bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Isolates of Streptococcus pneumoniae Bind the Complement Inhibitor C4b-Binding Protein in a PspC Allele-Dependent Fashion
Authors: Dieudonné-Vatran Antoine , Krentz Stefanie , Blom Anna M. , Meri Seppo , Henriques-Normark Birgitta , Riesbeck Kristian , Albiger Barbara 
Published: June 2009

Abstract
The complement system constitutes an important component of the innate immune system. To colonize their host and/or to cause disease, many pathogens have evolved strategies to avoid complement-mediated bacterial lysis and opsonophagocytosis. In this study, using a collection of 55 clinical isolates of Streptococcus pneumoniae, we demonstrate for the first time that pneumococci bind the complement inhibitor C4b-binding protein (C4BP). C4BP binding seems to be restricted to certain serotypes such as serotype 4, 6B, 7F, and 14, of which the strains of serotype 14 are the strongest binders. We show that bacteria-bound C4BP retains its functional activity and down-regulates the activation of the classical pathway. Thus, this major respiratory pathogen may escape immune recognition and eradication by the complement system. Furthermore, we show that C4BP binding varies between strains but is dependent on the expression of pneumococcal surface protein C, PspC of group 4. The study of the distribution of group 4 pspC locus shows that most of high-binder serotype 14 isolates harbor an allelic variant of group 4 pspC. Using PspC-negative mutant strains, we identified a new allelic variant of PspC (PspC4.4) as a major ligand for C4BP, revealing a new function for this important pneumococcal virulence factor. Thus pneumococci exploit host C4BP for complement evasion in a PspC allele-dependent manner.
GITR Triggering Induces Expansion of Both Effector and Regulatory CD4+ T Cells In Vivo
Authors: van Olffen Ronald W. , Koning Nathalie , van Gisbergen Klaas P. J. M. , Wensveen Felix M. , Hoek Robert M. , Boon Louis , Hamann Jörg , van Lier Rene A. W. , Nolte Martijn A. 
Published: June 2009

Abstract
Glucocorticoid-induced TNF receptor family-related protein (GITR) is expressed on activated and regulatory T cells, but its role on these functionally opposing cell types is not fully understood. Here we describe that transgenic expression of GITR’s unique ligand (GITRL) induces a prominent increase of both effector and regulatory CD4+ T cells, but not CD8+ T cells. Regulatory T cells from GITRL transgenic mice are phenotypically activated and retain their suppressive capacity. The accumulation of effector and regulatory T cells is not due to enhanced differentiation of naive T cells, but is a direct result of increased proliferation. Functional consequences of increased numbers of both regulatory and effector T cells were tested in an autoimmune model and show that GITR stimulation is protective, as it significantly delays disease induction. These data indicate that GITR regulates the balance between regulatory and effector CD4+ T cells by enhancing proliferation of both populations in parallel.
B Cell Receptor-Mediated Internalization of Salmonella: A Novel Pathway for Autonomous B Cell Activation and Antibody Production
Authors: Souwer Yuri , Griekspoor Alexander , Jorritsma Tineke , de Wit Jelle , Janssen Hans , Neefjes Jacques , van Ham S. Marieke 
Published: June 2009

Abstract
The present paradigm is that primary B cells are nonphagocytosing cells. In this study, we demonstrate that human primary B cells are able to internalize bacteria when the bacteria are recognized by the BCR. BCR-mediated internalization of Salmonella typhimurium results in B cell differentiation and secretion of anti-Salmonella Ab by the Salmonella-specific B cells. In addition, BCR-mediated internalization leads to efficient Ag delivery to the MHC class II Ag-loading compartments, even though Salmonella remains vital intracellularly in primary B cells. Consequently, BCR-mediated bacterial uptake induces efficient CD4+ T cell help, which boosts Salmonella-specific Ab production. BCR-mediated internalization of Salmonella by B cells is superior over extracellular Ag extraction to induce rapid and specific humoral immune responses and efficiently combat infection.
Lipopolysaccharide Stimulates Platelet Secretion and Potentiates Platelet Aggregation via TLR4/MyD88 and the cGMP-Dependent Protein Kinase Pathway
Authors: Zhang Guoying , Han Jingyan , Welch Emily J. , Ye Richard D. , Voyno-Yasenetskaya Tatyana A. , Malik Asrar B. , Du Xiaoping , Li Zhenyu 
Published: June 2009

Abstract
Bacterial LPS induces rapid thrombocytopenia, hypotension, and sepsis. Although growing evidence suggests that platelet activation plays a critical role in LPS-induced thrombocytopenia and tissue damage, the mechanism of LPS-mediated platelet activation is unclear. In this study, we show that LPS stimulates platelet secretion of dense and α granules as indicated by ATP release and P-selectin expression, and thus enhances platelet activation induced by low concentrations of platelet agonists. Platelets express components of the LPS receptor-signaling complex, including TLR (TLR4), CD14, MD2, and MyD88, and the effect of LPS on platelet activation was abolished by an anti-TLR4-blocking Ab or TLR4 knockout, suggesting that the effect of LPS on platelet aggregation requires the TLR4 pathway. Furthermore, LPS-potentiated thrombin- and collagen-induced platelet aggregation and FeCl3-induced thrombus formation were abolished in MyD88 knockout mice. LPS also induced cGMP elevation and the stimulatory effect of LPS on platelet aggregation was abolished by inhibitors of NO synthase and the cGMP-dependent protein kinase (PKG). LPS-induced cGMP elevation was inhibited by an anti-TLR4 Ab or by TLR4 deficiency, suggesting that activation of the cGMP/protein kinase G pathway by LPS involves the TLR4 pathway. Taken together, our data indicate that LPS stimulates platelet secretion and potentiates platelet aggregation through a TLR4/MyD88- and cGMP/PKG-dependent pathway.
IFN-α Enhances Peptide Vaccine-Induced CD8+ T Cell Numbers, Effector Function, and Antitumor Activity
Authors: Sikora Andrew G. , Jaffarzad Nina , Hailemichael Yared , Gelbard Alexander , Stonier Spencer W. , Schluns Kimberly S. , Frasca Loredana , Lou Yanyan , Liu Chengwen , Andersson Helen A. , Hwu Patrick , Overwijk Willem W. 
Published: June 2009

Abstract
Type I IFNs, including IFN-α, enhance Ag presentation and promote the expansion, survival, and effector function of CD8+ CTL during viral infection. Because these are ideal characteristics for a vaccine adjuvant, we examined the efficacy and mechanism of exogenous IFN-α as an adjuvant for antimelanoma peptide vaccination. We studied the expansion of pmel-1 transgenic CD8+ T cells specific for the gp100 melanocyte differentiation Ag after vaccination of mice with gp10025–33 peptide in IFA. IFN-α synergized with peptide vaccination in a dose-dependent manner by boosting relative and absolute numbers of gp100-specific T cells that suppressed B16 melanoma growth. IFN-α dramatically increased the accumulation of gp100-specific, IFN-γ-secreting, CD8+ T cells in the tumor through reduced apoptosis and enhanced proliferation of Ag-specific CD8+ T cells. IFN-α treatment also greatly increased the long-term maintenance of pmel-1 CD8+ T cells with an effector memory phenotype, a process that required expression of IFN-α receptor on the T cells and IL-15 in the host. These results demonstrate the efficacy of IFN-α as an adjuvant for peptide vaccination, give insight into its mechanism of action, and provide a rationale for clinical trials in which vaccination is combined with standard-of-care IFN-α therapy for melanoma.
IL-17 Receptor Signaling Is Required to Control Polymicrobial Sepsis
Authors: Freitas Andressa , Alves-Filho José C. , Victoni Tatiana , Secher Thomas , Lemos Henrique P. , Sônego Fabiane , Cunha Fernando Q. , Ryffel Bernhard 
Published: June 2009

Abstract
Sepsis is a systemic inflammatory response resulting from the inability of the host to contain the infection locally. Previously, we demonstrated that during severe sepsis there is a marked failure of neutrophil migration to the infection site, which contributes to dissemination of infection, resulting in high mortality. IL-17 plays an important role in neutrophil recruitment. Herein, we investigated the role of IL-17R signaling in polymicrobial sepsis induced by cecal ligation and puncture (CLP). It was observed that IL-17R-deficient mice, subjected to CLP-induced non-severe sepsis, show reduced neutrophil recruitment into the peritoneal cavity, spread of infection, and increased systemic inflammatory response as compared with C57BL/6 littermates. As a consequence, the mice showed an increased mortality rate. The ability of IL-17 to induce neutrophil migration was demonstrated in vivo and in vitro. Beside its role in neutrophil recruitment to the infection focus, IL-17 enhanced the microbicidal activity of the migrating neutrophils by a mechanism dependent on NO. Therefore, IL-17 plays a critical role in host protection during polymicrobial sepsis.
B Cell Receptor-Mediated Sustained c-Rel Activation Facilitates Late Transitional B Cell Survival through Control of B Cell Activating Factor Receptor and NF-κB2
Authors: Castro Iris , Wright Jacqueline A. , Damdinsuren Bazarragchaa , Hoek Kristen L. , Carlesso Gianluca , Shinners Nicholas P. , Gerstein Rachel M. , Woodland Robert T. , Sen Ranjan , Khan Wasif N. 
Published: June 2009

AbstractSignaling from the BCR and B cell activating factor receptor (BAFF-R or BR3) differentially regulates apoptosis within early transitional (T1) and late transitional (T2; CD21int-T2) B cells during selection processes to generate mature B lymphocytes. However, molecular mechanisms underlying the differential sensitivity of transitional B cells to apoptosis remain unclear. In this study, we demonstrate that BCR signaling induced more long-term c-Rel activation in T2 and mature than in T1 B cells leading to increased expression of anti-apoptotic genes as well as prosurvival BAFF-R and its downstream substrate p100 (NF-κB2). Sustained c-Rel activation required de novo c-Rel gene transcription and translation via Btk-dependent mechanisms. Like T1 cells, mature B cells from Btk- and c-Rel-deficient mice also failed to activate these genes. These findings suggest that the gain of survival potential within transitional B cells is dependent on the ability to produce a long-term c-Rel response, which plays a critical role in T2 B cell survival and differentiation in vivo by inducing anti-apoptotic genes, BAFF-R and NF-κB2, an essential component for BAFF-R survival signaling. Thus, acquisition of resistance to apoptosis during transitional B cell maturation is achieved by integration of BCR and BAFF-R signals.
Vaccination with Aβ-Displaying Virus-Like Particles Reduces Soluble and Insoluble Cerebral Aβ and Lowers Plaque Burden in APP Transgenic Mice
Authors: Bach Patricia , Tschäpe Jakob-A. , Kopietz Ferdinand , Braun Gundula , Baade Janina K. , Wiederhold Karl-Heinz , Staufenbiel Matthias , Prinz Marco , Deller Thomas , Kalinke Ulrich , Buchholz Christian J. , Müller Ulrike C. 
Published: June 2009

Abstract
In transgenic animal models, humoral immunity directed against the β-amyloid peptide (Aβ), which is deposited in the brains of AD patients, can reduce Aβ plaques and restore memory. However, initial clinical trials using active immunization with Aβ1–42 (plus adjuvant) had to be stopped as a subset of patients developed meningoencephalitis, likely due to cytotoxic T cell reactions against Aβ. Previously, we demonstrated that retrovirus-like particles displaying on their surface repetitive arrays of self and foreign Ags can serve as potent immunogens. In this study, we generated retrovirus-like particles that display the 15 N-terminal residues of human Aβ (lacking known T cell epitopes) fused to the transmembrane domain of platelet-derived growth factor receptor (Aβ retroparticles). Western blot analysis, ELISA, and immunogold electron microscopy revealed efficient incorporation of the fusion proteins into the particle membrane. Without the use of adjuvants, single immunization of WT mice with Aβ retroparticles evoked high and long-lived Aβ-specific IgG titers of noninflammatory Th2 isotypes (IgG1 and IgG2b) and led to restimulatable B cell memory. Likewise, immunization of transgenic APP23 model mice induced comparable Ab levels. The CNS of immunized wild-type mice revealed neither infiltrating lymphocytes nor activated microglia, and no peripheral autoreactive T cells were detectable. Importantly, vaccination not only reduced Aβ plaque load to ∼60% of controls and lowered both insoluble Aβ40 as well as Aβ42 in APP23 brain, but also significantly reduced cerebral soluble Aβ species. In summary, Aβ retroparticle vaccination may thus hold promise as a novel efficient future candidate vaccine for active immunotherapy of Alzheimer’s disease.
Metformin Attenuated the Autoimmune Disease of the Central Nervous System in Animal Models of Multiple Sclerosis
Authors: Nath Narender , Khan Musfiquidin , Paintlia Manjeet K. , Hoda Md Nasrul , Giri Shailendra 
Published: June 2009

Abstract
Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune disease of the CNS. Metformin is the most widely used drug for diabetes and mediates its action via activating AMP-activated protein kinase (AMPK). We provide evidence that metformin attenuates the induction of EAE by restricting the infiltration of mononuclear cells into the CNS, down-regulating the expression of proinflammatory cytokines (IFN-γ, TNF-α, IL-6, IL-17, and inducible NO synthase (iNOS)), cell adhesion molecules, matrix metalloproteinase 9, and chemokine (RANTES). Furthermore, the AMPK activity and lipids alterations (total phospholipids and in free fatty acids) were restored by metformin treatment in the CNS of treated EAE animals, suggesting the possible involvement of AMPK. Metformin activated AMPK in macrophages and thereby inhibited biosynthesis of phospholipids as well as neutral lipids and also down-regulated the expression of endotoxin (LPS)-induced proinflammatory cytokines and their mediators (iNOS and cyclooxygenase 2). It also attenuated IFN-γ and IL-17-induced iNOS and cyclooxygenase 2 expression in RAW267.4 cells, further supporting its anti-inflammatory property. Metformin inhibited T cell-mediated immune responses including Ag-specific recall responses and production of Th1 or Th17 cytokines, while it induced the generation of IL-10 in spleen cells of treated EAE animals. Altogether these findings reveal that metformin may have a possible therapeutic value for the treatment of multiple sclerosis and other inflammatory diseases.
Neutrophil-Derived Proteinase 3 Induces Kallikrein-Independent Release of a Novel Vasoactive Kinin
Authors: Kahn Robin , Hellmark Thomas , Leeb-Lundberg L. M. Fredrik , Akbari Nasrin , Todiras Mihail , Olofsson Tor , Wieslander Jörgen , Christensson Anders , Westman Kerstin , Bader Michael , Müller-Esterl Werner , Karpman Diana 
Published: June 2009

AbstractThe kinin-forming pathway is activated on endothelial cells and neutrophils when high-molecular weight kininogen (HK) is cleaved by plasma kallikrein liberating bradykinin, a potent mediator of inflammation. Kinins are released during inflammatory conditions such as vasculitis, associated with neutrophil influx around blood vessels. Some patients with vasculitis have elevated plasma levels of neutrophil-derived proteinase 3 (PR3) and anti-PR3 Abs. This study investigated if neutrophil-derived PR3 could induce activation of the kinin pathway. PR3 incubated with HK, or a synthetic peptide derived from HK, induced breakdown and release of a novel tridecapeptide termed PR3-kinin, NH2-MKRPPGFSPFRSS-COOH, consisting of bradykinin with two additional amino acids on each terminus. The reaction was specific and inhibited by anti-PR3 and α1-antitrypsin. Recombinant wild-type PR3 incubated with HK induced HK breakdown, whereas mutated PR3, lacking enzymatic activity, did not. PR3-kinin bound to and activated human kinin B1 receptors, but did not bind to B2 receptors, expressed by transfected HEK293 cells in vitro. In human plasma PR3-kinin was further processed to the B2 receptor agonist bradykinin. PR3-kinin exerted a hypotensive effect in vivo through both B1 and B2 receptors as demonstrated using wild-type and B1 overexpressing rats as well as wild-type and B2 receptor knockout mice. Neutrophil extracts from vasculitis patients and healthy controls contained comparable amounts of PR3 and induced HK proteolysis, an effect that was abolished when PR3 was immunoadsorbed. Neutrophil-derived PR3 can proteolyze HK and liberate PR3-kinin, thereby initiating kallikrein-independent activation of the kinin pathway.
The T Cell STAT Signaling Network Is Reprogrammed within Hours of Bacteremia via Secondary Signals
Authors: Hotson Andrew N. , Hardy Jonathan W. , Hale Matthew B. , Contag Christopher H. , Nolan Garry P. 
Published: June 2009

Abstract
The delicate balance between protective immunity and inflammatory disease is challenged during sepsis, a pathologic state characterized by aspects of both a hyperactive immune response and immunosuppression. The events driven by systemic infection by bacterial pathogens on the T cell signaling network that likely control these responses have not been illustrated in great detail. We characterized how intracellular signaling within the immune compartment is reprogrammed at the single cell level when the host is challenged with a high level of pathogen. To accomplish this, we applied flow cytometry to measure the phosphorylation potential of key signal transduction proteins during acute bacterial challenge. We modeled the onset of sepsis by i.v. administration of avirulent strains of Listeria monocytogenes and Escherichia coli to mice. Within 6 h of bacterial challenge, T cells were globally restricted in their ability to respond to specific cytokine stimulations as determined by assessing the extent of STAT protein phosphorylation. Mechanisms by which this negative feedback response occurred included SOCS1 and SOCS3 gene up-regulation and IL-6-induced endocystosis of the IL-6 receptor. Additionally, macrophages were partially tolerized in their ability to respond to TLR agonists. Thus, in contrast to the view that there is a wholesale immune activation during sepsis, one immediate host response to blood-borne bacteria was induction of a refractory period during which leukocyte activation by specific stimulations was attenuated.
Bcl-3-Regulated Transcription from Major Immediate-Early Promoter of Human Cytomegalovirus in Monocyte-Derived Macrophages
Authors: Khan Kashif Aziz , Coaquette Alain , Davrinche Christian , Herbein Georges 
Published: June 2009

Abstract
Monocytes/macrophages are key cells in the pathogenesis of human CMV (HCMV) infection, but the in vitro rate of viral production in primary human monocyte-derived macrophages (MDM) is considerably lower than in fibroblasts. Considering that the NF-κB signaling pathway is potentially involved in the replication strategy of HCMV through efficient transactivation of the major immediate-early promoter (MIEP), efficient viral replication, and late gene expression, we investigated the composition of the NF-κB complex in HCMV-infected MDMs and fibroblasts. Preliminary studies showed that HCMV could grow in primary MDM culture but that the viral titer in culture supernatants was lower than that observed in the supernatants of more permissive MRC5 fibroblasts. EMSA and microwell colorimetric NF-κB assay demonstrated that HCMV infection of MDMs increased p52 binding activity without activating the canonical p50/p65 complex. Moreover, Bcl-3 was up-regulated and was demonstrated to associate with p52, indicating p52/Bcl-3 complexes as the major component of the NF-κB complex in MDMs. Luciferase assays in promonocytic U937 cells transfected with an MIEP-luciferase reporter construct demonstrated MIEP activation in response to p52 and Bcl-3 overexpression. Chromatin immunoprecipitation assay demonstrated that p52 and Bcl-3 bind the MIEP in acutely HCMV-infected MDMs. In contrast, HCMV infection of MRC5 fibroblasts resulted in activation of p50/p65 heterodimers. Thus, activation of p52/Bcl-3 complexes in MDMs and p50/p65 heterodimers in fibroblasts in response to HCMV infection might explain the low-level growth of the virus in MDMs vs efficient growth in fibroblasts.
Cytokine Modulation of TLR Expression and Activation in Mesenchymal Stromal Cells Leads to a Proinflammatory Phenotype
Authors: Romieu-Mourez Raphaëlle , François Moïra , Boivin Marie-Noëlle , Bouchentouf Manaf , Spaner David E. , Galipeau Jacques 
Published: June 2009

Abstract
Bone marrow-derived mesenchymal stromal cells (MSC) possess an immune plasticity manifested by either an immunosuppressive or, when activated with IFN-γ, an APC phenotype. Herein, TLR expression by MSC and their immune regulatory role were investigated. We observed that human MSC and macrophages expressed TLR3 and TLR4 at comparable levels and TLR-mediated activation of MSC resulted in the production of inflammatory mediators such as IL-1β, IL-6, IL-8/CXCL8, and CCL5. IFN-α or IFN-γ priming up-regulated production of these inflammatory mediators and expression of IFNB, inducible NO synthase (iNOS), and TRAIL upon TLR activation in MSC and macrophages, but failed to induce IL-12 and TNF-α production in MSC. Nonetheless, TLR activation in MSC resulted in the formation of an inflammatory site attracting innate immune cells, as evaluated by human neutrophil chemotaxis assays and by the analysis of immune effectors retrieved from Matrigel-embedded MSC injected into mice after in vitro preactivation with cytokines and/or TLR ligands. Hence, TLR-activated MSC are capable of recruiting immune inflammatory cells. In addition, IFN priming combined with TLR activation may increase immune responses induced by Ag-presenting MSC through presentation of Ag in an inflammatory context, a mechanism that could be applied in a cell-based vaccine.
Fetal Exposure to Ethanol Has Long-Term Effects on the Severity of Influenza Virus Infections
Authors: McGill Jodi , Meyerholz David K. , Edsen-Moore Michelle , Young Betty , Coleman Ruth A. , Schlueter Annette J. , Waldschmidt Thomas J. , Cook Robert T. , Legge Kevin L. 
Published: June 2009

Abstract
Alcohol use by pregnant women is a significant public health issue despite well-described risks to the fetus including physical and intellectual growth retardation and malformations. Although clinical studies are limited, they suggest that in utero alcohol exposure also results in significant immune deficiencies in naive neonates. However, little is known about fetal alcohol exposure (FAE) effects on adult infections. Therefore, to determine the long-term effects of FAE on disease susceptibility and the adult immune system, we infected FAE adult mice with influenza virus. In this study, we demonstrate that mice exposed to ethanol during gestation and nursing exhibit enhanced disease severity as well as increased and sustained pulmonary viral titers following influenza virus infection. Secondary exposure to alcohol as an adult further exacerbates these effects. Moreover, we demonstrate that FAE mice have impaired adaptive immune responses, including decreased numbers of virus-specific pulmonary CD8 T cells, a decreased size and frequency of pulmonary B cell foci, and reduced production of influenza-specific Ab following influenza infection. Together, our results suggest that FAE induces significant and long-term defects in immunity and susceptibility to influenza virus infection and that FAE individuals could be at increased risk for severe and fatal respiratory infections.