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Results for “Immunity, Innate”

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PubMed2006

Innate immunity of the human newborn is polarized toward a high ratio of IL-6/TNF-alpha production in vitro and in vivo.

Human newborns are susceptible to microbial infection related to incompletely defined aspects of the neonatal immune system. To characterize neonatal innate immunity, we studied production of two early response cytokines in response to Toll-like receptor (TLR)-activating microbial stimuli in vitro: the pro-inflammatory cytokine tumor necrosis factor (TNF)-alpha and IL-6, a multifunctional cytokine with antiinflammatory and Th2-polarizing properties. Neonatal cord blood responses to multiple TLR agonists, including poly dI:dC (TLR3), lipopolysaccharide (LPS) (TLR4), flagellin (TLR5), and CpG DNA (TLR9), are characterized by a higher IL-6/TNF-alpha ratio than in adult peripheral blood. Robust LPS-induced IL-6 production is due to both neonatal cellular (monocyte-) and humoral (serum-) factors. Remarkably, serum collected from newborns during the first week of life demonstrates higher IL-6/TNF-alpha ratios than does cord blood, associated with elevations of the IL-6-inducible acute phase reactants CRP and LPS-binding protein in the first days of life. A high ratio of stimulus-induced IL-6/TNF-alpha production is likely to profoundly modulate both innate and adaptive immune responses in the human newborn.

Adult↗

PubMed2006

A role for BLyS in the activation of innate immune cells.

B-lymphocyte stimulator (BLyS) is a member of the tumor necrosis factor (TNF) ligand superfamily. Although BLyS costimulates adaptive immune cells, the ability of BLyS to stimulate innate immune cells has not been described. Here, we show that BLyS strongly induces human monocyte survival, and activation as measured by proinflammatory cytokine secretion and up-regulation of costimulatory molecule expression. In addition, monocytes cultured with BLyS differentiated into macrophage-like cells. Regarding BLyS receptor(s) expression, freshly isolated monocytes bound low levels of exogenous BLyS and expressed primarily intracellular TACI, and cell surface TACI levels increased following monocyte activation. Of interest, bone marrow monocytes from some multiple myeloma patients expressed significant levels of cell surface TACI at isolation. Our findings indicate that BLyS plays a role in activating innate immune cells. Moreover, this study may explain more clearly why high BLyS production is often correlated with certain inflammatory autoimmune diseases and B-lymphocyte malignancies.

Apoptosis↗

PubMed2004

CpG oligodeoxynucleotides stimulate protective innate immunity against pulmonary Klebsiella infection.

Bacterial pneumonia is a leading cause of mortality in the United States. Innate immune responses, including type-1 cytokine production, are critical to the effective clearance of bacterial pathogens from the lung. Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG dinucleotide motifs (CpG ODN), which mimic the effects of bacterial DNA, have been shown to enhance type-1 cytokine responses during infection due to intracellular pathogens, resulting in enhanced microbial clearance. The role of CpG ODN in modulating protective innate immunity against extracellular pathogens is unknown. Using a murine model of Gram-negative pneumonia, we found that CpG ODN administration stimulated protective immunity against Klebsiella pneumoniae. Specifically, intratracheal (i.t.) administration of CpG ODN (30 microg) 48 h before i.t. K. pneumoniae challenge resulted in increased survival, compared with animals pretreated with control ODN or saline. Pretreatment with CpG ODN resulted in enhanced bacterial clearance in lung and blood, and higher numbers of pulmonary neutrophils, NKT cells, gammadelta-T cells, and activated NK1.1+ cells and gammadelta-T lymphocytes during infection. Furthermore, pretreatment with CpG ODN enhanced the production of TNF-alpha, and type-1 cytokines, including IL-12, IFN-gamma, and the IFN-gamma-dependent ELR- CXC chemokines IFN-gamma-inducible protein-10 and monokine induced by IFN-gamma in response to Klebsiella challenge, compared with control mice. These findings indicate that i.t. administration of CpG ODN can stimulate multiple components of innate immunity in the lung, and may form the basis for novel therapies directed at enhancing protective immune responses to severe bacterial infections of the lung.

Adjuvants, Immunologic↗

PubMed2005

Association study of functional genetic variants of innate immunity related genes in celiac disease.

BACKGROUND: Recent evidence suggest that the innate immune system is implicated in the early events of celiac disease (CD) pathogenesis. In this work for the first time we have assessed the relevance of different proinflammatory mediators typically related to innate immunity in CD predisposition. METHODS: We performed a familial study in which 105 celiac families characterized by the presence of an affected child with CD were genotyped for functional polymorphisms located at regulatory regions of IL-1alpha, IL-1beta, IL-1RN, IL-18, RANTES and MCP-1 genes. Familial data was analysed with a transmission disequilibrium test (TDT) that revealed no statistically significant differences in the transmission pattern of the different genetic markers considered. RESULTS: The TDT analysis for IL-1alpha, IL-1beta, IL-1RN, IL-18, and MCP-1 genes genetic variants did not reveal biased transmission to the affected offspring. Only a borderline association of RANTES promoter genetic variants with CD predisposition was observed. CONCLUSION: Our results suggest that the analysed polymorphisms of IL-1alpha, IL-1beta, IL-1RN, IL-18, RANTES and MCP-1 genes do not seem to play a major role in CD genetic predisposition in our population.

Celiac Disease↗

PubMed2001

Two receptor theory in innate immune activation: studies on the receptors for bacillus Culmet Guillen-cell wall skeleton.

Activation of the innate immune system is a prerequisite for the maturation of dendritic cells (DC) and macrophages (Mphi) followed by clonal expansion of the lymphocytes, targeting cells expressing "non-self' antigens. Microbes usually have a component competent to activate DC/Mphi for antigen presentation. This component has been called adjuvant, but recently renamed "pathogen-associated molecular pattern" (PAMP) or modulin based on its molecular identification. Here, we propose the hypothesis that DC/Mphi express two sorts of receptors for PAMP, whose signaling pathways lead to a sufficient antigen (Ag)-presenting state. In bacterial infection, a Toll-like receptor (TLR) and an uptake receptor participate in DC maturation and Mphi activation. Likewise, with a number of viruses, two of the receptors, with short consensus repeats (SCR), immunoglobulin-like domains or chemokine receptor-like motifs etc. induce functional modulation of DC/Mphi. In immune therapy for cancer, primary activation of the innate system would be essential for tumor Ag-specific T cell augmentation. Cancer cells express tumor-associated Ag but barely co-express PAMP, which situation does not allow for the activation of innate immune responses. Supplementing tumor-associated Ag with PAMP may be an effective therapy for patients with cancer. Here, we discuss the possibility of an innate immune therapy for cancer with reference to bacillus Culmet Guillen cell-wall skeleton (BCG-CWS).

Adjuvants, Immunologic↗

PubMed2005

The innate immune system and its role in allergic disorders.

BACKGROUND: There has been an increasing prevalence of allergic diseases in the Western world over the last decades. The hygiene hypothesis has been proposed as a possible explanation for this epidemical trend in allergy. A key role in this theory is assigned to the reduced microbial stimulation of the Toll-like receptors (TLRs) in early life, which could lead to a weaker Th1 response and a stronger Th2 response to allergens. The individual immunological response is determined by the interplay between the dose and timing of exposure to endotoxins, other environmental factors and genetic predisposition. In the development and progression of allergic disorders, the innate immune system plays an important role. OBJECTIVE: In this review, we discuss the paradoxical effects that may appear when the innate immune components are triggered. We review the influence of changes in the gene sequence and TLR expression in relation to the overall pattern of commensals and pathogens. We explored the possibility of alternative stimulations of the immune system by CpG oligodeoxynucleotides and probiotics as therapeutic devices against this endemic disease in Western society. METHODS: Selection of papers was based on the importance of their contribution to the understanding of innate immunity and its implications. RESULTS AND CONCLUSION: The innate immune system plays an important role in both the protection against and the enhancement of allergic disorders, but the mechanisms are still unclear. Nevertheless, gene polymorphisms and triggers of the innate immune system provide therapeutic targets for protection against and treatment of allergic disorders.

Humans↗

PubMed2003

Innate immunity in the liver.

PURPOSE OF REVIEW: The liver is constantly exposed to large varieties of antigens that are derived from the gastrointestinal tract, including dietary antigens, pathogens, and toxins. Its function as a major immune organ is now being appreciated. The liver lymphocyte population is enriched in macrophages (ie, Kupffer cells), natural killer and natural killer T cells, which constitute the innate immune system. This review will focus on recent advances in the understanding of mechanisms that regulate the hepatic innate immune system because the innate immune system may mediate many chronic liver diseases, including nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis. RECENT FINDINGS: Hepatic natural killer T cells modulate liver injury by balancing local production of proinflammatory (Th-1) and antiinflammatory (Th-2) cytokines. Hepatic natural killer T cell depletion leads to Th-1 polarization of hepatic cytokine production, increasing tumor necrosis factor alpha and interferon gamma. This potentates lipopolysaccharide-induced hepatotoxicity. The hepatic natural killer T cells themselves are regulated by Kupffer-cell-produced cytokines, dietary factors, and certain neurotransmitters, such as norepinephrine. In leptin-deficient ob/ob mice, an animal model for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, insufficient norepinephrine increases hepatic natural killer T cell apoptosis, depleting hepatic natural killer T cells and inducing proinflammatory cytokine polarization. This contributes to chronic inflammation, increased lipopolysaccharide-induced hepatotoxicity, and insulin resistance in ob/ob mice. SUMMARY: Assuming that defects in the hepatic innate immune system that promote Th-1 cytokine polarization are common pathogenic mechanisms for hepatic insulin resistance and nonalcoholic steatohepatitis, therapies that inhibit inflammatory activity may be beneficial for these disorders.

Journal Article↗

PubMed2005

Direct T-cell stimulations by drugs--bypassing the innate immune system.

Some drug induced immune mediated side effects appear rapidly (6-<48hrs) and are hard to reconcile with the generation of a new immune response to the drug. By extending the previously presented p-i concept (pharmacological interaction with immune receptors), I propose that drugs might stimulate memory T-cells via their T-cell receptors, which happen to react not only with a peptide antigen, but also with a (chemically inert) drug. In this model, the generation of a new, drug specific immune response is actually bypassed: the innate immune system must not be stimulated, as no naive T-cells are stimulated. Only previously activated memory T-cells are re-activated, as they have a lower threshold of reactivity to a T-cell receptor transmitted signal, whereby certain cofactors like an ongoing immune response to a virus might facilitate reactivity to the drug. This concept has major implications for preclinical testing of the allergenic potential of a drug, which normally is measured by the ability of the drug to cause a new immune response.

Adjuvants, Immunologic↗

PubMed2003

Innate immune response to encephalomyocarditis virus infection mediated by CD1d.

CD1d-reactive natural killer T (NKT) cells can rapidly produce T helper type 1 (Th1) and/or Th2 cytokines, can activate antigen-presenting cell (APC) interleukin-12 (IL-12) production, and are implicated in the regulation of adaptive immune responses. The role of the CD1d system was assessed during infection with encephalomyocarditis virus (EMCV-D), a picornavirus that causes acute diabetes, paralysis and myocarditis. EMCV-D resistance depends on IL-12-mediated interferon-gamma (IFN-gamma) production. CD1d-deficient mice, which also lack CD1d-reactive NKT cells, were substantially more sensitive to infection with EMCV-D. Infected CD1d knockout mice had decreased IL-12 levels in vitro and in vivo, and indeed were protected by treatment with exogenous IL-12. IFN-gamma production in CD1d knockout mice was decreased compared with that in wild-type (WT) mice in response to EMCV-D in vitro, although differences were not detected in vivo. Treatment with anti-asialo-GM1 antibody, to deplete NK cells, caused a marked increase in susceptibility of WT mice to EMCV-D infection, whereas CD1d knockout mice were little affected, suggesting that NK-cell-mediated protection is CD1d-dependent. Therefore, these data indicate that CD1d is essential for optimal responses to acute picornaviral infection. We propose that CD1d-reactive T cells respond to early immune signals and function in the innate immune response to a physiological viral infection by rapidly augmenting APC IL-12 production and activating NK cells.

Animals↗

PubMed2001

Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: regulatory role in the innate immune response.

The importance of the macrophage in innate immunity is underscored by its secretion of an array of powerful immunoregulatory and effector molecules. We report herein that macrophage migration inhibitory factor (MIF), a product of activated macrophages, sustains macrophage survival and function by suppressing activation-induced, p53-dependent apoptosis. Endotoxin administration to MIF(-/-) mice results in decreased macrophage viability, decreased proinflammatory function, and increased apoptosis when compared with wild-type controls. Moreover, inhibition of p53 in endotoxin-treated, MIF-deficient macrophages suppresses enhanced apoptosis and restores proinflammatory function. MIF inhibits p53 activity in macrophages via an autocrine regulatory pathway, resulting in a decrease in cellular p53 accumulation and subsequent function. Inhibition of p53 by MIF coincides with the induction of arachidonic acid metabolism and cyclooxygenase-2 (Cox-2) expression, which is required for MIF regulation of p53. MIF's effect on macrophage viability and survival provides a previously unrecognized mechanism to explain its critical proinflammatory action in conditions such as sepsis, and suggests new approaches for the modulation of innate immune responses.

Animals↗

PubMed2005

Purified beta-glucan as an abiotic feed additive up-regulates the innate immune response in immature chickens against Salmonella enterica serovar Enteritidis.

Functionally, the innate immune system of immature chickens is inefficient during the first week posthatch. This immunological inefficiency enables pathogens such as Salmonella enterica serovar Enteritidis (SE) to invade and colonize the visceral organs of immature chickens. The objective of this study was to evaluate the effect of purified beta-glucan as an immunomodulator of the innate immune response. beta-glucan, as a feed additive, significantly provided protection against SE organ invasion in young chickens (P<0.05). The functional efficiency of heterophils isolated from neonatal chickens fed a beta-glucan ration was significantly (P<0.05) up-regulated when compared to heterophils isolated from chickens fed a control ration as determined with an array of functional assays. Phagocytosis, bactericidal killing, and oxidative burst were significantly increased in heterophils isolated from chickens fed the purified beta-glucan ration (P<0.05). To our knowledge, this is the first report of a purified beta-glucan feed additive significantly decreasing the incidence of SE organ invasion in immature chickens and up-regulating the functional abilities of heterophils isolated from immature chickens against an invading pathogen, SE.

Administration, Oral↗

PubMed1997

Cytokine-induced apoptosis of human natural killer cells identifies a novel mechanism to regulate the innate immune response.

Interferon-gamma (IFN-gamma) is critical for an effective innate immune response against infection. A combination of interleukins (ILs) derived from activated T cells (IL-2) and monocytes (IL-12), or monocytes alone (IL-15 and IL-12), induces optimal production of IFN-gamma from natural killer (NK) cells. The mechanism by which human NK cells downregulate their production of IFN-gamma is unknown. Here we show that the same cytokines that induce human NK cell IFN-gamma production subsequently induce apoptosis of the NK cells. Fas, bcl-2, or bax do not appear to be involved in this process. The mechanism of cytokine-induced apoptosis of human NK cells appears to involve NK cell production of tumor necrosis factor-alpha (TNF-alpha). Neutralization of TNF-alpha or inhibition of TNF-alpha binding to the p80 TNF-alpha receptor partially inhibited apoptosis. Transforming growth factor-beta, which inhibits cytokine-induced NK cell production of IFN-gamma and TNF-alpha, also decreased cytokine-induced NK cell apoptosis. Costimulation of a CD3-CD56+ NK leukemia cell line with IL-2 and IL-12 or IL-15 and IL-12 induced apoptosis in vitro, which increased when combined with a chemotherapeutic agent. In summary, costimulation of human NK cells via the IL-2 receptor and the IL-12 receptor induces significant IFN-gamma production, followed by NK cell apoptosis and a decline in IFN-gamma production. Hence, cytokines that activate this innate immune response may also serve to limit it via apoptosis. This novel observation may have implications for the regulation of the innate immune response during infection, the toxicity of combination cytokine therapy, and the treatment of NK cell leukemia.

Apoptosis↗

PubMed2004

Complement-induced impairment of the innate immune system during sepsis.

The complement system is an integral part of innate immunity and is chiefly responsible for controlling bacterial infections, especially those involving gram- negative organisms. To accomplish this task, serum proteins engage in a series of enzymatic cascades. The cleaved proteins assemble pores on membranous structures, which lead to cell lysis. During this process, powerful inflammatory mediators are produced, including the anaphylatoxins, C5a, C3a, and the membrane attack complex (MAC). Under systemic inflammatory conditions, an overactive complement system may compromise the effectiveness of innate immunity. We review the detrimental effects that are caused by uncontrolled complement activation during sepsis.

Anaphylatoxins↗

PubMed2002

A component of innate immunity prevents bacterial biofilm development.

Antimicrobial factors form one arm of the innate immune system, which protects mucosal surfaces from bacterial infection. These factors can rapidly kill bacteria deposited on mucosal surfaces and prevent acute invasive infections. In many chronic infections, however, bacteria live in biofilms, which are distinct, matrix-encased communities specialized for surface persistence. The transition from a free-living, independent existence to a biofilm lifestyle can be devastating, because biofilms notoriously resist killing by host defence mechanisms and antibiotics. We hypothesized that the innate immune system possesses specific activity to protect against biofilm infections. Here we show that lactoferrin, a ubiquitous and abundant constituent of human external secretions, blocks biofilm development by the opportunistic pathogen Pseudomonas aeruginosa. This occurs at lactoferrin concentrations below those that kill or prevent growth. By chelating iron, lactoferrin stimulates twitching, a specialized form of surface motility, causing the bacteria to wander across the surface instead of forming cell clusters and biofilms. These findings reveal a specific anti-biofilm defence mechanism acting at a critical juncture in biofilm development, the time bacteria stop roaming as individuals and aggregate into durable communities.

Biofilms↗

PubMed2003

Molecular insights on the cerebral innate immune system.

All species need an immediate reply to the microbial pathogens that is part of an effective immune response and is essential for the survival of most organisms. This reply is known as the innate immune response and is characterized by the de novo production of mediators that either kill the microbes directly or activate phagocytic cells to ingest and kill them. The innate immune response can be driven through specific recognition systems, the best example being an interaction between the endotoxin lipopolysaccharide (LPS) and its receptors CD14 and Toll-like receptor 4 (TLR4). For a long time, the brain was considered to be a privileged organ from an immunological point of view, owing to its inability to mount an immune response and process antigens. Although this is partly true, the CNS shows a well-organized innate immune reaction in response to systemic bacterial infection and cerebral injury. The CD14 and TLR4 receptors are constitutively expressed in the circumventricular organs (CVOs), choroid plexus and leptomeninges. Circulating LPS is able to cause a rapid transcriptional activation of genes encoding CD14 and TLR2, as well as a wide variety of pro-inflammatory molecules in CVOs. A delayed response to LPS takes place in cells located at boundaries of the CVOs and in microglia across the CNS. Therefore, without having direct access to the brain parenchyma, pathogens have the ability to trigger an innate immune reaction throughout cerebral tissue. This review presents evidence supporting the existence of such a system in the brain, which is finely regulated at the transcription level. Transient activation of this system is not harmful toward neuronal elements.

Animals↗

PubMed2002

Innate immunity in host-microbial interactions: beyond B27 in the spondyloarthropathies.

The spondyloarthropathies are diseases influenced by genetic predisposition and, to a varying extent, infectious triggers. A causal role for bacterial infections is most clear for reactive arthritis. Recent insights into arthritogenic components of bacteria may set the stage for a better understanding of disease pathogenesis, the role of heat shock proteins in antigen processing and immune activation, and the adjuvant effect of CpG-DNA. Recent developments in the area of innate immunity broaden current concepts of genetically defined factors in host-pathogen interactions. In particular, the biology of toll-like receptors as important elements in the innate immune response to pathogens is being defined. These factors in innate immunity may have important implications for sequelae of infections, such as reactive arthritis.

Animals↗

PubMed2006

The nitrosative stress response of Staphylococcus aureus is required for resistance to innate immunity.

Staphylococcus aureus is a highly virulent human pathogen with an extensive array of strategies to subvert the innate immune response. An important aspect of innate immunity is the production of the nitrogen monoxide radical (Nitric Oxide, NO.). Here we describe an adaptive response to nitrosative stress that allows S. aureus to replicate at high concentrations of NO.. Microarray analysis revealed 84 staphylococcal genes with significantly altered expression following NO. exposure. Of these, 30 are involved with iron-homeostasis, potentially under the control of the Fur regulator. Another seven induced genes are involved in hypoxic/fermentative metabolism, including the flavohaemoprotein, Hmp. The SrrAB two-component system has been shown to regulate the expression of many of the NO.-induced metabolic genes. Indeed, inactivation of hmp, srrAB and fur resulted in heightened NO. sensitivity. Hmp was responsible for c. 90% of measurable staphylococcal NO. consumption and therefore critical for efficient NO. detoxification. While SrrAB was required for maximal hmp expression, srrAB mutants still exhibited significant NO. scavenging and NO.-dependent induction of hmp. Yet S. aureus lacking SrrAB were more sensitive to nitrosative stress than hmp mutants, indicating that the contribution of SrrAB to NO. resistance extends beyond the regulation of hmp expression. Both Hmp and SrrAB were required for full virulence in a murine sepsis model, however, only the attenuation of the hmp mutant was restored by the abrogation of host NO. production. Thus, the S. aureus Hmp protein has evolved to serve as an iNOS-dependent virulence determinant.

Animals↗

PubMed2005

Viral induction of central nervous system innate immune responses.

The ability of the central nervous system (CNS) to generate innate immune responses was investigated in an in vitro model of CNS infection. Cultures containing CNS cells were infected with mouse hepatitis virus-JHM, which causes fatal encephalitis in mice. Immunostaining indicated that viral infection had a limited effect on culture characteristics, overall cell survival, or cell morphology at the early postinfection times studied. Results from Affymetrix gene array analysis, assessed on RNA isolated from virally and sham-infected cultures, were compared with parallel protein assays for cytokine, chemokine, and cell surface markers. Of the 126 transcripts found to be differentially expressed between viral and sham infections, the majority were related to immunological responses. Virally induced increases in interleukin-6 and tumor necrosis factor alpha mRNA and protein expression correlated with the genomic induction of acute-phase proteins. Genomic and protein analysis indicated that viral infection resulted in prominent expression of neutrophil and macrophage chemotactic proteins. In addition, mRNA expression of nonclassical class I molecules H2-T10, -T17, -M2, and -Q10, were enhanced three- to fivefold in virus-infected cells compared to sham-infected cells. Thus, upon infection, resident brain cells induced a breadth of innate immune responses that could be vital in directing the outcome of the infection and, in vivo, would provide signals which would summon the peripheral immune system to respond to the infection. Further understanding of how these innate responses participate in immune protection or immunopathology in the CNS will be critical in efforts to intervene in severe encephalitis.

Animals↗