bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered p38 Mitogen-Activated Protein Kinase Expression in Different Leukocytes with Increment of Immunosuppressive Mediators in Patients with Severe Acute Respiratory Syndrome
Authors: Lee Chen-Hsiang , Chen Rong-Fu , Liu Jien-Wei , Yeh Wen-Tien , Chang Jen-Chieh , Liu Po-Mai , Eng Hock-Liew , Lin Meng-Chih , Yang Kuender D. 
Published: April 2014

Abstract
Severe acute respiratory syndrome (SARS) has spread to a global pandemic, especially in Asia. The transmission route of SARS has been clarified, but the immunopathogenesis of SARS is unclear. In an age-matched case-control design, we studied immune parameters in 15 SARS patients who were previously healthy. Plasma was harvested for detection of virus load, cytokines, and nitrite/nitrate levels, and blood leukocytes were subjected to flow cytometric analysis of intracellular mitogen-activated protein kinases (MAPKs) in different leukocytes. Patients with SARS had significantly higher IL-8 levels (p = 0.016) in early stage, and higher IL-2 levels (p = 0.039) in late stage than normal controls. Blood TNF-α, IL-6, and IL-10, and nitrite/nitrate levels were not significantly elevated. In contrast, TGF-β and PGE2 levels were significantly elevated in SARS patients. Five of the 15 SARS patients had detectable coronaviruses in blood, but patients with detectable and undetectable viremia had no different profiles of immune mediators. Flow cytometric analysis of MAPKs activation by phospho-p38 and phospho-p44/42 (extracellular signal-regulated kinase) expression showed that augmented p38 activation (p = 0.044) of CD14 monocytes associated with suppressed p38 activation (p = 0.033) of CD8 lymphocytes was found in SARS patients. These results suggest that regulation of TGF-β and PGE2 production and MAPKs activation in different leukocytes may be considered while developing therapeutics for the SARS treatment.
The Fourth Way? Harnessing Aggressive Tendencies in the Thymus
Authors: Baldwin Troy A. , Hogquist Kristin A. , Jameson Stephen C. 
Published: April 2014

AbstractDuring late stages of thymic development, T cells must chose between different fates, dictated by their TCR specificity. Typically, this is thought of as a choice between three alternatives (being positive selection for useful T cells vs negative selection or neglect for harmful or useless T cells). However, there is growing evidence for a fourth alternative, in which T cells are positively selected by agonist ligands, which would normally be expected to induce T cell deletion. In this review, we will discuss where and when agonist selection is induced and whether this should be considered as a novel form of thymic selection or as an alternative differentiation state for Ag-exposed T cells.
Cutting Edge: TGF-β Signaling Is Required for the In Vivo Expansion and Immunosuppressive Capacity of Regulatory CD4+CD25+ T Cells
Authors: Huber Samuel , Schramm Christoph , Lehr Hans A. , Mann Amrit , Schmitt Steffen , Becker Christoph , Protschka Martina , Galle Peter R. , Neurath Markus F. , Blessing Manfred 
Published: April 2014

Abstract
Data regarding the role of TGF-β for the in vivo function of regulatory CD4+CD25+ T cells (Treg) are controversial. A transgenic mouse model with impaired TGF-β signaling specifically in T cells was used to assess the role of endogenous TGF-β for the in vivo function of CD4+CD25+ Treg in a murine model of colitis induced by dextran sulfate. Transfer of wild-type, but not transgenic CD4+CD25+ Treg was found to suppress colitis in wild-type mice. In addition, by transferring CFSE-labeled CD4+CD25+ Treg we could demonstrate that endogenous TGF-β promotes the expansion of CD4+CD25+ Treg in vivo. Transgenic mice themselves developed reduced numbers of peripheral CD4+CD25+ Treg and were more susceptible to the induction of colitis, which could be prevented by the transfer of wild-type Treg. These data indicate that TGF-β signaling in CD4+CD25+ Treg is required for their in vivo expansion and suppressive capacity.
Cutting Edge: TCR Revision Occurs in Germinal Centers
Authors: Cooper Cristine J. , Turk Gail L. , Sun Mingyi , Farr Andrew G. , Fink Pamela J. 
Published: April 2014

AbstractMouse CD4+Vβ5+ T cells recognize a peripherally expressed superantigen encoded by an endogenous retrovirus. Ag encounter tolerizes the mature CD4 T cell compartment, either by deletion of autoreactive cells or by TCR revision. This latter process is driven by TCRβ rearrangement through RAG activity and results in the rescue of cells expressing novel TCRs that no longer recognize the tolerogen. Consistent with the notion that revising T cells represent a distinct peripheral T cell population, we now show that these lymphocyte blasts express a hybrid effector/memory phenotype and are not undergoing cell division. A population of revising T cells is CD40+, expresses the germinal center (GC) marker CXCR5, and is Vβ5lowThy-1low. Histology reveals that, consistent with their surface Ag phenotype, T cells undergoing TCR revision are enriched in splenic GCs. These data demonstrate that TCR revision is a multistep tolerance pathway supported by the unique microenvironment provided by GCs.
Cutting Edge: A Critical Role for CD70 in CD8 T Cell Priming by CD40-Licensed APCs
Authors: Taraban Vadim Y. , Rowley Tania F. , Al-Shamkhani Aymen 
Published: April 2014

AbstractThe CD154/CD40 interaction is an important pathway of CD4 T cell help for CD8 T cell responses. In this study, we address the role of CD70, a member of the TNF superfamily and the ligand for the T cell costimulatory receptor CD27, in CD40-mediated priming of CD8 T cells. Using an agonistic anti-CD40 mAb to mimic the CD154/CD40 interaction we demonstrate that the priming of OT-I TCR transgenic or endogenous mouse OVA-specific CD8 T cells is critically dependent on CD70/CD27 interaction. CD70 blockade inhibited CD40-mediated clonal expansion of CD8 T cells and reduced the number of memory CD8 T cells generated. Furthermore, CD70 blockade during the initial priming of CD8 T cells inhibited the ability of memory CD8 T cells to expand in response to a second encounter with Ag. Our data indicate that CD70 expression on APCs plays a key role in CD40-dependent CD8 T cell responses.
Plasmacytoid Dendritic Cell Recruitment by Immobilized CXCR3 Ligands
Authors: Kohrgruber Norbert , Gröger Marion , Meraner Paul , Kriehuber Ernst , Petzelbauer Peter , Brandt Sabine , Stingl Georg , Rot Antal , Maurer Dieter 
Published: April 2014

Abstract
Plasmacytoid dendritic cells (pDCs) recognize microbes, viruses in particular, and provide unique means of innate defense against them. The mechanism of pDC tissue recruitment remained enigmatic because the ligands of CXCR3, the cardinal chemokine receptor on pDCs, have failed to induce in vitro chemotaxis of pDCs in the absence of additional chemokines. In this study, we demonstrate that CXCR3 is sufficient to induce pDC migration, however, by a migratory mechanism that amalgamates the features of haptotaxis and chemorepulsion. To mediate “haptorepulsion” of pDCs, CXCR3 requires the encounter of its cognate ligands immobilized, optimally by heparan sulfate, in a form of a negative gradient. This is the first report of the absolute requirement of chemokine immobilization and presentation for its in vitro promigratory activity. The paradigmatic example of pDC haptorepulsion described here may represent a new pathophysiologically relevant migratory mechanism potentially used by other cells in response to other chemokines.
IL-12 Gene Therapy Is an Effective Therapeutic Strategy for Hepatocellular Carcinoma in Immunosuppressed Mice
Authors: Harada Noboru , Shimada Mitsuo , Okano Shinji , Suehiro Taketoshi , Soejima Yuji , Tomita Yukihiro , Maehara Yoshihiko 
Published: April 2014

AbstractImmunosuppressive therapy for organ transplantation is essential for controlling rejection. When liver transplantation is performed as a therapy for hepatocellular carcinoma (HCC), recurrent HCC is one of the most fatal complications. In this study, we show that intratumoral murine IL-12 (mIL-12) gene therapy has the potential to be an effective treatment for malignancies under immunosuppression. C3H mice (H-2k), injected with FK506 (3 mg/kg) i.p., were s.c. implanted with 2.5 × 106 MH134 cells (H-2k) and we treated the established HCC with electroporation-mediated gene therapy using mIL-12 plasmid DNA. Intratumoral gene transfer of mIL-12 elevated intratumoral mIL-12, IFN-γ, and IFN-γ-inducible protein-10, significantly reduced the number of microvessels and inhibited the growth of HCC, compared with HCC-transferred control pCAGGS plasmid. The inhibition of tumor growth in immunosuppressed mice was comparable with that of mIL-12 gene therapy in immunocompetent mice. Intratumoral mIL-12 gene therapy enhanced lymphocytic infiltration into the tumor and elicited the MH134-specific CTL response even under FK506. The dose of FK506 was sufficient to prevent the rejection of distant allogenic skin grafts (BALB/c mice, H-2d) and tumors, B7-p815 (H-2d) used as transplants, during mIL-12 gene therapy against MH134. Ab-mediated depletion studies suggested that the inhibition of tumor growth, neovascularization, and spontaneous lung metastasis by mIL-12 was dependent almost entirely on NK cells and partially on T cells. These results suggest that intratumoral mIL-12 gene therapy is a potent effective strategy not only to treat recurrences of HCC in liver transplantation, but also to treat solid malignant tumors in immunosuppressed patients with transplanted organ.
IFNβ Accelerates Autoimmune Type 1 Diabetes in Nonobese Diabetic Mice and Breaks the Tolerance to β Cells in Nondiabetes-Prone Mice
Authors: Alba Aurora , Puertas M. Carmen , Carrillo Jorge , Planas Raquel , Ampudia Rosa , Pastor Xavier , Bosch Fatima , Pujol-Borrell Ricardo , Verdaguer Joan , Vives-Pi Marta 
Published: April 2014

AbstractGenetic and environmental factors are decisive in the etiology of type 1 diabetes. Viruses have been proposed as a triggering environmental event and some evidences have been reported: type I IFNs exist in the pancreata of diabetic patients and transgenic mice expressing these cytokines in β cells develop diabetes. To determine the role of IFNβ in diabetes, we studied transgenic mice expressing human IFNβ in the β cells. Autoimmune features were found: MHC class I islet hyperexpression, T and B cells infiltrating the islets and transfer of the disease by lymphocytes. Moreover, the expression of β2-microglobulin, preproinsulin, and glucagon in the thymus was not altered by IFNβ, thus suggesting that the disease is caused by a local effect of IFNβ, strong enough to break the peripheral tolerance to β cells. This is the first report of the generation of NOD (a model of spontaneous autoimmune diabetes) and nonobese-resistant (its homologous resistant) transgenic mice expressing a type I IFN in the islets: transgenic NOD and nonobese-resistant mice developed accelerated autoimmune diabetes with a high incidence of the disease. These results indicate that the antiviral cytokine IFNβ breaks peripheral tolerance to β cells, influences the insulitis progression and contributes to autoimmunity in diabetes and nondiabetes- prone mice.
Follicular Dendritic Cells Produce IL-15 That Enhances Germinal Center B Cell Proliferation in Membrane-Bound Form
Authors: Park Chan-Sik , Yoon Sun-Ok , Armitage Richard J. , Choi Yong Sung 
Published: April 2014

AbstractFactors that control the survival and proliferation of Ag-stimulated B cells within the germinal center (GC) are crucial for humoral immune responses with high affinity Abs against infectious agents. The follicular dendritic cell (FDC) is known as a key cellular component of the GC microenvironment for GC-B cell survival and proliferation. In this study, we report that IL-15 is produced by human FDC in vivo and by an FDC cell line, FDC/HK cells, in vitro. IL-15 is captured by IL-15Rα on the surface of FDC/HK cells. The surface IL-15 is functionally active and augments GC-B cell proliferation. Because GC-B cells have the signal-transducing components (IL-2/15Rβγ), but not a receptor for binding of soluble IL-15 (IL-15Rα), IL-15 signaling is possibly transduced by transpresentation from FDCs to GC-B cells via cell-cell contact. Together, these results suggest that IL-15 from FDC, in membrane-bound form, plays an important role in supporting GC-B cell proliferation, proposing a new target for immune modulation as well as treatment of B cell tumors of GC origin.
IL-19 Induced Th2 Cytokines and Was Up-Regulated in Asthma Patients
Authors: Liao Sheng-Chin , Cheng Yung-Chih , Wang Yo-Ching , Wang Chiung-Wen , Yang San-Ming , Yu Chun-Keung , Shieh Chi-Chang , Cheng Kuo-Chen , Lee Meng-Feng , Chiang Shyh-Ren , Shieh Jiunn-Min , Chang Ming-Shi 
Published: April 2014

AbstractIL-19 belongs to the IL-10 family, which includes IL-10, IL-19, IL-20, IL-22, melanoma differentiation-associated gene-7 (IL-24), and AK155 (IL-26). IL-10 has been shown to inhibit allergen-induced airway hyperreactivity and inflammation. To determine whether IL-19 was also associated with asthma, we used ELISA to analyze the serum level of IL-19 in patients with asthma and found that their serum IL-19 levels were twice those of healthy controls. Patients with a high level of IL-19 also had high levels of IL-4 and IL-13. In a dust mite-induced murine model of asthma, we found that IL-19 level in asthmatic BALB/cJ mice was also twice that of healthy control mice. IL-19 transcript was also induced in the lungs of asthmatic mice. Electroporation i.m. of the IL-19 gene into healthy mice up-regulated IL-4 and IL-5, but not IL-13. However, IL-19 up-regulated IL-13 in asthmatic mice. In vitro, IL-19 induced IL-4, IL-5, IL-10, and IL-13 production by activated T cells. Activation of T cells was required for induction of IL-13 because IL-19 did not induce IL-13 production on nonstimulated T cells. Taken together, these results demonstrated that IL-19 up-regulates Th2 cytokines on activated T cells and might play an important role in the pathogenesis of asthma.
Biochemical Analysis of the Regulatory T Cell Protein Lymphocyte Activation Gene-3 (LAG-3; CD223)
Authors: Li Nianyu , Workman Creg J. , Martin Stefani M. , Vignali Dario A. A. 
Published: April 2014

AbstractLymphocyte activation gene-3 (LAG-3; CD223) is a CD4-related transmembrane protein that binds to MHC class II molecules. We have recently shown that LAG-3 is required for maximal regulatory T cell function, and that ectopic expression of LAG-3 is sufficient to confer regulatory activity. In this study we show that LAG-3 is cleaved within the D4 transmembrane domain connecting peptide into two fragments that remain membrane associated: a 54-kDa fragment that contains all the extracellular domains and oligomerizes with full-length LAG-3 (70 kDa) on the cell surface via the D1 domain, and a 16-kDa peptide that contains the transmembrane and cytoplasmic domains. This NH2-terminal fragment is subsequently released as soluble LAG-3 (sLAG-3), a process that is increased after T cell activation in vitro and in vivo, and is found in the sera of C57BL/6 and RAG-1−/− mice. Modulation of LAG-3 cleavage may contribute to the function of this key regulatory T cell protein.
A Novel Adjuvant for Mucosal Immunity to HIV-1 gp120 in Nonhuman Primates
Authors: Yoshino Naoto , Lü Fabien X.-S. , Fujihashi Kohtaro , Hagiwara Yukari , Kataoka Kosuke , Lu Ding , Hirst Linda , Honda Mitsuo , van Ginkel Frederik W. , Takeda Yoshifumi , Miller Christopher J. , Kiyono Hiroshi , McGhee Jerry R. 
Published: April 2014

AbstractThe development of a safe and effective mucosal adjuvant is a crucial step toward a mucosal HIV/AIDS vaccine. This study seeks to determine the promise of a nontoxic mutant of cholera toxin (mCT; E112K) as a mucosal adjuvant in nonhuman primates. HIV-1 gp120 was nasally administered together with mCT E112K or native CT (nCT) as adjuvant on five to six occasions over a 6- to 8-wk period to groups of four rhesus macaques and alone to two monkeys that acted as controls. Macaques given nasal gp120 with either mCT E112K or nCT showed elevated gp120-specific IgG and IgA Ab responses with virus-neutralizing activity in both their plasma and mucosal external secretions, as well as higher numbers of gp120-specific IgA Ab-forming cells in their mucosal and peripheral lymphoid tissues and of IL-4-producing Th2-type CD4-positive (CD4+) T cells than did controls. Even though significant mucosal adjuvanticity was seen with both mCT E112K and nCT, neuronal damage was observed only in the nCT-treated, but not in the control or mCT E112K-treated groups. These results clearly show that mCT E112K is an effective and safe mucosal adjuvant for the development of a nasal HIV/AIDS vaccine.
Gene Expression Profiling of Host Response in Models of Acute HIV Infection
Authors: Bosinger Steven E. , Hosiawa Karoline A. , Cameron Mark J. , Persad Desmond , Ran Longsi , Xu Luoling , Boulassel Mohamed R. , Parenteau Monique , Fournier Jocelyn , Rud Erling W. , Kelvin David J. 
Published: April 2014

AbstractHIV infection is characterized by a host response composed of adaptive and innate immunity that partially limits viral replication; however, it ultimately fails in eradicating the virus. To model host gene expression during acute HIV infection, we infected cynomolgus macaques with the SIV/HIV-1 chimeric virus, SHIV89.6P, and profiled gene expression in peripheral blood over a 5-wk period using a high density cDNA microarray. We demonstrate that viral challenge induced a widespread suppression of genes regulating innate immunity, including the LPS receptors, CD14 and TLR4. An overexpression of 16 IFN-stimulated genes was also observed in response to infection; however, it did not correlate with control over viral titers. A statistical analysis of the dataset identified 10 genes regulating apoptosis with differential expression during the first 2 wk of infection (p &lt; 0.004). Quantitative real-time PCR verified transcriptional increases in IFN-α-inducible genes and decreases in genes regulating innate immunity. Therefore, the persistence of high viral loads despite an extensive IFN response suggests that HIV can resist in vivo IFN treatment despite published reports of in vitro efficacy. The transcriptional suppression of genes regulating innate immunity may allow HIV to evade acute host responses and establish a chronic infection and may reduce innate host defense against opportunistic infections.
Viral Activation of Macrophages through TLR-Dependent and -Independent Pathways
Authors: Malmgaard Lene , Melchjorsen Jesper , Bowie Andrew G. , Mogensen Søren C. , Paludan Søren R. 
Published: April 2014

AbstractInduction of cytokine production is important for activation of an efficient host defense response. Macrophages constitute an important source of cytokines. In this study we have investigated the virus-cell interactions triggering induction of cytokine expression in macrophages during viral infections. We found that viral entry and viral gene products produced inside the cell are responsible for activation of induction pathways leading to IFN-αβ expression, indicating that virus-cell interactions on the cell surface are not enough. Moreover, by the use of cell lines expressing dominant negative versions of TLR-associated adaptor proteins we demonstrate that Toll/IL-1 receptor domain-containing adaptor inducing IFN-β is dispensable for all virus-induced cytokine expression examined. However, a cell line expressing dominant negative MyD88 revealed the existence of distinct induction pathways because virus-induced expression of RANTES and TNF-α was totally blocked in this cell line whereas IFN-αβ expression was much less affected in the absence of signaling via MyD88. In support of this, we also found that inhibitory CpG motifs, which block TLR9 signaling inhibited early HSV-2-induced TNF-α and RANTES expression dramatically whereas IFN-αβ induction was only slightly affected. This suggests that virus activates macrophages through distinct pathways, of which some are dependent on TLRs signaling through MyD88, whereas others seem to be independent of TLR signaling. Finally we demonstrate that IFN-αβ induction in HSV-2-infected macrophages requires a functional dsRNA-activated protein kinase molecule because cells expressing a dsRNA-dependent protein kinase version unable to bind dsRNA do not express IFN-αβ on infection.
Interaction between Complement Regulators andStreptococcus pyogenes: Binding of C4b-Binding Protein and Factor H/Factor H-Like Protein 1 to M18 Strains Involves Two Different Cell Surface Molecules
Authors: Pérez-Caballero David , García-Laorden Isabel , Cortés Guadalupe , Wessels Michael R. , de Córdoba Santiago Rodríguez , Albertí Sebastián 
Published: April 2014

AbstractStreptococcus pyogenes, or group A Streptococcus, is one of the most frequent causes of pharyngitis and skin infections in humans. Many virulence mechanisms have been suggested to be involved in the infectious process. Among them is the binding to the bacterial cell surface of the complement regulatory proteins factor H, factor H-like protein 1 (FHL-1), and C4b-binding protein. Previous studies indicate that binding of these three regulators to the streptococcal cell involves the M protein encoded by the emm gene. M-type 18 strains are prevalent among clinical isolates and have been shown to interact with all three complement regulators simultaneously. Using isogenic strains lacking expression of the Emm18 or the Enn18 proteins, we demonstrate in this study that, in contradistinction to previously described S. pyogenes strains, M18 strains bind the complement regulators factor H, FHL-1, and C4b-binding protein through two distinct cell surface proteins. Factor H and FHL-1 bind to the Emm18 protein, while C4BP binds to the Enn18 protein. We propose that expression of two distinct surface structures that bind complement regulatory proteins represents a unique adaptation of M18 strains that enhances their resistance to opsonization by human plasma and increases survival of this particular S. pyogenes strain in the human host. These new findings illustrate that S. pyogenes has evolved diverse mechanisms for recruitment of complement regulatory proteins to the bacterial surface to evade immune clearance in the human host.
NF-κB Activation in Airways Modulates Allergic Inflammation but Not Hyperresponsiveness
Authors: Poynter Matthew E. , Cloots Roy , van Woerkom Tiest , Butnor Kelly J. , Vacek Pamela , Taatjes Douglas J. , Irvin Charles G. , Janssen-Heininger Yvonne M. W. 
Published: April 2014

AbstractAirways display robust NF-κB activation and represent targets for anti-inflammatory asthma therapies, but the functional importance of NF-κB activation in airway epithelium remains enigmatic. Therefore, transgenic mice were created in which NF-κB activation is repressed specifically in airways (CC10-IκBαSR mice). In response to inhaled Ag, transgenic mice demonstrated significantly ameliorated inflammation, reduced levels of chemokines, T cell cytokines, mucus cell metaplasia, and circulating IgE compared with littermate controls. Despite these findings, Ag-driven airways hyperresponsiveness was not attenuated in CC10-IκBαSR mice. This study clearly demonstrates that airway epithelial NF-κB activation orchestrates Ag-induced inflammation and subsequent adaptive immune responses, but does not contribute to airways hyperresponsiveness, the cardinal feature that underlies asthma.