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Results for “Innate Immunity Recognition”

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PubMed2007

Regulation of interferon-stimulated genes in peripheral blood leukocytes in pregnant and bred, nonpregnant dairy cows.

In ruminants, pregnancy results in up-regulation of a large number of IFN-stimulated genes (ISG) in the uterus. Recently, one of these genes was also shown to increase in peripheral blood leukocytes (PBL) during early pregnancy in sheep. Our working hypothesis is that conceptus signaling activates maternal gene expression in PBL in dairy cattle. The objectives of this study were to characterize ISG expression in PBL from pregnant (n = 20) and bred, nonpregnant (n = 30) dairy cows. Steady-state levels of mRNA for Mx1, Mx2, beta2-microglobulin, ISG-15, IFN regulatory factor-1, and IFN regulatory factor-2 were quantified. Holstein cows were synchronized to estrus and artificially inseminated (d 0). Blood samples were collected (coccygeal venipuncture) on d 0 and 16, 18, and 20 d after insemination for progesterone analysis and PBL isolation. Pregnancy was confirmed by transrectal ultrasonography at approximately 40 d after breeding. A status x day interaction was detected for Mx1, Mx2, and ISG-15 gene expression. When analyzed within day, levels of mRNA for ISG-15 and Mx1 were greater in pregnant compared with bred, nonpregnant cows on d 18 and 20, respectively. Expression of the Mx2 gene increased in the pregnant group compared with bred, nonpregnant cows on d 16, 18, and 20 after insemination. beta2-Microglobulin, IFN regulatory factor-1, and IFN regulatory factor-2 were not different between groups. The results clearly indicated that components of the innate immune response are activated in PBL during the period of pregnancy recognition and early embryo signaling. The physiological implications of these changes on maternal immune function are as yet unknown; however, they do provide a unique opportunity to identify bred, nonpregnant, cows 18 d after insemination in dairy cattle.

Animals↗

PubMed2006

Function of natural killer cells in immune defence against human leukaemia.

Although progress has been made in the management of acute leukaemias, most patients who fail to respond to front-line therapies with cytostatic agents and stem cell transplantation, or who relapse after an initial response die from progressive disease. Novel treatment modalities exploiting donor-derived natural killer (NK) cells generate an alloreactive graft-versus-leukaemia response and eliminate the residual malignant clones in transplanted patients. NK cells are components of the innate immunity playing an important role in the surveillance of human tumours. Recognition of malignant cells depends on a dynamic balance between antagonistic functions of an array of NK activating and inhibitory receptors. The natural cytotoxicity receptors (NCRs) are NK cell-specific and together with the NKG2D receptor are responsible for NK cell activation and tumour cell killing. The killer immunoglobulin-like receptors (KIRs) recruit phosphatases and can antagonise the activating signals and prevent the cytolytic NK cell programme. Understanding of the integration of these multiple signals at the molecular level is central for exploring the cytolytic function of NK cells. This review describes molecular mechanisms of NK receptor-ligand interactions controlling target cell recognition and addresses the potential of NK cells for the specific elimination of leukaemic clones with the goal of advancing immunotherapy of leukaemia.

Humans↗

PubMed2000

[Autoimmune processes and biocompatibility in local damage of endothelium of the heart and its vessels].

At immunoproductive processes in endothelium of patients with coronary atherosclerosis and endocarditis a phase dynamics of innate immunity represented by polytypic Ca(2+)-dependent autoprecipitating proteins of nonclonal recognition of surface cell membrane components (CMC) have been revealed. In case of coronary atherosclerosis the organism reaction to expressed CMC is manifested basically by intensified synthesis of cathodic complement-C3-similar autoprecipitin, but in case of endocarditis--by consumption of one with formation of anodic autoprecipitin and by intensified synthesis of autoprecipitating immunoglobulin G. These membranotropic autoimmune reactions are identical with the organism reactions to alien (heterologous) agents and differentially participate in development both of basic disease and perioperational complications after cardiac operations using trans- and implants, hence, they should be taken into account during membrane-stabilising and immunocorrecting therapy of recipients.

Cell Membrane↗

PubMed2006

The IFN-independent response to virus particle entry provides a first line of antiviral defense that is independent of TLRs and retinoic acid-inducible gene I.

The innate immune system responds to pathogen infection by eliciting a nonspecific immune response following the recognition of various pathogen-associated molecular patterns. TLRs and the RNA helicases retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 recognize foreign nucleic acid within endosomal and cytoplasmic compartments, respectively, initiating a signaling cascade that involves the induction of type I IFN through the transcription factors IFN regulatory factor (IRF) 3 and NF-kappaB. However, a recent paradigm has emerged in which bacterial DNA and double-stranded B-form DNA trigger type I IFN production through an uncharacterized TLR- and RIG-I-independent pathway. We have previously described a response in primary fibroblasts wherein the entry of diverse RNA- and DNA-enveloped virus particles is sufficient to induce a subset of IFN-stimulated genes and a complete antiviral response in an IRF3-dependent, IFN-independent manner. In this study, we show that the innate immune response to virus particle entry is independent of both TLR and RIG-I pathways, confirming the existence of novel innate immune mechanisms that result in the activation of IRF3. Furthermore, we propose a model of innate antiviral immunity in which exposure to increasing numbers of virus particles elevates the complexity of the cellular response from an intracellular, IFN-independent response to one involving secretion of cytokines and activation of infiltrating immune cells.

DEAD Box Protein 58↗

PubMed1998

[Complement and its role in immune response].

The complement system as a part of innate immunity is considered to provide rapid tough incomplete antimicrobial activity. However, besides providing a first-line defence, innate immunity plays additional important roles: it initiates and improves the slower, but more specific, acquired immune response. The recognition and destruction of noxious substances, as well as initiation of the acquired immune response, are accompanied by potentially hazardous inflammation. The inflammatory process has thus to be tightly regulated. In this overview, innate immunity and its interactions with acquired immunity are discussed with the main focus on the complement system. Our scientific interests are integrated into the discussion on complement.

Animals↗

PubMed2006

[Protective immunity against Mycobacterium tuberculosis].

Mycobacterium tuberculosis (MTB) is a facultative intracellular pathogen with which over a billion people have been infected and 3 million people die annually. The bacterium induces vigorous immune responses, yet evades host immunity, persisting within phagosomes of the infected macrophages. Thus, it is necessary to delineate that the virulence-related intracellular survival mechanism and the host immune responses to eradicate M. tuberculosis on the molecular basis. In this regard, recent findings clearly indicated that Toll-like receptors (TLRs) play an essential role in the recognition of MTB components by macrophages and dendritic cells, resulting in not only activation of innate immunity but also development of antigen-specific adaptive immunity. It has been also reported that induction of early death of the infected cells may be one of the strategy of host defense against MTB because macrophages go into apoptosis upon infection with MTB, resulting in suppression of the intracellular replication. Furthermore, recent report has shown that autophagy is induced by IFN-gamma and suppress intracellular survival of mycobacteria, suggesting that activation of autophagy pathway is required to overcome phagosome maturation arrest induced by MTB. In addition, it is known that IFN-gamma plays an important role in protection. The cytokine that is produced from NK cells and dendritic cells at the early period of infection strongly induces not only macrophage activation but also development of antigen-specific IFN-gamma-producing CD4+T cells. Since antigen-specific CD8+ T cells and CD1-restricted T cells are also reported to contribute to the protective immunity, cooperation of these T cells is essential for the host resistance. In this paper, I am going to summarize the recent progress of the understanding of protective immunity against MTB.

Antigens, CD1↗

PubMed2001

The role of Toll-like receptors in host defense against microbial infection.

The Toll family of proteins is central to Drosophila host defense against microbial infection. Maintained throughout evolution, mammalian Toll-like receptors (TLRs) are proteins that participate in innate immunity to bacteria in at least four ways. First, TLRs participate in the recognition of molecular patterns present on microorganisms. Second, TLRs are expressed at the interface with the environment, the site of microbial invasion. Third, activation of TLRs induces expression of co-stimulatory molecules and the release of cytokines that instruct the adaptive immune response. Fourth, activation of TLRs leads to direct antimicrobial effector pathways that can result in elimination of the foreign invader. The recent investigation of TLRs in these areas has provided new insights into mechanisms of innate immunity.

Animals↗

PubMed2005

Siderocalin (Lcn 2) also binds carboxymycobactins, potentially defending against mycobacterial infections through iron sequestration.

Siderocalin, a member of the lipocalin family of binding proteins, is found in neutrophil granules, uterine secretions, and at markedly elevated levels in serum and synovium during bacterial infection; it is also secreted from epithelial cells in response to inflammation or tumorigenesis. Identification of high-affinity ligands, bacterial catecholate-type siderophores (such as enterochelin), suggested a possible function for siderocalin: an antibacterial agent, complementing the general antimicrobial innate immune system iron-depletion strategy, sequestering iron as ferric siderophore complexes. Supporting this hypothesis, siderocalin is a potent bacteriostatic agent in vitro under iron-limiting conditions and, when knocked out, renders mice remarkably susceptible to bacterial infection. Here we show that siderocalin also binds soluble siderophores of mycobacteria, including M. tuberculosis: carboxymycobactins. Siderocalin employs a degenerate recognition mechanism to cross react with these dissimilar types of siderophores, broadening the potential utility of this innate immune defense.

Acute-Phase Proteins↗

PubMed2002

Decoding the patterns of self and nonself by the innate immune system.

The innate immune system evolved several strategies of self/nonself discrimination that are based on the recognition of molecular patterns demarcating infectious nonself, as well as normal and abnormal self. These patterns are deciphered by receptors that either induce or inhibit an immune response, depending on the meaning of these signals.

Animals↗

PubMed2005

The presumptive phosphatidylserine receptor is dispensable for innate anti-inflammatory recognition and clearance of apoptotic cells.

The role of the presumptive phosphatidylserine receptor (PSR) in the recognition and engulfment of apoptotic cells, and the antiinflammatory response they exert, has been of great interest. Genetic deficiency of PSR in the mouse is lethal perinatally, and results to date have been ambiguous with regard to the phagocytic and inflammatory phenotypes associated with that deficiency. Recently, we found that the specific functional recognition of apoptotic cells is a ubiquitous property of virtually all cell types, including mouse embryo fibroblasts, and reflects an innate immunity that discriminates live from effete cells. Taking advantage of this property of fibroblasts, we generated, PSR(+/+), PSR(+/-), and PSR(-/-) fibroblast cell lines to examine definitively the involvement of PSR in apoptotic recognition and inflammatory modulation. Our data demonstrate that PSR-deficient cells are fully competent to recognize, engulf, and respond to apoptotic cells. Signal transduction in the responder cells, including the activation of Akt and Rac1, is unimpaired in the absence of PSR. We confirm as well that PSR is localized predominantly to the nucleus. However, it does not play a role in pro-inflammatory transcription or in the anti-inflammatory modulation of that transcriptional response triggered by apoptotic cells. We conclude that PSR is not involved generally in either specific innate recognition or engulfment of apoptotic cells.

Animals↗

PubMed2007

Innate immune response by ficolin binding in apoptotic placenta is associated with the clinical syndrome of preeclampsia.

BACKGROUND: Unidentified circulating factors derived from placenta are thought to be responsible for the exaggerated systemic inflammation leading to preeclampsia. Our aim was to identify the circulating factors present in preeclampsia and to investigate their relationship to the underlying systemic immune response responsible for the associated clinical manifestations. METHODS: We obtained blood samples from pregnant women with and without preeclampsia and performed comparative proteomic analyses to identify the abnormal circulating factors by 2-dimensional polyacrylamide gel electrophoresis and matrix-assisted laser desorption ionization time of flight for protein separation and identification. In placentas from preeclamptic pregnancies, we evaluated the potential role of the candidate proteins identified by Western and immunohistochemical analysis. We also used proinflammatory cytokine antibody arrays to investigate local and systemic immune responses. RESULTS: We found that ficolins, the pattern-recognition proteins involved in the lectin-complement pathway, were differentially expressed in plasma from preeclamptic pregnancies. Ficolins were present in low concentrations in plasma but at high concentrations in the placenta, particularly in syncytiotrophoblasts undergoing apoptosis. The binding of ficolins in apoptotic trophoblasts induced innate immunity through local and systemic cytokine activation and correlated with the clinical manifestation of preeclampsia. CONCLUSIONS: We identified specific in vivo circulating factors derived from the placenta that are responsible for the local immune recognition and systemic inflammatory response in the development of clinical manifestations of preeclampsia. These findings may have predictive value and also therapeutic applications to lessen adverse clinical outcomes of preeclampsia.

Apoptosis↗

PubMed2006

Innate immune responses: crosstalk of signaling and regulation of gene transcription.

Innate immune responses to pathogens such as bacteria and viruses are triggered by recognition of specific structures of invading pathogens called pathogen-associated molecular patterns (PAMPs) by cellular pattern recognition receptors (PRRs) that are located at plasma membrane or inside cells. Stimulation of different PAMPs activates Toll-like receptor (TLR)-dependent and -independent signaling pathways that lead to activation of transcription factors nuclear factor-kappaB (NF-kappaB), interferon regulatory factor 3/7 (IRF3/7) and/or activator protein-1 (AP-1), which collaborate to induce transcription of a large number of downstream genes. This review focuses on the rapid progress that has recently improved our understanding of the crosstalk among the pathways and the precise regulation of transcription of the downstream genes.

Adaptor Proteins, Signal Transducing↗

PubMed2006

TLR9 and the recognition of self and non-self nucleic acids.

Toll-like receptors (TLRs) are involved in the innate recognition of foreign material and their activation leads to both innate and adaptive immune responses directed against invading pathogens. TLR9 is intracellularly expressed in the endo-lysosomal compartments of specialized immune cells. TLR9 is activated in response to DNA, in particular DNA containing unmethylated CpG motifs that are more prevalent in microbial than mammalian DNA. By detecting foreign DNA signatures TLR9 can sense the presence of certain viruses or bacteria inside the cell and mount an immune response. However, under certain conditions, TLR9 can also recognize self-DNA and this may promote immune pathologies with uncontrolled chronic inflammation. The autoimmune disease systemic lupus erythematosis (SLE) is characterized by the presence of immune stimulatory complexes containing autoantibodies against endogenous DNA and DNA- and RNA-associated proteins. Recent evidence indicates that the autoimmune response to these complexes involves TLR9 and the related single-stranded RNA-responsive TLRs 7 and 8, and therefore some breakdown in the normal ability of these TLRs to distinguish self and foreign DNA. Evidence suggests that immune cells use several mechanisms to discriminate between stimulatory and nonstimulatory DNA; however, it appears that TLR9 itself binds rather indiscriminately to a broad range of DNAs. We therefore propose that there is an additional recognition step by which TLR9 senses differences in the structures of bound DNA.

Autoantibodies↗

PubMed2001

Carrier protein-modulated presentation and recognition of an N-glycan: observations on the interactions of Man(8) glycoform of ribonuclease B with conglutinin.

Conglutinin is a serum lectin of the innate immune system, which binds high mannose N-glycans when these are appropriately presented on proteins. Here we use the conglutinin-ribonuclease B (RNaseB)-recognition system as a model to investigate the structural basis of selective recognition of protein-bound oligosaccharides by this carbohydrate-binding receptor. Conglutinin shows little binding to the isolated RNaseB-Man(8 )glycoform, and no binding to Man(5-6) glycoforms. In contrast, when the protein moiety is reduced and denatured we observe that conglutinin binds strongly to the isolated RNaseB-Man(8) glycoform and weakly to the Man(5-6) glycoforms. These results are in accord with observations on the binding to the N-glycans in the absence of carrier protein. NMR analyses of native RNaseB-Man(8) and -Man(5-6) glycoforms reveal that the three-dimensional structure of the protein moiety is essentially identical to that of non-glycosylated RNase (RNaseA). Thus there are no perceptible differences between the RNase protein forms that could account for differential availability of the N-glycan for conglutinin-binding. After reduction and denaturation, the NMR spectrum became typical of a non-structured polypeptide, although the conformational preferences of the N-glycosidic linkage were unchanged, and most importantly, the Man(8 )oligosaccharide retained the average conformational behavior of the free oligosaccharide irrespective of the carrier protein fold. This conformational freedom is clearly not translated into full availability of the oligosaccharide for the carbohydrate-recognition protein. We propose, therefore, that the differing bioactivity of the N-glycan is a reflection of the existence of different geometries of presentation of the carbohydrate determinant in relation to the protein surface within the glycan:carrier protein ensemble.

Carbohydrate Conformation↗

PubMed2004

Protein kinase C epsilon: a new target to control inflammation and immune-mediated disorders.

Recent advances in understanding the molecular basis for mammalian host immune responses to microbial invasion suggest that the first line of defense against microbes is the recognition of pathogen-associated molecular patterns by a set of germline-encoded receptors: the Toll-like receptors (TLRs). TLRs have been identified as being part of a large family of pathogen-recognition receptors that play a decisive role in the induction of both innate and adaptive immunity. Indeed, activation of T lymphocytes depends on their interaction with dendritic cells previously stimulated by TLR agonists such as bacterial lipopolysaccharide (LPS), a TLR-4 ligand. A novel PKC epsilon (epsilon) was recently found to be a critical component of TLR-4 signaling pathway and thereby to play a key role in macrophage and dendritic cell (DC) activation in response to LPS. Thus, controlling the kinase activity of PKC epsilon might represent an efficient strategy to prevent or treat certain inflammatory disorders of microbial origin.

Animals↗

PubMed2006

Solution structure of NOD1 CARD and mutational analysis of its interaction with the CARD of downstream kinase RICK.

NOD1 is a cytosolic signalling host pattern-recognition receptor composed of a caspase-activating and recruitment domain (CARD), a nucleotide-binding and oligomerization domain (NOD) and leucine-rich repeats. It plays a crucial role in innate immunity by activating the NF-kappaB pathway via its downstream effector the kinase RICK (RIP2) following the recognition of a specific bacterial ligand. RICK is recruited by NOD1 through interaction of their respective CARDs. Here we present the high resolution NMR structure of the NOD1 CARD. It is generally similar to other CARDs of known structure, consisting of six tightly packed helices, although the length and orientation of the last helix is unusual. Mutations in both the NOD1 and RICK CARD domains were assayed by immuno-precipitation of cell lysates and in vivo NF-kappaB activation in order to define residues important for CARD-CARD interaction and downstream signalling. The results show that the interaction is critically dependent on three acidic residues on NOD1 CARD and three basic residues on RICK CARD and thus is likely to have a strong electrostatic component, similar to other characterised CARD-CARD interactions.

Amino Acid Sequence↗

PubMed1997

The natural killer gene complex: a genetic basis for understanding natural killer cell function and innate immunity.

The natural killer gene complex encodes proteins, some of which are structurally unrelated, that impact on NK-cell function. Detailed analyses have indicated that these molecules are involved in NK-cell recognition, activation, and inhibition. The importance of this genomic region is highlighted by studies indicating that NKC-associated genes significantly influence NK cell-mediated innate host defense against life-threatening pathogens and that the NKC is conserved among diverse species. Thus, further elucidation of the NKC and its gene products will provide a genetic basis for understanding innate immunity and NK-cell activity at the molecular level.

Animals↗

PubMed2025

Dengue Virus Replicative-Form dsRNA Is Recognized by Both RIG-I and MDA5 to Activate Innate Immunity.

RIG-I like receptors (RLRs) are a family of cytosolic RNA sensors that sense RNA virus infection to activate innate immune response. It is generally believed that different RNA viruses are recognized by either RIG-I or MDA5, two important RLR members, depending on the nature of pathogen-associated molecular patterns (PAMPs) that are generated by RNA virus replication. Dengue virus (DENV) is an important RNA virus causing serious human diseases. Despite extensive investigations, the molecular basis of the DENV PAMP recognized by the host RLR has been poorly defined. Here, we demonstrated that the DENV infection-induced interferon response is dependent upon both RIG-I and MDA5, with RIG-I playing a predominant role. Next we purified the DENV PAMP RNA from the DENV-infected cells, and demonstrated that the purified DENV PAMP is viral full-length double-stranded RNA bearing 5'ppp modifications, likely representing the viral replicative-form RNA. Finally, we confirmed the nature of the DENV PAMP by reconstituting the viral replicative-form RNA from in vitro synthesized DENV genomic RNA. In conclusion, our work not only defined the molecular basis of the RLR-PAMP interaction during DENV infection, but also revealed the previously underappreciated recognition of a distinct moiety of the same PAMP by different RLRs in innate immunity against RNA viruses.

Interferon-Induced Helicase, IFIH1↗