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Results for “Innate Immunity Recognition”

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PubMed2005

Heteroligomeric forms of codon 54 mannose binding lectin (MBL) in circulation demonstrate reduced in vitro function.

Mannose binding lectin (MBL) is a pattern recognition molecule that plays a pivotal role in innate immunity. This liver derived, circulating plasma protein binds organisms displaying high-density carbohydrate structures and flags them for destruction via opsonisation and initiation of the lectin pathway of the complement cascade. The present study reveals native, oligomeric forms of human MBL in plasma from healthy blood donors of differing genotypes and correlates the relative abundance of observed molecular weight species with mannan binding activity and C4 deposition in vitro. Wild type (A/A) individuals demonstrate predominately high molecular weight MBL that correlated with high mannan binding capacity and C4 deposition. A/C individuals demonstrated predominantly low molecular weight MBL with decreased mannan binding and C4 deposition activity. A/D individuals demonstrated both high molecular weight and low molecular weight MBL with reduced mannan binding and C4 deposition predominantly seen in combination with LX promoter. We identified A/B individuals as a unique group with large variation in MBL level, mannan binding activity and C4 deposition and propose a model for C4 deposition based on differential binding of MASP.

Blood Donors↗

PubMed2006

Association of polymorphisms within the promoter region of the tumor necrosis factor-alpha with clinical outcomes of rheumatic fever.

Rheumatic fever (RF)/rheumatic heart disease (RHD) is an inflammatory disease with a complex etiology in which Group A streptococci within a genetically susceptible host untreated for strep-throat may deviate the innate and adaptive arms of the immune system towards recognition of autoantigens. The TNFA gene has been associated with a number of autoimmune diseases, including RF. We investigated whether the G-308A and G-238A polymorphisms of the TNFA gene are associated with clinical outcomes of RF in a cohort of 318 patients and 281 healthy controls (HC). Both polymorphisms showed borderline associations with RF (TNFA -308G/A, OR=1.4 [1-2.2], P=0.026; TNFA -238G/A, OR=1.9 [1-3.3], P=0.015). The presence of either one of the minor alleles (-308A and -238A) was more common among patients with RF/RHD than controls (P=0.0006). Stratification of patients according to clinical phenotype also showed significant associations between presence of either one of the minor alleles and RHD (Pc=0.0006) when compared with controls. This association was stronger with the development of aortic valve lesions. In contrast, there was no association between genotype and Sydenham's chorea or RF patients with mild carditis. In conclusion, we show that the TNFA is a susceptibility locus for RF. The ability to predict which RF patients will develop valve lesion may have therapeutic, economic and social implications.

Adolescent↗

PubMedDate not supplied

Dendritic cells and fungi.

Fungi comprise a group of microorganisms that in the past 20 years has become increasingly important as a cause of human disease. Few fungi are professional but instead opportunistic pathogens, and some fungi can even act as allergens. Dendritic antigen-presenting cells function as a link between innate and adaptive immunity and are therefore important in recognition of pathogens. Effective defense requires the host to discriminate between different pathogens to induce an appropriate response. Signaling from different groups of microbes can be mediated via the Toll-like receptors (TLRs), leading to activation of conserved host defense signaling pathways that control the expression of a variety of immune response genes. Different dendritic cells (DCs) express different patterns of recognition molecules, which indicate that they are more or less efficient when responding to certain pathogens. DCs have an important role in the induction of cell-mediated immune responses to fungi, and the studies reviewed here show that fungi, or possibly fungi-derived factors, provide a powerful activation stimulus to DCs, resulting in DC maturation with upregulation of co-stimulatory molecules and production of cytokine patterns leading to different T cell responses. The possibility of using ex vivo-generated DCs as therapeutic tools for restoring anti-fungal immunity is a challenge for the future.

Antigen Presentation↗

PubMed2006

Protozoan encounters with Toll-like receptor signalling pathways: implications for host parasitism.

Toll-like receptors (TLRs) have emerged as a major receptor family involved in non-self recognition. They have a vital role in triggering innate immunity and orchestrate the acquired immune response during bacterial and viral infection. However, the role of TLRs during infection with protozoan pathogens is less clear. Nevertheless, our understanding of how these parasitic microorganisms engage the host TLR signalling system has now entered a phase of rapid expansion. This Review describes recent insights into how parasitic protozoans are sensed by TLR molecules, and how the TLR system itself can be targeted by these microbial pathogens for their own survival.

Animals↗

PubMed2003

Phosphatidic acid regulates systemic inflammatory responses by modulating the Akt-mammalian target of rapamycin-p70 S6 kinase 1 pathway.

Macrophages are pivotal effector cells in the innate immune system. When microbial products bind to pathogen recognition receptors, macrophages are activated and release a broad array of mediators, such as cytokines, that orchestrate the inflammatory responses of the host. Phosphatidic acid (PA) has been implicated as an important metabolite of phospholipid biosynthesis and in membrane remodeling and has been further suggested to be a crucial second messenger in various cellular signaling events. Here we show that PA is an essential regulator of inflammatory response. Deleterious effects of PA are associated with the secretion of proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and the production of nitric oxide, prostaglandin E2, which are predominantly released by macrophage Raw264.7 cells. Furthermore, the administration of PA to mice increased the serum cytokine level. Moreover, direct or lipopolysaccharide-induced PA accumulation by macrophages led to the Akt-dependent activation of the mammalian target of rapamycin-p70 S6 kinase 1, a process required for the induction of inflammatory mediators. These findings demonstrate the importance of the role of PA in systemic inflammatory responses, and provide a potential usefulness as specific targets for the development of therapies.

Animals↗

PubMed2005

Human airway epithelial cells sense Pseudomonas aeruginosa infection via recognition of flagellin by Toll-like receptor 5.

Pseudomonas aeruginosa, an opportunistic respiratory pathogen that infects the majority of patients with cystic fibrosis, initiates host inflammatory responses through interaction with airway epithelial cells. The Toll-like receptors (TLRs) are a family of pathogen pattern recognition receptors that play key roles in host innate immunity. In this study we aimed to determine whether TLRs mediate the interaction between P. aeruginosa and airway epithelial cells. Individual murine TLRs (TLR1 to TLR9) and dual combinations of these TLRs that activate an NF-kappaB-driven luciferase reporter in response to PAO1 were screened in HEK 293 cells. TLR5, TLR2, a combination of TLR1 and TLR2, or a combination of TLR2 and TLR6 responded to PAO1. Another P. aeruginosa strain, strain PAK, activated TLR5 similarly, while the isogenic flagellin-deficient strain PAK/fliC and the flagellum-free bacterium Haemophilus influenzae failed to activate TLR5. Reverse transcription-PCR was used to probe the presence of multiple TLRs (including TLR5) in primary human airway epithelial cells (HAECs). Immunostaining with TLR5 antibodies showed that TLR5 was expressed in HAECs and on the apical surface of the human trachea epithelium. In HAECs, PAO1, PAK, and Burkholderia cepacia, but not flagellin-deficient strain PAK/fliC or a B. cepacia fliC mutant, activated the NF-kappaB reporter. Dominant negative TLR5 specifically blocked the response to P. aeruginosa but not to the response to lipoteichoic acid, a specific ligand of TLR2. We also determined that MyD88, IRAK, TRAF6, and Toll-interacting protein (Tollip), but not TIRAP, were involved in the TLR-mediated response to P. aeruginosa in HAECs. These findings demonstrate that the airway epithelial receptor TLR5 senses P. aeruginosa through its flagellin protein, which may have an important role in the initiation of the host inflammatory reaction to clear the invading pathogen.

Cell Line↗

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↗

PubMed2006

Toll-like receptor 2 modulates left ventricular function following ischemia-reperfusion injury.

Production of proinflammatory cytokines contributes to cardiac dysfunction during ischemia-reperfusion. The principal mechanism responsible for the induction of this innate stress response during periods of myocardial ischemia-reperfusion remains unknown. Toll-like receptor 2 (TLR2) is a highly conserved pattern recognition receptor that has been implicated in the innate immune response to a variety of pathogens. However, TLR2 may also mediate inflammation in response to noninfectious injury. We therefore hypothesized that TLR2 is essential for modulating myocardial inflammation and left ventricular (LV) function during ischemia-reperfusion injury. Susceptibility to myocardial ischemia-reperfusion injury following ischemia-reperfusion was determined in Langendorff-perfused hearts isolated from wild-type mice and mice deficient in TLR2 (TLR2D) and Toll interleukin receptor domain-containing adaptor protein. After ischemia-reperfusion, contractile performance was significantly impaired in hearts from wild-type mice as demonstrated by a lower recovery of LV developed pressure relative to TLR2D hearts. Creatinine kinase levels were similar in both groups after reperfusion. Contractile dysfunction in wild-type hearts was associated with elevated cardiac levels of TNF and IL-1beta. Ischemia-reperfusion-induced LV dysfunction was reversed by treatment with the recombinant TNF blocking protein etanercept. These studies show for the first time that TLR2 signaling importantly contributes to the LV dysfunction that occurs following ischemia-reperfusion. Thus disruption of TLR2-mediated signaling may be helpful to induce immediate or delayed myocardial protection from ischemia-reperfusion injury.

Animals↗

PubMed2006

[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↗

PubMed2003

Identification of antigenic epitopes on human allergens: studies with HLA transgenic mice.

Environmental factors play an important role in the rise and manifestation of allergic conditions in genetically predisposed subjects. Increased exposure to indoor/outdoor allergens is a significant factor in the development of allergic sensitization and asthma. Recently, strong relationships between the immune response to several highly purified allergens and specific human leukocyte antigen (HLA)-DQ and -DR haplotypes have been reported. The major antigens from clinically important allergens have been cloned and sequenced. However, whether innate structural features of major allergens or peculiar immune recognition of these molecules contribute to the overly robust immune responses is not known. We generated and used transgenic (tg) mice expressing single HLA class II transgene(s) to characterize the allergen epitopes presented by particular HLA class II molecules. Next, we generated in vivo models for asthma in the HLA tg mice by intranasal challenge with allergenic extracts. Furthermore, we used a single epitope to induce an allergic lung inflammation. Our system offers a sophisticated technique for systematically identifying the genetic (individual human class II) and antigenic (individual allergenic epitopes) basis of asthma sensitivity and has important implications for new treatment strategies.

Allergens↗

PubMed2002

Interactions of oral pathogens with toll-like receptors: possible role in atherosclerosis.

Toll-like receptors (TLR) function as important signal transducers that mediate innate immune and inflammatory responses to pathogens through pattern recognition of virulence molecules. Although TLRs mediate protection against infection, it is also likely that they may have a pathophysiologic role in certain inflammatory diseases, such as atherosclerosis. In atherosclerotic lesions, endothelial cells and macrophages have been shown to upregulate TLR expression and may respond to TLR agonists of microbial origin, resulting in detrimental inflammatory reactions. Some of these potential TLR-activating virulence factors may be of oral origin. The detection in atherosclerotic plaques of DNA specific for Porphyromonas gingivalis and other periodontal pathogens suggests that these pathogens disseminate into the systemic circulation and localize in atheromas. The potential of periodontal and some other oral pathogens to activate TLRs in vivo is suggested by findings from cell culture experiments on interactions of selected virulence protein adhesins with TLRs and their coreceptors. Specifically, we have shown that proinflammatory cytokine induction by P. gingivalis fimbriae was inhibited by monoclonal antibodies to TLR2, TLR4, CD14, and beta2 integrins, but not by immunoglobulin isotype controls. Cytokine induction by Bacteroides forsythus protein A depended heavily on CD14 and TLR2. We also found that the ability of Streptococcus mutans protein AgI/II to stimulate cytokine release was partially dependent on CD14 and TLR4. Moreover, P. gingivalis fimbriae induced TLR-dependent activation of nuclear factor-kappaB and upregulation of costimulatory molecules in monocytic cells. These proinflammatory activities have been implicated in the pathogenesis of periodontitis, and similar inflammatory mechanisms could potentially operate in atherosclerosis. Studies by other groups have shown that P. gingivalis is capable of stimulating low-density lipoprotein oxidation, foam cell formation, and rupture of atherosclerotic plaque through induction of matrix metalloproteinases. Interestingly, at least some of these activities can be induced by TLR agonists (lipopolysaccharide and heat-shock protein-60) from Chlamydia pneumoniae, a major risk factor in atherosclerosis. Future research in animal models and in vitro cellular systems with defined mutations in TLRs may implicate TLR participation in oral pathogen-mediated atherosclerotic processes, thereby providing a mechanistic basis for the epidemiological findings linking oral pathogens to atherosclerotic disease.

Arteriosclerosis↗

PubMed2002

Blebs and apoptotic bodies are B cell autoantigens.

Mounting evidence suggests that systemic lupus erythematosus autoantigens are derived from apoptotic cells. To characterize the potential interactions between apoptotic cells and B cells, the D56R/S76R variant of 3H9, a murine autoantibody that binds to DNA, chromatin, and anionic phospholipids, was compared with DNA4/1, a human anti-DNA autoantibody. Flow cytometry revealed that only D56R/S76R bound to Jurkat cells treated with either of three distinct proapoptotic stimuli, Ab binding was dependent on caspase activity, and immunoreactivity developed subsequent to annexin V binding. Confocal microscopy established a structural basis for the distinct kinetics of binding. D56R/S76R preferentially bound to membrane blebs of apoptotic cells, whereas annexin V binding did not require blebs. Inhibition of ROCK I kinase, an enzyme that stimulates nuclear fragmentation and fragment distribution into blebs, significantly reduced Ab binding. Because members of the collectin and pentraxin families of serum proteins bind to blebs on apoptotic cells and assist in the clearance of cellular remains, our results suggest that Abs to blebs could affect the recognition of apoptotic cells by cells of the innate immune system and thus modify tolerance to nuclear Ags.

Apoptosis↗

PubMed2006

Deficiency of mannose-binding lectin greatly increases susceptibility to postburn infection with Pseudomonas aeruginosa.

Burn injury disrupts the mechanical and biological barrier that the skin presents against infection by symbionts like the Pseudomonas aeruginosa, a Gram-negative bacteria. A combination of local factors, antimicrobial peptides, and resident effector cells form the initial response to mechanical injury of the skin. This activity is followed by an inflammatory response that includes influx of phagocytes and serum factors, such as complement and mannose-binding lectin (MBL), which is a broad-spectrum pattern recognition molecule that plays a key role in innate immunity. A growing consensus from studies in humans and mice suggests that lack of MBL together with other comorbid factors predisposes the host to infection. In this study we examined whether MBL deficiency increases the risk of P. aeruginosa infection in a burned host. We found that both wild-type and MBL null mice were resistant to a 5% total body surface area burn alone or s.c. infection with P. aeruginosa alone. However, when mice were burned then inoculated s.c. with P. aeruginosa at the burn site, all MBL null mice died by 42 h from septicemia, whereas only one-third of wild-type mice succumbed (p = 0.0005). This result indicates that MBL plays a key role in containing and preventing a systemic spread of P. aeruginosa infection following burn injury and suggests that MBL deficiency in humans maybe a premorbid variable in the predisposition to infection in burn victims.

Animals↗

PubMed2006

Differences in innate immune responses upon stimulation with gram-positive and gram-negative bacteria.

BACKGROUND AND OBJECTIVES: Host recognition pathways for gram-negative and gram-positive bacteria comprise pattern recognition receptors among which Toll-like receptors (TLRs) play a pivotal role. TLRs share common signaling pathways yet exhibit specificity as well. Periodontal disease is initiated and maintained in the first line by gram-negative but also gram-positive bacterial infection of the gingival sulcus. To date only limited information is available on whether gram-positive and gram-negative bacteria induce different host responses (strength or quality). MATERIALS AND METHODS: To elucidate these differential effects we focused on proinflammatory cytokine releases by assessing ex vivo stimulation of whole blood with heat-killed gram-negative and gram-positive bacteria and thereof derived microbial products associated with distinct TLRs. Tumor necrosis factor-alpha and interleukin-8 release were measured in the supernatants by enzyme-linked immunosorbent assay. In addition, innate immune responses of peritoneal macrophages from mice lacking TLR2 and TLR4 were tested. RESULTS: We observed that gram-negative and gram-positive species induced distinct patterns of cytokine production. Gram-negative species produced higher amounts of tumor necrosis factor-alpha while gram-positive species released higher amounts of the chemokine interleukin-8. Data from TLR knockout mice and TLR-transfected HEK cells revealed a somehow specific role of TLR4 and TLR2 for the recognition of gram-negative and gram-positive bacteria, respectively, an observation that goes along with the dominant recognition of the respective pathogen associated molecular patterns lipopolysaccharide and lipoteichoic acid. CONCLUSIONS: The results show that gram-negative and gram-positive bacterial species induce different patterns of immunoregulatory activity, which might be the result of activation of different TLRs.

Animals↗

PubMed2006

Innate immunity in plants: a continuum of layered defenses.

Plant responses to pathogenic invaders result from recognition of nonself elicitors. Host surveillance proteins activate distinct signaling pathways that induce partially overlapping defensive responses. Pathogen virulence is promoted by inhibition of these pathways. This evolutionary struggle has produced plant immune systems that rely on a continuum of layered defenses.

Bacteria↗

PubMed2000

The role of CpG motifs in immunostimulation and gene therapy.

The mammalian immune system has evolved mechanisms to recognize and respond to 'danger' signals arising from pathogens. Among those danger signals are the unmethylated CpG dinucleotide motifs found in bacteria. At least some of the recognition of these sequences is through cellular components of the innate immune system, such as macrophages. Cytokines released by these cells in response to CpG motifs in turn activate other immune cells, such as NK cells and T cells, and can drive the development of adaptive immune responses. These proinflammatory, Th1 responses can also be generated intentionally with small oligodeoxynucleotides containing stimulatory CpG motifs, and have beneficial properties as vaccine adjuvants and in cancer immunotherapy. These proinflammatory responses have also been seen in gene therapy applications, especially in systemic delivery systems in which plasmid DNA vectors have been introduced with a vehicle such as a cationic lipid. For many gene therapy applications, finding ways to counter the immunostimulatory properties of plasmid DNA vectors is an important approach designed to enhance the vector safety profile, thereby increasing its effective therapeutic index.

B-Lymphocytes↗

PubMed2005

Role of macrophage apoptosis in the pathogenesis of Yersinia.

Yersinia species that are pathogenic for humans (Yersinia pestis, Yersinia pseudotuberculosis, and Yersinia enterocolitica) induce apoptosis in macrophages. Yersinia-induced apoptosis utilizes the mitochondrial pathway and is executed by activation of caspase cascades. The mechanism of Yersinia-induced apoptosis in macrophages has two essential components. One component is the innate immune response of macrophages to the pathogen, which leads to the activation of a survival response and a death response. Recognition of the bacterial cell envelope component lipopolysaccharide by Toll-like receptor 4 (TLR4) constitutes an important part of the innate immune response to the pathogen. The second essential component is YopJ, a protein secreted into Yersinia-infected macrophages via a bacterial type III secretion system, which selectively shuts down the survival pathway. In the absence of the survival pathway, the death pathway is executed, and Yersinia-infected macrophages undergo apoptosis. In this review, we introduce the basic features of Yersinia pathogenesis, summarize our current understanding of Yersinia-induced apoptosis, and discuss the role of apoptosis during Yersinia infection.

Apoptosis↗

PubMed2005

Bruton's Tyrosine Kinase is involved in innate and adaptive immunity.

Btk is a cytoplasmic tyrosine kinase, which is mainly involved in B cell receptor signalling. Gene targeting experiments revealed that Btk is important for B cell development and function. However, Btk is not only expressed in B cells, but also in most other haematopoietic lineages except for T cells and plasma cells. Recently we found that Btk is involved in Toll-like receptor signalling. Toll-like receptors play an important role in innate immunity. They are highly expressed on mast cells, macrophages and dendritic cells, which are essential for the recognition and consequently for the elimination of microbial pathogens. Therefore Btk might play an important role for the function of immunocompetent cells of innate as well as adaptive immunity.

Agammaglobulinaemia Tyrosine Kinase↗