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PubMed2006

Natural IgM antibodies: the orphaned molecules in immune surveillance.

Natural IgM antibodies are typical victims of prejudices which originated in the mid 80 s. Over the years, these molecules were considered as the pariahs among the immune competent molecules and their characteristic properties, like low affinity, cross-reactivity and pentameric structure, were assessed as useless, difficult, nebulous, etc. Today, mainly based on a few scientists' persistent work and the key discoveries on innate immune recognition, natural IgM antibodies are "back on stage". Their role in the immune response against bacteria, viruses, fungi and possibly modified self-components as well as in therapy and diagnosis of malignancies is accepted. All the so far negatively judged features are seen in a different light, e.g. low affinity seems to be good for function and does not exclude specificity, and cross-reactivity is no longer judged as unspecific, but instead as a very economic way of immune recognition. And at last, with the use of natural IgM antibodies, a new field of tumor-specific targets has been encountered, the carbo-neo-epitopes. Therefore, by having learned from nature, the renaissance of natural IgM antibodies opens a new area of cancer therapeutics and diagnostics.

Animals↗

PubMed2005

Tetradecanoyl phorbol acetate induces expression of Toll-like receptor 2 in U937 cells: involvement of PKC, ERK, and NF-kappaB.

Toll-like receptors (TLRs) have been identified recently as crucial signaling receptors mediating the innate immune recognition. Though induction of TLR2 or TLR4 by 12-O-tetradecanoyl phorbol 13-acetate (TPA) in leukemia cells has been reported, however, the mechanism by which TPA up-regulates TLR2 or TLR4 remains poorly understood. In this study, we investigated the effect of TPA on induction of TLR2 in U937 cells. TPA markedly induced TLR2 mRNA and protein expressions. TLR2 expression in response to TPA was attenuated by pretreatments with GF109203X and Go6976 (inhibitors of protein kinase C (PKC)) and PD98059 (an inhibitor of extracellular signal-regulated kinases (ERKs)), but not SB203580 (an inhibitor of p38s) and SP600125 (an inhibitor of c-Jun N-terminal kinases), suggesting involvement of PKC and ERKs in this response. Moreover, TPA-induced PKC activation was linked to generation of reactive oxygen species, which were dispensable for TLR2 expression in U937 cells. Pretreatments with GF109203X blocked TPA-induced phosphorylation of ERKs, suggesting activation of ERKs by PKC. In addition, TPA induced nuclear factor-kappaB (NF-kappaB) activation, which was shown by increased nuclear translocation of p65 NF-kappaB and degradation of IkappaB-alpha, a NF-kappaB inhibitory protein. Importantly, TPA-induced TLR2 expression was inhibited by blockage of NF-kappaB activation using NF-kappaB inhibitors, including MG132 and BAY11-7085. Specifically, TPA-induced nuclear translocation of NF-kappaB was effectively attenuated by GF109203X and PD98059, suggesting PKC and ERK regulation of NF-kappaB nuclear localization in response to TPA. Together, these results suggest that TPA-induced TLR2 expression in U937 cells may be at least in part mediated through activation of PKC and ERKs as well as NF-kappaB transcription factor, and that cross-talk between PKC or ERKs and NF-kappaB may exist.

Extracellular Signal-Regulated MAP Kinases↗

PubMed2004

Flow cytometric analysis of crayfish haemocytes activated by lipopolysaccharides.

Lipopolysaccharides (LPS) from Gram-negative bacteria are strong stimulators of white river crayfish, Procambarus zonangulus, haemocytes in vitro. Following haemocyte treatment with LPS and with LPS from rough mutant R5 (LPS Rc) from Salmonella minnesota, flow cytometric analysis revealed a conspicuous and reproducible decrease in cell size as compared to control haemocytes. These LPS molecules also caused a reduction in haemocyte viability as assessed by flow cytometry with the fluorescent dyes calcein-AM and ethidium homodimer. The onset of cell size reduction was gradual and occurred prior to cell death. Haemocytes treated with LPS from S. minnesota without the Lipid A moiety (detoxified LPS) decreased in size without a reduction of viability. The action of LPS on crayfish haemocytes appeared to be related to the activation of the prophenoloxidase system because phenoloxidase (PO)-specific activity in the supernatants from control and detoxified LPS-treated cells was significantly lower than that from LPS and LPS-Rc treated cells (P</=0.05). Furthermore, addition of trypsin inhibitor to the LPS treatments caused noticeable delays in cell size and viability changes. These patterns of cellular activation by LPS formulations indicated that crayfish haemocytes react differently to the polysaccharide and lipid A moieties of LPS, where lipid A is cytotoxic and the polysaccharide portion is stimulatory. These effects concur with the general pattern of mammalian cell activation by LPS, thereby indicating common innate immune recognition mechanisms to bacterial antigens between cells from mammals and invertebrates. These definitive molecular approaches used to verify and identify mechanisms of invertebrate haemocyte responses to LPS could be applied with other glycoconjugates, soluble mediators, or xenobiotic compounds.

Animals↗

PubMed2006

Role of toll-like receptors in spontaneous commensal-dependent colitis.

Inflammatory bowel disease (IBD) is thought to result from a dysregulated interaction between the host immune system and its commensal microflora. Heterogeneity of disease susceptibility in humans and rodents suggest that multiple mechanisms are responsible for the etiology of IBD. In particular, deficiencies in anti-inflammatory and immune-suppressive mechanisms play an important role in the development of IBD. However, it is unknown how the indigenous microflora stimulates the immune system and how this response is regulated. To address these questions, we investigated the role of Toll-like receptor (TLR) signaling in the development of spontaneous, commensal-dependent colitis in interleukin (IL)-2- and IL-10-deficient mice. We report that colitis was dependent on TLR signaling in Il10(-/-) mice. In contrast, Il2(-/-) mice developed intestinal inflammation in the absence of TLR signaling pathways. These results demonstrate a differential role of innate immune recognition by TLRs in the development of commensal-dependent colitis.

Adaptor Proteins, Signal Transducing↗

PubMed2005

In response to pathogens, glial cells dynamically and differentially regulate Toll-like receptor gene expression.

The mechanisms that mediate innate immune recognition of CNS infections are unknown. This study provides a comparison of Toll-like receptor (TLR) gene expression in resting and virus infected CNS cells. N2a neuroblastoma cells expressed TLR 3 but demonstrated no change in TLR gene expression in response to either LPS or virus infection. N9 microglia and differentiated primary astrocytes expressed most TLR genes. TLR 2 expression was highest in N9 microglia and TLR 7 in astrocytes. In both glial cell types, LPS stimulation upregulated pro-inflammatory cytokines, TLR 2 and TLR 3 gene expression but down-regulated other TLR genes. RNA virus infection substantially increased levels of type-I interferon (IFN) and TLR 3 transcripts and to a lesser extent TLR 9 transcripts. Microglia and astrocytes thus have the ability to discriminate between pathogens and elicit an appropriate response.

Alphavirus Infections↗

PubMed2005

Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease.

Toll-like receptors (TLRs) play an important part in the innate immune recognition of invading microorganisms, initiating sufficient immune responses. Growing amounts of data suggest that the ability of certain individuals to respond properly to TLR ligands may be impaired by single nucleotide polymorphisms (SNPs) within TLR genes, resulting in an altered susceptibility to, or course of, infectious or inflammatory disease. Most studies have focused on two cosegregating SNPs-Asp299gly and Thr399Ile-within the gene encoding TLR4, the receptor for bacterial lipopolysaccharide. These SNPs are present in approximately 10% of white individuals, and have been found to be positively correlated with several infectious diseases. However, these SNPs seem to protect from atherosclerosis and related diseases, which is reviewed in this article also. Meanwhile, SNPs of genes encoding other TLRs-eg, TLR2, which recognises a wide variety of microbial ligands-have been reported, and preliminary studies indicate an impact on susceptibility to infectious and inflammatory diseases as well. This review summarises and discusses the results obtained, and draws conclusions from these data.

Case-Control Studies↗

PubMed2001

Ligands for natural killer cell receptors: redundancy or specificity.

Several inhibitory and activating receptors involved in natural killer cell activation have been characterized. The increasing knowledge about their ligands, including classical MHC class I molecules, non-classical MHC class I molecules and MHC class I-related molecules, is shedding new light on the targets of innate immune recognition. While classical MHC class I molecules are constitutively expressed, some MHC class I-related (MIC) molecules, however, are stress-induced by ill-defined stimuli. Two families of ligands for the human activating NKG2D receptor have been identified. These are the MIC proteins encoded by two highly polymorphic genes within the MHC class I and the retinoic acid-inducible early gene-1-like (also designated UL16-binding) proteins encoded by genes outside the MHC. For the mouse NKG2D receptor, one family, containing at least five distinct ligands, has been described. A better understanding about how targets signal their distress, which renders them susceptible to natural killer (NK)-cell attack, will help to define the role of NK cells in antimicrobial and antitumor immunity and transplantation.

Animals↗

PubMed2006

Lipopolysaccharide signaling in endothelial cells.

Sepsis is the systemic immune response to severe bacterial infection. The innate immune recognition of bacterial and viral products is mediated by a family of transmembrane receptors known as Toll-like receptors (TLRs). In endothelial cells, exposure to lipopolysaccharide (LPS), a major cell wall constituent of Gram-negative bacteria, results in endothelial activation through a receptor complex consisting of TLR4, CD14 and MD2. Recruitment of the adaptor protein myeloid differentiation factor (MyD88) initiates an MyD88-dependent pathway that culminates in the early activation of nuclear factor-kappaB (NF-kappaB) and the mitogen-activated protein kinases. In parallel, a MyD88-independent pathway results in a late-phase activation of NF-kappaB. The outcome is the production of various proinflammatory mediators and ultimately cellular injury, leading to the various vascular sequelae of sepsis. This review will focus on the signaling pathways initiated by LPS binding to the TLR4 receptor in endothelial cells and the coordinated regulation of this pathway.

Animals↗

PubMed2001

LPS-hyporesponsiveness of mnd mice is associated with a mutation in Toll-like receptor 4.

Toll-like receptors (Tlrs) are transmembrane proteins that have recently been shown to play a critical role in the innate immune recognition of microbial constituents. Among this family, Tlr4 is a crucial signal transducer for lipopolysaccharide (LPS), the major component of the Gram-negative bacteria outer cell membrane. In this paper, we report that C57BL/6.KB2-mnd mice, a model of neuronal ceroid lipofuscinosis, do not respond to LPS. This defect is associated with a spontaneous mutation in Tlr4 consisting of a large insertion within exon 2 predicting a frameshift mutation and a truncated protein.

Animals↗

PubMed2005

Virulent Coxiella burnetii does not activate human dendritic cells: role of lipopolysaccharide as a shielding molecule.

Coxiella burnetii is an obligate intracellular bacterium and the etiological agent of the zoonotic disease Q fever. Acute human Q fever is characterized by flu-like symptoms that, in some cases, can result in a persistent infection that may reactivate months or years after initial exposure. Mechanisms by which this obligate parasite evades clearance by the host immune response during persistent infection are unknown. Here, we characterized the interaction of C. burnetii with dendritic cells (DC), critical components of both innate and adaptive immunity. Human DC were infected with two isogenic C. burnetii strains that differ in LPS length. Infection by the Nine Mile phase I (NMI) strain, which is fully virulent and produces full-length LPS, did not result in DC maturation. In contrast, infection by the avirulent Nine Mile phase II strain, producing a severely truncated LPS, resulted in toll-like receptor 4-independent DC maturation and approximately 10-fold more IL-12 and TNF production. NMI did not actively inhibit DC maturation as NMI-infected DC subsequently matured if treated with Escherichia coli LPS or Nine Mile phase II. Furthermore, removal of LPS from NMI dramatically increased its ability to stimulate DC. We propose a model whereby LPS of virulent C. burnetii masks toll-like receptor ligands from innate immune recognition by DC, thereby allowing replication without significant maturation or inflammatory cytokine production. This immune evasion strategy may allow C. burnetii to persist in an immunocompetent host.

Coxiella burnetii↗

PubMed2001

Drosophila MyD88 is an adapter in the Toll signaling pathway.

Toll-like receptors comprise a family of cell surface receptors that play a crucial role in the innate immune recognition of both Drosophila and mammals. Previous studies have shown that Drosophila Toll-1 mediates the induction of antifungal peptides during fungal infection of adult flies. Through genetic studies, Tube, Pelle, Cactus, and Dif have been identified as downstream components of the Toll-1 signaling pathway. Here we report characterization of a Drosophila homologue of human MyD88, dMyD88. We show that dMyD88 is an adapter in the Toll signaling pathway that associates with both the Toll receptor and the downstream kinase Pelle. Expression of dMyD88 in S2 cells strongly induced activity of a Drosomycin reporter gene, whereas a dominant-negative version of dMyD88 potently inhibited Toll-mediated signaling. We also show that dMyD88 associates with the death domain-containing adapter Drosophila Fas-associated death domain-containing protein (dFADD), which in turn interacts with the apical caspase Dredd. This pathway links a cell surface receptor to an apical caspase in invertebrate cells and therefore suggests that the Toll-mediated pathway of caspase activation may be the evolutionary ancestor of the death receptor-mediated pathway for apoptosis induction in mammals.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Staphylococcus aureus activates immune cells via Toll-like receptor (TLR)-2, lipopolysaccharide-binding protein (LBP), and CD14, whereas TLR-4 and MD-2 are not involved.

Lipoteichoic acid (LTA) derived from Streptococcus pneumoniae, purified employing a chloroform/methanol protocol, and from Staphylococcus aureus, prepared by the recently described butanol extraction procedure, was investigated regarding its interaction with lipopolysaccharide (LPS)-binding protein (LBP), CD14, Toll-like receptors (TLRs)-2 and -4, and MD-2. LTA from both organisms induced cytokine synthesis in human mononuclear phagocytes. Activation was LBP- and CD14-dependent, and formation of complexes of LTA with LBP and soluble CD14 as well as catalytic transfer of LTA to CD14 by LBP was verified by PhastGel(TM) native gel electrophoresis. Human embryonic kidney (HEK) 293/CD14 cells and Chinese hamster ovary (CHO) cells were responsive to LTA only after transfection with TLR-2. Additional transfection with MD-2 did not affect stimulation of these cells by LTA. Our data suggest that innate immune recognition of LTA via LBP, CD14, and TLR-2 represents an important mechanism in the pathogenesis of systemic complications in the course of infectious diseases brought about by the clinically most important Gram-positive pathogens. However, the involvement of TLR-4 and MD-2 in this process was ruled out.

Acute-Phase Proteins↗

PubMed2006

Cell activation of human macrophages by lipoteichoic acid is strongly attenuated by lipopolysaccharide-binding protein.

Lipoteichoic acid (LTA) represents immunostimulatory molecules expressed by Gram-positive bacteria. They activate the innate immune system via Toll-like receptors. We have investigated the role of serum proteins in activation of human macrophages by LTA from Staphylococcus aureus and found it to be strongly attenuated by serum. In contrast, the same cells showed a sensitive response to LTA and a significantly enhanced production of tumor necrosis factor alpha under serum-free conditions. We show that LTA interacts with the serum protein lipopolysaccharide-binding protein (LBP) and inhibits the integration of LBP into phospholipid membranes, indicating the formation of complexes of LTA and soluble LBP. The addition of recombinant human LBP to serum-free medium inhibited the production of tumor necrosis factor alpha and interleukins 6 and 8 after stimulation of human macrophages with LTA in a dose-dependent manner. Using anti-LBP antibodies, this inhibitory effect could be attributed to soluble LBP, whereas LBP in its recently described transmembrane configuration did not modulate cell activation. Also, using primary alveolar macrophages from rats, we show a sensitive cytokine response to LTA under serum-free culture conditions that was strongly attenuated in the presence of serum. In summary, our data suggest that innate immune recognition of LTA is organ-specific with negative regulation by LBP in serum-containing compartments and sensitive recognition in serum-free compartments like the lung.

Acute-Phase Proteins↗

PubMed2002

Toll-like receptor 4 resides in the Golgi apparatus and colocalizes with internalized lipopolysaccharide in intestinal epithelial cells.

Toll-like receptor (TLR) 4 is mainly found on cells of the myelopoietic lineage. It recognizes lipopolysaccharide (LPS) and mediates cellular activation and production of proinflammatory cytokines. Less is known about the distribution and role of TLR4 in epithelial cells that are continuously exposed to microbes and microbial products. Here we show that the murine small intestinal epithelial cell line m-IC(cl2) is highly responsive to LPS and expresses both CD14 and TLR4. Transcription and surface membrane staining for CD14 were up-regulated upon LPS exposure. Surprisingly, TLR4 immunostaining revealed a strictly cytoplasmic paranuclear distribution. This paranuclear compartment could be identified as the Golgi apparatus. LPS added to the supernatant was internalized by m-IC(cl2) cells and colocalized with TLR4. Continuous exposure to LPS led to a tolerant phenotype but did not alter TLR4 expression nor cellular distribution. Thus, intestinal epithelial cells might be able to provide the initial proinflammatory signal to attract professional immune cells to the side of infection. The cytoplasmic location of TLR4, which is identical to the final location of internalized LPS, further indicates an important role of cellular internalization and cytoplasmic traffic in the process of innate immune recognition.

Amino Acid Sequence↗

PubMed2006

Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells.

The role of innate immune recognition by intestinal epithelial cells (IECs) in vivo is ill-defined. Here, we used highly enriched primary IECs to analyze Toll-like receptor (TLR) signaling and mechanisms that prevent inappropriate stimulation by the colonizing microflora. Although the lipopolysaccharide (LPS) receptor complex TLR4/MD-2 was present in fetal, neonatal, and adult IECs, LPS-induced nuclear factor kappaB (NF-kappaB) activation and chemokine (macrophage inflammatory protein 2 [MIP-2]) secretion was only detected in fetal IECs. Fetal intestinal macrophages, in contrast, were constitutively nonresponsive to LPS. Acquisition of LPS resistance was paralleled by a spontaneous activation of IECs shortly after birth as illustrated by phosphorylation of IkappaB-alpha and nuclear translocation of NF-kappaB p65 in situ as well as transcriptional activation of MIP-2. Importantly, the spontaneous IEC activation occurred in vaginally born mice but not in neonates delivered by Caesarean section or in TLR4-deficient mice, which together with local endotoxin measurements identified LPS as stimulatory agent. The postnatal loss of LPS responsiveness of IECs was associated with a posttranscriptional down-regulation of the interleukin 1 receptor-associated kinase 1, which was essential for epithelial TLR4 signaling in vitro. Thus, unlike intestinal macrophages, IECs acquire TLR tolerance immediately after birth by exposure to exogenous endotoxin to facilitate microbial colonization and the development of a stable intestinal host-microbe homeostasis.

Animals↗

PubMed2006

Characterization of monoclonal antibodies to human soluble MD-2 protein.

Toll-like receptors (TLRs) are mammalian innate immune recognition receptors that are activated by pathogen associated molecular patterns (PAMPs). TLR4 is the signaling molecule of the lipopolysaccharide (LPS) receptor complex. TLR4 associates with its adapter molecule, MD-2, which is absolutely required for LPS-induced activation of TLR4. MD-2 exists as a cell surface protein in association with TLR4 and as secreted forms consisting of MD-2 monomers and multimers. To facilitate the studies of MD-2 distribution, abundance, and function, we produced monoclonal antibodies (MAbs) to baculovirally expressed soluble MD-2 (sMD-2). Eleven MAbs were characterized by enzyme-linked immunosorbent assay (ELISA) with soluble TLR4/MD-2 complex (sTLR4/MD-2) and sMD-2, Western blotting against sMD-2 monomer and multimers, and inhibition of direct LPS binding to sMD-2. Four MAbs preferentially recognized mainly MD-2 oligomers, not monomers, as judged by Western blotting and ELISA. Anti-MD-2 MAbs useful for indirect immunofluorescent staining of cells expressing TLR4 and MD-2 were identified. One MAb that recognized all forms of MD-2 was used in an ELISA to measure sMD-2 in normal human sera as well as sera from intensive care patients with and without sepsis. Serum levels of sMD-2 were undetectable or very low in normal and in nonsepsis patients but significantly (p < 0.05) increased in sepsis patients. These MAbs should therefore be very useful new tools for studies of MD-2 expression and function in health and disease.

Animals↗

PubMed2003

Clinical use of high sensitivity C-reactive protein for the prediction of adverse cardiovascular events.

PURPOSE OF REVIEW: Inflammation plays a central role in the initiation, progression, and destabilization of vascular atheroma. In an attempt to improve global cardiovascular risk assessment, considerable research has focused on markers of inflammation; in particular, high-sensitivity C-reactive protein, a pentraxin innate immune recognition molecule and classic acute-phase reactant. RECENT FINDINGS: Multiple prospective studies now demonstrate that high-sensitivity C-reactive protein is a potent predictor of future cardiovascular events at all levels of low-density lipoprotein cholesterol, all levels of the Framingham Risk Score, and all levels of severity of the metabolic syndrome. Moreover, high-sensitivity C-reactive protein appears to be implicated in acute coronary syndromes and provides prognostic information on vascular risk among patients with renal dysfunction. In clinical settings, high-sensitivity C-reactive protein levels more than 3 mg/L are associated with the highest vascular risk. SUMMARY: High-sensitivity C-reactive protein evaluation has recently been endorsed by the Centers for Disease Control and Prevention and by the American Heart Association to be used in conjunction with lipid evaluation as part of global risk prediction. Emerging evidence further suggests that high-sensitivity C-reactive protein can be used to target pharmacologic and lifestyle interventions designed to prevent first as well as recurrent cardiovascular events.

Biomarkers↗

PubMed2005

Immunity, inflammation, and allergy in the gut.

The gut immune system has the challenge of responding to pathogens while remaining relatively unresponsive to food antigens and the commensal microflora. In the developed world, this ability appears to be breaking down, with chronic inflammatory diseases of the gut commonplace in the apparent absence of overt infections. In both mouse and man, mutations in genes that control innate immune recognition, adaptive immunity, and epithelial permeability are all associated with gut inflammation. This suggests that perturbing homeostasis between gut antigens and host immunity represents a critical determinant in the development of gut inflammation and allergy.

Animals↗