bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasmodium falciparum Variant Surface Antigen Expression Varies Between Isolates Causing Severe and Nonsevere Malaria and Is Modified by Acquired Immunity
Authors: Nielsen Morten A. , Staalsoe Trine , Kurtzhals Jørgen A. L. , Goka Bamenla Q. , Dodoo Daniel , Alifrangis Michael , Theander Thor G. , Akanmori Bartholomew D. , Hviid Lars 
Published: April 2014

Abstract
In areas of endemic parasite transmission, protective immunity to Plasmodium falciparum malaria is acquired over several years with numerous disease episodes. Acquisition of Abs to parasite-encoded variant surface Ags (VSA) on the infected erythrocyte membrane is important in the development of immunity, as disease-causing parasites appear to be those not controlled by preexisting VSA-specific Abs. In this work we report that VSA expressed by parasites from young Ghanaian children with P. falciparum malaria were commonly and strongly recognized by plasma Abs from healthy children in the same area, whereas recognition of VSA expressed by parasites from older children was weaker and less frequent. Independent of this, parasites isolated from children with severe malaria (cerebral malaria and severe anemia) were better recognized by VSA-specific plasma Abs than parasites obtained from children with nonsevere disease. This was not due to a higher infection multiplicity in younger patients or in patients with severe disease. Our data suggest that acquisition of VSA-specific Ab responses gradually restricts the VSA repertoire that is compatible with parasite survival in the semi-immune host. This appears to limit the risk of severe disease by discriminating against the expression of VSA likely to cause life-threatening complications, such as cerebral malaria and severe anemia. Such VSA seem to be preferred by parasites infecting a nonimmune host, suggesting that VSA expression and switching are not random, and that the VSA expression pattern is modulated by immunity. This opens the possibility of developing morbidity-reducing vaccines targeting a limited subset of common and particularly virulent VSA.
The NKp46 Receptor Contributes to NK Cell Lysis of Mononuclear Phagocytes Infected with an Intracellular Bacterium
Authors: Vankayalapati Ramakrishna , Wizel Benjamin , Weis Stephen E. , Safi Hassan , Lakey David L. , Mandelboim Ofer , Samten Buka , Porgador Angel , Barnes Peter F. 
Published: April 2014

AbstractWe used human tuberculosis as a model to investigate the role of NK cytotoxic mechanisms in the immune response to intracellular infection. Freshly isolated NK cells and NK cell lines from healthy donors lysed Mycobacterium tuberculosis-infected monocytes to a greater extent than uninfected monocytes. Lysis of infected monocytes was associated with increased expression of mRNA for the NKp46 receptor, but not the NKp44 receptor. Antisera to NKp46 markedly inhibited lysis of infected monocytes. NK cell-mediated lysis was not due to reduced expression of MHC class I molecules on the surface of infected monocytes or to enhanced production of IL-18 or IFN-γ. NK cell lytic activity against M. tuberculosis-infected monocytes and NKp46 mRNA expression were reduced in tuberculosis patients with ineffective immunity to M. tuberculosis compared with findings in healthy donors. These observations suggest that 1) the NKp46 receptor participates in NK cell-mediated lysis of cells infected with an intracellular pathogen, and 2) the reduced functional capacity of NK cells is associated with severe manifestations of infectious disease.
Iron Chelation Via Deferoxamine Exacerbates Experimental Salmonellosis Via Inhibition of the Nicotinamide Adenine Dinucleotide Phosphate Oxidase-Dependent Respiratory Burst
Authors: Collins Helen L. , Kaufmann Stefan H. E. , Schaible Ulrich E. 
Published: April 2014

Abstract
Competition for cellular iron (Fe) is a vital component of the interaction between host and intracellular pathogen. The host cell requires Fe for the execution of antimicrobial effector mechanisms, whereas most bacteria have an obligate requirement for Fe to sustain growth and intracellular survival. In this study, we show that chelation of host Fe in vivo exacerbates murine salmonellosis, resulting in increased bacterial load and decreased survival times. We further demonstrate that host Fe deprivation results in an inability to induce the NADPH oxidase-dependent production of reactive oxygen, an essential host defense mechanism for the early control of Salmonella typhimurium infection. Thus, altering the equilibrium of intracellular Fe influences the course of infection to the benefit of the pathogen.
Gq Signaling Is Required for Allergen-Induced Pulmonary Eosinophilia
Authors: Borchers Michael T. , Justice Paul J. , Ansay Tracy , Mancino Valeria , McGarry Michael P. , Crosby Jeffrey , Simon Melvin I. , Lee Nancy A. , Lee James J. 
Published: April 2014

AbstractThe complexity and magnitude of interactions leading to the selective infiltration of eosinophils in response to inhaled allergens are formidable obstacles to a larger understanding of the pulmonary pathology associated with allergic asthma. This study uses knockout mice to demonstrate a novel function for the heterotrimeric G protein, Gq, in the regulation of pulmonary eosinophil recruitment. In the absence of Gq signaling, eosinophils failed to accumulate in the lungs following allergen challenge. These studies demonstrate that the inhibition of eosinophil accumulation in the airways is attributed to the failure of hemopoietically derived cells to elaborate GM-CSF in the airways. The data suggest that activation of a Gq-coupled receptor(s) on resident leukocytes in the lung elicits expression of GM-CSF, which, in turn, is required for allergen-induced pulmonary eosinophilia, identifying a novel pathway of eosinophil-associated effector functions leading to pulmonary pathology in diseases such as asthma.
Tissue-Specific Mechanisms Control the Retention of IL-8 in Lungs and Skin
Authors: Frevert Charles W. , Goodman Richard B. , Kinsella Michael G. , Kajikawa Osamu , Ballman Kimberly , Clark-Lewis Ian , Proudfoot Amanda E. I. , Wells Timothy N. C. , Martin Thomas R. 
Published: April 2014

AbstractChemokines are a group of structurally related peptides that promote the directed migration of leukocytes in tissue. Mechanisms controlling the retention of chemokines in tissue are not well understood. In this study we present evidence that two different mechanisms control the persistence of the CXC chemokine, IL-8, in lungs and skin. 125I-labeled IL-8 was injected into the airspaces of the lungs and the dermis of the skin and the amount of 125I-labeled IL-8 that remained at specified times was measured by scintillation counting. The 125I-labeled IL-8 was cleared much more rapidly from skin than lungs, as only 2% of the 125I-labeled IL-8 remained in skin at 4 h whereas 50% of the 125I-labeled IL-8 remained in lungs at 4 h. Studies in neutropenic rabbits showed that neutrophils shortened the retention of 125I-labeled IL-8 in skin but not lungs. A monomeric form of IL-8, N-methyl-leucine 25 IL-8, was not retained as long in lungs as recombinant human IL-8, indicating that dimerization of IL-8 is a mechanism that increases the local concentration and prolongs the retention of 125I-labeled IL-8 in lungs. These observations show that the mechanisms that control the retention of IL-8 in tissue include neutrophil migration and dimerization, and that the importance of these varies in different tissues.
15-Deoxy-Δ12,1412,14-prostaglandins D2 and J2 Are Potent Activators of Human Eosinophils
Authors: Monneret Guillaume , Li Hongping , Vasilescu Julian , Rokach Joshua , Powell William S. 
Published: April 2014

Abstract15-Deoxy-Δ12,14-PDJ2 (15d-PGJ2) is a degradation product of PGD2 that has been proposed as an anti-inflammatory compound because of its various inhibitory effects, some of which are mediated by peroxisome proliferator-activated receptor-γ. In contrast to its reported inhibitory effects on macrophages and other cells, we found that this compound is a potent activator of eosinophils, inducing calcium mobilization, actin polymerization, and CD11b expression. It is selective for eosinophils, having little or no effect on neutrophils or monocytes. 15d-PGJ2 has an EC50 of ∼10 nM, similar to that of its precursor, PGD2. The concentrations of 15d-PGJ2 required to activate eosinophils are thus much lower than those required for its anti-inflammatory effects (usually micromolar). 15-Deoxy-Δ12,14-prostaglandin D2 (15d-PGD2) is also a potent activator of eosinophils, with an EC50 about the same as that of PGD2, whereas Δ12-PGJ2 is slightly less potent. Eosinophils pretreated with PGD2 no longer respond to 15d-PGJ2, and vice versa, but in both cases the cells still respond to another eicosanoid proinflammatory mediator, 5-oxo-6,8,11,14-eicosatetraenoic acid. This indicates that the effects of 15d-PGJ2 are mediated by the DP2/chemoattractant receptor-homologous molecule expressed on Th2 cells that has recently been identified in eosinophils. 15d-PGJ2 is selective for the DP2 receptor, in that it has no effect on DP1 receptor-mediated adenylyl cyclase activity in platelets. We conclude that 15d-PGJ2 and 15d-PGD2 are selective DP2 receptor agonists that activate human eosinophils with potencies at least 100 times greater than those for the proposed anti-inflammatory effects of 15d-PGJ2 on other cells.
Modulation of Leukotriene B4 Receptor-1 Expression by Dexamethasone: Potential Mechanism for Enhanced Neutrophil Survival
Authors: Stankova Jana , Turcotte Sylvie , Harris Jennifer , Rola-Pleszczynski Marek 
Published: April 2014

AbstractGlucocorticoids can down-regulate many inflammatory and immune responses and constitute a powerful therapeutic tool in a number of diseases. However, they have a somewhat paradoxical effect on neutrophils, in that they prolong their survival. Because leukotriene B4 (LTB4) can also extend neutrophil survival, we proposed that glucocorticoids could prevent neutrophil apoptosis by up-regulating their expression of the high-affinity LTB4 receptor (BLT1). Here we show that, indeed, dexamethasone (DEX) up-regulates the steady-state levels of BLT1 mRNA in human neutrophils. The effect was time and concentration dependent, being maximal at 4 h and at 10–100 nM DEX. The effect was also dependent on transcriptional activity, whereas BLT1 mRNA stability was not affected. DEX-induced up-regulation of BLT1 expression was prevented by pretreatment with the LTB4 antagonist LY255283. Moreover, LTB4 itself up-regulated the expression of BLT1 mRNA. BLT1 protein expression on neutrophils exposed to DEX for 24 h was also up-regulated 2- to 3-fold, and DEX-treated as well as LTB4-treated cells showed enhanced responsiveness to LTB4 in terms of intracellular Ca2+ mobilization and chemotaxis. Whereas DEX and LTB4 alone decreased neutrophil apoptosis by ∼50%, neutrophils treated with both LTB4 and DEX showed &gt;90% survival at 24 h. Moreover, BLT1 antagonists prevented the increased neutrophil survival induced by DEX as well as by LTB4. Taken together, our results suggest that DEX-induced up-regulation of BLT1 expression in neutrophils may be one mechanism through which glucocorticoids can prolong neutrophil survival, namely by enhancing cell responses to the antiapoptotic effect of LTB4.
Antibodies Against Cerebral M1 Cholinergic Muscarinic Receptor from Schizophrenic Patients: Molecular Interaction
Authors: Borda Tania , Perez Rivera Ricardo , Joensen Lilian , Gomez Ricardo M. , Sterin-Borda Leonor 
Published: April 2014

Abstract
We demonstrated the presence of circulating Abs from schizophrenic patients able to interact with cerebral frontal cortex-activating muscarinic acetylcholine receptors (mAChR). Sera and purified IgG from 21 paranoid schizophrenic and 25 age-matched normal subjects were studied by indirect immunofluorescence, flow cytometry, immunoblotting, dot blot, ELISA, and radioligand competition assays. Rat cerebral frontal cortex membranes and/or a synthetic peptide, with an amino acid sequence identical with that of human M1 mAChR, were used as Ags. By indirect immunofluorescence and flow cytometry procedures, we proved that serum-purified IgG fraction from schizophrenic patients reacted to neural cell surfaces from rat cerebral frontal cortex. The same Abs were able to inhibit the binding of the specific M1 mAChR radioligand [3H]pirenzepine. Immunoblotting experiments showed that IgG from schizophrenic patients revealed a band with a molecular mass coincident to that labeled by an anti-M1 mAChR Ab. Using synthetic peptide for dot blot and ELISA, we demonstrated that these Abs reacted against the second extracellular loop of human cerebral M1 mAChR. Also, the corresponding affinity-purified antipeptide Ab displayed an agonistic-like activity associated to specific receptor activation, increasing cyclic GMP production and inositol phosphate accumulation, and protein kinase C translocation. This paper gave support to the participation of an autoimmune process in schizophrenia.
Spleen Is a Primary Site for Activation of Platelet-Reactive T and B Cells in Patients with Immune Thrombocytopenic Purpura
Authors: Kuwana Masataka , Okazaki Yuka , Kaburaki Junichi , Kawakami Yutaka , Ikeda Yasuo 
Published: April 2014

Abstract
We have recently reported that in patients with chronic immune thrombocytopenic purpura (IMTP), circulating T and B cells that are responsive to gpIIb-IIIa can induce anti-platelet autoantibody production. In this study, the frequencies and activation status of gpIIb-IIIa-reactive T and B cells were evaluated in the peripheral blood and spleen obtained from nine IMTP patients undergoing splenectomy. There was no difference in gpIIb-IIIa-reactive T cell frequencies between peripheral blood and spleen (6.4 ± 2.6 vs 5.2 ± 2.4 per 105 T cells), as determined by limiting dilution analysis, but activated T cells responsive to gpIIb-IIIa showing accelerated proliferation kinetics and those expressing CD154 were more frequent in spleen than in peripheral blood. The frequencies of anti-gpIIb-IIIa Ab-producing B cells, as determined by ELISPOT assay, were also similar in peripheral blood and spleen (61.2 ± 24.0 vs 77.7 ± 45.3 per 105 B cells); however, an anti-gpIIb-IIIa Ab was spontaneously produced by splenocytes in vitro, but scarcely secreted by PBMCs. CD19−/surface Ig−/CD38+/CD138+ plasma cells secreting anti-gpIIb-IIIa Ab were exclusively detected in the spleen. In serial analysis, the frequencies of circulating gpIIb-IIIa-reactive T and B cells were markedly decreased after splenectomy in patients with a complete response, but were unchanged in nonresponders. These findings indicate that an interaction between gpIIb-IIIa-reactive T and B cells inducing anti-platelet Ab production in IMTP patients occurs primarily in the spleen and that the significant number of gpIIb-IIIa-reactive T and B cells activated in the spleen are released into the circulation as memory cells.
Cutting Edge: Role of Toll-Like Receptor 1 in Mediating Immune Response to Microbial Lipoproteins
Authors: Takeuchi Osamu , Sato Shintaro , Horiuchi Takao , Hoshino Katsuaki , Takeda Kiyoshi , Dong Zhongyun , Modlin Robert L. , Akira Shizuo 
Published: April 2014

Abstract
The Toll-like receptor (TLR) family acts as pattern recognition receptors for pathogen-specific molecular patterns (PAMPs). TLR2 is essential for the signaling of a variety of PAMPs, including bacterial lipoprotein/lipopeptides, peptidoglycan, and GPI anchors. TLR6 associates with TLR2 and recognizes diacylated mycoplasmal lipopeptide along with TLR2. We report here that TLR1 associates with TLR2 and recognizes the native mycobacterial 19-kDa lipoprotein along with TLR2. Macrophages from TLR1-deficient (TLR1−/−) mice showed impaired proinflammatory cytokine production in response to the 19-kDa lipoprotein and a synthetic triacylated lipopeptide. In contrast, TLR1−/− cells responded normally to diacylated lipopeptide. TLR1 interacts with TLR2 and coexpression of TLR1 and TLR2 enhanced the NF-κB activation in response to a synthetic lipopeptide. Furthermore, lipoprotein analogs whose acylation was modified were preferentially recognized by TLR1. Taken together, TLR1 interacts with TLR2 to recognize the lipid configuration of the native mycobacterial lipoprotein as well as several triacylated lipopeptides.
A Defective NF-κB/RelB Pathway in Autoimmune-Prone New Zealand Black Mice Is Associated with Inefficient Expansion of Thymocyte and Dendritic Cells
Authors: Valéro René , Baron Marie-Laurence , Guérin Sandrine , Béliard Sophie , Lelouard Hugues , Kahn-Perles Brigitte , Vialettes Bernard , Nguyen Cathy , Imbert Jean , Naquet Philippe 
Published: April 2014

Abstract
New Zeland Black (NZB) mice develop an autoimmune disease involving an abnormal B cell response to peripheral self Ags. This disease is associated with defects in other cell types and thymic stromal organization. We present evidence that NZB cells of various lineages, including thymocytes, fibroblasts, and dendritic precursor cells, show impaired proliferation and enhanced cell death in culture upon stimulation compared with non-autoimmune-prone mice such as C57BL/6. This phenotype explains the reduced efficiency of maturation of bone marrow-derived dendritic cells and the loss of TNF- or IL-1-dependent thymocyte costimulation. Upon TNF-induced activation of NZB thymocytes, nuclear translocation and DNA binding of RelA- and RelB-dependent NF-κB heterodimers are significantly reduced. This phenotype has a transcriptional signature, since the NZB, but not the nonobese diabetic, thymic transcriptome shows striking similarities with that of RelB-deficient thymuses. This partial NF-κB deficiency detected upon activation by proinflammatory cytokines could explain the disorganization of thymic microenvironments in NZB mice. These combined effects might reduce the efficiency of central tolerance and expose apoptotic debris generated during inflammatory processes to self recognition.
Functional Human T Lymphocyte Development from Cord Blood CD34+ Cells in Nonobese Diabetic/Shi-scid, IL-2 Receptor γ Null Mice
Authors: Yahata Takashi , Ando Kiyoshi , Nakamura Yoshihiko , Ueyama Yoshito , Shimamura Kazuo , Tamaoki Norikazu , Kato Shunichi , Hotta Tomomitsu 
Published: April 2014

Abstract
An experimental model for human T lymphocyte development from hemopoietic stem cells is necessary to study the complex processes of T cell differentiation in vivo. In this study, we report a newly developed nonobese diabetic (NOD)/Shi-scid, IL-2Rγ null (NOD/SCID/γcnull) mouse model for human T lymphopoiesis. When these mice were transplanted with human cord blood CD34+ cells, the mice reproductively developed human T cells in their thymus and migrated into peripheral lymphoid organs. Furthermore, these T cells bear polyclonal TCR-αβ, and respond not only to mitogenic stimuli, such as PHA and IL-2, but to allogenic human cells. These results indicate that functional human T lymphocytes can be reconstituted from CD34+ cells in NOD/SCID/γcnull mice. This newly developed mouse model is expected to become a useful tool for the analysis of human T lymphopoiesis and immune response, and an animal model for studying T lymphotropic viral infections, such as HIV.
Ly-49s3 Is a Promiscuous Activating Rat NK Cell Receptor for Nonclassical MHC Class I-Encoded Target Ligands
Authors: Naper Christian , Hayashi Shigenari , Kveberg Lise , Niemi Eréne C. , Lanier Lewis L. , Vaage John T. , Ryan James C. 
Published: April 2014

AbstractPrevious studies of the rapid rejection of MHC-disparate lymphocytes in rats, named allogeneic lymphocyte cytotoxicity, have indicated that rat NK cells express activating receptors for nonclassical MHC class I allodeterminants from the RT1-C/E/M region. Using an expression cloning system that identifies activating receptors associated with the transmembrane adapter molecule DAP12, we have cloned a novel rat Ly-49 receptor that we have termed Ly-49 stimulatory receptor 3 (Ly-49s3). A newly generated anti-Ly-49s3 Ab, mAb DAR13, identified subpopulations of resting and IL-2-activated NK cells, but not T or B lymphocytes. Depletion of Ly-49s3-expressing NK cells drastically reduced alloreactivity in vitro, indicating that this subpopulation is responsible for a major part of the observed NK alloreactivity. DAR13-mediated blockade of Ly-49s3 inhibited killing of MHC-congenic target cells from the av1, n, lv1, and c haplotypes, but not from the u or b haplotypes. A putative ligand was mapped to the nonclassical MHC class I region (RT1-C/E/M) using intra-MHC recombinant strains. Relative numbers of Ly-49s3+ NK cells were reduced, and surface levels of Ly-49s3 were lower, in MHC congenic strains expressing the putative Ly-49s3 ligand(s). In conclusion, we have identified a novel Ly-49 receptor that triggers rat NK cell-mediated responses.
Cloning and Characterization of a Promoter Flanking the Early B Cell Factor (EBF) Gene Indicates Roles for E-Proteins and Autoregulation in the Control of EBF Expression
Authors: Smith Emma M. K. , Gisler Ramiro , Sigvardsson Mikael 
Published: April 2014

Abstract
The early B cell factor (EBF) is a transcription factor shown crucial for the development of B lymphocytes. The protein is expressed from the earliest stages of B cell development until the mature B cell stage, but the control elements responsible for the regulation of the gene are unknown. In this study, we report of the identification of a promoter region flanking the EBF gene. Several transcription start sites were identified by primer extension analysis in a region ∼3.1 kb from the predicted ATG. Transient transfections revealed that this region was able to stimulate transcription of a reporter gene in B lymphoid and to a lesser extent, myeloid cells, but not in a pre-T cell line. The promoter was also able to functionally interact with E47, suggesting that the EBF gene may be a direct target for activation by E-proteins. In addition, functional binding of EBF to its own promoter was confirmed by EMSA and transfection assays indicating that the EBF protein may be involved in an autoregulatory loop. Finally, a tissue-restricted factor was able to bind an upstream regulatory region in B-lineage cells, further supporting the idea that the cloned promoter participates in the regulation of stage and lineage specific expression of the EBF gene.
NKT Cell-Derived RANTES Recruits APCs and CD8+ T Cells to the Spleen During the Generation of Regulatory T Cells in Tolerance
Authors: Faunce Douglas E. , Stein-Streilein Joan 
Published: April 2014

Abstract
The induction of peripheral tolerance via immune privileged sites such as the eye requires splenic colocalization of NKT cells and CD1d+ tolerogenic F4/80+ APCs, both of which are needed for the generation of CD8+-regulatory T (Tr) cells. Whereas tolerogenic APCs secrete the chemokine macrophage-inflammatory protein-2 for the purpose of recruiting NKT cells, the signals responsible for recruiting potential Tr cells and additional APCs to the spleen are not known. Here we examined the ability of CD1d-stimulated NKT cells to produce chemokines that can recruit other cells needed for tolerance. Our results show that NKT cells stimulated by either CD1d-transfected fibroblasts in vitro or CD1d+ tolerogenic APCs both in vivo and ex vivo produced RANTES in a CD1d-dependent manner. The requirement for RANTES in tolerance was demonstrated by studies in which RANTES blockade in vivo prevented not only APC accumulation in the spleen but also the generation of CD8+ Tr cells that suppress Th1 immunity. Thus, CD1d-restricted NKT cells provide critical signals for orchestrating the accumulation of cells needed for tolerance induction. These data expand our current knowledge of RANTES beyond its role in Th1 immune responses to show its importance in tolerance induction and add a novel aspect to our understanding of the role of NKT cells in tolerance. Understanding the precise mechanisms involved in tolerance induction may lead to more effective therapeutic strategies for autoimmunity and graft rejection.