bluuebunny/crossref_metadata_2025_split huggingface dataset:
Complement Inhibitor, Complement Receptor 1-Related Gene/Protein y-Ig Attenuates Intestinal Damage After the Onset of Mesenteric Ischemia/Reperfusion Injury in Mice
Authors: Rehrig Scott , Fleming Sherry D. , Anderson Jimie , Guthridge Joel M. , Rakstang Jonathan , E. McQueen Charles , Holers V. Michael , Tsokos George C. , Shea-Donohue Terez 
Published: April 2014

AbstractComplement receptor 1-related gene/protein y (Crry) is a murine membrane protein that regulates the activity of both classical and alternative complement pathways. We used a recombinant soluble form of Crry fused to the hinge, CH2, and CH3 domains of mouse IgG1 (Crry-Ig) to determine whether inhibition of complement activation prevents and/or reverses mesenteric ischemia/reperfusion-induced injury in mice. Mice were subjected to 30 min of ischemia, followed by 2 h of reperfusion. Crry-Ig was administered either 5 min before or 30 min after initiation of the reperfusion phase. Pretreatment with Crry-Ig reduced local intestinal mucosal injury and decreased generation of leukotriene B4 (LTB4). When given 30 min after the beginning of the reperfusion phase, Crry-Ig resulted in a decrease in ischemia/reperfusion-induced intestinal mucosal injury comparable to that occurring when it was given 5 min before initiation of the reperfusion phase. The beneficial effect of Crry-Ig administered 30 min after the initiation of reperfusion coincided with a decrease in PGE2 generation despite the fact that it did not prevent local infiltration of neutrophils and did not have a significant effect on LTB4 production. These data suggest that complement inhibition protects animals from reperfusion-induced intestinal damage even if administered as late as 30 min into reperfusion and that the mechanism of protection is independent of neutrophil infiltration or LTB4 inhibition.
Plasmodium bergheiInfection in Mice Induces Liver Injury by an IL-12- and Toll-Like Receptor/Myeloid Differentiation Factor 88-Dependent Mechanism
Authors: Adachi Keishi , Tsutsui Hiroko , Kashiwamura Shin-Ichiro , Seki Ekihiro , Nakano Hiroki , Takeuchi Osamu , Takeda Kazuyoshi , Okumura Ko , Van Kaer Luc , Okamura Haruki , Akira Shizuo , Nakanishi Kenji 
Published: April 2014

AbstractMalaria, caused by infection with Plasmodium spp., is a life cycle-specific disease that includes liver injury at the erythrocyte stage of the parasite. In this study, we have investigated the mechanisms underlying Plasmodium berghei-induced liver injury, which is characterized by the presence of apoptotic and necrotic hepatocytes and dense infiltration of lymphocytes. Although both IL-12 and IL-18 serum levels were elevated after infection, IL-12-deficient, but not IL-18-deficient, mice were resistant to liver injury induced by P. berghei. Neither elevation of serum IL-12 levels nor liver injury was observed in mice deficient in myeloid differentiation factor 88 (MyD88), an adaptor molecule shared by Toll-like receptors (TLRs). These results demonstrated a requirement of the TLR-MyD88 pathway for induction of IL-12 production during P. berghei infection. Hepatic lymphocytes from P. berghei-infected wild-type mice lysed hepatocytes from both uninfected and infected mice. The hepatocytotoxic action of these cells was blocked by a perforin inhibitor but not by a neutralizing anti-Fas ligand Ab and was up-regulated by IL-12. Surprisingly, these cells killed hepatocytes in an MHC-unrestricted manner. However, CD1d-deficient mice that lack CD1d-restricted NK T cells, were susceptible to liver injury induced by P. berghei. Collectively, our results indicate that the liver injury induced by P. berghei infection of mice induces activation of the TLR-MyD88 signaling pathway which results in IL-12 production and activation of the perforin-dependent cytotoxic activities of MHC-unrestricted hepatic lymphocytes.
Human Eosinophils Induce Mucin Production in Airway Epithelial Cells Via Epidermal Growth Factor Receptor Activation
Authors: Burgel Pierre-Regis , Lazarus Stephen C. , Tam Dominic Cheng-Wei , Ueki Iris F. , Atabai Kamran , Birch Martha , Nadel Jay A. 
Published: April 2014

AbstractEosinophil recruitment and mucus hypersecretion are characteristic of asthmatic airway inflammation, but eosinophils have not been shown to induce mucin production. Because an epidermal growth factor receptor (EGFR) cascade induces MUC5AC mucin in airways, and because EGFR is up-regulated in asthmatic airways, we examined the effect of eosinophils on MUC5AC mucin production in NCI-H292 cells (a human airway epithelial cell line that produces mucins). Eosinophils were isolated from the peripheral blood of allergic patients, and their effects on MUC5AC mucin gene and protein synthesis were assessed using in situ hybridization and ELISAs. When IL-3 plus GM-CSF or IL-3 plus IL-5 were added to eosinophils cultured with NCI-H292 cells, MUC5AC mucin production increased; eosinophils or cytokines alone had no effect. Eosinophil supernatant obtained by culturing eosinophils with IL-3 plus GM-CSF or IL-3 plus IL-5 also increased MUC5AC synthesis in NCI-H292 cells, an effect that was prevented by selective EGFR inhibitors (AG1478, BIBX1522). Supernatant of activated eosinophils induced EGFR phosphorylation in NCI-H292 cells. Supernatant of activated eosinophils contained increased concentrations of TGF-α protein (an EGFR ligand) and induced up-regulation of TGF-α expression and release in NCI-H292 cells. A blocking Ab to TGF-α reduced activated eosinophil-induced MUC5AC synthesis in NCI-H292 cells. These results show that activated eosinophils induce mucin synthesis in human airway epithelial cells via EGFR activation, and they implicate TGF-α produced by eosinophils and epithelial cells in the EGFR activation that results in mucin production in human airway epithelium.
Accelerated Fas-Mediated Apoptosis of Monocytes and Maturing Macrophages from Patients with Systemic Lupus Erythematosus: Relevance to In Vitro Impairment of Interaction with iC3b-Opsonized Apoptotic Cells
Authors: Shoshan Yigal , Shapira Izhak , Toubi Elias , Frolkis Inna , Yaron Michael , Mevorach Dror 
Published: April 2014

AbstractImpaired handling of apoptotic cells has been suggested as an important factor in the development of systemic lupus erythematosus (SLE), and a role for complement in the removal of apoptotic cells was shown recently. We studied the in vitro function of macrophages from 40 patients with SLE and their matched controls in the removal of heterologous apoptotic cells opsonized by iC3b. Interaction index of apoptotic cells opsonized by iC3b was significantly lower in patients with SLE and averaged 71% ± 37 of that of healthy individuals (p &lt; 0.002) and 69% ± 35 of patients with rheumatoid arthritis (p &lt; 0.007). SLE patients had increased apoptosis of both freshly isolated monocytes (p &lt; 0.001) and maturing macrophages (p &lt; 0.04) that led to decreased density of monocyte-derived macrophages. Apoptosis was inhibited by adding soluble Fas receptor indicating Fas-mediated apoptosis. As demonstrated in both healthy controls and patients with SLE, decreased macrophage density by itself caused significant decreased uptake of apoptotic cells by the remaining macrophages. Maintaining normal density in SLE patients either by an increased initial density or by using soluble Fas restored the interaction capacity of the individual macrophages in the majority of patients. We concluded that impaired in vitro interaction of iC3b-opsonized apoptotic cells with macrophages from patients with SLE was mainly associated with Fas-dependent accelerated apoptosis of the monocytes/macrophages. Accelerated apoptosis of phagocytes may represent a novel in vitro mechanism of impairment of interaction with apoptotic cells that, apart from reducing the number of professional phagocytes, alters the function of the remaining macrophages.
Y Box-Binding Factor Promotes Eosinophil Survival by Stabilizing Granulocyte-Macrophage Colony-Stimulating Factor mRNA
Authors: Capowski Elizabeth E. , Esnault Stéphane , Bhattacharya Saswati , Malter James S. 
Published: April 2014

AbstractShort-lived peripheral blood eosinophils are recruited to the lungs of asthmatics after allergen challenge, where they become long-lived effector cells central to disease pathophysiology. GM-CSF is an important cytokine which promotes eosinophil differentiation, function, and survival after transit into the lung. In human eosinophils, GM-CSF production is controlled by regulated mRNA stability mediated by the 3′ untranslated region, AU-rich elements (ARE). We identified human Y box-binding factor 1 (YB-1) as a GM-CSF mRNA ARE-specific binding protein that is capable of enhancing GM-CSF-dependent survival of eosinophils. Using a transfection system that mimics GM-CSF metabolism in eosinophils, we have shown that transduced YB-1 stabilized GM-CSF mRNA in an ARE-dependent mechanism, causing increased GM-CSF production and enhanced in vitro survival. RNA EMSAs indicate that YB-1 interacts with the GM-CSF mRNA through its 3′ untranslated region ARE. In addition, endogenous GM-CSF mRNA coimmunoprecipitates with endogenous YB-1 protein in activated eosinophils but not resting cells. Thus, we propose a model whereby activation of eosinophils leads to YB-1 binding to and stabilization of GM-CSF mRNA, ultimately resulting in GM-CSF release and prolonged eosinophil survival.
Ceramide Regulates Lipopolysaccharide-Induced Phosphatidylinositol 3-Kinase and Akt Activity in Human Alveolar Macrophages
Authors: Monick Martha M. , Mallampalli Rama K. , Carter Aaron B. , Flaherty Dawn M. , McCoy Diann , Robeff Pamela K. , Peterson Michael W. , Hunninghake Gary W. 
Published: April 2014

AbstractThe phosphatidylinositol (PI) 3-kinase pathway is an important regulator of cell survival. In human alveolar macrophages, we found that LPS activates PI 3-kinase and its downstream effector, Akt. LPS exposure of alveolar macrophages also results in the generation of ceramide. Because ceramide exposure induces apoptosis in other cell types and the PI 3-kinase pathway is known to inhibit apoptosis, we determined the relationship between LPS-induced ceramide and PI 3-kinase activation in alveolar macrophages. We found that ceramide exposure activated PI 3-kinase and Akt. When we blocked LPS-induced ceramide with the inhibitor D609, we blocked LPS-induced PI 3-kinase and Akt activation. Evaluating cell survival after ceramide or LPS exposure, we found that blocking PI 3-kinase induced a significant increase in cell death. Because these effects of PI 3-kinase inhibition were more pronounced in ceramide- vs LPS-treated alveolar macrophages, we also evaluated NF-κB, which has also been linked to cell survival. We found that LPS, to a greater degree than ceramide, induced NF-κB translocation to the nucleus. As a composite, these studies suggest that the effects of ceramide exposure in alveolar macrophages may be very different from the effects described for other cell types. We believe that LPS induction of ceramide results in PI 3-kinase activation and represents a novel effector mechanism that promotes survival of human alveolar macrophages in the setting of pulmonary sepsis.
Inhibition of NF-κB-Dependent T Cell Activation Abrogates Acute Allograft Rejection
Authors: Finn Patricia W. , Stone James R. , Boothby Mark R. , Perkins David L. 
Published: April 2014

AbstractUsing a heterotopic model of transplantation, we investigated the role of T cell activation in vivo during allograft rejection in I-κB(ΔN)-transgenic mice that express a transdominant inhibitor of NF-κB in T cells. Our results show indefinite prolongation of graft survival in the I-κB(ΔN)-transgenic recipients. Interestingly, at the time of rejection of grafts in wild-type recipients, histology of grafts in the I-κB(ΔN)-transgenic recipients showed moderate rejection; nevertheless, grafts in the I-κB(ΔN) recipients survived &gt;100 days. Analysis of acute phase cytokines, chemokine, chemokine receptors, and immune responses shows that the blockade of NF-κB activation in T cells inhibits up-regulation of many of these parameters. Interestingly, our data also suggest that the T cell component of the immune response exerted positive feedback regulation on the expression of multiple chemokines that are produced predominantly by non-T cells. In conclusion, our studies indicate NF-κB activation in T cells is necessary for acute allograft rejection.
Preferential Usage of TCR-Vβ17 by Peripheral and Cutaneous T Cells in Nickel-Induced Contact Dermatitis
Authors: Büdinger Lioba , Neuser Nicole , Totzke Uwe , Merk Hans F. , Hertl Michael 
Published: April 2014

AbstractNickel (Ni) is one of the most common contact sensitizers in man, and Ni-induced contact dermatitis is considered as a model of hapten-induced delayed type hypersensitivity. Previous studies indicated that Ni-reactive T cells derived from Ni-allergic individuals preferentially express distinct TCR-Vβ chains. However, data on the TCR-Vβ repertoire of Ni-responsive T cells are not consistent. Therefore, the aim of this study was to identify the TCR-Vβ receptors of Ni-responsive peripheral and cutaneous T cells in a cohort of 17 donors with Ni-induced contact dermatitis in comparison with those of 6 healthy controls. Peripheral NiSO4-responsive T lymphocytes showed a significant overexpression of TCR-Vβ17 and the frequency of TCR-Vβ17+ T cells correlated significantly with the in vitro reactivity of PBMC to NiSO4. In addition, the cutaneous infiltrate of Ni-induced patch test reactions consisted primarily of Vβ17+ T cells. The majority of patch test-derived NiSO4-responsive T cells of three allergic donors were TCR-Vβ17+, whereas patch test-derived NiSO4 unresponsive T cells of four additional donors did not express TCR-Vβ17. Skin-derived Ni-responsive T cell lines from three donors uniformly secreted the Th2 cytokine, IL-5, but no IFN-γ or IL-10. These in vitro and in vivo findings strongly suggest that T cells with a restricted TCR-Vβ repertoire, i.e., Vβ17, predominate in NiSO4-induced contact dermatitis and may be crucial in the effector phase of Ni hypersensitivity.
Cutting Edge: A/WySnJ Transitional B Cells Overexpress the Chromosome 15 ProapoptoticBlkGene and Succumb to Premature Apoptosis
Authors: Amanna Ian J. , Clise-Dwyer Karen , Nashold Faye E. , Hoag Kathleen A. , Hayes Colleen E. 
Published: April 2014

AbstractBetter knowledge of peripheral B lymphocyte homeostasis is needed to address the human hypogammaglobulinemia diseases. A defect in the Bcmd gene shortens the B cell life span and causes B cell deficiency in A/WySnJ mice. Previous genetic mapping placed Bcmd near Srebf2 on chromosome 15. Inspection of the human chromosome 22 syntenic region identified the proapoptotic Bik gene as a candidate. Two mapping methods placed the homologous mouse gene, Blk, near Srebf2. The Blk genomic structure was highly homologous to Bik. Sequence analysis ruled out coding region mutations, but Blk transcripts were overly abundant in sorted A/WySnJ T1 B cells. Moreover, enriched transitional B cells showed a cell-autonomous defect leading to excessive apoptosis. Thus, Bcmd may be a direct mutation in Blk, or in a gene involved in Blk regulation, such that excess expression pushes the A/WySnJ transitional B cells past the apoptosis checkpoint to cell death.
Cutting Edge: Histone Acetylation and Recombination at the TCRγ Locus Follows IL-7 Induction
Authors: Huang Jiaqiang , Durum Scott K. , Muegge Kathrin 
Published: April 2014

Abstract
IL-7 signaling is required for V(D)J recombination at the TCRγ locus. We have recently reported that IL-7 controls chromatin accessibility for RAG-mediated cleavage. Inhibition of histone deacetylase substituted for the IL-7 signal, indicating a role for histone acetylation in altering chromatin accessibility. We found a greatly reduced histone 3 and histone 4 acetylation level in IL-7Rα−/− thymocytes in comparison with RAG−/− thymocytes or fetal thymocytes. Sterile transcripts, indicating an open chromatin configuration, were suppressed in IL-7Rα−/− and IL-7−/−RAG−/− thymocytes. Moreover, exogenously added IL-7 induced sterile transcripts from the TCRγ constant region in cultured thymocytes from IL-7−/−RAG−/− mice. This induction correlated with increased histone acetylation at the J-promoter and C-enhancer regulatory elements at the TCRγ locus. These results suggest that IL-7 regulates chromatin accessibility for V(D)J recombination by specifically altering histone acetylation within the TCRγ locus.
Cutting Edge: Induction of Follicular Homing Precedes Effector Th Cell Development
Authors: Schaerli Patrick , Loetscher Pius , Moser Bernhard 
Published: April 2014

Abstract
Transition from naive to Ag-experienced effector/memory CD4+ T cells is initiated during contact with APC in secondary lymphoid tissue. Here, we demonstrate that the CXCR5 is a marker for recently activated memory CD4+ T cells. CXCR5 is rapidly induced during contact with Ag-presenting dendritic cells, well before T cell expansion and effector cell development, and is irreversibly lost on terminally differentiated effector cells. Furthermore, immunization of human volunteers with a recall Ag results in rapid accumulation of Ag-responsive, CXCR5-expressing CD4+ T cells in peripheral blood. Early acquisition of a new migration program enables T zone CD4+ T cells to develop into follicular B helper T cells or, alternatively, into circulating memory CD4+ T cells. Together, CXCR5 unequivocally defines pre-effector memory CD4+ T cells generated during ongoing immune responses.
Cutting Edge: Positive Selection Induced by a Self-Peptide with TCR Antagonist Activity
Authors: Santori Fabio R. , Brown Stuart M. , Lu Yun , Neubert Thomas A. , Vukmanović Stanislav 
Published: April 2014

Abstract
Antagonist-like engagement of the TCR has been proposed to induce T cell selection in the thymus. However, no natural TCR ligand with TCR antagonist activity is presently known. Using a combination of bioinformatics and functional testing we identified the first self-peptide that can both deliver antagonist-like signals and promote T cell selection in the thymus. The peptide is presented by appropriate MHC class I molecules in vivo. Thus, endogenous antagonist peptides exist and may be involved in TCR repertoire selection.
The Activatory Receptor 2B4 Is Expressed In Vivo by Human CD8+ Effector αβ T Cells
Authors: Speiser Daniel E. , Colonna Marco , Ayyoub Maha , Cella Marina , Pittet Mikaël J. , Batard Pascal , Valmori Danila , Guillaume Philippe , Liénard Danielle , Cerottini Jean-Charles , Romero Pedro 
Published: April 2014

Abstract
The membrane receptor 2B4 is a CD2 family member that is involved in lymphocyte activation. A fraction of human CD8+ αβ T cells up-regulate 2B4 in vivo, and here we demonstrate that this correlates with the acquisition of effector cell properties such as granzyme B and perforin expression, rapid IFN-γ production, and down-regulation of the lymph node homing chemokine receptor CCR7. In PBLs from healthy donors, cytomegalovirus-specific effector T cells were 2B4 positive, whereas naive melanoma Ag (Melan-A/melanoma Ag recognized by T cells-1)-specific T cells were 2B4 negative. In melanoma patients, Melan-A-specific T cells up-regulated 2B4 in parallel with in vivo differentiation. This occurred in PBLs after vaccination with Melan-A peptides and in tumor-infiltrated lymph nodes, likely through disease-associated activation of Melan-A-specific T cells. Thus, 2B4 expression correlates with CD8+ T cell differentiation in vivo.
Human Vγ2Vδ2 T Cells Produce IFN-γ and TNF-α with an On/Off/On Cycling Pattern in Response to Live Bacterial Products
Authors: Wang Lisheng , Das Hiranmoy , Kamath Arati , Bukowski Jack F. 
Published: April 2014

Abstract
Whereas cytokine production in αβ T cells is rapidly regulated by exposure to peptide Ag, the mechanisms regulating cytokine production by γδ T cells are unknown. In this study, we demonstrate that human Vγ2Vδ2 T cells produce IFN-γ and TNF-α as early as 2 h after Ag exposure, and that they produce these cytokines in a dose- and time- dependent manner in response to stimulation with a live bacterial product, iso-butylamine (IBA), but not to dead bacteria or LPS. γδ T cells began, ceased, and then resumed IFN-γ and TNF-α generation in an on/off/on cycling pattern, both in vitro and in vivo, depending on the presence or absence of IBA. IFN-γ and TNF-α, whose optimum production was dependent on IBA-stimulated γδ T cells, were critical for monocyte-mediated killing of Escherichia coli. By limiting cytokine production to periods of direct contact with live bacteria, γδ T cells focus their resources at the site of infection, while limiting systemic immunopathology. Thus, human γδ T cells may mediate innate resistance to extracellular bacteria via tightly regulated cytokine production without necessarily expanding in number.
TCRβ Chain Influences But Does Not Solely Control Autoreactivity of Vα14J281T Cells
Authors: Gui Ming , Li Jin , Wen Li-Jun , Hardy Richard R. , Hayakawa Kyoko 
Published: April 2014

Abstract
CD1d-dependent accumulation of αβ T cells bearing a canonical Vα14Jα281 α-chain (Vα14+ T cells) is thought to model positive selection of lipid-specific T cells, based on their ability to recognize CD1d-presented self glycolipid(s). However, it has been difficult to demonstrate self ligand specificity in this system, as most Vα14+ T cells do not exhibit significant autoreactivity despite high reactivity to α-galactosylceramide presented by CD1d (α-GalCer/CD1d). To assess the role of TCRβ chain in determining the α-GalCer/CD1d vs autoreactive specificity of Vα14+ T cells, we conducted TCRα or TCRβ chain transduction experiments. In this study we demonstrate, by combining different TCRβ chains with the Vα14 α-chain in retrovirally transduced T cell lines, that the Vα14 α-chain plays a primary role, necessary but not sufficient for imparting α-GalCer/CD1d recognition. β-Chain usage alone is not the sole factor that controls the extent of autoreactivity in Vα14+ T cells, since transduction of TCRαβ chains from a high CD1d autoreactive Vα14+ T cell line conferred the α-GalCer/CD1d specificity without induction of autoreactivity. Thus, heterogeneity of Vα14+ T cell reactivity is due to both β-chain diversity and control mechanism(s) beyond primary TCR structure.
Evidence for a Compartmentalized B Cell Response as Characterized by IgG Epitope Specificity in Human Ocular Toxoplasmosis
Authors: Klaren Vincent N. A. , Peek Ron 
Published: April 2014

Abstract
Infectious agents in the eye induce both a local and a systemic humoral immune response. Previously, differences in Ag recognition were observed between systemic and ocular derived IgG of patients with ocular toxoplasmosis. This finding implied a nonrandom distribution of IgG-producing B cells in the inflamed eye. In the present study, we compared the intraocular and systemic B cell responses of patients with ocular toxoplasmosis to a single Toxoplasma gondii Ag. Two series of C-terminally deleted recombinant T. gondii GRA-2 proteins were constructed to delineate IgG B cell epitopes of paired ocular and serum samples. Differences in epitope region recognition between the ocular and systemic compartment were detected in 9 of 13 patients. The difference in distribution of GRA-2 epitopes between paired samples is indicative of a local GRA-2 specific B cell population functionally different from the systemic GRA-2-specific B cell population. Our results suggest a selective activation of a subset of B cells locally in nonlymphoid tissue.