bluuebunny/crossref_metadata_2025_split huggingface dataset:
Flagellin Promotes Myeloid Differentiation Factor 88-Dependent Development of Th2-Type Response
Authors: Didierlaurent Arnaud , Ferrero Isabel , Otten Luc A. , Dubois Bertrand , Reinhardt Monique , Carlsen Harald , Blomhoff Rune , Akira Shikuo , Kraehenbuhl Jean-Pierre , Sirard Jean-Claude 
Published: April 2014

Abstract
Activation of dendritic cells (DC) by microbial products via Toll-like receptors (TLR) is instrumental in the induction of immunity. In particular, TLR signaling plays a major role in the instruction of Th1 responses. The development of Th2 responses has been proposed to be independent of the adapter molecule myeloid differentiation factor 88 (MyD88) involved in signal transduction by TLRs. In this study we show that flagellin, the bacterial stimulus for TLR5, drives MyD88-dependent Th2-type immunity in mice. Flagellin promotes the secretion of IL-4 and IL-13 by Ag-specific CD4+ T cells as well as IgG1 responses. The Th2-biased responses are associated with the maturation of DCs, which are shown to express TLR5. Flagellin-mediated DC activation requires MyD88 and induces NF-κB-dependent transcription and the production of low levels of proinflammatory cytokines. In addition, the flagellin-specific response is characterized by the lack of secretion of the Th1-promoting cytokine IL-12 p70. In conclusion, this study suggests that flagellin and, more generally, TLR ligands can control Th2 responses in a MyD88-dependent manner.
Altered EBV Viral Load Setpoint after HIV Seroconversion Is in Accordance with Lack of Predictive Value of EBV Load for the Occurrence of AIDS-Related Non-Hodgkin Lymphoma
Authors: Piriou Erwan R. , van Dort Karel , Nanlohy Nening M. , Miedema Frank , van Oers Marinus H. , van Baarle Debbie 
Published: April 2014

Abstract
In contrast to the situation in the post-transplant setting, in HIV-infected individuals an elevated EBV load is not predictive of EBV-related malignancies. To study whether a high EBV load is already a normal situation early in HIV infection and is not related to a decrease in immune function over time, we investigated EBV load and EBV-specific CD8+ T cells ∼1 year before and 1 year after HIV seroconversion. EBV load significantly increased after HIV seroconversion from 205 to 1002 copies/106 PBMC (p &lt; 0.001), whereas no further increase in EBV load was observed between 1 and 5 years after HIV seroconversion (median, 1827–2478 copies/106 PBMC; p = 0.530). Interestingly, the absolute number of EBV lytic epitope, RAKFKQLL-specific CD8+ T cells increased over HIV seroconversion (4.78 to 9.54/μl; p = 0.011). Furthermore, the fraction of CD27-negative effector, RAK-specific CD8+ T cells tended to increase (from 12.2 to 17.31% CD27−; p = 0.051), in accordance with Ag-driven differentiation. In conclusion, both virological and immunological data support the idea that a new EBV viral setpoint is reached early in HIV infection, probably by EBV reactivation, as suggested by the preferential increase in EBV lytic epitope-specific CD8+ T cells. These data may thus help to explain the lack of predictive value of EBV load for the occurrence of AIDS-related lymphoma.
Toxoplasma gondiiTriggers Myeloid Differentiation Factor 88-Dependent IL-12 and Chemokine Ligand 2 (Monocyte Chemoattractant Protein 1) Responses Using Distinct Parasite Molecules and Host Receptors
Authors: Del Rio Laura , Butcher Barbara A. , Bennouna Soumaya , Hieny Sara , Sher Alan , Denkers Eric Y. 
Published: April 2014

AbstractToll-like receptors (TLR) that signal through the common adaptor molecule myeloid differentiation factor 88 (MyD88) are essential in proinflammatory cytokine responses to many microbial pathogens. In this study we report that Toxoplasma gondii triggers neutrophil IL-12 and chemokine ligand 2 (CCL2; monocyte chemoattractant protein 1) production in strict dependence upon functional MyD88. Nevertheless, the responses are distinct. Although we identify TLR2 as the receptor triggering CCL2 production, parasite-induced IL-12 release did not involve this TLR. The production of both IL-12 and CCL2 was increased after neutrophil activation with IFN-γ. However, the synergistic effect of IFN-γ on IL-12, but not CCL2, was dependent upon Stat1 signal transduction. Although IL-10 was a potent down-regulator of Toxoplasma-triggered neutrophil IL-12 release, the cytokine had no effect on parasite-induced CCL2 production. Soluble tachyzoite Ag fractionation demonstrated that CCL2- and IL-12 inducing activities are biochemically distinct. Importantly, Toxoplasma cyclophilin-18, a molecule previously shown to induce dendritic cell IL-12, was not involved in neutrophil IL-12 production. Our results show for the first time that T. gondii possesses multiple molecules triggering distinct MyD88-dependent signaling cascades, that these pathways are independently regulated, and that they lead to distinct profiles of cytokine production.
Toll-Like Receptor 4 Signaling by Intestinal Microbes Influences Susceptibility to Food Allergy
Authors: Bashir Mohamed Elfatih H. , Louie Steve , Shi Hai Ning , Nagler-Anderson Cathryn 
Published: April 2014

Abstract
The mechanisms by which signaling by the innate immune system controls susceptibility to allergy are poorly understood. In this report, we show that intragastric administration of a food allergen with a mucosal adjuvant induces allergen-specific IgE, elevated plasma histamine levels, and anaphylactic symptoms in three different strains of mice lacking a functional receptor for bacterial LPS (Toll-like receptor 4 (TLR4)), but not in MHC-matched or congenic controls. Susceptibility to allergy correlates with a Th2-biased cytokine response in both the mucosal (mesenteric lymph node and Peyer’s patch) and systemic (spleen) tissues of TLR4-mutant or -deficient mice. TLR4-mutant mice are not inherently impaired in their ability to regulate Th1 cytokine production because they respond to stimulation via TLR9. Coadministration of CpG oligodeoxynucleotides during sensitization of TLR4-mutant mice with allergen plus CT abrogates anaphylactic symptoms and Ag-specific IgE, and results in a Th1-polarized cytokine response. When the composition of the bacterial flora is reduced and altered by antibiotic administration (beginning at 2 wk of age), TLR4 wild-type mice become as susceptible to the induction of allergy as their TLR4-mutant counterparts. Both allergen-specific IgE and Th2 cytokine responses are reduced in antibiotic-treated mice in which the flora has been allowed to repopulate. Taken together, our results suggest that TLR4-dependent signals provided by the intestinal commensal flora inhibit the development of allergic responses to food Ags.
Chemotaxis Inhibitory Protein of Staphylococcus aureus Binds Specifically to the C5a and Formylated Peptide Receptor
Authors: Postma Bent , Poppelier Miriam J. , van Galen Joost C. , Prossnitz Eric R. , van Strijp Jos A. G. , de Haas Carla J. C. , van Kessel Kok P. M. 
Published: April 2014

Abstract
Chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS) is an exoprotein produced by several strains of S. aureus, and a potent inhibitor of neutrophil and monocyte chemotaxis toward C5a and formylated peptides like fMLP. These chemoattractants act on their target cells by binding and activating the C5aR and formylated peptide receptor (FPR), respectively. In the present report, we examined the mechanism by which CHIPS affects both of these receptors. We showed that CHIPS blocked binding of anti-C5aR mAb and formylated peptide to human neutrophils as efficiently at temperatures of 0 and 37°C, implying that it is independent of signal transducing systems. This was confirmed by showing that CHIPS acts completely independently of ATP. Additionally, CHIPS was not internalized upon binding to neutrophils. Furthermore, we showed that CHIPS binds specifically to the C5aR and FPR expressed on U937 cells. This binding was functional in blocking C5a- and fMLP-induced calcium mobilization in these cell lines. These results suggest that CHIPS binds directly to the C5aR and FPR, thereby preventing the natural ligands from activating these receptors. The apparent Kd values of CHIPS for the C5aR and FPR were 1.1 ± 0.2 nM and 35.4 ± 7.7 nM, respectively. Moreover, after screening a wide variety of other G protein-coupled receptors, CHIPS was found to affect exclusively the C5aR and FPR. This selectivity and high-affinity binding with potent antagonistic effects makes CHIPS a promising lead for the development of new anti-inflammatory compounds for diseases in which damage by neutrophils plays a key role.
TL1A Synergizes with IL-12 and IL-18 to Enhance IFN-γ Production in Human T Cells and NK Cells
Authors: Papadakis Konstantinos A. , Prehn John L. , Landers Carol , Han Qiwei , Luo Xia , Cha Stephanie C. , Wei Ping , Targan Stephan R. 
Published: April 2014

Abstract
TL1A, a recently described TNF-like cytokine that interacts with DR3, costimulates T cells and augments anti-CD3 plus anti-CD28 IFN-γ production. In the current study we show that TL1A or an agonistic anti-DR3 mAb synergize with IL-12/IL-18 to augment IFN-γ production in human peripheral blood T cells and NK cells. TL1A also enhanced IFN-γ production by IL-12/IL-18 stimulated CD56+ T cells. When expressed as fold change, the synergistic effect of TL1A on cytokine-induced IFN-γ production was more pronounced on CD4+ and CD8+ T cells than on CD56+ T cells or NK cells. Intracellular cytokine staining showed that TL1A significantly enhanced both the percentage and the mean fluorescence intensity of IFN-γ-producing T cells in response to IL-12/IL-18. The combination of IL-12 and IL-18 markedly up-regulated DR3 expression in NK cells, whereas it had minimal effect in T cells. Our data suggest that TL1A/DR3 pathway plays an important role in the augmentation of cytokine-induced IFN-γ production in T cells and that DR3 expression is differentially regulated by IL-12/IL-18 in T cells and NK cells.
TGF-β1 Represses Activation and Resultant Death of Microglia via Inhibition of Phosphatidylinositol 3-Kinase Activity
Authors: Kim Won-Ki , Hwang So-Young , Oh Eok-Soo , Piao Hua Zi , Kim Ki-Wan , Han Inn-Oc 
Published: April 2014

AbstractOveractivation of microglial cells may cause severe brain tissue damage in various neurodegenerative diseases. Therefore, the overactivation of microglia should be repressed by any means. The present study investigated the potential mechanism and signaling pathway for the repressive effect of TGF-β1, a major anti-inflammatory cytokine, on overactivation and resultant death of microglial cells. A bacterial endotoxin LPS stimulated expression of inducible NO synthase (iNOS) and caused death in cultured microglial cells. TGF-β1 markedly blocked these LPS effects. However, the LPS-evoked death of microglial cells was not solely attributed to excess production of NO. Because phosphatidylinositol 3-kinase (PI3K) was previously shown to play a crucial role in iNOS expression and cell survival signals, we further studied whether PI3K signaling was associated with the suppressive effect of TGF-β1. Like TGF-β1, the PI3K inhibitor LY294002 blocked iNOS expression and death in cultured microglial cells. Both TGF-β1 and LY294002 decreased the activation of caspases 3 and 11 and the mRNA expression of various kinds of inflammatory molecules caused by LPS. TGF-β1 was further found to decrease LPS-induced activation of PI3K and Akt. TGF-β1 and LY294002 suppressed LPS-induced p38 mitogen-activated kinase and c-Jun N-terminal kinase activity. In contrast, TGF-β1 and LY294002 enhanced LPS-induced NF-κB activity. Our data indicate that TGF-β1 protect normal or damaged brain tissue by repressing overactivation of microglial cells via inhibition of PI3K and its downstream signaling molecules.
Bid Truncation, Bid/Bax Targeting to the Mitochondria, and Caspase Activation Associated with Neutrophil Apoptosis Are Inhibited by Granulocyte Colony-Stimulating Factor
Authors: Maianski Nikolai A. , Roos Dirk , Kuijpers Taco W. 
Published: April 2014

Abstract
Neutrophil apoptosis constitutes a way of managing neutrophil-mediated reactions. It allows coping with infections, but avoiding overt bystander tissue damage. Using digitonin-based subcellular fractionation and Western blotting, we found that spontaneous apoptosis of human neutrophils (after ∼20 h of culture) was associated with translocation of two proapoptotic Bcl-2 homologues, Bid and Bax, to the mitochondria and truncation of Bid, with subsequent release of Omi/HtrA2 and Smac/DIABLO into the cytosol. These events were accompanied by processing and increased enzymatic activity of caspase-8, -9, and -3. A G-CSF-mediated reduction in apoptosis coincided with inhibition of all these reactions. The G-CSF-induced effects were differentially dependent on newly synthesized mediators. Whereas inhibition of Bax targeting to the mitochondria and inhibition of caspase activation by G-CSF were dependent on protein synthesis, Bid truncation and redistribution were prevented by G-CSF regardless of the presence of the protein synthesis inhibitor cycloheximide. Apparently, the observed Bid changes were dispensable for neutrophil apoptosis. Although the regulators of the inhibitor of apoptosis proteins (IAPs), Omi/HtrA2 and Smac/DIABLO, were released into the cytosol during apoptosis, we did not observe cleavage of X-linked IAP, which suggests that another mechanism of IAP deactivation is involved. Together our results support an integrative role of the mitochondria in induction and/or amplification of caspase activity and show that G-CSF may act by blocking Bid/Bax redistribution and inhibiting caspase activation.
Effects of TNF-α and IFN-γ on Nitric Oxide-Induced Neurotoxicity in the Mouse Brain
Authors: Blais Véronique , Rivest Serge 
Published: April 2014

Abstract
The present study investigated the interaction between highly reactive gaseous-free radical NO and cytokines that are produced by activated Th-1 cells on the cerebral immune response and neuronal integrity. CD-1 mice received an intrastriatal infusion of different solutions containing the NO synthase inhibitor N(G)-nitro-l-arginine methylester, NO-releasing substance sodium nitroprusside (SNP), IFN-γ, and/or TNF-α. The solution containing both cytokines caused a profound and transient transcriptional activation of numerous genes encoding proinflammatory proteins in microglial/monocytic cells ipsilateral to infusion site. This increase in gene expression peaked 1 day after the cerebral bolus of cytokines and returned to basal levels from 3 to 7 days post administration. N(G)-nitro-l-arginine methylester further stimulated this immune reaction to IFN-γ and TNF-α, but the brain of these mice failed to exhibit signs of neurodegeneration and demyelination. In contrast, a single bolus of SNP in the striatal region caused neuronal death and demyelination as early as 1 to 3 days following the infusion with the NO donor. This phenomenon was greatly exacerbated by the coadministration of both cytokines, although TNF-α remained the most critical cytokine to enhance the damage of cerebral elements. These data provide evidence that NO has the ability to modulate the immune response, which is not by itself detrimental for the brain. However, SNP-induced NO production together with TNF-α in the cerebral environment are critical events leading to intense neurodegeneration and demyelination in vivo.
Genomic and Proteomic Determinants of Outcome in Patients Undergoing Thoracoabdominal Aortic Aneurysm Repair
Authors: Feezor Robert J. , Baker Henry V. , Xiao Wenzhong , Lee W. Anthony , Huber Thomas S. , Mindrinos Michael , Kim Raymond A. , Ruiz-Taylor Laurence , Moldawer Lyle L. , Davis Ronald W. , Seeger James M. 
Published: April 2014

Abstract
Thoracoabdominal aortic aneurysm repair, with its requisite intraoperative mesenteric ischemia-reperfusion, often results in the development of systemic inflammatory response syndrome, multiorgan dysfunction syndrome (MODS), and death. In the present study, an adverse clinical outcome following thoracoabdominal aortic aneurysm repair was identified by blood leukocyte genomic and plasma proteomic responses. Time-dependent changes in the expression of 146 genes from blood leukocytes were observed (p &lt; 0.001). Expression of 138 genes (p &lt; 0.001) and the concentration of seven plasma proteins discriminated between patients who developed MODS and those who did not, and many of these differences were evident even before surgery. These findings suggest that changes in blood leukocyte gene expression and plasma protein concentrations can illuminate pathophysiological processes that are subsequently associated with the clinical sequelae of systemic inflammatory response syndrome and MODS. These changes in gene expression and plasma protein concentrations are often observed before surgery, consistent with either a genetic predisposition or pre-existing inflammatory state.
A Promoter Haplotype of the Immunoreceptor Tyrosine-Based Inhibitory Motif-Bearing FcγRIIb Alters Receptor Expression and Associates with Autoimmunity. I. Regulatory FCGR2B Polymorphisms and Their Association with Systemic Lupus Erythematosus
Authors: Su Kaihong , Wu Jianming , Edberg Jeffrey C. , Li Xiaoli , Ferguson Polly , Cooper Glinda S. , Langefeld Carl D. , Kimberly Robert P. 
Published: April 2014

Abstract
FcγRIIb, the immunoreceptor tyrosine-based inhibitory motif-containing receptor for IgG (Mendelian Inheritance in Man no. 604590), plays an important role in maintaining the homeostasis of immune responses. We have identified 10 novel single-nucleotide polymorphisms in the promoter region of human FCGR2B gene and characterized two functionally distinct haplotypes in its proximal promoter. In luciferase reporter assays, the less frequent promoter haplotype leads to increased expression of the reporter gene in both B lymphoid and myeloid cell lines under constitutive and stimulated conditions. Four independent genome-wide scans support linkage of the human FcγR region to the systemic lupus erythematosus (SLE; Online Mendelian Inheritance in Man no. 152700) phenotype. Our case-control study in 600 Caucasians indicates a significant association of the less frequent FCGR2B promoter haplotype with the SLE phenotype (odds ratio = 1.65; p = 0.0054). The FCGR2B haplotype has no linkage disequilibrium with previously identified FCGR2A and FCGR3A polymorphisms, and after adjustment for FCGR2A and FCGR3A, FCGR2B showed a persistent association with SLE (odds ratio = 1.72; p = 0.0083). These results suggest that an expression variant of FCGR2B is a risk factor for human lupus and implicate FCGR2B in disease pathogenesis.
Development of the Dendritic Cell System during Mouse Ontogeny
Authors: Dakic Aleksandar , Shao Qi-xiang , D’Amico Angela , O’Keeffe Meredith , Chen Wei-feng , Shortman Ken , Wu Li 
Published: April 2014

Abstract
Based on the view that the efficacy of the immune system is associated with the maturation state of the immune cells, including dendritic cells (DC), we investigated the development and functional potential of conventional DC and plasmacytoid pre-DC (p-preDC) in spleen, thymus, and lymph nodes during mouse development. Both CD11c+ DC and CD45RA+ p-preDC were detected in small numbers in the thymus as early as embryonic day 17. The ratio of DC to thymocytes reached adult levels by 1 wk, although the normal CD8α+ phenotype was not acquired until later. Significant, but low, numbers of DC and p-preDC were present in the spleen of day 1 newborn mice. The full complement of DC and p-preDC was not acquired until 5 wk of age. The composition of DC populations in the spleen of young mice differed significantly from that found in adult mice, with a much higher percentage (50–60% compared with 20–25%) of the CD4−CD8α+ DC population and a much lower percentage (10–20% compared with 50–60%) of the CD4+CD8α− DC population. Although the p-preDC of young mice showed a capacity to produce IFN-α comparable with that of adult mice, the conventional DC of young mice were less efficient than those of their adult counterparts in IL-12p70 and IFN-γ production and in Ag presentation. These results suggest that the neonatal DC system is not fully developed, and innate immunity is the dominant form of response. The complete DC system required for adaptive immunity in the mouse is not fully developed until 5 wk of age.
Ultraviolet Radiation-Induced Regulatory T Cells Not Only Inhibit the Induction but Can Suppress the Effector Phase of Contact Hypersensitivity
Authors: Schwarz Agatha , Maeda Akira , Wild Martin K. , Kernebeck Kerstin , Gross Nicole , Aragane Yoshinori , Beissert Stefan , Vestweber Dietmar , Schwarz Thomas 
Published: April 2014

Abstract
Epicutaneous application of haptens to UV-exposed skin induces hapten-specific tolerance. This is mediated via regulatory T cells (Tr), as i.v. injection of T cells from UV-tolerized mice into naive animals renders the recipients unresponsive to the respective hapten. However, when UV-induced Tr are injected i.v. into sensitized mice, contact hypersensitivity (CHS) is not suppressed, suggesting that Tr inhibit the induction, but not the elicitation, of CHS and are inferior to T effector cells. As sensitization takes place in the lymph nodes, but elicitation occurs in the area of challenge, we postulated that Tr injected i.v. locate to the lymph nodes and not to the periphery and therefore only suppress the induction, not the elicitation, of CHS. Indeed, i.v. injection of Tr into sensitized mice did not inhibit CHS, although injection of Tr into the ears of sensitized mice suppressed the challenge. Inhibition was hapten specific, as injection of dinitrofluorobenzene (DNFB)-specific Tr into the ears of oxazolone (OXA)-sensitized mice did not affect challenge with OXA. However, when ears of OXA-sensitized mice were injected with DNFB-specific Tr and painted with DNFB before OXA challenge, CHS was suppressed. Inhibition correlated with the local expression of IL-10. Depletion studies and FACS analysis revealed that Tr express the lymph node-homing receptor L-selectin, but not the ligands for the skin-homing receptors E- and P-selectin, suggesting that UV-induced Tr, although able to inhibit T effector cells, do not suppress the elicitation of CHS upon i.v. injection, because they obviously do not migrate into the skin.
CD23 Trimers Are Preassociated on the Cell Surface Even in the Absence of Its Ligand, IgE
Authors: Kilmon Michelle A. , Shelburne Anne E. , Chan-Li Yee , Holmes Kevin L. , Conrad Daniel H. 
Published: April 2014

Abstract
Allergic disease is mediated by high levels of allergen-specific IgE. IgE binding to CD23, the low affinity receptor for IgE, results in a negative feedback signal leading to a decrease in IgE production. Previous studies have shown that CD23 associates as an oligomer and that cooperative binding of at least two lectin domains is required for high affinity IgE binding to CD23. We have previously shown that cooperative binding is required for regulation of IgE production. This study describes the production of several mAbs that bind the stalk region of murine CD23. One of the Abs, 19G5, inhibited the IgE/CD23 interaction at 37°C, but not at 4°C. Analysis of the binding properties of these Abs revealed that CD23 dissociates at high temperatures, such as 37°C; however, the N terminus is constitutively associated, indicating partial, rather than complete, dissociation. A novel finding was that the stalk region, previously thought to mediate trimer association, was not required for oligomerization. These data reveal important information about the structure of CD23 that may be useful in modulating IgE production.