bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Cytotoxic and Specific Migratory Potencies of Senescent CD8+CD57+ Cells in HIV-Infected and Uninfected Individuals
Authors: Le Priol Yannick , Puthier Denis , Lécureuil Cédric , Combadière Christophe , Debré Patrice , Nguyen Catherine , Combadière Béhazine 
Published: April 2014

AbstractCD8+CD57+ T lymphocytes, present at low levels in the peripheral blood of healthy individuals expand during HIV infection and remain elevated during chronic infection. Their role in the immune response remains unclear. We performed a large-scale gene array analysis (3158 genes) to characterize them and, interestingly, found no distinction in the transcriptional profiles of CD8+CD57+ T lymphocytes from HIV-infected and uninfected subjects. In both groups, these cells showed specificity for multiple Ags and produced large amounts of IFN-γ and TNF-α. The transcriptional profiles of CD8+CD57+ and CD8+CD57− cells, however, differed substantially. We propose that CD8+CD57+ cells were Ag-driven effector cells with very high cytotoxic effector potential including perforin, granzymes, and granulysin, regardless of HIV status. At both the messenger and protein levels, they expressed more adhesion molecules and fewer chemokine receptors (CCR7 and CXCR4) than CD8+CD57− cells but expressed preferentially CX3CR1. The lower expression level of genes involved in cell cycle regulation showed limited proliferation capacities of CD8+CD57+ even in response to TCR and IL-2, IL-7, and IL-15 stimulation. CD8+CD57+ T cells from both HIV and uninfected subjects maintain effective cytotoxic potentials but are destined to migrate to nonlymphoid tissues without further cycling.
A Novel Mechanism for Complement Activation at the Surface of B Cells Following Antigen Binding
Authors: Manderson Anthony P. , Quah Ben , Botto Marina , Goodnow Chris C. , Walport Mark J. , Parish Chris R. 
Published: April 2014

AbstractColigation of CD21 with BCR on the surface of B cells provides a costimulatory signal essential for efficient Ab responses to T-dependent Ags. To achieve this, Ag must be directly linked to C3 fragments, but how this occurs in vivo is not fully understood. Using BCR transgenic mice, we demonstrated that C3 was deposited on the surface of B cells following both high- and moderate-affinity Ag binding. This was dependent on the specific binding of IgM to the BCR-bound Ag and can occur independently of soluble immune complex formation. Based on these data, we propose a novel model in which immune complexes can form directly on the surface of the B cell following Ag binding. This model has implications for our understanding of B lymphocyte activation.
The Src Homology 2 Domain-Containing Leukocyte Protein of 76-kDa Adaptor Links Integrin Ligation with p44/42 MAPK Phosphorylation and Podosome Distribution in Murine Dendritic Cells
Authors: Luckashenak Nancy A. , Ryszkiewicz Rebecca L. , Ramsey Kimberley D. , Clements James L. 
Published: April 2014

Abstract
The Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP-76) is an important molecular intermediate in multiple signaling pathways governing immune cell function. In this study, we report that SLP-76 is expressed in CD11c+B220− dendritic cells (DCs) isolated from murine thymus or spleen, and that SLP-76 is rapidly phosphorylated on tyrosine residues upon plating of bone marrow-derived DCs (BMDCs) on integrin agonists. SLP-76 is not required for the in vitro or in vivo generation of DCs, but SLP-76-deficient BMDCs adhere poorly to fibronectin, suggesting impaired integrin function. Consistent with impaired adhesion, cutaneous SLP-76-deficient DCs leave ear tissue at an elevated frequency compared with wild-type DCs. In addition, the pattern and distribution of actin-based podosome formation are visibly altered in BMDCs lacking SLP-76 following integrin engagement. SLP-76-deficient BMDCs manifest multiple signaling defects following integrin ligation, including reduced global tyrosine phosphorylation and markedly impaired phosphorylation of p44/42 MAPK (ERK1/2). These data implicate SLP-76 as an important molecular intermediate in the signaling pathways regulating multiple integrin-dependent DC functions, and add to the growing body of evidence that hemopoietic cells may use unique molecular intermediates and mechanisms for regulating integrin signaling.
Aspergillus fumigatus Generates an Enhanced Th2-Biased Immune Response in Mice with Defective Cystic Fibrosis Transmembrane Conductance Regulator
Authors: Allard Jenna B. , Poynter Matthew E. , Marr Kieren A. , Cohn Lauren , Rincon Mercedes , Whittaker Laurie A. 
Published: April 2014

Abstract
Cystic fibrosis (CF) lung disease is characterized by persistent airway inflammation and airway infection that ultimately leads to respiratory failure. Aspergillus sp. are present in the airways of 20–40% of CF patients and are of unclear clinical significance. In this study, we demonstrate that CF transmembrane conductance regulator (CFTR)-deficient (CFTR knockout, Cftrtm1Unc-TgN(fatty acid-binding protein)CFTR) and mutant (ΔF508) mice develop profound lung inflammation in response to Aspergillus fumigatus hyphal Ag exposure. CFTR-deficient mice also develop an enhanced Th2 inflammatory response to A. fumigatus, characterized by elevated IL-4 in the lung and IgE and IgG1 in serum. In contrast, CFTR deficiency does not promote a Th1 immune response. Furthermore, we demonstrate that CD4+ T cells from naive CFTR-deficient mice produce higher levels of IL-4 in response to TCR ligation than wild-type CD4+ T cells. The Th2 bias of CD4+ T cells in the absence of functional CFTR correlates with elevated nuclear levels of NFAT. Thus, CFTR is important to maintain the Th1/Th2 balance in CD4+ T cells.
DOCK2 is Required for Chemokine-Promoted Human T Lymphocyte Adhesion Under Shear Stress Mediated by the Integrin α4β1
Authors: García-Bernal David , Sotillo-Mallo Elena , Nombela-Arrieta César , Samaniego Rafael , Fukui Yoshinori , Stein Jens V. , Teixidó Joaquin 
Published: April 2014

AbstractThe α4β1 integrin is an essential adhesion molecule for recruitment of circulating lymphocytes into lymphoid organs and peripheral sites of inflammation. Chemokines stimulate α4β1 adhesive activity allowing lymphocyte arrest on endothelium and subsequent diapedesis. Activation of the GTPase Rac by the guanine-nucleotide exchange factor Vav1 promoted by CXCL12 controls T lymphocyte adhesion mediated by α4β1. In this study, we investigated the role of DOCK2, a lymphocyte guanine-nucleotide exchange factor also involved in Rac activation, in CXCL12-stimulated human T lymphocyte adhesion mediated by α4β1. Using T cells transfected with DOCK2 mutant forms defective in Rac activation or with DOCK2 small interfering RNA, we demonstrate that DOCK2 is needed for efficient chemokine-stimulated lymphocyte attachment to VCAM-1 under shear stress. Flow chamber, soluble binding, and cell spreading assays identified the strengthening of α4β1-VCAM-1 interaction, involving high affinity α4β1 conformations, as the adhesion step mainly controlled by DOCK2 activity. The comparison of DOCK2 and Vav1 involvement in CXCL12-promoted Rac activation and α4β1-dependent human T cell adhesion indicated a more prominent role of Vav1 than DOCK2. These results suggest that DOCK2-mediated signaling regulates chemokine-stimulated human T lymphocyte α4β1 adhesive activity, and that cooperation with Vav1 might be required to induce sufficient Rac activation for efficient adhesion. In contrast, flow chamber experiments using lymph node and spleen T cells from DOCK2−/− mice revealed no significant alterations in CXCL12-promoted adhesion mediated by α4β1, indicating that DOCK2 activity is dispensable for triggering of this adhesion in mouse T cells, and suggesting that Rac activation plays minor roles in this process.
Induced Expression of Murine γ2a by CD40 Ligation Independently of IFN-γ
Authors: Collins John T. , Shi Jian , Burrell Bryna E. , Bishop D. Keith , Dunnick Wesley A. 
Published: April 2014

AbstractIgG2a, with γ2a H chains, is important for protection against viruses and other intracellular pathogens. Although a large portion of IgG2a expression is dependent upon IFN-γ, some germline transcription and switch recombination to the murine γ2a H chain gene expression are independent of IFN-γ. We found that agonistic anti-CD40 Abs injected into IFN-γ-deficient mice induce a &gt;200-fold increase in the amount of serum Ig2a, while other Ig isotypes are increased by 16-fold or less. In vitro, ligation of CD40 on B cells, without the addition of other B cell activators or cytokines, results in germline transcription and switch recombination that are largely restricted to the γ2a gene. These results suggest that some immune responses to infectious agents can result in large amounts of IgG2a expression through ligation of CD40, without the expression of IFN-γ by Th1 or other cells.
Increased Human IgE Induced by Killing Schistosoma mansoni In Vivo Is Associated with Pretreatment Th2 Cytokine Responsiveness to Worm Antigens
Authors: Walter Klaudia , Fulford Anthony J. C. , McBeath Rowena , Joseph Sarah , Jones Frances M. , Kariuki H. Curtis , Mwatha Joseph K. , Kimani Gachuhi , Kabatereine Narcis B. , Vennervald Birgitte J. , Ouma John H. , Dunne David W. 
Published: April 2014

Abstract
In schistosomiasis endemic areas, children are very susceptible to postchemotherapy reinfection, whereas adults are relatively resistant. Different studies have reported that schistosome-specific IL-4 and IL-5 responses, or posttreatment worm-IgE levels, correlate with subsequent low reinfection. Chemotherapy kills i.v. worms providing an in vivo Ag challenge. We measured anti-worm (soluble worm Ag (SWA) and recombinant tegumental Ag (rSm22.6)) and anti-egg (soluble egg Ag) Ab levels in 177 Ugandans (aged 7–50) in a high Schistosoma mansoni transmission area, both before and 7 wk posttreatment, and analyzed these data in relation to whole blood in vitro cytokine responses at the same time points. Soluble egg Ag-Ig levels were unaffected by treatment but worm-IgG1 and -IgG4 increased, whereas worm-IgE increased in many but not all individuals. An increase in worm-IgE was mainly seen in &gt;15-year-olds and, unlike in children, was inversely correlated to pretreatment infection intensities, suggesting this response was associated both with resistance to pretreatment infection, as well as posttreatment reinfection. The increases in SWA-IgE and rSm22.6-IgE positively correlated with pretreatment Th2 cytokines, but not IFN-γ, induced by SWA. These relationships remained significant after allowing for the confounding effects of pretreatment infection intensity, age, and pretreatment IgE levels, indicating a link between SWA-specific Th2 cytokine responsiveness and subsequent increases in worm-IgE. An exceptionally strong relationship between IL-5 and posttreatment worm-IgE levels in &lt;15-year-olds suggested that the failure of younger children to respond to in vivo Ag stimulation with increased levels of IgE, is related to their lack of pretreatment SWA Th2 cytokine responsiveness.
In the Absence of Reactive Oxygen Species, T Cells Default to a Th1 Phenotype and Mediate Protection against Pulmonary Cryptococcus neoformans Infection
Authors: Snelgrove Robert J. , Edwards Lorna , Williams Andrew E. , Rae Aaron J. , Hussell Tracy 
Published: April 2014

Abstract
In recent years, the prevalence of invasive fungal infections has increased, attributed mostly to the rising population of immunocompromised individuals. Cryptococcus neoformans has been one of the most devastating, with an estimated 6–8% of AIDS-infected patients succumbing to Cryptococcus-associated meningitis. Reactive oxygen species (ROS) are potent antimicrobial agents but also play a significant role in regulating immune cell phenotype, but cause immunopathology when produced in excess. We now show that mice lacking phagocyte NADPH oxidase have heightened macrophage and Th1 responses and improved pathogen containment within pulmonary granulomatous lesions. Consequently, dissemination of this fungus to the brain is diminished, an effect that is independent of IL-12. Similar results are described using the metalloporphyrin antioxidant manganese(III) tetrakis(N-ethyl pyridinium-2-yl)porphyrin, which also promoted a protective Th1 response and reduced dissemination to the brain. These findings are in sharp contrast to the protective potential of ROS against other fungal pathogens, and highlight the pivotal role that ROS can fulfill in shaping the profile of the host’s immune response.
Mannose-Binding Lectin Augments the Uptake of Lipid A, Staphylococcus aureus, and Escherichia coli by Kupffer Cells through Increased Cell Surface Expression of Scavenger Receptor A
Authors: Ono Kei , Nishitani Chiaki , Mitsuzawa Hiroaki , Shimizu Takeyuki , Sano Hitomi , Suzuki Hiroshi , Kodama Tatsuhiko , Fujii Nobuhiro , Fukase Koichi , Hirata Koichi , Kuroki Yoshio 
Published: April 2014

Abstract
We investigated roles of scavenger receptor A (SR-A) and mannose-binding lectin (MBL) in the uptake of endotoxin and bacteria by Kupffer cells. When [3H]lipid A was injected into retro-orbital plexus of mice, significantly less accumulation of lipid A in the liver was observed in SR-A-deficient mice and wild-type mice coinjected with fucoidan or acetylated low-density lipoprotein, which are known ligands for SR-A. Isolated Kupffer cells were able to take up [3H]lipid A in a time-dependent manner. The amount of lipid A associated with nonadherent Kupffer cells derived from SR-A-deficient mice was reduced by ∼80% when compared with wild-type cells, indicating an important role of SR-A in endotoxin uptake by Kupffer cells. The lipid A uptake by Kupffer cells was significantly enhanced in the presence of rMBL. Coincubation of fucoidan with [3H]lipid A significantly inhibited the basal and the MBL-stimulated uptake of lipid A by Kupffer cells. Preincubation of MBL with Kupffer cells also increased the uptake of lipid A. These results indicate that MBL augments the SR-A-mediated uptake of lipid A by Kupffer cells. Consistently, the exposure of MBL to Kupffer cells increased cell surface SR-A expression. The phagocytosis of Staphylococcus aureus and Escherichia coli by Kupffer cells was also enhanced by preincubation of MBL with the cells. In addition, MBL bound to lipid A, LPS, and S. aureus, and precipitated S. aureus. This study demonstrates important roles of SR-A and MBL in the uptake of endotoxin and bacteria by Kupffer cells.
Retrovirus-Mediated Over-Expression of Decay-Accelerating Factor Rescues Crry-Deficient Erythrocytes from Acute Alternative Pathway Complement Attack
Authors: Kim David D. , Miwa Takashi , Song Wen-Chao 
Published: April 2014

AbstractDecay-accelerating factor (DAF) and complement receptor 1-related gene/protein y (Crry) are two membrane-bound complement regulators on murine erythrocytes that inhibit C3/C5 convertases. Previously, we found that Crry- but not DAF-deficient erythrocytes were susceptible to alternative pathway complement-mediated elimination in vivo. To determine whether it is a unique activity or a higher level expression of Crry makes it indispensable on murine erythrocytes, we over-expressed DAF on Crry-deficient (Crry−/−) erythrocytes by retroviral vector-mediated DAF gene transduction of bone marrow stem cells. DAF retrovirus-transduced erythrocytes expressed 846 ± 127 DAF molecules/cell (DAFhigh) compared with 249 ± 94 DAF molecules/cell (DAFlow) and 774 ± 135 Crry molecules/cell on control mouse erythrocytes. DAFhigh-Crry−/− erythrocytes were significantly more resistant than either DAFlow-Crry−/−, DAF−/− -Crry+/+ or wild-type erythrocytes to classical pathway complement-mediated C3 deposition in vitro. Furthermore, increased DAF expression rescued Crry−/− erythrocytes from acute alternative pathway complement attack in vivo. Notably, long term monitoring revealed that DAFhigh-Crry−/− erythrocytes were still more susceptible than wild-type erythrocytes to complement-mediated elimination as they had a shorter half-life in complement-sufficient mice but survived equally well in complement-deficient mice. These results suggest that both a high level expression and a more potent anti-alternative pathway complement activity of Crry contributed to its indispensable role on murine erythrocytes. Additionally, they demonstrate the feasibility of using stem cell gene therapy to correct membrane complement regulator deficiency on blood cells in vivo.
Membrane-Bound CC Chemokine Inhibitor 35K Provides Localized Inhibition of CC Chemokine Activity In Vitro and In Vivo
Authors: Bursill Christina A. , Cash Jenna L. , Channon Keith M. , Greaves David R. 
Published: April 2014

AbstractCC chemokines mediate mononuclear cell recruitment and activation in chronic inflammation. We have shown previously that gene transfer using recombinant adenoviruses, encoding a soluble CC chemokine-binding protein of vaccinia virus 35K, can dramatically reduce atherosclerosis and vein graft remodeling in apolipoprotein E knockout mice. In this study, we report the development of a membrane-bound form of 35K (m35K), tagged with GFP, which allows for localized, broad-spectrum CC chemokine blockade. In vitro experiments indicate that m35K-expressing cells no longer undergo CC chemokine-induced chemotaxis, and m35K-expressing cells can locally deplete the CC chemokines RANTES (CCL5) and MIP-1α (CCL3) from supernatant medium. This sequestration of CC chemokines can prevent chemotaxis of bystander cells to CC, but not CX3C chemokines. Intraperitoneal injection of mice with an adenovirus-encoding m35K leads to a significant (44%) decrease in leukocyte recruitment into the peritoneal cavity in a sterile peritonitis model. Intravenous adenovirus-encoding m35K delivery leads to m35K expression in hepatocytes, which confers significant protection against liver damage (75% reduction in liver enzymes) in a Con A-induced hepatitis model. In summary, we have generated a membrane-bound CC chemokine-binding protein (m35K) that provides localized broad-spectrum CC chemokine inhibition in vitro and in vivo. m35K may be a useful tool to study the role of CC chemokines in leukocyte trafficking and block the recruitment of monocytes in chronic inflammation.
Deguelin, an Akt Inhibitor, Suppresses IκBα Kinase Activation Leading to Suppression of NF-κB-Regulated Gene Expression, Potentiation of Apoptosis, and Inhibition of Cellular Invasion
Authors: Nair Asha S. , Shishodia Shishir , Ahn Kwang Seok , Kunnumakkara Ajaikumar B. , Sethi Gautam , Aggarwal Bharat B. 
Published: April 2014

Abstract
Deguelin, a constituent of the bark of the African plant Mundulea sericea (Leguminosae), exhibits antiproliferative and anticarcinogenic activities through a mechanism that is not well understood. Because various steps in carcinogenesis are regulated by NF-κB, we postulated that the activity of deguelin is mediated through this transcription factor. We found that deguelin suppressed NF-κB activation induced by carcinogens, tumor promoters, growth factors, and inflammatory stimuli. This suppression was not cell-type specific, because NF-κB activation was suppressed in both lymphoid and epithelial cells. Moreover, constitutive NF-κB activation was also blocked by deguelin. The suppression of TNF-induced NF-κB activation by deguelin occurred through the inhibition of the activation of IκBα kinase, leading to sequential suppression of IκBα phosphorylation, IκBα degradation, p65 phosphorylation, p65 nuclear translocation, and NF-κB-dependent reporter gene expression. Deguelin also suppressed the NF-κB reporter activity induced by TNFR1, TNFR-associated death domain, TNFR-associated factor 2, and IκBα kinase, but not that induced by p65. The inhibition of NF-κB activation thereby led to the down-regulation of gene products involved in cell survival, proliferation, and invasion. Suppression of these gene products by deguelin enhanced the apoptosis induced by TNF and chemotherapeutic agents and suppressed TNF-induced cellular invasion. Our results demonstrate that deguelin inhibits the NF-κB activation pathway, which may explain its role in the suppression of carcinogenesis and cellular proliferation.
Development of Autoimmunity in IL-14α-Transgenic Mice
Authors: Shen Long , Zhang Chongjie , Wang Tao , Brooks Stephen , Ford Richard J. , Lin-Lee Yen Chiu , Kasianowicz Amy , Kumar Vijay , Martin Lisa , Liang Ping , Cowell John , Ambrus Julian L. 
Published: April 2014

AbstractMultiple genetic loci contribute to the development of systemic lupus erythematosus (SLE). In murine models for SLE, various genes on chromosome four have been implicated. IL-14 is a cytokine originally identified as a B cell growth factor. The il14 gene is located on chromosome 4. IL-14α is a cytokine encoded by the plus strand of the IL-14 gene using exons 3–10. The expression of IL-14α is increased in (NZB × NZW)F1 mice. In this study, we produced IL-14α-transgenic mice to study the role of IL-14α in the development of autoimmunity. At age 3–9 mo, IL-14α-transgenic mice demonstrate increased numbers of B1 cells in the peritoneum, increased serum IgM, IgG, and IgG 2a and show enhanced responses to T-dependent and T-independent Ags compared with littermate controls. At age 9–17 mo, IL-14α-transgenic mice develop autoantibodies, sialadenitis, as in Sjögren’s syndrome, and immune complex-mediated nephritis, as in World Health Organization class II SLE nephritis. Between the ages 14–18 mo, 95% of IL-14α-transgenic mice developed CD5+ B cell lymphomas, consistent with the lymphomas seen in elderly patients with Sjögren’s syndrome and SLE. These data support a role for IL-14α in the development of both autoimmunity and lymphomagenesis. These studies may provide a genetic link between these often related disorders.
Cutting Edge: Deficiency of Macrophage Migration Inhibitory Factor Impairs Murine Airway Allergic Responses
Authors: Wang Bing , Huang Xiaozhu , Wolters Paul J. , Sun Jiusong , Kitamoto Shiro , Yang Min , Riese Richard , Leng Lin , Chapman Harold A. , Finn Patricia W. , David John R. , Bucala Richard , Shi Guo-Ping 
Published: April 2014

Abstract
Increased levels of macrophage migration inhibitory factor (MIF) in serum, sputum, and bronchioalveolar lavage fluid (BALF) from asthmatic patients and time/dose-dependent expression of MIF in eosinophils in response to phorbol myristate acetate suggest the participation of MIF in airway inflammation. In this study, we examined inflammation in OVA-sensitized mouse lungs in wild-type and MIF-deficient mice (MIF−/−). We report increased MIF in the lung and BALF of sensitized wild-type mice. MIF−/− mice demonstrated significant reductions in serum IgE and alveolar inflammatory cell recruitment. Reduced Th1/Th2 cytokines and chemokines also were detected in serum or BALF from MIF−/− mice. Importantly, alveolar macrophages and mast cells, but not dendritic cells or splenocytes, from MIF−/− mice demonstrated impaired CD4+ T cell activation, and the reconstitution of wild-type mast cells in MIF−/− mice restored the phenotype of OVA-induced airway inflammation, revealing a novel and essential role of mast cell-derived MIF in experimentally induced airway allergic diseases.