal permeability and macrophage proinflammatory gene expression and cytokine secretion. Gliadin-induced zonulin release, increased intestinal permeability, and cytokine production were dependent on myeloid differentiation factor 88 (MyD88), a key adapter molecule in the TLR/IL-1R signaling pathways, but were neither TLR2- nor TLR4-dependent. Our data support the following model for the innate immune response to gliadin in the initiation of CD. Gliadin interaction with the intestinal epithelium increases intestinal permeability through the MyD88-dependent release of zonulin that, in turn, enables paracellular translocation of gliadin and its subsequent interaction with macrophages within the intestinal submucosa. There, the interaction of gliadin with macrophages elicits a MyD88-dependent proinflammatory cytokine milieu that facilitates the interaction of T cells with APCs, leading ultimately to the Ag-specific adaptive immune response seen in patients with CD.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Toll and Toll-9 in Drosophila innate immune response.

In both insects and mammals, members of the Toll receptor family play important roles in the initial events leading to the activation of immunity genes. The prototypic Toll in Drosophila appears to be activated by a host protein ligand after microbial stimulation. The cellular events and the biological response after Toll activation, however, require further investigation. We used transgenic Drosophila strains expressing NF-kappaB and Toll proteins to investigate innate immune response in whole larvae and dissected larval fat bodies. Substantial activation of antimicrobial peptide genes was observed after septic injury. To circumvent the contribution of injury-induced response, we used dissected larval fat bodies to show that commercially available microbial compounds were able to alter the cellular distribution of Toll. The results also demonstrate that complex cellular events, including receptor trafficking, likely take place after stimulation of the larval immune tissue. By genome-wide expression analysis, we further show that Toll and Toll-9 may utilize the same signaling pathway in activating many immunity genes. Thus, the innate immune response in Drosophila is regulated by complex mechanisms, which involve Toll and other Toll-related proteins.

Animals↗

PubMedDate not supplied

Eicosanoid regulation of pulmonary innate immunity post-hematopoietic stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) is a therapeutic option for a number of malignant and inherited disorders. However, the efficacy of this therapy is limited by a number of serious infectious and noninfectious complications. Pulmonary infections represent a significant cause of morbidity and mortality post-HSCT and can occur both pre- and post-hematopoietic reconstitution. Susceptibility to Gram-negative bacterial infections despite full hematopoietic engraftment suggests that innate immunity remains impaired months to years post-HSCT. This review will describe the process and complications of HSCT and will summarize what is known about innate immune reconstitution post-HSCT. Data from the literature as well as our own laboratory will be presented to suggest that an eicosanoid imbalance characterized by over-production of prostaglandins and under-production of leukotrienes leads to impaired lung phagocyte function post-HSCT. Of therapeutic interest, strategies which limit production of prostaglandins can improve pulmonary host defense in animal HSCT models, which suggests that this may also be beneficial for human HSCT recipients.

Animals↗

PubMed2006

[Contribution of dectin-1 to the recognition of fungal cell wall products and the activation of innate immune response].

1,3-Beta-glucans is a major cell wall component in fungi. Receptor molecules relating to innate immunity may recognize such cell wall products, and affect host defense systems. A beta-glucan receptor, dectin-1, is a C-type lectin and may contribute to the innate immune responses. To examine the role of dectin-1 in recognition of 1,3-beta-glucans and subsequent activation of intracellular signaling, the molecular characteristics of a carbohydrate recognition domain (CRD) of dectin-1 were investigated. The binding ability to beta-glucans was abolished by mutating two amino acid residues, Trp221 and His223, on the CRD. Dectin-1 increased TLR2-mediated NF-kappaB activation in response to zymosan. However, dectin-1 alone could not affect the activation pathway for NF-kappaB, nor did co-expression of dectin-1 mutant and TLR2 increase the NF-kappaB activation. These results suggest that dectin-1 may have a co-stimulatory effect on leukocyte activation in response to fungal infection.

Candida↗

PubMed2003

Induction of innate immunity by IL-2-expressing Salmonella confers protection against lethal infection.

Previously, we demonstrated that an attenuated Salmonella strain expressing IL-2 (designated GIDIL2) is cleared from the circulation at a much faster rate than the non-cytokine-expressing parental strain (designated BRD509). These findings suggested that IL-2 expression led to the rapid induction of innate immune responses that, in turn, accounted for the accelerated rate of bacterial clearance. In the present study, the mechanism by which this early antibacterial response is mediated was investigated. We demonstrate that as early as 2 h after infection with GIDIL2, but not BRD509, peritoneal excudate cells exhibited enhanced NK cytotoxic activity and upregulated NOS2 mRNA and NO production. This early response coincided with an enhancement of GIDIL2 clearance from the peritoneal cavity, first evidenced 22 h post-infection. Moreover, it conferred a high level of protection against virulent Salmonella challenge given within 16-20 h of GIDIL2 administration. These findings highlight the importance of innate immunity in the control of early bacterial proliferation and demonstrate the rapidity by which these responses are induced following bacterial entry.

Animals↗

PubMed2002

Evolution of the lectin-complement pathway and its role in innate immunity.

Discrimination between self and non-self by lectins (carbohydrate-binding proteins) is a strategy of innate immunity that is found in both vertebrates and invertebrates. In vertebrates, immune recognition mediated by ficolins (lectins that consist of a fibrinogen-like and a collagen-like domain), as well as by mannose-binding lectins, triggers the activation of the complement system, which results in the activation of novel serine proteases. The presence of a similar lectin-based complement system in ascidians, our closest invertebrate relatives, indicates that the complement system probably had a pivotal role in innate immunity before the evolution of an adaptive immune system in jawed vertebrates.

Animals↗

PubMed2005

Limiting inflammatory responses during activation of innate immunity.

The idea of the importance of mounting an inflammatory response for effective immunity is supported by a multiplicity of experimental data. It is also well understood that resolution of inflammation is essential for maintaining the balance between health and disease. When the normal regulatory mechanisms are disturbed, the potential for developing chronic inflammatory diseases is increased. Inflammation is a key element in the response of the innate immune system to a variety of challenges, including those provided by bacterial and viral infection as well as by damaged or dying host cells. Here we review elements of innate immunity that lead to inflammation and some of the host mechanisms that allow for the resolution of the inflammatory responses.

Animals↗

PubMed2006

Innate immunity in triggering and resolution of acute gouty inflammation.

Gout has long been recognized as a disease of recurrent bouts of acute inflammation that undergo self-resolution. This inflammation is triggered by the body's response to monosodium urate (MSU) crystals. In this paper, we focus on recent studies that describe how interactions of MSU crystals with the components of the innate immune system trigger acute gouty inflammation as well as mechanisms that are involved in the resolution of this inflammation. Specifically, we describe how toll-like receptors mediate the uptake of MSU crystals involved in the initiation and resolution of gouty inflammation. We also describe recent findings on the role of apoptotic clearance in the resolution of gouty inflammation. In addition, how therapies used to treat gout act on the innate immune system to inhibit MSU crystal-induced inflammation and promote the resolution of inflammation is discussed.

Acute Disease↗