Home About us Contact
|
Home About us Contact | ||
|
|
||
Adaptive Immunity (adaptive + immunity)
Selected AbstractsThe Effect of Acute Ethanol Intoxication on Salivary Proteins of Innate and Adaptive ImmunityALCOHOLISM, Issue 4 2008Napoleon Waszkiewicz Background:, Human salivary proteins: peroxidase, lysozyme, lactoferrin, and IgA, participate in the protection of oral tissues, as well as upper digestive and respiratory tracts, against a number of microbial pathogens. In the current study, we investigated the effect of acute consumption of a large dose of ethanol on representative human salivary proteins of the innate and adaptive immune systems. Methods:, Eight healthy male volunteers drank an average of 2.0 g (1.4 to 2.5 g/kg) body weight of ethanol, in the form of vodka, in the 6-hour period. Samples of resting whole saliva were collected 12 hours before, then 36 and 108 hours after, the alcohol consumption. The levels of total protein, immunoglobulin A, lysozyme and lactoferrin as well as peroxidase activity were determined in saliva. Results:, At 36 hours after alcohol consumption, salivary protein and lysozyme concentrations as well as peroxidase activity were significantly decreased (p = 0.002, p = 0.043, and p = 0.003, respectively), in comparison to the values obtained at 12 hours before drinking. Between 36 and 108 hours after alcohol consumption, the salivary protein and lysozyme concentrations, as well as peroxidase activity showed a tendency to increase, although at 108 hours after the drinking session, the concentration of protein and peroxidase activity were still significantly lower than before drinking. There was no significant change in the level of lactoferrin, after the drinking session. The salivary concentration of IgA tended to increase at 36 hours after alcohol consumption, and at 108 hours it was significantly higher (p = 0.028), when compared to IgA concentration in the saliva collected before drinking (from 8% to 26% and 32% of total protein content, respectively). Conclusion:, Our report is the first to show that acute ingestion of relatively large, yet tolerable dose of alcohol, significantly disturbs salivary antimicrobial defense system. Reduced lysozyme level and decreased peroxidase activity may contribute to increased susceptibility to infections, when acute alcohol intake coincides with exposure to pathogens. [source] Monocyte Chemoattractant Protein-1 (CCL2) in Inflammatory Disease and Adaptive Immunity: Therapeutic Opportunities and ControversiesMICROCIRCULATION, Issue 3-4 2003CHRISTINE DALY ABSTRACT Monocyte chemoattractant protein (MCP)-1 (CCL2) specifically attracts monocytes and memory T cells. Its expression occurs in a variety of diseases characterized by mononuclear cell infiltration, and there is substantial biological and genetic evidence for its essential role in atherosclerosis and multiple sclerosis. Despite intensive screening, there are as yet no small-molecule antagonists of the receptor of MCP-1/CCL2, CCR2. However, biological agents, including antibodies and inhibitory peptides, have been developed and may be useful for these indications. Recent evidence from genetically modified mice indicates that MCP-1 and CCR2 have unanticipated effects on T helper (Th) cell development. However, unlike the identical phenotypes of MCP-1/CCL2,/, and CCR2,/, mice in inflammatory diseases, the phenotypes of these mice are disparate in adaptive immunity: MCP-1 stimulates Th2 polarization, whereas CCR2 activation stimulates Th1 polarization. This presents both a challenge and an opportunity for targeting the MCP-1/CCL2/CCR2 axis in disease. [source] Immune response profiles in human skinBRITISH JOURNAL OF DERMATOLOGY, Issue 2007T. Meyer Summary In addition to the function as a physical barrier human skin has been shown to be an important immune organ displaying various defense mechanisms, which can be divided into three major functional compartiments: (i) Epithelial defense, which is characterized by antimicrobial peptides and proteins (AP) and which can be induced in inflammatory lesions but also in the absence of inflammation. (ii) Innate-inflammatory immunity, which involves recognition of microbial compounds by particular receptors like Toll-like receptors (TLR) and subsequent activation of signalling pathways resulting in expression of pro-inflammatory cytokines and interferons, as well as genes of adaptive immunity. Interferon , (IFN,) produced by plasmacytoid dendritic cells (DC) may stimulate myeloid DC to produce IL-12 resulting in classical T-cell activation or to produce IL-23 activating IL-17 producing T-cells (IL-23/IL-17 pathway). (iii) Adaptive immunity, which is based on antigen presenting cells, T-cells and B-cells and which is characterized by specificity and memory. In contrast to epithelial defense and innate-inflammatory immunity, adaptive immune functions provide slowly reacting protection. Recent improvements of our knowledge of dysregulated immune pathways associated with inflammatory skin diseases represent an important basis of novel immunomodulatory treatment modalities. [source] Alcohol Exposure Impairs Myeloid Dendritic Cell Function in Rhesus MacaquesALCOHOLISM, Issue 9 2009Robert W. Siggins Background:, Alcohol intoxication suppresses both the innate and adaptive immunities. Dendritic cells (DCs) are the major cell type bridging the innate and acquired immune responses. At the present time, the effects of alcohol on DC development in hematopoietic tissues and the functional activities of DCs are incompletely elucidated. This study investigated the impact of chronic alcohol exposure on the alteration of hematopoietic precursor cell and DC populations in the bone marrow and peripheral blood of rhesus macaques. Methods:, Rhesus macaques were administered alcohol or isocaloric sucrose daily for a period of 3 months through surgically implanted gastric catheters. Peripheral blood mononuclear cells (PBMCs) and bone marrow cells (BMCs) were isolated for flow cytometric analysis after 3 months. Monocytes were cultured with human IL-4 (10 ng/ml) and GM-CSF (50 ng/ml) in the absence and presence of alcohol (50 mM). On day 6 of the culture, a cocktail of stimulants including IL-1, (18 ng), IL-6 (1800 U), TNF-, (18 ng), and PGE2 (1.8 ,g) were added to the designated wells for transformation of immature dendritic cells (iDCs) to mature myeloid DCs. The cells were analyzed on day 8 by flow cytometry for expression of DC costimulatory molecule expression. Results:, EtOH-treated animals had significantly lower numbers of myeloid DCs (lineage-HLA-DR+CD11c+CD123,) in both the PBMCs and BMCs compared to controls (5,654 ± 1,273/106 vs. 2,353 ± 660/106 PBMCs and 503 ± 34 vs. 195 ± 44/106 BMCs). Under culture conditions, the number of lineage-HLA-DR+CD83+ cells was low in control wells (0.38 ± 0.08%). Alcohol inhibited the increase in the number of lineage-HLA-DR+CD83+ cells in iDC wells (2.30 ± 0.79% vs. 5.73 ± 1.40%). Alcohol also inhibited the increase in the number of lineage-HLA-DR+CD83+ cells in mature DC wells (1.23 ± 0.15% vs. 4.13 ± 0.62%). Conclusions:, Chronic EtOH decreases the bone marrow and circulating pools of myeloid DCs. Additionally, EtOH suppresses costimulatory molecule CD83 expression during DC transformation, which may attenuate the ability of DCs to initiate T-cell expansion. [source] Protective effect of a marine oligopeptide preparation from Chum Salmon (Oncorhynchus keta) on radiation-induced immune suppression in miceJOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 13 2010Ruiyue Yang Abstract BACKGROUND: A marine oligopeptide preparation (MOP) obtained from Chum Salmon (Oncorhynchus keta) by the method of enzymatic hydrolysis, has been found to enhance the innate and adaptive immunities through stimulation of the secretion of cytokines in mice. The current study aimed to further investigate the protective effect of MOP on radiation-induced immune suppression in mice. RESULTS: Female ICR mice (6,8 weeks old) were randomly divided into three groups, i.e. blank control, irradiation control and MOP (1.350 g kg,1 body weight) plus irradiation-treated group. MOP significantly increased the survival rate and prolonged the survival times for 30 days after irradiation, and lessened the radiation-induced suppression of T- or B-lymphocyte proliferation, resulting in the recovery of cell-mediated and humoral immune functions. This effect may be produced by augmentation of the relative numbers of radioresistant CD4+ T cells, enhancement of the level of immunostimulatory cytokine, IL-12, reduction of the level of total cellular NF-,B through the induction of I,B in spleen and inhibition of the apoptosis of splenocytes. CONCLUSION: We propose that MOP be used as an ideal adjuvant therapy to alleviate radiation-induced injuries in cancer patients. Copyright © 2010 Society of Chemical Industry [source] Solvation effects in calculated electrostatic association free energies for the C3d-CR2 complex and comparison with experimental dataBIOPOLYMERS, Issue 6 2010Alexander S. Cheung Abstract The complement system is an integral part of the innate immune system that participates in the clearance of pathogens from the body. The association between complement protein fragment C3d and B or T cell-receptor complement receptor (CR) 2 represents a crucial link between innate and adaptive immunities. The goal of this study is to predict association abilities of C3d and CR2 mutants by theoretically calculating electrostatic free energies of association and to assess the importance of solvation effects in the calculations. We demonstrate that calculated solvation free energy differences and Coulombic free energies of association are more sensitive than electrostatic free energies of association in solution and, thus, more accurate in predicting previously published experimental data for the association abilities (relative to the parent proteins) of specific C3d and CR2 mutants. We show that a proportional relationship exists between the predicted solvation free energy differences and the experimental data, while an inversely proportional relationship exists between the predicted Coulombic free energies of association and the experimental data. Our results yield new insights into the physicochemical properties underlying C3d-CR2 association. We discuss the predictive validity of Coulombic, solvation, and solution electrostatic free energies of association and the generalization of our method for theoretical mutagenesis studies of other systems. This is a basic study, aimed toward improving our understanding of the theoretical basis of immune system regulation at the molecular level. Such insight can serve as the groundwork for the design of regulators with tailored properties, vaccines, and other biotechnology products. © 2010 Wiley Periodicals, Inc. Biopolymers 93:509,519, 2010. This article was originally published online as an accepted preprint. The "Published Online" date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com [source] Maladaptation to mental stress mitigated by the adaptive immune system via depletion of naturally occurring regulatory CD4+CD25+ cellsDEVELOPMENTAL NEUROBIOLOGY, Issue 6 2006Hagit Cohen Abstract Peripheral cellular immunity was recently shown to play a critical role in brain plasticity and performance. The antigenic specificity of the participating T cells, however, was not investigated, and nor was their relevance to psychological stress. Here we show, using a mouse model, that adaptive immunity mitigates maladaptation to the acute psychological stress known to trigger abnormal behaviors reminiscent of human post-traumatic stress disorder. Assessment of behavioral adaptation (measured by the acoustic startle response and avoidance behavior) in mice after their exposure to predator odor revealed that maladaptation was several times more prevalent in T cell-deficient mice than in their wild-type counterparts. A single population of T cells reactive to central nervous system (CNS)-associated self-protein was sufficient to endow immune-deficient mice with the ability to withstand the psychological stress. Naturally occurring CD4+CD25+ regulatory T cells were found to suppress this endogenous anti-stress attribute. These findings suggest that T cells specific to abundantly expressed CNS antigens are responsible for brain tissue homeostasis and help the individual to cope with stressful life episodes. They might also point the way to development of immune-based therapies for mental disorders, based either on up-regulation of T cells that partially cross-react with self-antigens or on weakening of the activity of regulatory T cells. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006 [source] A role for innate immunity in type 1 diabetes?DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 2 2003H. Beyan Abstract Two arms of the immune system, innate and adaptive immunity, differ in their mode of immune recognition. The innate immune system recognizes a few highly conserved structures on a broad range of microorganisms. On the other hand, recognition of self or autoreactivity is generally confined to the adaptive immune response. Whilst autoimmune features are relatively common, they should be distinguished from autoimmune disease that is infrequent. Type 1 diabetes is an immune-mediated disease due to the destruction of insulin secreting cells mediated by aggressive immune responses, including activation of the adaptive immune system following genetic and environmental interaction. Hypotheses for the cause of the immune dysfunction leading to type 1 diabetes include self-reactive T-cell clones that (1) escape deletion in the thymus, (2) escape from peripheral tolerance or (3) escape from homeostatic control with an alteration in the immune balance leading to autoimmunity. Evidence, outlined in this review, raises the possibility that changes in the innate immune system could lead to autoimmunity, by either priming or promoting aggressive adaptive immune responses. Hostile microorganisms are identified by genetically determined surface receptors on innate effector cells, thereby promoting clearance of these invaders. These innate effectors include a few relatively inflexible cell populations such as monocytes/macrophages, dendritic cells (DC), natural killer (NK) cells, natural killer T (NKT) cells and ,, T cells. Recent studies have identified abnormalities in some of these cells both in patients with type 1 diabetes and in those at risk of the disease. However, it remains unclear whether these abnormalities in innate effector cells predispose to autoimmune disease. If they were to do so, then modulation of the innate immune system could be of therapeutic value in preventing immune-mediated diseases such as type 1 diabetes. Copyright © 2002 John Wiley & Sons, Ltd. [source] Stress for maintaining memory: HSP70 as a mobile messenger for innate and adaptive immunityEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2010Taoyong Chen Abstract HSP are abundant and conserved proteins present in all cells. Upon temperature shock or other stress stimuli, HSP are synthesized intracellularly, which may protect cells from protein denaturation or from death. Although HSP are synthesized intracellularly, HSP can also be mobilized to the plasma membrane or even be released under stress conditions. Elucidating the roles of cell surface and extracellular HSP in immune regulation has attracted much attention in recent years. Extracellularly, HSP can serve a cytokine function to initiate both innate and adaptive immunity through activation of APC. HSP serves also a chaperone function and facilitates presentation of antigen peptide to T cells. Similarly, cell surface HSP may activate APC and promote antigen presentation through cell,cell contact. A study in this issue of the European Journal of Immunology demonstrates that cell surface HSP70 on DC induced by stress can upregulate membrane-associated IL-15, which in turn promotes the proliferation of CD4+CD45RA memory T cells. Moreover, a DC-CD4+ T-cell interacting circuit formed by CD40L on T cells and CD40 on DC is proposed to play a role in the maintenance of memory homeostasis. This study has widened our view of HSP in adaptive immunity as well as their classical functions such as APC activator and antigen carrier. [source] Update on animal models for HIV researchEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2009Nancy L. Haigwood Abstract Animal models for HIV research have been indispensible in fulfilling Koch's postulate and in exploring issues of viral infectivity and pathogenesis, sequence divergence, route(s) of acquisition, tissue distribution and tropism, immunogenicity and protection capacity of vaccine candidates, escape from adaptive immunity, and more. Did they fail to predict the efficacy of T-cell vaccines in humans? This article summarizes progress and status of models to inform and complement clinical work. [source] Severe functional impairment and elevated PD-1 expression in CD1d-restricted NKT cells retained during chronic HIV-1 infectionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2009Markus Moll Abstract Invariant CD1d-restricted NKT cells play important roles in regulating both innate and adaptive immunity. They are targeted by HIV-1 infection and severely reduced in number or even lost in many infected subjects. Here, we have investigated the characteristics of NKT cells retained by some patients despite chronic HIV-1 infection. NKT cells preserved under these circumstances displayed an impaired ability to proliferate and produce IFN-, in response to CD1d-restricted lipid antigen as compared with cells from uninfected control subjects. HIV-1 infection was associated with an elevated expression of the inhibitory programmed death-1 (PD-1) receptor (CD279) on the CD4, subset of NKT cells. However, blocking experiments indicated that the functional defects in NKT cells were largely PD-1-independent. Furthermore, the elevated PD-1 expression and the functional defects were not restored by anti-retroviral treatment, and the NKT cell numbers in blood did not recover significantly in response to treatment. The functional phenotype of NKT cells in these patients suggests an irreversible immune exhaustion due to chronic activation in vivo. The data demonstrate a severe functional impairment in the remaining NKT-cell compartment in HIV-1-infected patients, which limits the prospects to mobilize these cells in immunotherapy approaches in patients. [source] Killers and beyond: NK-cell-mediated control of immune responsesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2008Christopher E. Andoniou Abstract Effective immunity requires coordinated activation of innate and adaptive immune responses. NK cells are principal mediators of innate immunity, able to respond to challenge quickly and generally without prior activation. The most acknowledged functions of NK cells are their cytotoxic potential and their ability to release large amounts of cytokines, especially IFN-,. Recently, it has become clear that NK cells are more than assassins. Indeed, NK cells play critical roles in shaping adaptive immunity. [source] Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN-, induction via X-box binding protein 1EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2008Judith A. Smith Dr. Abstract Type,I IFN are strongly induced upon engagement of certain pattern recognition receptors by microbial products, and play key roles in regulating innate and adaptive immunity. It has become apparent that the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR), in addition to restoring ER homeostasis, also influences the expression of certain inflammatory cytokines. However, the extent to which UPR signaling regulates type,I IFN remains unclear. Here we show that cells undergoing a UPR respond to TLR4 and TLR3 ligands, and intracellular dsRNA, with log-fold greater IFN-, induction. This synergy is not dependent on autocrine type,I IFN signaling, but unexpectedly requires the UPR transcription factor X-box binding protein,1 (XBP-1). Synergistic IFN-, induction also occurs in HLA-B27/human ,2m-transgenic rat macrophages exhibiting a UPR as a consequence of HLA-B27 up-regulation, where it correlates with activation of XBP-1 splicing. Together these findings indicate that the cellular response to endogenous ,danger' that disrupts ER homeostasis is coupled to IFN-, induction by XBP-1, which has implications for the immune response and the pathogenesis of diseases involving the UPR. [source] CD303 (BDCA-2) signals in plasmacytoid dendritic cells via a BCR-like signalosome involving Syk, Slp65 and PLC,2EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2007Jürgen Röck Abstract Plasmacytoid dendritic cells (PDC) are the main type,I interferon (IFN-I) producers and play a central role in innate and adaptive immunity. CD303 (BDCA-2) is a type,II c-type lectin specifically expressed by human PDC. CD303 signaling induces tyrosine phosphorylation and Src kinase dependent calcium influx. Cross-linking CD303 results in the inhibition of IFN-I production in stimulated PDC. Here, we demonstrate that PDC express a signalosome similar to the BCR signalosome, consisting of Lyn, Syk, Btk, Slp65 (Blnk) and PLC,2. CD303 associates with the signaling adapter FcR ,-chain. Triggering CD303 leads to tyrosine phosphorylation of Syk, Slp65, PLC,2 and cytoskeletal proteins. Analogous to BCR signaling, CD303 signaling is likely linked with its internalization by clathrin-mediated endocytosis. Furthermore, CD303 signaling leads to reduced levels of transcripts for IFN-I genes and IFN-I-responsive genes, indicating that the inhibition of IFN-I production by stimulated PDC is at least partially regulated at the transcriptional level. These results support a possible therapeutic value of an anti-CD303 mAb strategy, since the production of IFN-I by PDC is considered to be a major pathophysiological factor in systemic lupus erythematosus patients. See accompanying commentary at http://dx.doi.org/10.1002/eji200737944 [source] Expression of the NKG2D ligand UL16 binding protein-1 (ULBP-1) on dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2006David Schrama Abstract Innate and adaptive immunity have not evolved separately. In this regard, the NKG2D molecule first identified on NK cells and classified as an activating NK cell receptor is also an important receptor for CD8+ T,cells. Functional analyses of human NKG2D and its ligands, i.e. UL16 binding proteins (ULBP) and MHC class I chain-related (MIC), have so far focused on immune cell-target cell situations because of the expression of NKG2D ligands on infected, stressed or transformed cells. Here, however, we address a possible function of NKG2D/ULBP-1 during the initiation of T cell responses. ULBP-1 can be detected on mature dendritic cells both in situ in the T cell areas of lymph nodes as well as in vitro after artificial maturation. FCM analysis further demonstrated that although NKG2D is expressed to some degree on all analyzed T cell subsets from peripheral blood, in vitro stimulation of T cells results in up-regulation of NKG2D on proliferating T cells. Using the sentinel lymph nodes of primary melanoma as a model for induction of defined T cell responses in vivo, we were able to demonstrate the expression of NKG2D on melanoma-associated antigen-specific T cells. Thus, our results suggest a role for NGK2D-ULBP-1 in the induction or reactivation of T cell responses. [source] Cooperation between toll-like receptor,2 and,4 in the brain of mice challenged with cell wall components derived from gram-negative and gram-positive bacteriaEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2003Nathalie Laflamme Abstract In this study we investigated whether induction of toll-like receptor,2 (TLR2) amplifies the effect of a cell wall component derived from gram-positive bacteria, namely peptidoglycan (PGN). Mice received a first systemic lipopolysaccharide (LPS) injection to pre-induce TLR2 in various regions of the brain, and 6,h later, a second administration of either LPS or PGN. The data show a robust transcriptional activation of TLR2, TNF-, and monocyte chemotactic protein-1 (MCP-1) in microglial cells of mice challenged twice with LPS, whereas PGN essentially abolished this response. TLR4 plays a critical role in this process, because C3H/HeJ mice no longer responded to LPS but exhibited a normal reaction to PGN. Conversely, a robust signal for genes encoding innate immune proteinswas found in the brain of TLR2-deficient mice challenged with LPS. However, the second LPS bolus failed to trigger TNF-, and IL-12 in TLR2-deficient mice, while the same treatment caused a strong induction of these genes in the cerebral tissue of wild-type littermates. The present data provide evidence that cooperation exists between TLR4 and TLR2. While TLR4 is absolutely necessary to engage the innate immune response in the brain, TLR2 participates in the regulation of genes encoding TNF-, and IL-12 during severe endotoxemia. Such collaboration between TLR4 and TLR2 may be determinant for the transfer from the innate to the adaptive immunity within the CNS of infected animals. [source] CD2+/CD14+ monocytes rapidly differentiate into CD83+ dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2003Di Pucchio, Tiziana Abstract Since denditric cells (DC) represent the main players linking innate and adaptive immunity, their prompt generation from blood cells would be instrumental for an efficient immune response to infections. Consistent with this, CD2+ monocytes were found to express the DC maturation marker CD83, along with acquisition of high antigen-presenting activity, after a surprisingly short time in culture. This rapid process is associated with expression of IFN-,/, genes and secretion of low levels of pro-inflammatory cytokines. Exposure of monocytes to IFN-,, but not to IL-4, induced persistence of CD2+/CD83+ cells, which were fully competent in stimulating primary responses by naive T cells. These results unravel the natural pathway by which infection-induced signals rapidly transform pre-armed monocytes into active DC. [source] A new paradigm of eosinophil granulocytes: neuroimmune interactionsEXPERIMENTAL DERMATOLOGY, Issue 9 2008Ulrike Raap Abstract:, Eosinophil granulocytes have long been regarded as potent effector cells with the potential to release an array of inflammatory mediators involved in cytotoxicity to helminths and tissue destruction in chronic inflammatory diseases such as asthma. However, it has become evident that eosinophils are also involved in regulatory mechanisms modulating local tissue immune responses. Eosinophils take part in remodelling and repair mechanisms and contribute to the localized innate and acquired immune response as well as systemic adaptive immunity. In addition, eosinophils are involved in neuroimmune interactions modulating the functional activity of peripheral nerves. Neuromediators can also modulate the functional activity of eosinophils, revealing bidirectional interactions between the two cell types. Eosinophils are tissue-resident cells and have been found in close vicinity of peripheral nerves. This review describes neuroimmune interactions between eosinophil granulocytes and peripheral nerves and highlights why eosinophils are important in allergic diseases such as asthma. [source] Roles of Toll-like receptors in innate immune responsesGENES TO CELLS, Issue 9 2001Kiyoshi Takeda Innate immunity recognizes invading micro-organisms and triggers a host defence response. However, the molecular mechanism for innate immune recognition was unclear. Recently, a family of Toll-like receptors (TLRs) was identified, and crucial roles for these receptors in the recognition of microbial components have been elucidated. The TLR family consists of 10 members and will be expanding. Each TLR distinguishes between specific patterns of microbial components to provoke innate immune responses. The activation of innate immunity then leads to the development of antigen-specific adaptive immunity. Thus, TLRs control both innate and adaptive immune responses. [source] Regulation of innate immunity against hepatitis C virus infectionHEPATOLOGY RESEARCH, Issue 2 2008Takeshi Saito Chronic hepatitis C virus (HCV) infection is a global public health problem. HCV infection is treated with type I interferon (IFN), a natural product that is produced by cells during virus infection as a result of innate immune signaling events. The secreted IFN alert the surrounding cells to turn on an "antiviral state" that resists infection. In general, the role of innate immune response is to suppress viral replication and to induce cytokines and other factors that promote adaptive immunity and the resolution of infection. The mechanisms by which the innate immune response and IFN actions limit HCV infection are not well defined, but are likely to involve the function of specific IFN-stimulated genes. HCV also copesintensively with immune responses in order to establish persistent infection. Recent studies reveal that a other viruses use similar tactics to regulate the antiviral innate immune response. In the case of HCV, innate immune signaling is strictly controlled by the viral NS3/4A protease, resulting in the disruption of IFN production. Here, we summarize the current understanding of how HCV evades the innate immune system. [source] Harnessing human dendritic cell subsets for medicineIMMUNOLOGICAL REVIEWS, Issue 1 2010Hideki Ueno Summary:, Immunity results from a complex interplay between the antigen-non-specific innate immune system and the antigen-specific adaptive immune system. The cells and molecules of the innate system employ non-clonal recognition receptors including lectins, Toll-like receptors, NOD-like receptors, and helicases. B and T lymphocytes of the adaptive immune system employ clonal receptors recognizing antigens or their derived peptides in a highly specific manner. An essential link between innate and adaptive immunity is provided by dendritic cells (DCs). DCs can induce such contrasting states as immunity and tolerance. The recent years have brought a wealth of information on the biology of DCs revealing the complexity of this cell system. Indeed, DC plasticity and subsets are prominent determinants of the type and quality of elicited immune responses. In this article, we summarize our recent studies aimed at a better understanding of the DC system to unravel the pathophysiology of human diseases and design novel human vaccines. [source] The ancestral complement system in sea urchinsIMMUNOLOGICAL REVIEWS, Issue 1 2001L. Courtney Smith Summary: The origin of adaptive immunity in the vertebrates can be traced to the appearance of the ancestral RAG genes in the ancestral jawed vertebrate; however, the innate immune system is more ancient. A central subsystem within innate immunity is the complement system, which has been identified throughout and seems to be restricted to the deuterostomes. The evolutionary history of complement can be traced from the sea urchins (members of the echinoderm phylum), which have a simplified system homologous to the alternative pathway, through the agnathans (hagfish and lamprey) and the elasmobranchs (sharks and rays) to the teleosts (bony fish) and tetrapods, with increases in the numbers of complement components and duplications in complement pathways. Increasing complexity in the complement system parallels increasing complexity in the deuterostome animals. This review focuses on the simplest of the complement systems that is present in the sea urchin. Two components have been identified that show significant homology to vertebrate C3 and factor B (Bf), called SpC3 and SpBf, respectively. Sequence analysis from both molecules reveals their ancestral characteristics. Immune challenge of sea urchins indicates that SpC3 is inducible and is present in coelomic fluid (the body fluids) in relatively high concentrations, while SpBf expression is constitutive and is present in much lower concentrations. Opsonization of foreign cells and particles followed by augmented uptake by phagocytic coelomocytes appears to be a central function for this simpler complement system and important for host defense in the sea urchin. These activities are similar to some of the functions of the homologous proteins in the vertebrate complement system. The selective advantage for the ancestral deuterostome may have been the amplification feedback loop that is still of central importance in the alternative pathway of complement in higher vertebrates. Feedback loop functions would quickly coat pathogens with complement leading to phagocytosis and removal of foreign cells, a system that would be significantly more effective than an opsonin that binds upon contact as a result of simple diffusion. An understanding of the immune response of the sea urchin, an animal that is a good estimator of what the ancestral deuterostome immune system was like, will aid us in understanding how adaptive immunity might have been selected for during the early evolution of the vertebrates and how it might have been integrated into the pre-existing innate immune system that was already in place in those animals. The authors are grateful to Drs Sham Nair and Paul Gross for their critique of the manuscript and helpful suggestions. This work was supported by the National Science Foundation (MCB 9603086). [source] Autophagy and adaptive immunityIMMUNOLOGY, Issue 1 2010Victoria L. Crotzer Summary Autophagy plays an important role in maintaining intracellular homeostasis by promoting the transit of cytoplasmic material, such as proteins, organelles and pathogens, for degradation within acidic organelles. Yet, in immune cells, autophagy pathways serve an additional role in facilitating intracellular surveillance for pathogens and changes in self. Autophagy pathways can modulate key steps in the development of innate and adaptive immunity. In terms of adaptive immunity, autophagy regulates the development and survival of lymphocytes as well as the modulation of antigen processing and presentation. Specialized forms of autophagy may be induced by some viral pathogens, providing a novel route for major histocompatibility complex (MHC) class I antigen presentation and enhanced CD8+ T-cell responses. Autophagy induction in target cells also increases their potential to serve as immunogens for dendritic cell cross-presentation to CD8+ T cells. The requirement for autophagy in MHC class II presentation of cytoplasmic and nuclear antigens is well established, yet recent studies also point to a critical role for autophagy in modulating CD4+ T-cell responses to phagocytosed pathogens. Autophagy pathways can also modulate the selection and survival of some CD4+ T cells in the thymus. However, much still remains to be learned mechanistically with respect to how autophagy and autophagy-linked genes regulate pathogen recognition and antigen presentation, as well as the development and survival of immune cells. [source] Natural killer T-cell characterization through gene expression profiling: an account of versatility bridging T helper type 1 (Th1), Th2 and Th17 immune responsesIMMUNOLOGY, Issue 1 2008Marcus Niemeyer Summary Natural killer T (NKT) cells constitute a distinct lymphocyte lineage at the interface between innate and adaptive immunity, yet their role in the immune response remains elusive. Whilst NKT cells share features with other conventional T lymphocytes, they are unique in their rapid, concomitant production of T helper type 1 (Th1) and Th2 cytokines upon T-cell receptor (TCR) ligation. In order to characterize the gene expression of NKT cells, we performed comparative microarray analyses of murine resting NKT cells, natural killer (NK) cells and naïve conventional CD4+ T helper (Th) and regulatory T cells (Treg). We then compared the gene expression profiles of resting and alpha-galactosylceramide (,GalCer)-activated NKT cells to elucidate the gene expression signature upon activation. We describe here profound differences in gene expression among the various cell types and the identification of a unique NKT cell gene expression profile. In addition to known NKT cell-specific markers, many genes were expressed in NKT cells that had not been attributed to this population before. NKT cells share features not only with Th1 and Th2 cells but also with Th17 cells. Our data provide new insights into the functional competence of NKT cells which will facilitate a better understanding of their versatile role during immune responses. [source] The impact of successive infections on the lung microenvironmentIMMUNOLOGY, Issue 4 2007Arnaud Didierlaurent Summary The effect of infection history on the immune response is ignored in most models of infectious disease and in preclinical vaccination studies. No one, however, is naïve and repeated microbial exposure, in particular during childhood, shapes the immune system to respond more efficiently later in life. Concurrent or sequential infections influence the immune response to secondary unrelated pathogens. The involvement of cross-reactive acquired immunity, in particular T-cell responses, is extensively documented. In this review, we discuss the impact of successive infections on the infected tissue itself, with a particular focus on the innate response of the respiratory tract, including a persistent alteration of (1) epithelial or macrophage expression of Toll-like receptors or adherence molecules used by subsequent bacteria to invade the host, (2) the responsiveness of macrophages and neutrophils and (3) the local cytokine milieu that affects the activation of local antigen-presenting cells and hence adaptive immunity to the next infection. We emphasize that such alterations not only occur during coinfection, but are maintained long after the initial pathogen is cleared. As innate responses are crucial to the fight against local pathogens but are also involved in the maintenance of the homeostasis of mucosal tissues, dysregulation of these responses by repeated infections is likely to have a major impact on the outcome of infectious or allergic disease. [source] Impact of class A, B and C CpG-oligodeoxynucleotides on in vitro activation of innate immune cells in human immunodeficiency virus-1 infected individualsIMMUNOLOGY, Issue 4 2007Jeffrey A. Martinson Summary Oligodeoxynucleotides (ODN) with unmethylated deoxycytidyl-deoxyguanosine dinucleotides (CpG-ODNs) stimulate Toll-like receptor 9 (TLR9) in plasmacytoid dendritic cells (pDC) and B cells and activate innate and adaptive immunity. Three classes of synthetic CpG-ODNs, class A, B and C, activate cells through TLR9; our goal was to evaluate their effect on cells from human immunodeficiency virus (HIV)-1+ individuals. We compared the frequencies and the unstimulated activation status of immune effector cells in HIV-1+ and HIV-1, individuals. Fewer pDC, myeloid dendritic cells (mDC), B cells, natural killer (NK) cells and invariant natural killer T cells (iNKT) were present in HIV-1+ peripheral blood mononuclear cells (PBMC) and their baseline activation status was higher than HIV-1, PBMC. Exposure of HIV-1+ PBMC to all classes of CpG-ODNs led to activation and maturation of pDC based on CD86, CD80, and CD83 expression similar to that of cells from HIV-1, individuals. The percentage of CpG-ODN stimulated pDC that express CD40 was dramatically higher when cells were obtained from HIV-1+ than from HIV-1, individuals. B-lymphocytes were activated similarly in HIV-1+ and HIV-1, individuals. mDC, NK and iNKT cell, which lack TLR9, were indirectly activated. Interferon-, (IFN-,) and interferon inducible protein 10 (IP-10) secretion was induced by class A or C but not class B CpG-ODN, but the concentrations were less than those produced by HIV-1, PBMC. HIV-1 infected individuals have fewer innate effector cells that are chronically activated, but these cells can be further activated by CpG-ODN, which suggests that synthetic CpG-ODNs could be used to enhance the immune system in HIV-1 infected individuals. [source] Immune-privileged embryonic Swiss mouse STO and STO cell-derived progenitor cells: major histocompatibility complex and cell differentiation antigen expression patterns resemble those of human embryonic stem cell linesIMMUNOLOGY, Issue 1 2006Katherine S. Koch Summary Embryonic mouse STO (S, SIM; T, 6-thioguanine resistant; O, ouabain resistant) and 3(8)21-enhanced green fluorescent protein (EGFP) cell lines exhibit long-term survival and hepatic progenitor cell behaviour after xenogeneic engraftment in non-immunosuppressed inbred rats, and were previously designated major histocompatibility complex (MHC) class I- and class II-negative lines. To determine the molecular basis for undetectable MHC determinants, the expression and haplotype of H-2K, H-2D, H-2L and I-A proteins were reassessed by reverse transcriptase,polymerase chain reaction (RT-PCR), cDNA sequencing, RNA hybridization, immunoblotting, quantitative RT-PCR (QPCR), immunocytochemistry and flow cytometry. To detect cell differentiation (CD) surface antigens characteristic of stem cells, apoptotic regulation or adaptive immunity that might facilitate progenitor cell status or immune privilege, flow cytometry was also used to screen untreated and cytokine [interferon (IFN)-,]-treated cultures. Despite prior PCR genotyping analyses suggestive of H-2q haplotypes in STO, 3(8)21-EGFP and parental 3(8)21 cells, all three lines expressed H-2K cDNA sequences identical to those of d-haplotype BALB/c mice, as well as constitutive and cytokine-inducible H-2Kd determinants. In contrast, apart from H-2Ld[LOW] display in 3(8)21 cells, H-2Dd, H-2Ld and I-Ad determinants were undetectable. All three lines expressed constitutive and cytokine-inducible CD34; however, except for inducible CD117[LOW] expression in 3(8)21 cells, no expression of CD45, CD117, CD62L, CD80, CD86, CD90·1 or CD95L/CD178 was observed. Constitutive and cytokine-inducible CD95[LOW] expression was detected in STO and 3(8)21 cells, but not in 3(8)21-EGFP cells. MHC (class I+[LOW]/class II,) and CD (CD34+/CD80,/CD86,/CD95L,) expression patterns in STO and STO cell-derived progenitor cells resemble patterns reported for human embryonic stem cell lines. Whether these patterns reflect associations with mechanisms that are regulatory of immune privilege or functional tissue-specific plasticity is unknown. [source] Analysis of differential immune responses induced by innate and adaptive immunity following transplantationIMMUNOLOGY, Issue 2 2003Hongzhen He Summary The roles of innate and adaptive immunity in allograft rejection remain incompletely understood. Previous studies analysing lymphocyte deficient or syngeneic graft recipients have identified subsets of inflammatory chemokines and cytokines induced by antigen independent mechanisms. In the current study, we analysed a panel of 60 inflammatory parameters including serum cytokines, intragraft chemokines and cytokines, receptors, and cellular markers. Our results confirmed the up-regulation of a subset of markers by innate mechanisms and also identified a subset of parameters up-regulated only in the context of an adaptive response. Thus, we successfully differentiated markers of the innate and adaptive phases of rejection. Current paradigms emphasize that innate signals can promote a subsequent adaptive response. Interestingly, in our studies, expression of the markers induced by innate mechanisms was markedly amplified in the allogeneic, but not syngeneic or lymphocyte deficient, recipients. These results suggest that inflammatory mediators can have functional overlap between the innate and adaptive responses, and that the adaptive component of the rejection process amplifies the innate response by positive feedback regulation. [source] CD1d-restricted natural killer T cells are potent targets for human immunodeficiency virus infectionIMMUNOLOGY, Issue 1 2003Richardson Fleuridor Summary Invariant human natural killer T cells (NKT) express a restricted T-cell receptor (TCR) V,24V,11 repertoire. These cells share both phenotypic and functional similarities between NK and T cells. Given the emerging role of NKT cells as critical cells in bridging the gap between innate and adaptive immunity, we examined their susceptibility to productive human immunodeficiency virus (HIV) infection by T-tropic, M-tropic, and primary isolates of HIV. We generated three human NKT cell clones (CA5, CA29, and CA31). Phenotypic characterization of these V,24+ V,11+ clones indicated that they were predominately positive for CD4, CD161, HLA-DR, CD38, CD45RO, and CD95 expression. The NKT cell clones expressed significantly more surface CCR5 molecules/cell and lower CXCR4 molecules/cell than phytohaemagglutinin-stimulated peripheral blood mononuclear cells (PBMC). Consistent with the surface expression of CCR5 and CXCR4, the NKT clones were also selectively susceptible to HIV M-tropic, T-tropic, and primary isolate infection, as evaluated by both HIV p24 enzyme-linked immunosorbent assay and intracellular staining of HIV proteins. The amount of p24 production was dependent on the NKT clone studied and the HIV strain used. Clones CA29 and CA31 were also susceptible to HIV IIIB infection. The virions produced by these clones were able to productively infect PHA-stimulated PBMCs with the same kinetics as for primary infection of CD4+ blast. Collectively, this data demonstrates that NKT cells can be a target for productive HIV infection but with a lag in the time to peak p24 production. [source] Expression of ,-defensin 1 and 2 mRNA by human monocytes, macrophages and dendritic cellsIMMUNOLOGY, Issue 4 2002Louise A. Duits Summary Human ,-defensins are broad-spectrum antimicrobial peptides known to be produced by epithelial cells. It was recently shown that ,-defensins also display chemotactic activity for dendritic cells (DC) and T cells, and thus may serve to link innate and adaptive immunity. The aim of the present study was to explore expression of mRNA for these peptides in mononuclear phagocytes and DC. The results revealed that monocytes, monocyte-derived-macrophages (MDM), and monocyte-derived-dendritic cells (DC) all express human-,-defensin-1 (hBD-1) mRNA. hBD-1 mRNA expression by monocytes and MDM was increased after activation with interferon-, (IFN-,) and/or lipopolysaccharide (LPS) in a dose- and time-dependent fashion. Alveolar macrophages showed an intense hBD-1 expression, which could not be further increased. Expression of hBD-1 mRNA by immature DC was low, and increased considerably after maturation. Monocytes, MDM, alveolar macrophages and DC showed a limited expression of human ,-defensin-2 (hBD-2) mRNA, which could only be increased in monocytes and alveolar macrophages by IFN-, and/or LPS in a dose- and time-dependent fashion. Immunocytochemical stainings demonstrated the expression of hBD-2 peptide by freshly isolated blood monocytes and alveolar macrophages in cytospin preparations. [source] | ||||||||||||||||||||||||||||||||||