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Results for “Innate Immunity Recognition”

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PubMed2006

Cancer despite immunosurveillance: immunoselection and immunosubversion.

Numerous innate and adaptive immune effector cells and molecules participate in the recognition and destruction of cancer cells, a process that is known as cancer immunosurveillance. But cancer cells avoid such immunosurveillance through the outgrowth of poorly immunogenic tumour-cell variants (immunoselection) and through subversion of the immune system (immunosubversion). At the early stages of carcinogenesis, cell-intrinsic barriers to tumour development seem to be associated with stimulation of an active antitumour immune response, whereas overt tumour development seems to correlate with changes in the immunogenic properties of tumour cells. The permanent success of treatments for cancer might depend on using immunogenic chemotherapy to re-establish antitumour immune responses.

Animals↗

PubMed2005

IL-32 synergizes with nucleotide oligomerization domain (NOD) 1 and NOD2 ligands for IL-1beta and IL-6 production through a caspase 1-dependent mechanism.

The activation of innate immunity requires the amplification of signals induced by pattern-recognition receptors for bacterial products. We have investigated the role of the newly described cytokine IL-32 in the amplification of cytokine production induced by the two most clinically relevant families of microbial receptors, the cell-surface Toll-like receptors (TLRs) and the intracellular nuclear oligomerization domain (NOD) receptor family. IL-32 synergized with the NOD1- and NOD2-specific muropeptides of peptidoglycans for the release of IL-1beta and IL-6 (a 3- to 10-fold increase). In contrast, IL-32 did not influence the cytokine production induced via TLRs. The synergistic effect of IL-32 and synthetic muramyl dipeptide (MDP) on cytokine production was absent in the cells of patients with Crohn's disease bearing the NOD2 frameshift mutation 3020insC, demonstrating that the IL-32/MDP synergism depends on NOD2. This in vitro synergism between IL-32 and NOD2 ligands was consistent with a marked constitutive expression of IL-32 in human colon epithelial tissue. In addition, the potentiating effect of IL-32 on the cytokine production induced by the synthetic muropeptide FK-156 was absent in NOD1-deficient macrophages, supporting the interaction between IL-32 and NOD1 pathways. When specific caspase inhibitors were used, the synergism between IL-32 and MDP/NOD2 depended on the activation of caspase 1. Only additive effects of IL-32 and muropeptides were observed for TNF-alpha production. The modulation of intracellular NOD2 pathways by IL-32, but not cell-surface TLRs, and the marked expression of IL-32 in colon mucosa suggest a role of IL-32 in the pathogenesis of Crohn's disease.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed2002

Glucocorticoids synergistically enhance nontypeable Haemophilus influenzae-induced Toll-like receptor 2 expression via a negative cross-talk with p38 MAP kinase.

The recognition of invading microbes followed by the induction of effective innate immune response is crucial for host survival. Human surface epithelial cells are situated at host-environment boundaries and thus act as the first line of host defense against invading microbes. They recognize the microbial ligands via Toll-like receptors (TLRs) expressed on the surface of epithelial cells. TLR2 has gained importance as a major receptor for a variety of microbial ligands. In contrast to its high expression in lymphoid tissues, TLR2 is expressed at low level in epithelial cells. Thus, it remains unclear whether the low amount of TLR2 expressed in epithelial cells is sufficient for mediating bacteria-induced host defense and immune response and whether TLR2 expression can be up-regulated by bacteria during infection. Here, we show that TLR2, although expressed at very low level in unstimulated human epithelial cells, is greatly up-regulated by nontypeable Hemophilus influenzae (NTHi), an important human bacterial pathogen causing otitis media and chronic obstructive pulmonary diseases. Activation of an IKKbeta-IkappaBalpha-dependent NF-kappaB pathway is required for TLR2 induction, whereas inhibition of the MKK3/6-p38alpha/beta pathway leads to enhancement of NTHi-induced TLR2 up-regulation. Surprisingly, glucocorticoids, well known potent anti-inflammatory agents, synergistically enhance NTHi-induced TLR2 up-regulation likely via a negative cross-talk with the p38 MAP kinase pathway. These studies may bring new insights into the role of bacteria and glucocorticoids in regulating host defense and immune response and lead to novel therapeutic strategies for modulating innate immune and inflammatory responses for otitis media and chronic obstructive pulmonary diseases.

Bacterial Proteins↗

PubMed2003

Selective induction of matrix metalloproteinases by Borrelia burgdorferi via toll-like receptor 2 in monocytes.

Regulation of secretion of matrix metalloproteinase (MMP) underlies the basis of numerous physiological and pathological processes in multicellular organisms. The Toll receptor family, which is conserved from Drosophila species to humans, mediates pattern recognition of a diversity of ligands involved in morphogenesis and innate immunity. Here, we show that secretion of MMP-9 is selectively induced through Toll-like receptor (TLR) 2 in human and murine monocytic cells stimulated with Borrelia burgdorferi. Secretion of MMP-1 was shown to be stimulated through a pathway other than TLR2, under identical conditions. Analysis of nuclear extracts indicated that activator protein (AP)-1 was reduced in TLR2-neutralized monocytic cells, suggesting that AP-1 plays a role in the transcriptional activation of MMP-9 through TLR2. The specific induction of MMP-9 through TLR2 provides direct evidence of a new role for this ancient receptor family in regulating secretion of MMPs and demonstrates evolutionary convergence between invertebrate morphogenesis and the vertebrate innate immune system.

Animals↗

PubMed2003

Control of filarial infections: not the beginning of the end, but more research is needed.

PURPOSE OF REVIEW: Infections with the filarial nematodes affect more than 150 million people mainly in the tropics. The very successful efforts to control filarial infections, however, have to be sustained by new tools that require long-term commitment to research. This review, focusing on reports from 2002 and 2003, highlights recent advances in research on immunology, understanding of pathogenesis and drug development in lymphatic filariasis and onchocerciasis research with potential relevance to the generation of new tools for control. RECENT FINDINGS: Dramatic improvement has been achieved in the control of lymphatic filariasis and onchocerciasis by vector control and mass treatment with microfilaricidal drugs. Additional tools that could help in regional elimination or, ultimately, eradication of filariasis may arise from the development of new drugs or a vaccine. Research into the immune responses mediating protection or pathology has provided new insights into the pathways that lead to effector function and immunosuppression, such as T regulatory responses, as well as into genetic predispositions from the host's side, and to the identification of vaccine candidates that show protection in animal models. Recognition of the role the Wolbachia endosymbionts may play in activating the innate immune system has altered our understanding of immunopathology of filariasis and adverse reactions to microfilaricidal drugs. Wolbachia spp. have also proven to be suitable targets for the development of a long-term sterilizing or potentially macrofilaricidal drug. SUMMARY: This review summarizes recent developments in the control of filariasis, in particular lymphatic filariasis and onchocerciasis, as well as in modern research into the immunity of filariasis and new drug development that could lead to additional tools necessary for sustained success in filariasis control.

Clinical Trials as Topic↗

PubMed2004

Polyinosinic-polycytidylic acid-mediated stimulation of human gammadelta T cells via CD11c dendritic cell-derived type I interferons.

The recognition of pathogen-associated molecular patterns (PAMPs) by the innate immune system is a crucial step in inducing effective immune responses. Double-stranded RNA [mimicked by polyinosinic-polycytidylic acid (poly(I:C)], synthesized by various types of viruses, represents one important member of these immunostimulatory microbial components. Here we report that poly(I:C) has potent gammadelta T-cell costimulatory capacity. Within peripheral blood mononuclear cells, poly(I:C)-stimulated gammadelta T cells expressed increased levels of CD69 and exhibited significantly enhanced antigen-mediated proliferation in response to isopentenylpyrophosphate (IPP). Among several recombinant cytokines tested, type I interferons (IFN-alpha, IFN-beta) and interleukin-15 (IL-15) showed a similar activation pattern of gammadelta T cells. gammadelta T-cell clones and purified gammadelta T cells did not respond to poly(I:C), indicating indirect effects of this compound. Depletion of CD11c(+) dendritic cells (DC), which express Toll-like receptor 3 (TLR3), known to recognize poly(I:C), abrogated poly(I:C)-mediated stimulation of gammadelta T cells. In addition, the supernatant of poly(I:C)-treated CD11c(+) DC was able to mimic the stimulatory effects of poly(I:C) on gammadelta T cells. Experiments with neutralizing antibodies indicated that type I IFNs, but not IL-15, contributed to the poly(I:C)-mediated activation of gammadelta T cells. In conclusion, gammadelta T-cell activation by immunostimulatory double-stranded RNA, such as poly(I:C), is indirectly mediated via type I IFNs derived from TLR3-expressing CD11c(+) DCs. These results suggest that upon confrontation with certain viruses, gammadelta T cells can be rapidly activated by type I interferons and may contribute to effective antiviral responses.

Allergens↗

PubMed1999

Fighting infection: the role of lipopolysaccharide binding proteins CD14 and LBP.

An invading pathogen must be held in check by the innate immune system until a specific immune response is mounted. Nonclonal pattern recognition receptors like CD14 or lipopolysaccharide (LPS) binding protein (LBP) recognize ubiquitous pathogen-associated molecular patterns, e.g. LPS. LBP mediates the binding of minute amounts of LPS to membrane-bound CD14 (mCD14) triggering a proinflammatory response of macrophages, which is crucial for keeping an infection under control. Moreover, in vitro mCD14 and LBP are involved in recognition and phagocytosis of heat-killed bacteria. Living Salmonella typhimurium or Escherichia coli depend on the presence of LBP to induce the generation of reactive oxygen species in human or murine macrophages. Using LBP-deficient mice it could be demonstrated that LBP is essential to control low dose (100 CFU S. typhimurium) infection. Therefore, LPS binding proteins play a pivotal role in physiology as well as pathophysiology of Gram-negative infection.

Acute-Phase Proteins↗

PubMed2005

Pentraxin 3 inhibits fibroblast growth factor 2-dependent activation of smooth muscle cells in vitro and neointima formation in vivo.

OBJECTIVE: The fibroblast growth factor (FGF)/FGF receptor system plays an important role in smooth muscle cell (SMC) activation. Long-pentraxin 3 (PTX3) is a soluble pattern recognition receptor with non-redundant functions in inflammation and innate immunity. PTX3 is produced by different cell types of the vessel wall, including SMCs. PTX3 binds FGF2 and inhibits its angiogenic activity on endothelial cells. We investigated the capacity of PTX3 to affect FGF2-dependent SMC activation in vitro and in vivo. METHODS AND RESULTS: When added to human coronary artery SMCs, human PTX3 inhibits cell proliferation driven by endogenous FGF2 and the mitogenic and chemotactic activity exerted by exogenous recombinant FGF2. Accordingly, PTX3 prevents (125)I-FGF2 interaction with FGF receptors on the same cells. Also, PTX3 overexpression after recombinant adeno-associated virus-PTX3 gene transfer inhibits human coronary artery SMC proliferation and survival promoted by FGF2 in vitro. Consistently, a single local endovascular injection of recombinant adeno-associated virus-PTX3 gene inhibits intimal thickening after balloon injury in rat carotid arteries. CONCLUSIONS: PTX3 is a potent inhibitor of the autocrine and paracrine stimulation exerted by FGF2 on SMCs. Local PTX3 upregulation may modulate SMC activation after arterial injury.

Animals↗

PubMed2006

Toll-like receptor mRNA levels in alveolar macrophages after inhalation of endotoxin.

Toll-like receptors (TLRs) are pattern-recognition receptors that have been implicated in the initiation of innate immune responses upon the first encounter with invading pathogens. The airways are frequently exposed to various types of lipopolysaccharide (LPS) from the environment or from pathogens. The current study was designed to determine the effect of LPS on TLR gene expression in human alveolar macrophages in vivo. In total, 16 healthy subjects were enrolled in a single-blinded, placebo-controlled study. Subjects inhaled 100 microg LPS or normal saline (n = 8 per group). Measurements were performed in alveolar macrophages purified from bronchoalveolar lavage fluid obtained 6 h post-challenge. Inhalation of LPS by healthy human volunteers resulted in enhanced alveolar macrophage expression of mRNAs encoding TLRs 1, 2, 7, 8 and CD14, and reduced expression of mRNAs encoding TLR4 and lymphocyte antigen 96. In conclusion, lipopolysaccharide differentially influences the toll-like receptor mRNA expression profile in human alveolar macrophages in vivo.

Administration, Inhalation↗

PubMed2007

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↗

PubMed2003

The Toll-like receptors and their role in septic shock.

The Toll-like receptors (TLRs) are a class of pattern recognition molecules with unique functions in the innate and the acquired immune systems. The innate immune response has evolved as the immediate host defence system in response to foreign structures and it also serves to prime the adaptive immune response. As such, the TLRs set the tone and pace of the inflammatory response that follows initial contact with a microbial pathogen over the course of the following minutes, hours and days. Sepsis, a leading cause of death in critically ill patients worldwide, is defined as 'the systemic inflammatory response syndrome that occurs during infection' [1]; that is, sepsis is the orchestration of the events controlled by the gene products triggered by signals transduced through the TLRs. Through analysis of the human genome, ten TLRs have been identified, and several of them have been characterised with respect to their associated ligands. Following engagement of the cognate ligand to the ectodomain of each TLR, the assembly of intracellular homo- or heterodimers or multimers induces cell signalling. The receptors are variably expressed on different types of cells, such as neutrophils, dendritic cells, lymphocytes, endothelial cells etc. and can be up- and downregulated, blocked or triggered by mimetic substances. By controlling or modifying TLR responses, the trajectory of the entire septic process may be modified. This review covers the events responsible for TLR activation in detail, with an emphasis on possible points of pharmacological intervention.

Animals↗

PubMed2003

[Biologic activity of lipopolysaccharides].

Lipopolysaccharides (LPS, endotoxin) are known to be responsible for the initiation of endotoxic shock, therefore they can be targets for new preventive and therapeutic strategies. This review describes the biological and physicochemical properties of endotoxin--major component of the outer membrane of Gram-negative bacteria. The paper focuses on response of the host to endotoxin, recent knowledge about the target cells and receptors for LPS, mechanisms of innate immune response and cell signal transduction due to the LPS recognition. It also summarises results of studies on LPS structure influence on its biological activity.

Animals↗

PubMed2004

[TIR domain--containing adaptors regulate TLR-mediated signaling pathways].

Recognition of pathogens by Toll-like receptors (TLRs) triggers innate immune responses via signaling pathways mediated by several Toll/IL-1R (TIR) domain-containing adaptors such as MyD88, TIRAP, and TRIF. MyD88 is a common adaptor that is essential for proinflammatory cytokine production, whereas TRIF mediates the MyD88-independent pathway from TLR3 and TLR4 that is responsible for type I interferon production in response to double-stranded RNA and LPS, respectively. TIRAP specifically participates in the MyD88-dependent pathways shared by TLR2 and TLR4, and TRAM is essential for the TLR4-mediated MyD88-independent pathway. Thus, TIR domain-containing adaptors play an important role in the TLR mediated signaling pathways.

Animals↗

PubMed2003

Constitutive expression of a bacterial pattern recognition receptor, CD14, in human salivary glands and secretion as a soluble form in saliva.

Saliva contains a number of proteins and glycoproteins that protect oral tissues, but little is known about the role of human saliva in innate immunity. Here we showed that human major salivary gland cells constitutively expressed a bacterial pattern recognition receptor, CD14, by immunohistochemistry. Human salivary gland cells in culture express CD14 mRNA and a 55-kDa CD14 protein in, but not on the cells, and secrete a soluble form with the same molecular mass. Human whole saliva contains a 55-kDa CD14, and the concentration of parotid saliva was 10-fold higher than whole saliva, which is comparable to that of serum CD14. Levels of CD14 in unstimulated whole and parotid saliva were unchanged before and after a meal and between unstimulated and stimulated saliva, indicating that saliva CD14 is constitutively secreted into the oral cavity. In contrast, lipopolysaccharide (LPS)-binding protein was below the detectable level. The saliva CD14 is functionally active in that it mediated the activation of CD14-lacking intestinal epithelial cells by LPS in a Toll-like receptor 4-dependent manner. These results suggested that saliva CD14 is important for the maintenance of oral health and possibly intestinal homeostasis.

Epithelial Cells↗

PubMed2004

PTX3 function as an opsonin for the dectin-1-dependent internalization of zymosan by macrophages.

Pentraxin 3 (PTX3) is a tumor necrosis factor and interleukin-1beta-stimulated gene that encodes a long PTX with proinflammatory activity. Here, we show that peritoneal macrophages derived from PTX3 transgenic (Tg) mice express higher levels of PTX3 mRNA than macrophages from wild-type (WT) mice, at basal level as well as upon stimulation with zymosan (Zy). Macrophages from Tg mice also showed improved opsonin-independent phagocytosis of Zy particles and the yeast form of the fungus Paracoccidioides brasiliensis. In the case of P. brasiliensis, an enhanced microbicidal activity accompanied by higher production of nitric oxide was also observed in macrophages from Tg mice. Using fluorescein-activated cell sorter analysis and reverse transcriptase-polymerase chain reaction, we demonstrated that basal level of Toll-like receptor-6 and Zy-induced dectin-1 expression was slightly but consistently higher in macrophages from Tg mice than in macrophages from WT mice. Recombinant (r)PTX3 protein binds to Zy particles as well as to yeast cells of P. brasiliensis and addition of rPTX3, to a culture of WT-derived macrophages containing Zy leads to an increase in the phagocytic index, which parallels that of Tg-derived macrophages, demonstrating the opsonin-like activity of PTX3. It is important that blockade of dectin-1 receptor inhibited the phagocytosis of Zy particles by WT and PTX3 Tg macrophages, pointing out the relevant role of dectin-1 as the main receptor involved in Zy uptake. Our results provide evidence for a role of PTX3 as an important component of the innate-immune response and as part of the host mechanisms that control fungal recognition and phagocytosis.

Animals↗

PubMed2002

Roles of toll-like receptors in natural interferon-producing cells as sensors in immune surveillance.

Natural IFN-alpha/beta producing cells (IPCs) play a central role in innate immunity against microbial infections. In primary immune responses, toll-like receptors (TLRs), as major pattern-recognition receptors, are essential for IPCs as well as other antigen presenting cell (APC) subsets to recognize microbes. IPCs unequivocally express TLR7 and TLR9, and can respond to the respective ligand to produce IFN-alpha/beta and to rapidly differentiate into dendritic cells (DCs). Thereby, IPCs can not only activate innate immune system but also provoke T cell responses. Thus, IPCs link innate and adaptive immunity through TLR system. In addition, recent work has revealed the regulatory system of DC subsets in response to microbial invasion. In this context, by the different but complementary expression profile of TLRs, IPCs together with myeloid APC subsets constitute a rational system of immune surveillance that can cover a wide variety of pathogens and enlarge immune adjuvant effects.

Antigen-Presenting Cells↗

PubMed2006

Cloning and characterization of a shrimp clip domain serine protease homolog (c-SPH) as a cell adhesion molecule.

Clip domain serine protease homologs (c-SPHs) are involved in various innate immune functions in arthropods such as antimicrobial activity, cell adhesion, pattern recognition, opsonization, and regulation of the prophenoloxidase system. In the present study, we cloned a c-SPH cDNA from tiger shrimp (Penaeus monodon) hemocytes. It is 1337 bp in length with a coding region of 1068 bp consisting a protein of 355 amino acid residues. The deduced protein includes one clip domain and one catalytically inactive serine protease-like (SP-like) domain. Its molecular weight is estimated to be 38 kDa with an isoelectric point of 7.9. The predicted cutting site of the signal peptide is located between Gly(21) and Gln(22). We aligned 15 single clip domain SPH protein sequences from 12 arthropod species; the identity of these clip domains is low and that of SP-like domains is from 34% to 46%. The conserved regions are located near the amino acid residues which served as substrate interaction sites in catalytically active serine protease. Phylogenetically, the tiger shrimp c-SPH is most similar to a low molecular mass masquerade-like protein of crayfish, but less similar to c-SPHs in Chelicerata and Insecta. Nested reverse transcription polymerase chain reaction (RT-PCR) revealed that c-SPH mRNA is expressed most in tissues with the highest hemocyte abundance. Antimicrobial and opsonization activities of the molecule were not detected. The expression of c-SPH mRNA in hemocytes was up-regulated at the 12-day post beta-glucan immersion. Recombinant c-SPH could significantly enhance hemocyte adhesion. The result suggests that the shrimp c-SPH protein plays a role in innate immunity.

Amino Acid Sequence↗

PubMed2006

Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity.

Fungal infections are increasing worldwide due to the marked rise in immunodeficiencies including AIDS; however, immune responses to fungi are poorly understood. Dectin-1 is the major mammalian pattern recognition receptor for the fungal component zymosan. Dectin-1 represents the prototype of innate non-Toll-like receptors (TLRs) containing immunoreceptor tyrosine-based activation motifs (ITAMs) related to those of adaptive antigen receptors. Here we identify Card9 as a key transducer of Dectin-1 signalling. Although being dispensable for TLR/MyD88-induced responses, Card9 controls Dectin-1-mediated myeloid cell activation, cytokine production and innate anti-fungal immunity. Card9 couples to Bcl10 and regulates Bcl10-Malt1-mediated NF-kappaB activation induced by zymosan. Yet, Card9 is dispensable for antigen receptor signalling that uses Carma1 as a link to Bcl10-Malt1. Thus, our results define a novel innate immune pathway and indicate that evolutionarily distinct ITAM receptors in innate and adaptive immune cells use diverse adaptor proteins to engage selectively the conserved Bcl10-Malt1 module.

Adaptor Proteins, Signal Transducing↗