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Results for “Immunity, Innate”

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At least 415 records · Page 23Linked to original sources
PubMed2001

Innate immunity to viruses: control of vaccinia virus infection by gamma delta T cells.

The existence of gammadelta T cells has been known for over 15 years, but their significance in innate immunity to virus infections has not been determined. We show here that gammadelta T cells are well suited to provide a rapid response to virus infection and demonstrate their role in innate resistance to vaccinia virus (VV) infection in both normal C57BL/6 and beta TCR knockout (KO) mice. VV-infected mice deficient in gammadelta T cells had significantly higher VV titers early postinfection (PI) and increased mortality when compared with control mice. There was a rapid and profound VV-induced increase in IFN-gamma-producing gammadelta T cells in the peritoneal cavity and spleen of VV-infected mice beginning as early as day 2 PI. This rapid response occurred in the absence of priming, as there was constitutively a significant frequency of VV-specific gammadelta T cells in the spleen in uninfected beta TCR KO mice, as demonstrated by limiting dilution assay. Also, like NK cells, another mediator of innate immunity to viruses, gammadelta T cells in uninfected beta TCR KO mice expressed constitutive cytolytic activity. This cytotoxicity was enhanced and included a broader range of targets after VV infection. VV-infected beta TCR KO mice cleared most of the virus by day 8 PI, the peak of the gammadelta T cell response, but thereafter the gammadelta T cell number declined and the virus recrudesced. Thus, gammadelta T cells can be mediators of innate immunity to viruses, having a significant impact on virus replication early in infection in the presence or absence of the adaptive immune response.

Animals↗
PubMed2026

Heightened frequency of innate immunity risk alleles in south Indian diabetics with urinary tract infections.

Urinary Tract Infections are an emerging public health concern among individuals with diabetes mellitus, particularly in South Asia where high disease burden, genetic diversity and increasing drug resistance contribute to the progressive increase in burden. While metabolic and clinical risk factors are well studied, the role of host innate immune genetic variations in shaping UTI susceptibility among diabetics remains poorly understood. This case-control study evaluated functional polymorphisms in key innate immunity genes, TLR4 (rs4986790, rs4986791), MBL2 (rs1800450) and LTA (rs909253), in 70 T2D patients with UTI and 70 T2D patients without UTI. Genotyping was performed using 5'-hydrolysis probe assay. Across all the four SNPs, the risk allele consistently showed a higher frequency among T2D patients with UTI, indicating a directional trend suggestive of cumulative susceptibility. Also, a strong and significant protective association was observed for the LTA rs909253 'G' allele, which was less frequent in cases than controls. This low-inflammatory 'AA' genotype was also markedly enriched among rUTI cases compared to controls. Clinically, 34.3% of cases experienced rUTIs. This observed directional increase of risk alleles across all four innate immunity SNPs, along with the protective role of LTA rs909253 'G' allele, highlights cumulative host genetic modulation of UTI risk in T2D and supports translational use of genetic profiling in infection risk prediction.

Humans↗
PubMed2004

Suppression of innate immunity by acute ethanol administration: a global perspective and a new mechanism beginning with inhibition of signaling through TLR3.

Excessive consumption of ethanol (EtOH) suppresses innate immunity, but the mechanisms have not been fully delineated. The present study was conducted to determine whether EtOH suppresses TLR signaling in vivo in mice and to characterize the downstream effects of such suppression. Degradation of IL-1R-associated kinase 1 induced by a TLR3 ligand in peritoneal cells ( approximately 90% macrophages) was suppressed by EtOH. Phosphorylation of p38 kinase in peritoneal macrophages (F4/80(+)) was suppressed, as was nuclear translocation of p-c-Jun and p65 in peritoneal cells. EtOH decreased IL-6 and IL-12 (p40), but did not significantly affect IL-10 in peritoneal lavage fluid or in lysates of peritoneal cells. Changes in cytokine mRNAs (by RNase protection assay) in macrophages isolated by cell sorting or using Ficoll were generally consistent with changes in protein levels in cell lysates and peritoneal lavage fluid. Thus, suppression of TLR signaling and cytokine mRNA occurred in the same cells, and this suppression generally corresponded to changes in i.p. and intracellular cytokine concentrations. DNA microarray analysis revealed the suppression of an IFN-related amplification loop in peritoneal macrophages, associated with decreased expression of numerous innate immune effector genes (including cytokines and a chemokine also suppressed at the protein level). These results indicate that EtOH suppresses innate immunity at least in part by suppressing TLR3 signaling, suppressing an IFN-related amplification loop, and suppressing the induction of a wide range of innate effector molecules in addition to proinflammatory cytokines and chemokines.

Animals↗
PubMed2003

Innate immune responses to mycobacteria and the downregulation of atopic responses.

PURPOSE OF REVIEW: Exposure to certain environmental microorganisms can promote the induction of T regulatory cells via the innate immune system. This review explores the possibility that reduced exposure to such organisms is leading to increased immunoregulatory disorders in a subset of individuals in whom this regulatory T-cell-inducing pathway is less efficient. We concentrate on mycobacteria and on asthma, because these are well documented. RECENT FINDINGS: The blood cells of the children of farmers, who are partly protected from allergies, express increased levels of messenger RNA encoding CD14 and TLR2, and polymorphisms of CD14 are linked to allergic manifestations in some studies. Polymorphisms of TLR2 (which recognizes mycobacterial components in concert with CD14) are involved in the pattern of response to mycobacteria, and in the type of leprosy that develops. Similarly, polymorphisms of Nramp1, which affect the response to mycobacteria, are linked with the diseases of immunodysregulation that are increasing in parallel with allergic disorders. Moreover, congenic mice bearing different variants of Nramp1 differ in their allergic responses. These parallels are suggestive, in view of the observation that a saprophytic environmental mycobacterium is a potent inducer of regulatory T cells, and has shown significant effects in several phase I/II studies in man. SUMMARY: The components of the innate immune system that are involved in responses to mycobacteria overlap with those implicated in allergic disorders. Polymorphisms might define the subset of individuals who develop immunoregulatory disorders. Understanding the role of the innate immune system will facilitate the design of clinical trials using microbial products.

Animals↗
PubMed2005

Innate immunity and the lung: defense at the interface between host and environment.

The lung serves as a major interface between the host and the external environment. As such, numerous lines of defense protect the host from inhaled potential pathogens. A breach in pulmonary innate immunity can lead to deleterious outcomes, such as pneumonia and disseminated infection. Pulmonary innate immunity, the first line of defense, is mediated by airway and alveolar epithelial cells as well as resident and recruited leukocytes. This article will discuss the key cellular and secreted components of the pulmonary innate immune system.

Animals↗
PubMed2006

Innate immunity triggers oligodendrocyte progenitor reactivity and confines damages to brain injuries.

Regarded as a damaging reaction, innate immune response can either improve or worsen brain outcome after injury. Hence, inflammatory molecules might modulate cell susceptibility or healing events. The remyelination that follows brain lesions is dependent on the recruitment of oligodendrocyte progenitor cells (OPCs) and expression of genes controlling differentiation and myelin production, such as Olig1 and Olig2 bHLH transcription factors. We aimed to determine how innate immunity affects these processes. Here we report that lipopolysaccharide (LPS) infusion triggered OPC reactivity. Acute inflammation changed the distribution of Olig1- and Olig2-expressing cells following chemical demyelination, enhanced reappearance of transcription signals linked to remyelination and rapidly cleared myelin debris. Although cells expressing Olig1, Olig2, and proteolipid protein were attracted to demyelinated sites in the course of chronic inflammation, myelin loss was not associated with the effects of inflammation on OPC reactivity. In addition, the beneficial properties of brain immunity are broadened to an aggressive model of injury, wherein LPS through Toll-like receptor 4 (TLR4) reduced surfactant-mediated damage while anti-inflammatory treatment enlarged the lesion. In conclusion, TLR4 activation in microglia is a powerful mechanism for improving repair at the remyelination level and protecting the cerebral tissue in presence of agents with strong cytolytic properties.

Animals↗
PubMed2005

Innate immunity influences long-term outcomes after human lung transplant.

RATIONALE: Lung transplantation is characterized by very high rates of acute and chronic allograft rejection. We hypothesize that activation of innate immunity augments adaptive immunity, leading to rejection after lung transplantation. In support of this idea, we have recently demonstrated that lung recipients heterozygous for either of two functional polymorphisms (Asp299Gly or Thr399Ile) in Toll-like receptor 4 (TLR4) associated with endotoxin hyporesponsiveness have decreased acute rejection over the first 6 months after transplant. OBJECTIVES: In the current analysis, we sought to extend our initial observations and investigate the effect of these TLR4 polymorphisms on post-transplant acute rejection beyond the first 6 months, bacterial infections, bronchiolitis obliterans syndrome, and survival. METHODS: Genotyping was performed on 170 lung transplant recipients. MEASUREMENTS AND MAIN RESULTS: Recipients heterozygous for either Asp299Gly or Thr399Ile had significantly reduced frequency (p = 0.02) and incidence of acute rejection (p = 0.04) sustained over 3 years after transplant, but no differences were observed in the overall onset of bronchiolitis obliterans syndrome. A trend, however, toward reduced onset of bronchiolitis obliterans syndrome grade 2 or 3 was observed in TLR4 heterozygotes. CONCLUSION: Our results demonstrate that activation of recipient innate immune responses through TLR4 has a significant and sustained effect on the development of acute lung rejection. Targeting innate immune signaling represents a promising area for future clinical studies in the prevention of lung allograft rejection.

Adult↗
PubMed2005

Generation of improved mucosal vaccines by induction of innate immunity.

Vaccination is a highly effective means of disease prevention and has saved countless lives worldwide over the past 200 years. Traditional vaccines based on killed and attenuated organisms and inactivated toxins have constituted the majority of clinically used vaccines to date, but novel vaccines based on subunits of these organisms will be increasingly represented in future. In contrast to attenuated and whole cell vaccines, subunit vaccines do not generally contain immune-stimulatory components and are poorly immunogenic. As a result, new, potent and safe adjuvants and delivery systems are needed to enhance the immunogenicity of these vaccines. Furthermore, there is a drive to replace injected vaccines with those that can be administered by mucosal routes. Since the induction of innate immunity is crucial for vaccines to elicit potent antigen specific immune responses, a greater understanding of innate immunity at mucosal surfaces and the mechanism of action of adjuvants and delivery systems is required.

Adjuvants, Immunologic↗
PubMed2006

CCR4 is a key modulator of innate immune responses.

CCR4 is recognized as a key receptor in Th2-associated immune processes, although very little is known about its role in innate immunity. Previous studies reported increased resistance to LPS-induced lethality in CCR4(-/-) mice compared with wild-type mice. This study demonstrates that CCR4(-/-) mice are similarly resistant to challenge with other TLR agonists, as well as bacterial peritonitis. Resistance was associated with enhanced early leukocyte recruitment, increased TLR expression, a skewed type 2 cytokine/chemokine profile, and improved bacterial clearance. Macrophages from CCR4(-/-) mice exhibited many features consistent with alternative activation, including elevated secretion of type 2 cytokines/chemokines and the found in inflammatory zone 1 (FIZZ1) protein. MyD88-dependent NF-kappaB signaling was significantly down-regulated in CCR4(-/-) macrophages, whereas p38 MAPK and JNK activation were conversely increased. These data stress the importance of CCR4 in macrophage differentiation and innate immune responses to pathogens, as well as the involvement of chemokine receptor expression in TLR signaling regulation.

Animals↗
PubMedDate not supplied

A review of the interaction of Bacillus anthracis with cells of the innate immune response.

Bacillus anthracis spores cause natural infections and can be used as biological weapons. The innate immune response is the first line of defence against invading pathogens and is likely to play a central role in this acute infection. To date the immune evasion mechanisms of B. anthracis are not well understood. Infection by inhalation with B. anthracis, the etiological agent of anthrax, is almost always lethal, yet cutaneous infections usually remain localized and resolve spontaneously in the majority of cases. Neutrophils are typically recruited to cutaneous but seldom to other forms of anthrax infections, raising the possibility that neutrophils kill B. anthracis. This is an overview of the interaction of B. anthracis with innate immune cells which also focuses on recent data on the role neutrophils play in anthrax pathogenesis. These data suggest that the timely recruitment of neutrophils can control the cutaneous and possibly other forms of B. anthracis infections and that the neutrophil granule proteins, a-defensins, play an important role in the potent anti-B. anthracis activity of neutrophils.

Animals↗
PubMed2003

Treponemal phospholipids inhibit innate immune responses induced by pathogen-associated molecular patterns.

Host innate immune responses to microbial components, known as pathogen-associated molecular patterns (PAMPs), are regulated and modified by cellular receptors and serum proteins, including Toll-like receptors (TLRs), CD14, and LPS-binding protein (LBP). We demonstrated that a treponemal membrane lipid inhibited PAMPs-induced immune responses. The chemical structure of the lipid was elucidated as a phosphatidylglycerol (PG) derivative, which is scarce in most mammalian tissues, but relatively abundant in treponemal membrane lipids. Natural and synthetic PG counterparts as well as related natural anionic phospholipids, phosphatidylinositol, phosphatidylserine, and cardiolipin, also demonstrated an inhibitory effect. Further, we noted that PG inhibited PAMPs-induced immune responses by blocking the binding of PAMPs with LBP and CD14. In addition, PG decreased proinflammatory cytokine production in serum of LPS-injected mice and depressed abscess formation in mice infected with treponemes. These results suggest that treponemal phospholipid interfere the function of LBP/CD14 and act as a modulator of innate immune responses.

Abscess↗
PubMed2004

Escherichia coli and Staphylococcus aureus elicit differential innate immune responses following intramammary infection.

Staphylococcus aureus and Escherichia coli are among the most prevalent species of gram-positive and gram-negative bacteria, respectively, that induce clinical mastitis. The innate immune system comprises the immediate host defense mechanisms to protect against infection and contributes to the initial detection of and proinflammatory response to infectious pathogens. The objective of the present study was to characterize the different innate immune responses to experimental intramammary infection with E. coli and S. aureus during clinical mastitis. The cytokine response and changes in the levels of soluble CD14 (sCD14) and lipopolysaccharide-binding protein (LBP), two proteins that contribute to host recognition of bacterial cell wall products, were studied. Intramammary infection with either E. coli or S. aureus elicited systemic changes, including decreased milk output, a febrile response, and induction of the acute-phase synthesis of LBP. Infection with either bacterium resulted in increased levels of interleukin 1beta (IL-1beta), gamma interferon, IL-12, sCD14, and LBP in milk. High levels of the complement cleavage product C5a and the anti-inflammatory cytokine IL-10 were detected at several time points following E. coli infection, whereas S. aureus infection elicited a slight but detectable increase in these mediators at a single time point. Increases in IL-8 and tumor necrosis factor alpha were observed only in quarters infected with E. coli. Together, these data demonstrate the variability of the host innate immune response to E. coli and S. aureus and suggest that the limited cytokine response to S. aureus may contribute to the well-known ability of the bacterium to establish chronic intramammary infection.

Acute-Phase Proteins↗
PubMed2006

Molecular basis for invertebrate innate immune recognition of (1-->3)-beta-D-glucan as a pathogen-associated molecular pattern.

Innate immunity responds to various pathogen-associated molecular patterns (PAMPs) to evaluate the biological nature of foreign materials by using limited numbers of receptors. Analyses of interactions between PAMPs and its receptors are essential to understand the molecular basis regarding how we discriminate self and non-self materials. Upon infection of horseshoe crabs, an arthropod species, rapid hemolymph coagulation is induced to engulf invading microorganisms by a cascade-type reaction. The reaction is very sensitive to lipopolysaccharide and (1-->3)-beta-D-glucans on Gram-negative bacteria and fungi, respectively, and hence is utilized as assay reagents that detect and quantitate these PAMPs with a name of "limulus test." In this mini-review, recognition of (1-->3)-beta-D-glucans by a unique serine protease zymogen factor G of horseshoe crab is described. Molecular dissection and detailed kinetic analyses have revealed that multivalent binding to polymers of a simple target structure is one of the principles that allows stable and specific recognition of PAMPs by pattern recognition receptors in innate immunity.

Animals↗
PubMed2006

Lysozyme-modified probiotic components protect rats against polymicrobial sepsis: role of macrophages and cathelicidin-related innate immunity.

Severe sepsis is associated with dysfunction of the macrophage/monocyte, an important cellular effector of the innate immune system. Previous investigations suggested that probiotic components effectively enhance effector cell functions of the immune system in vivo. In this study, we produced bacteria-free, lysozyme-modified probiotic components (LzMPC) by treating the probiotic bacteria, Lactobacillus sp., with lysozyme. We showed that oral delivery of LzMPC effectively protected rats against lethality from polymicrobial sepsis induced by cecal ligation and puncture. We found that orally administrated LzMPC was engulfed by cells such as macrophages in the liver after crossing the intestinal barrier. Moreover, LzMPC-induced protection was associated with an increase in bacterial clearance in the liver. In vitro, LzMPC up-regulated the expression of cathelicidin-related antimicrobial peptide (CRAMP) in macrophages and enhanced bactericidal activity of these cells. Furthermore, we demonstrated that surgical stress or cecal ligation and puncture caused a decrease in CRAMP expression in the liver, whereas enteral administration of LzMPC restored CRAMP gene expression in these animals. Using a neutralizing Ab, we showed that protection against sepsis by LzMPC treatment required endogenous CRAMP. In addition, macrophages from LzMPC-treated rats had an enhanced capacity of cytokine production in response to LPS or LzMPC stimulation. Together, our data suggest that the protective effect of LzMPC in sepsis is related to an enhanced cathelicidin-related innate immunity in macrophages. Therefore, LzMPC, a novel probiotic product, is a potent immunomodulator for macrophages and may be beneficial for the treatment of sepsis.

Animals↗
PubMed2006

Innate immune response gene expression profiles of N9 microglia are pathogen-type specific.

Glial cells, particularly microglia, are thought to play a pivotal role in initiating and guiding innate immune responses to CNS infections and in perpetuating inflammation and pathology in CNS diseases such as multiple sclerosis and Alzheimer's disease. We describe here the development and use of a new microarray designed to specifically profile transcript expression of innate immunity genes. Microarray analysis validated by quantitative PCR demonstrated an extensive range of pattern recognition receptor gene expression in resting N9 microglia, including Toll-like receptors, scavenger receptors and lectins. Stimulation with LPS or infection with virus modulated pattern recognition receptor, cytokine, chemokine and other innate immune transcripts in a distinct and stimulus-specific manner. This study demonstrates that a single glial cell phenotype has an innate capability to detect infection, determine its form and generate specific responses.

Alphavirus Infections↗
PubMed2006

Innate immune molecular connections between atherosclerosis and statins: can the clinical laboratory venture beyond C-reactive protein?

Innate immunity was originally envisioned as a nonspecific host response to microbial pathogens. However, in the past few years, immunologists have discovered toll-like receptors (TLRs) and their role in recognizing pathogen-associated molecular patterns. TLRs and other components of innate immunity now help to explain the pathologic mechanisms underlying many common diseases, including atherosclerosis. At this time, C-reactive protein is the most useful biomarker for evaluating the inflammatory aspect of atherogenesis. Yet, operating beneath this commonly assayed biomarker are other components of the immune response. These inflammatory components of atherosclerosis and their genetic variations provide important insights. Today, novel antiatherogenic therapies are emerging, and at the same time a molecular groundwork is being laid for the genetic testing of statin efficacy. However, the adoption of clinical testing will need to wait until new therapeutic choices enter medical practice.

Animals↗