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Results for “Immunity, Innate”

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PubMed2005

Stimulation of innate immune responses by malarial glycosylphosphatidylinositol via pattern recognition receptors.

The glycosylphosphatidylinositol (GPI) anchor of Plasmodium falciparum is thought to function as a critical toxin that contributes to severe malarial pathogenesis by eliciting the production of proinflammatory responses by the innate immune system of mammalian hosts. Analysis of the fine structure of P. falciparum GPI suggests a requirement for the presence of both core glycan and lipid moieties in the recognition and signalling of parasite glycolipids by host immune cells. It has been demonstrated that GPI anchors of various parasitic protozoa can mediate cellular immune responses via members of the Toll-like family of pattern recognition receptors (TLRs). Recent studies indicate that GPI anchors of P. falciparum and other protozoa are preferentially recognized by TLR-2, involving the MyD88-dependent activation of specific signalling pathways that mediate the production of proinflammatory cytokines and nitric oxide from host macrophages in vitro. However, the contribution of malaria GPI toxin to severe disease syndromes and the role of specific TLRs or other pattern recognition receptors in innate immunity in vivo is only just beginning to be characterized. A better understanding of the molecular mechanisms underlying severe malarial pathogenesis may yet lead to substantial new insights with important implications for the development of novel therapeutics for malaria treatment.

Animals↗

PubMed2004

Comparative and functional genomics of the innate immune system in the malaria vector Anopheles gambiae.

In much of Africa, the mosquito Anopheles gambiae is the major vector of human malaria, a devastating infectious disease caused by Plasmodium parasites. Vector and parasite interact at multiple stages and locations, and the nature and effectiveness of this reciprocal interaction determines the success of transmission. Many of the interactions engage the mosquito's innate immunity, a primitive but very effective defense system. In some cases, the mosquito kills the parasite, thus blocking the transmission cycle. However, not all interactions are antagonistic; some represent immune evasion. The sequence of the A. gambiae genome revealed numerous potential components of the innate immune system, and it established that they evolve rapidly, as summarized in the present review. Their rapid evolution by gene family expansion diversification as well as the prevalence of haplotype alleles in the best-studied families may reflect selective adaptation of the immune system to the exigencies of multiple immune challenges in a variety of ecologic niches. As a follow-up to the comparative genomic analysis, the development of functional genomic methodologies has provided novel opportunities for understanding the immune system and the nature of its interactions with the parasite. In this context, identification of both Plasmodium antagonists and protectors in the mosquito represents a significant conceptual advance. In addition to providing fundamental understanding of primitive immune systems, studies of mosquito interactions with the parasite open unprecedented opportunities for novel interventions against malaria transmission. The generation of transgenic mosquitoes that resist malaria infection in the wild and the development of antimalarial 'smart sprays' capable of disrupting interactions that are protective of the parasite, or reinforcing others that are antagonistic, represent technical challenges but also immense opportunities for improvement of global health.

Animals↗

PubMed2005

TLR signaling tailors innate immune responses in human microglia and astrocytes.

The specific signals mediating the activation of microglia and astrocytes as a prelude to, or consequence of, CNS inflammation continue to be defined. We investigated TLRs as novel receptors mediating innate immune responses in human glial cells. We find that microglia express mRNA for TLRs 1-9, whereas astrocytes express robust TLR3, low-level TLR 1, 4, 5, and 9, and rare-to-undetectable TLR 2, 6, 7, 8, and 10 mRNA (quantitative real-time PCR). We focused on TLRs 3 and 4, which can signal through both the MyD88-dependent and -independent pathways, and on the MyD88-restricted TLR2. By flow cytometry, we established that microglia strongly express cell surface TLR2; TLR3 is expressed at higher levels intracellularly. Astrocytes express both cell surface and intracellular TLR3. All three TLRs trigger microglial activation upon ligation. TLR3 signaling induces the strongest proinflammatory polarizing response, characterized by secretion of high levels of IL-12, TNF-alpha, IL-6, CXCL-10, and IL-10, and the expression of IFN-beta. CXCL-10 and IL-10 secretion following TLR4 ligation are comparable to that of TLR3; however, other responses were lower or absent. TLR2-mediated responses are dominated by IL-6 and IL-10 secretion. Astrocytes respond to TLR3 ligation, producing IL-6, CXCL-10, and IFN-beta, implicating these cells as contributors to proinflammatory responses. Initial TLR-mediated glial activation also regulates consequent TLR expression; while TLR2 and TLR3 are subject to positive feedback, TLR4 is down-regulated in microglia. Astrocytes up-regulate all three TLRs following TLR3 ligation. Our data indicate that activation of innate immune responses in the CNS is not homogeneous but rather tailored according to cell type and environmental signal.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Innate immune responses induced by CpG oligodeoxyribonucleotide stimulation of ovine blood mononuclear cells.

Examples exist in the literature that demonstrate that treatment with immunostimulatory cytosine-phosphate-guanosine (CpG)-DNA can protect mice against infection by intracellular pathogens. There are, however, few studies reporting that CpG-DNA offers similar disease protection in other species. In this study, we assessed the potential of a class A and class B CpG oligodeoxynucleotide (ODN) to induce innate immune responses in sheep, an outbred species. Using peripheral blood mononuclear cells, we have for the first time demonstrated CpG-ODN-induced innate immune responses, including natural-killer-like activity [non-major histocompatibility complex (MHC)-restricted cytotoxicity], interferon-alpha secretion and 2'-5'A oligoadenylate synthetase activity, that could contribute to immune protection in sheep. The type and magnitude of these responses were dependent on ODN class and non-MHC-restricted killing was not associated with interferon-gamma production. The latter observation is in contrast with observations reported for mice and humans. These observations support the conclusion that differences in CpG-ODN-induced responses exist among species and that specific ODN sequences can significantly influence innate immune responses.

2',5'-Oligoadenylate Synthetase↗

PubMed2002

Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder.

OBJECTIVES: Children with autism spectrum disorder (ASD) frequently reveal various gastrointestinal (GI) symptoms that may resolve with an elimination diet along with apparent improvement of some of the behavioral symptoms. Evidence suggests that ASD may be accompanied by aberrant (inflammatory) innate immune responses. This may predispose ASD children to sensitization to common dietary proteins (DP), leading to GI inflammation and aggravation of some behavioral symptoms. METHODS: We measured IFN-gamma, IL-5, and TNF-alpha production against representative DPs [gliadin, cow's milk protein (CMP), and soy] by peripheral blood mononuclear cells (PBMCs) from ASD and control children [those with DP intolerance (DPI), ASD siblings, and healthy unrelated children]. We evaluated the results in association with proinflammatory and counter-regulatory cytokine production with endotoxin (LPS), a microbial product of intestinal flora and a surrogate stimulant for innate immune responses. RESULTS: ASD PBMCs produced elevated IFN-gamma and TNF-alpha, but not IL-5 with common DPs at high frequency as observed in DPI PBMCs. ASD PBMCs revealed increased proinflammatory cytokine responses with LPS at high frequency with positive correlation between proinflammatory cytokine production with LPS and IFN-gamma and TNF-alpha production against DPs. Such correlation was less evident in DPI PBMCs. CONCLUSION: Immune reactivity to DPs may be associated with apparent DPI and GI inflammation in ASD children that may be partly associated with aberrant innate immune response against endotoxin, a product of the gut bacteria.

Adolescent↗

PubMed2005

Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity.

Hepatitis C virus (HCV) is a global epidemic manifested mainly by chronic infection. One strategy that HCV employs to establish chronic infection is to use the viral Ser protease NS3/4A to cleave some unknown cellular targets involved in innate immunity. Here we show that the target of NS3/4A is the mitochondrial antiviral signaling protein, MAVS, that activates NF-kappaB and IFN regulatory factor 3 to induce type-I interferons. NS3/4A cleaves MAVS at Cys-508, resulting in the dislocation of the N-terminal fragment of MAVS from the mitochondria. Remarkably, a point mutation of MAVS at Cys-508 renders MAVS resistant to cleavage by NS3/4A, thus maintaining the ability of MAVS to induce interferons in HCV replicon cells. NS3/4A binds to and colocalizes with MAVS in the mitochondrial membrane, and it can cleave MAVS directly in vitro. These results provide an example of host-pathogen interaction in which the virus evades innate immunity by dislodging a pivotal antiviral protein from the mitochondria and suggest that blocking the cleavage of MAVS by NS3/4A may be applied to the prevention and treatment of HCV.

Amino Acid Sequence↗

PubMed2003

Innate immune responses following emergency vaccination against foot-and-mouth disease virus in pigs.

Inactivated "emergency" foot-and-mouth disease virus (FMDV) vaccine of high potency will induce early protection against the disease, implying a critical role for innate immune defences. At 3 and 6 days post-vaccination (dpv), there was no evidence of vaccine-induced specific anti-FMDV antibodies (Abs), nor enhanced uptake and destruction of opsonised virus by macrophages. Sera from vaccinates and control animals showed similar capacity to neutralise the virus, and were not different from the pre-vaccination sera. There were also no distinguishable changes in the distribution of the different peripheral blood leucocyte (PBL) subpopulations. Nor was any vaccine-induced increase in production of acute phase proteins noted. In contrast, chemotaxis assays identified an increase in PBL migratory activity which was vaccine-related. Furthermore, sera from 3 days post-vaccination contained elevated chemotactic potential. These results demonstrate that enhanced chemotaxis of cells of the innate immune defences, could play an important role during the early protection induced by emergency FMDV vaccines.

Acute-Phase Proteins↗

PubMed2005

Siglecs in innate immunity.

Siglecs are sialic acid-binding Ig-like lectins expressed in a highly specific manner, and which are implicated in signaling and adhesive functions. The CD33-related siglecs represent a distinct subgroup that is undergoing rapid evolution within the innate immune system, with the potential to trigger apoptosis and provide inhibitory signals. CD22 is a well-characterised B cell restricted siglec that has been shown to mediate both sialic acid-dependent and -independent signaling functions in B cell regulation. As endocytic receptors, siglecs provide portals of entry for certain viral and bacterial pathogens, as well as therapeutic opportunities for targeting innate immune cells in disease.

Animals↗

PubMed1983

Host specificity in mice selected for innate immunity to Nematospiroides dubius: infections with Nippostrongylus brasiliensis, Mesocestoides corti and Salmonella typhimurium.

The selection of mice for innate immunity to Nematospiroides dubius was not specific. Mice bred as refractory (R) to N. dubius infection were more refractory to primary infections with Nippostrongylus brasiliensis than other mice bred as liable (L) to infection with N. dubius. R and L, as well as randomly-bred (Rd) and inbred C3H mice were all immune to challenge infection with N. brasiliensis. Previous infections with N. brasiliensis failed to influence the course of N. dubius infections or the status of the selected mice as R, Rd and L to infection with N. dubius. R and L mice were equally susceptible to Mesocestoides corti infection but more resistant than Rd mice. R and L mice died sooner after infection with Salmonella typhimurium than Rd, although R survived longer than L mice.

Animals↗

PubMed1998

Functional roles of the lung surfactant proteins SP-A and SP-D in innate immunity.

The surfactant proteins SP-A and SP-D are known to play important roles in innate immunity in the lungs in the protection against a wide variety of potential pathogens, which include viruses, bacteria and fungi. Recognition of the pathogens is, in most cases, mediated by the Ca+2-dependent binding of the C-type lectin domains of SP-A, or SP-D, to carbohydrate structures on the surface of the microorganisms. This can cause agglutination of the pathogens and also possibly their enhanced killing and clearance by phagocytic cells which carry receptors for SP-A or SP-D. Both SP-A and SP-D are found in a number of other sites in the body, in various secretions, and therefore may play a wider protective role than was initially envisaged.

Bacteria↗

PubMed2006

ABIN-2 is required for optimal activation of Erk MAP kinase in innate immune responses.

The TPL-2 MEK kinase is essential for activation of the Erk MAP kinase pathway during innate immune responses. TPL-2 is found in complex with ABIN-2 (A20-binding inhibitor of NF-kappaB 2). Here, using antigen-presenting cells from ABIN-2-deficient mice, we show that ABIN-2 was required for optimal activation of Erk induced by receptors that signal via TPL-2, including Toll-like receptor 4 and tumor necrosis factor receptor 1 in macrophages, and CD40 in B cells. ABIN-2 was necessary for the maintenance of TPL-2 protein stability. In contrast, ABIN-2 deficiency did not affect agonist-induced regulation of transcription factor NF-kappaB. Stimulation of ABIN-2-deficient macrophages via Toll-like receptor 4 showed that different thresholds of Erk signaling were required for optimal induction of tumor necrosis factor and interleukin 1beta. Thus, ABIN-2 acts to positively regulate the Erk signaling potential by stabilizing TPL-2.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Molecular chaperone Hsp90 associates with resistance protein N and its signaling proteins SGT1 and Rar1 to modulate an innate immune response in plants.

SGT1 and Rar1 are important signaling components of resistance (R) gene-mediated plant innate immune responses. Here we report that SGT1 and Rar1 associate with the molecular chaperone Hsp90. In addition, we show that Hsp90 associates with the resistance protein N that confers resistance to tobacco mosaic virus. This suggests that Hsp90-SGT1-Rar1 and R proteins might exist in one complex. Suppression of Hsp90 in Nicotiana benthamiana plants shows that it plays an important role in plant growth and development. In addition, Hsp90 suppression in NN plants compromises N-mediated resistance to tobacco mosaic virus. Our results reveal a new role for SGT1- and Rar1-associated chaperone machinery in R gene-mediated defense signaling.

Amino Acid Sequence↗

PubMed2006

Cell-mediated cytotoxicity is the main innate immune mechanism involved in the cellular defence of gilthead seabream (Teleostei: Sparidae) against Enteromyxum leei (Myxozoa).

The cellular innate immune response of gilthead seabream (Sparus aurata L.) against the myxozoan Enteromyxum leei was studied. Enteromyxosis was transmitted by maintaining uninfected fish (recipients) together with infected animals. A group of fish not exposed to the infection served as controls. After 10, 22, 38, 52 and 108 days, control and recipient fish were sampled and leucocyte subpopulations and cellular immune responses (leucocyte peroxidases, phagocytosis, respiratory burst and cytotoxicity) of the head-kidney leucocytes were determined. The percentage of acidophilic granulocytes was significantly lower in non-parasitized and parasitized recipient fish than in control fish after 22 days but no significant differences were seen between non-parasitized and parasitized recipient animals. The leucocyte peroxidase content, phagocytosis and respiratory burst activity were seen to have decreased significantly at different sampling times in both non-parasitized and parasitized recipient fish with respect to the controls, whereas cytotoxic activity was up to 2.3 times higher than in control fish. Within the recipient group, little difference was observed in the studied parameters between non-parasitized and parasitized fish. These data demonstrate that cytotoxic activity may have an important role in the defence of gilthead seabream against the myxosporean E. leei. Immunological implications of E. leei infections are discussed.

Animals↗

PubMed2004

Innate immune responses in peptidoglycan recognition protein L-deficient mice.

Peptidoglycan recognition proteins (PGRPs) constitute a family of innate immune recognition molecules. In Drosophila, distinct PGRPs bind to peptidoglycans on gram-positive or gram-negative bacteria and provide essential signals upstream of the Toll and Imd pathways required for immunity against infection. Four PGRPs, PGRP-L, -S, -Ialpha, and -Ibeta, are expressed from three genes in mammals. In this paper, we provide direct evidence that the longest family member, PGRP-L, is a secreted serum protein with the capacity to multimerize. Using gene targeting to create PGRP-L-deficient mice, we demonstrate little contribution by PGRP-L to systemic challenge using gram-negative bacteria (Escherichia coli, slightly less susceptible), Gram-positive bacteria (Staphylococcus aureus), or yeast (Candida albicans). Peritoneal macrophages from PGRP-L-deficient mice produced decreased amounts of the inflammatory cytokines interleukin 6 and tumor necrosis factor alpha when stimulated with E. coli or lipopolysaccharide, but comparable amounts when stimulated with S. aureus, C. albicans, or their cell wall components. Additionally, these cells produced similar amounts of cytokines when challenged with gram-positive or -negative peptidoglycans. In contrast to its critical role in immunity in flies, PGRP-L is largely dispensable for mammalian immunity against bacteria and fungi.

Animals↗

PubMed2004

Innate immunity dictates cytokine polarization relevant to the development of pulmonary fibrosis.

New data support the importance of the innate immune response in the resolution or progression of pulmonary fibrosis. The presence of CXC chemokine receptor 3-expressing cells, specifically pulmonary NK cells, is necessary to produce IFN-gamma. This is critical in the polarization of the immune response to injury toward a favorable Th1 response and resolution. In contrast, a Th2 response is associated with progressive fibrosis.

Animals↗

PubMed2004

Mutations of genes involved in the innate immune system as predictors of sepsis in very low birth weight infants.

Mutations of genes involved in the innate immune system have been reported to be associated with an increased sepsis rate in adults. We determined the -159T mutation of the CD14 gene, the 896G mutation of the toll-like receptor 4 gene, the 3020insC mutation of the NOD2 gene (NOD2-3020insC), the IL-6 174G/C promoter polymorphism (IL6-174G/C), and the mannose-binding lectin genotype and their association to the subsequent development of neonatal sepsis in a large cohort of very low birth weight (VLBW) infants. Fifty (14%) of 356 VLBW infants developed blood culture-proven sepsis during their stay in the hospital. VLBW infants carrying the NOD2-3020insC allele (n =15) and the IL6-174G allele (n =121) had a significantly higher rate of blood culture-proven sepsis (33% and 19.8%, respectively) than VLBW infants without these genotypes (p = 0.046 and 0.035, respectively). In a multivariate logistic regression analysis, gestational age less than 28 wk (odds ratio, 3.2; 95% confidence interval, 1.7-6.0; p < 0.001) and the homozygous IL6-174G allele (odds ratio, 1.9; 95% confidence interval, 1.0-3.9; p = 0.039) were predictive for the development of sepsis, whereas the NOD2-3020insC allele was only of borderline significance (odds ratio, 3.2; 95% confidence interval, 1.0-10.4; p = 0.052). VLBW infants with repeated episodes of sepsis had higher frequencies of the NOD2-3020insC and IL6-174G allele. The increased sepsis rate of homozygous IL6-174G carriers was especially related to an increase in Gram-positive infections, and was not observed in VLBW infants who received prophylaxis with teicoplanin (frequency of Gram-positive sepsis in homozygous IL6-174G carriers without prophylaxis 16.5% versus 2.4% in homozygous IL6-174G carriers with prophylaxis; p = 0.033).

Adult↗

PubMed2006

Innate immunity in multiple sclerosis: myeloid dendritic cells in secondary progressive multiple sclerosis are activated and drive a proinflammatory immune response.

Multiple sclerosis (MS) is postulated to be a T cell-mediated autoimmune disease characterized clinically by a relapsing-remitting (RR) stage followed by a secondary progressive (SP) phase. The progressive phase is felt to be secondary to neuronal degenerative changes triggered by inflammation. The status of the innate immune system and its relationship to the stages of MS is not well understood. Dendritic cells (DCs) are professional APCs that are central cells of the innate immune system and have the unique capacity to induce primary immune responses. We investigated circulating myeloid DCs isolated directly from the blood to determine whether there were abnormalities in myeloid DCs in MS and whether they were related to disease stage. We found that SP-MS subjects had an increased percentage of DCs expressing CD80, a decreased percentage expressing PD-L1, and an increased percentage producing IL-12 and TNF-alpha compared with RR-MS or controls. A higher percentage of DCs from both RR and SP-MS patients expressed CD40 compared with controls. We then investigated the polarization effect of DCs from MS patients on naive T cells taken from cord blood using a MLR assay. Whereas DCs from RR-MS induced higher levels of Th1 (IFN-gamma, TNF-alpha) and Th2 (IL-4, IL-13) cytokines compared with controls, DCs from SP-MS only induced a polarized Th1 response. These results demonstrate abnormalities of DCs in MS and may explain the immunologic basis for the different stages and clinical patterns of MS.

Adult↗

PubMed2005

Natural killer cell receptors: regulating innate immune responses to hematologic malignancy.

Critical to innate immunity, the natural killer (NK) cell performs its function of immunosurveillance through its recognition of altered or missing self on damaged, infected, or transformed malignant cells. NK cell receptors responsible for detection of human leukocyte antigen (HLA) class I and class I-like proteins on potential target cells transmit inhibitory and activating signals that integrate to determine NK cell function. Advances in the fields of NK cell receptor biology and immunogenetics have enhanced our understanding of NK cell target recognition and may now guide studies to determine NK cell effects in the clinical setting. Analysis of NK cell receptor-ligand relationships, such as the inhibitory killer immunoglobulin-like receptors (KIRs) and their HLA class I ligands, has revealed the potential for NK cell-mediated benefit in allogeneic hematopoietic stem cell transplantation for hematologic malignancies.

Animals↗