bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of Virus-Induced IL-12 and IL-23 Expression in Human Macrophages
Authors: Pirhonen Jaana , Matikainen Sampsa , Julkunen Ilkka 
Published: April 2014

AbstractIL-23 is a novel cytokine that promotes the proliferation of naive and memory T cells and stimulates their IFN-γ production. Besides functional similarities, IL-23 bears structural resemblance to IL-12. Biologically active IL-23 is a heterodimer whose p40 subunit is identical to IL-12p40 while its p19 subunit is distantly related to IL-12p35. In the present study we demonstrate that human monocyte-derived macrophages are able to produce IL-23 in response to virus infection. Sendai virus stimulates the expression of p19 and p40 mRNAs in macrophages. Furthermore, it enhances p35 mRNA expression and the production of IL-12. Influenza A virus, in contrast, fails to stimulate IL-12 or IL-23 expression in macrophages. IL-12 and IL-23 contribute to the IFN-γ-inducing activity that cell culture supernatant from Sendai virus-infected macrophages show in NK-92 cells. The induction of IFN-γ production occurs in concert with IFN-αβ and IL-18, which are also secreted from the virus-infected cells. The IFN-γ-inducing activity is inhibited by IL-4, which down-regulates the transcription of p19 and p40 genes and the secretion of IFN-αβ, IL-12, and IL-18. IFN-γ, in contrast, up-regulates the p19 and p40 mRNA expression in Sendai virus infection. Thus, IL-4 and IFN-γ serve as opposing factors in the regulation of IFN-γ-inducing cytokines, including IL-23, in macrophages.
TGF-β1 Regulates Adhesion of Mucosal Mast Cell Homologues to Laminin-1 Through Expression of Integrin α7
Authors: Rosbottom Anne , Scudamore Cheryl L. , von der Mark Helga , Thornton Elizabeth M. , Wright Steven H. , Miller Hugh R. P. 
Published: April 2014

AbstractMucosal mast cells (MMC) or their precursors migrate through the intestinal lamina propria to reside intraepithelially, where expression of mouse mast cell protease-1 indicates the mature phenotype. Alterations in expression of integrins that govern cell adhesion to the extracellular matrix may regulate this process. As the key cytokine mediating differentiation of mouse mast cell protease-1-expressing MMC homologues in vitro, TGF-β1 was considered a likely candidate for regulation of the integrins that facilitate intraepithelial migration of MMC. Therefore, we examined adhesion of bone marrow-derived mast cells cultured with and without TGF-β1 to laminin-1, fibronectin, and vitronectin along with expression of integrins likely to regulate this adhesion. Adhesion of PMA-stimulated cultured mast cells to laminin-1 increased from 5.3 ± 3.6% (mean ± SEM) in the absence of TGF-β1 to 58.7 ± 4.0% (p &lt; 0.05) when cultured mast cells had differentiated into MMC homologues in the presence of TGF-β1. Increased adhesion of MMC homologues to laminin-1 was also stimulated by FcεRI cross-linking and the calcium ionophore A23187. Expression of the laminin-binding integrin α7 by MMC homologues grown in the presence of TGF-β1 was demonstrated by RT-PCR and flow cytometry, and preincubation of MMC homologues with the α7-neutralizing Ab 6A11 inhibited adhesion to laminin-1 by 98% (p &lt; 0.05), demonstrating a novel role for this molecule in adhesion of a hemopoietic cell to laminin-1.
Characterization of the Interaction Between L-Ficolin/P35 and Mannan-Binding Lectin-Associated Serine Proteases-1 and -2
Authors: Cseh Sandor , Vera Loanys , Matsushita Misao , Fujita Teizo , Arlaud Gérard J. , Thielens Nicole M. 
Published: April 2014

AbstractFicolins are oligomeric lectins comprising a collagen-like and a fibrinogen-like domain, with a binding specificity for N-acetylglucosamine. It has been reported recently that L-ficolin/P35 associates with mannan-binding lectin (MBL)-associated serine proteases (MASP-1 and -2) and MBL-associated protein 19 (MAp19) in serum and forms complexes able to activate complement. Using surface plasmon resonance spectroscopy we have shown that recombinant MASP-1 and -2, their N-terminal CUB1 (module originally found in complement proteins C1r/C1s, Uegf, and bone morphogenetic protein-1)-epidermal growth factor (EGF)-CUB2 and CUB1-EGF segments, and MAp19 bind to immobilized L-ficolin/P35 in the presence of Ca2+ ions. Comparable Kd values were obtained for the full-length proteases and their CUB1-EGF-CUB2 segments (9.2 and 10 nM for MASP-1 and 4.6 and 5.4 nM for MASP-2, respectively), whereas higher values were obtained for the CUB1-EGF segments (26.7, 15.6, and 14.3 nM for MASP-1, MASP-2, and MAp19). These values are in the same range as those determined for the interaction of these proteins with MBL. Binding was Ca2+ dependent and was only partly sensitive to EDTA for MASP-1, MASP-2, and MASP-2 CUB1-EGF-CUB2. Half-maximal binding was obtained at comparable Ca2+ concentrations for MASP-1 and MASP-2 (0.45 and 0.47 μM, respectively), their CUB1-EGF-CUB2 segments (0.37 and 0.72 μM), and their CUB1-EGF segments (0.31 and 0.79 μM). These values are lower than those determined in the case of MBL, indicating a difference between MBL and L-ficolin/P35 with respect to the Ca2+ dependence of their interaction with the MASPs. Preincubation of the MASPs with soluble MBL inhibited subsequent binding to immobilized L-ficolin/P35 and, conversely, suggesting that these lectins compete with each other for binding to the MASPs in vivo.
Proliferation Requirements of Cytomegalovirus-Specific, Effector-Type Human CD8+ T Cells
Authors: van Leeuwen Ester M. , Gamadia Laila E. , Baars Paul A. , Remmerswaal Ester B. , ten Berge Ineke J. , van Lier René A. 
Published: April 2014

Abstract
Two prototypic types of virus-specific CD8+ T cells can be found in latently infected individuals: CD45R0+CD27+CCR7− effector-memory, and CD45RA+CD27−CCR7− effector-type cells. It has recently been implied that CD45RA+CD27−CCR7− T cells are terminally differentiated effector cells and as such have lost all proliferative capacity. We show in this study, however, that stimulation of CMV-specific CD45RA+CD27−CCR7− T cells with their cognate peptide in concert with either CD4+ help or IL-2, IL-15, or IL-21 in fact induces massive clonal expansion. Concurrently, these stimulated effector T cells change cell surface phenotype from CD45RA to CD45R0 and regain CCR7, while effector functions are maintained. Our data imply that CD45RA+CD27−CCR7− effector-type T cells contribute to immunity not only by direct execution of effector functions, but also by yielding progeny in situations of viral reinfection or reactivation.
A Protease-Activated Pathway Underlying Th Cell Type 2 Activation and Allergic Lung Disease
Authors: Kheradmand Farrah , Kiss Attila , Xu Jie , Lee Seung-Hyo , Kolattukudy Pappachan E. , Corry David B. 
Published: April 2014

AbstractThe respiratory allergens that induce experimental Th cell type 2-dependent allergic lung inflammation may be grouped into two functional classes. One class of allergens, in this study termed type I, requires priming with adjuvants remote from the lung to overcome airway tolerogenic mechanisms that ordinarily preclude allergic responses to inhaled Ags. In contrast, the other, or type II, allergen class requires neither remote priming nor additional adjuvants to overcome airway tolerance and elicit robust allergic lung disease. In this study, we show in an experimental model that diverse type II allergens share in common proteolytic activity that is both necessary and sufficient for overcoming airway tolerance and induction of pulmonary allergic disease. Inactivated protease and protease-free Ag fragments showed no allergenic potency, demonstrating that only active protease acting on endogenous substrates was essential. Furthermore, induction of airway tolerance could be aborted and allergic lung disease established by simply adding purified protease to a type I allergen. Thus, exogenous proteases are common to type II allergens and may be generally required to overcome the innate resistance of the airway to Th cell type 2 activation and allergic inflammation, raising concern for their potential contribution to diseases such as asthma.
Absence of the Complement Anaphylatoxin C3a Receptor Suppresses Th2 Effector Functions in a Murine Model of Pulmonary Allergy
Authors: Drouin Scott M. , Corry David B. , Hollman Travis J. , Kildsgaard Jens , Wetsel Rick A. 
Published: April 2014

AbstractAsthma is a chronic inflammatory disease of the lung resulting in airway obstruction. The airway inflammation of asthma is strongly linked to Th2 lymphocytes and their cytokines, particularly IL-4, IL-5, and IL-13, which regulate airway hyperresponsiveness, eosinophil activation, mucus production, and IgE secretion. Historically, complement was not thought to contribute to the pathogenesis of asthma. However, our previous reports have demonstrated that complement contributes to bronchial hyperreactivity, recruitment of airway eosinophils, IL-4 production, and IgE responses in a mouse model of pulmonary allergy. To define the complement activation fragments that mediate these effects, we assessed the role of the complement anaphylatoxin C3a in a mouse model of pulmonary allergy by challenging C3aR-deficient mice intranasally with a mixed Ag preparation of Aspergillus fumigatus cell culture filtrate and OVA. Analysis by plethysmography after challenge revealed an attenuation in airway hyperresponsiveness in C3aR-deficient mice relative to wild-type mice. C3aR-deficient mice also had an 88% decrease in airway eosinophils and a 59% reduction in lung IL-4-producing cells. Consistent with the reduced numbers of IL-4-producing cells, C3aR-deficient mice had diminished bronchoalveolar lavage levels of the Th2 cytokines, IL-5 and IL-13. C3aR knockout mice also exhibited decreases in IgE titers as well as reduced mucus production. Collectively, these data highlight the importance of complement activation, the C3a anaphylatoxin, and its receptor during Th2 development in this experimental model and implicate these molecules as possible therapeutic targets in diseases such as asthma.
Dysregulation of IFN-γ Signaling Pathways in the Absence of TGF-β1
Authors: McCartney-Francis Nancy L. , Wahl Sharon M. 
Published: April 2014

AbstractDeficiency of TGF-β1 is associated with immune dysregulation and autoimmunity as exemplified by the multifocal inflammatory lesions and early demise of the TGF-β1 null mice. Elevated NO metabolites (nitrite and nitrate) in the plasma of these mice suggest a participatory role of NO in the pathogenic inflammatory response. To determine the mechanism for this dysregulation, we examined upstream elements that could contribute to the overexpression of NO, including inducible NO synthase (iNOS) and transcription factors Stat1α and IFN-regulatory factor-1 (IRF-1). The coincident up-regulation of IFN-γ, an iNOS inducer, and iNOS, before the appearance of inflammatory lesions, suggests that failed regulation of the IFN-γ signaling pathway may underlie the immunological disorder in TGF-β1 null mice. In fact, IFN-γ-driven transcription factors IRF-1 and Stat1α, both of which act as transcriptional activators of iNOS, were elevated in the null mice. Treatment of mice with a polyclonal anti-IFN-γ Ab reduced expression and activity not only of transcription factors Stat1α and IRF-1 but also of iNOS. Furthermore, anti-IFN-γ treatment delayed the cachexia normally seen in TGF-β1 null mice and increased their longevity. The global nature of immune dysregulation in TGF-β1 null mice documents TGF-β1 as an essential immunoregulatory molecule.
Expression and Function of C5a Receptor in Mouse Microvascular Endothelial Cells
Authors: Laudes Ines J. , Chu Jeffrey C. , Huber-Lang Markus , Guo Ren-Feng , Riedemann Niels C. , Sarma J. Vidya , Mahdi Fakhri , Murphy Hedwig S. , Speyer Cecilia , Lu Kristina T. , Lambris John D. , Zetoune Firas S. , Ward Peter A. 
Published: April 2014

Abstract
The complement-derived anaphylatoxin, C5a, is a potent phlogistic molecule that mediates its effects by binding to C5a receptor (C5aR; CD88). We now demonstrate specific binding of radiolabeled recombinant mouse C5a to mouse dermal microvascular endothelial cells (MDMEC) with a Kd50 of 3.6 nM and to ∼15,000–20,000 receptors/cell. Recombinant mC5a competed effectively with binding of [125I]rmC5a to MDMEC. Enhanced binding of C5a occurred, as well as increased mRNA for C5aR, after in vitro exposure of MDMEC to LPS, IFN-γ, or IL-6 in a time- and dose-dependent manner. By confocal microscopy, C5aR could be detected on surfaces of MDMEC using anti-C5aR Ab. In vitro expression of macrophage inflammatory protein-2 (MIP-2) and monocyte chemoattractant protein-1 (MCP-1) by MDMEC was also measured. Exposure of MDMEC to C5a or IL-6 did not result in changes in MIP-2 or MCP-1 production, but initial exposure of MDMEC to IL-6, followed by exposure to C5a, resulted in significantly enhanced production of MIP-2 and MCP-1 (but not TNF-α and MIP-1α). Although LPS or IFN-γ alone induced some release of MCP-1 and MIP-2, pre-exposure of these monolayers to LPS or IFN-γ, followed by addition of C5a, resulted in synergistic production of MIP-2 and MCP-1. Following i.v. infusion of LPS into mice, up-regulation of C5aR occurred in the capillary endothelium of mouse lung, as determined by immunostaining. These results support the hypothesis that C5aR expression on MDMEC and on the microvascular endothelium of lung can be up-regulated, suggesting that C5a in the co-presence of additional agonists may mediate pro-inflammatory effects of endothelial cells.
The T Cell Response to Art v 1, the Major Mugwort Pollen Allergen, Is Dominated by One Epitope
Authors: Jahn-Schmid Beatrice , Kelemen Peter , Himly Martin , Bohle Barbara , Fischer Gottfried , Ferreira Fatima , Ebner Christof 
Published: April 2014

Abstract
Mugwort (Artemisia vulgaris) pollen allergens represent the main cause of pollinosis in late summer in Europe. At least 95% of sera from mugwort pollen-allergic patients contain IgE against a highly glycosylated 24- to 28-kDa glycoprotein. Recently, this major allergen, termed Art v 1, was characterized, cloned in Escherichia coli, and produced in recombinant form. In the present study we characterized and compared the T cell responses to natural (nArt v 1) and recombinant Art v 1 (rArt v 1). In vitro T cell responses to nArt v 1 and rArt v 1 were studied in PBMC, T cell lines (TCL), and T cell clones (TCC) established from PBMC of mugwort-allergic patients. Stimulation of PBMC or allergen-specific TCL with either nArt v 1 or rArt v 1 resulted in comparable proliferative T cell responses. Eighty-five percent of the TCC reactive with rArt v 1 cross-reacted with the natural protein. The majority of the CD4+CD8−TCR αβ+ Art v 1-specific TCC, obtained from 10 different donors, belonged to the Th2 phenotype. Epitope mapping of TCL and TCC using overlapping peptides revealed a single immunodominant T cell epitope recognized by 81% of the patients. Inhibition experiments demonstrated that the presentation of this peptide is restricted by HLA-DR molecules. In conclusion, the T cell response to Art v 1 is characterized by one strong immunodominant epitope and evidently differs from the T cell responses to other common pollen allergens known to contain multiple T cell epitopes. Therefore, mugwort allergy may be an ideal candidate for a peptide-based immunotherapy approach.
Cutting Edge: Virus-Specific CD4+ Memory T Cells in Nonlymphoid Tissues Express a Highly Activated Phenotype
Authors: Cauley Linda S. , Cookenham Tres , Miller Timothy B. , Adams Pamela S. , Vignali Kate M. , Vignali Dario A. A. , Woodland David L. 
Published: April 2014

AbstractRecent studies have shown that CD4+ memory T cells persist in nonlymphoid organs following infections. However, the development and phenotype of these peripheral memory cells are poorly defined. In this study, multimerized MHC-Ig fusion proteins, with a covalently attached peptide sequence from the Sendai virus hemagglutinin/neuraminidase gene, have been used to identify virus-specific CD4+ T cells during Sendai virus infection and the establishment of peripheral CD4+ memory populations in the lungs. We show declining frequencies of virus-specific CD4+ T cells in the lungs over the course of ∼3 mo after infection. Like peripheral CD8+ T cells, the CD4+ have an acutely activated phenotype, suggesting that a high level of differentiation is required to reach the airways and persist as memory cells. Differences in CD25 and CD11a expression indicate that the CD4+ cells from the lung airways and parenchyma are distinct memory populations.
Cutting Edge: A Novel Toll/IL-1 Receptor Domain-Containing Adapter That Preferentially Activates the IFN-β Promoter in the Toll-Like Receptor Signaling
Authors: Yamamoto Masahiro , Sato Shintaro , Mori Kiyotoshi , Hoshino Katsuaki , Takeuchi Osamu , Takeda Kiyoshi , Akira Shizuo 
Published: April 2014

AbstractMyD88 is a Toll/IL-1 receptor (TIR) domain-containing adapter common to signaling pathways via Toll-like receptor (TLR) family. However, accumulating evidence demonstrates the existence of a MyD88-independent pathway, which may explain unique biological responses of individual TLRs, particularly TLR3 and TLR4. TIR domain-containing adapter protein (TIRAP)/MyD88 adapter-like, a second adapter harboring the TIR domain, is essential for MyD88-dependent TLR2 and TLR4 signaling pathways, but not for MyD88-independent pathways. Here, we identified a novel TIR domain-containing molecule, named TIR domain-containing adapter inducing IFN-β (TRIF). As is the case in MyD88 and TIRAP, overexpression of TRIF activated the NF-κB-dependent promoter. A dominant-negative form of TRIF inhibited TLR2-, TLR4-, and TLR7-dependent NF-κB activation. Furthermore, TRIF, but neither MyD88 nor TIRAP, activated the IFN-β promoter. Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-κB-dependent and IFN-β promoters. TRIF associated with TLR3 and IFN regulatory factor 3. These findings suggest that TRIF is involved in the TLR signaling, particularly in the MyD88-independent pathway.
Cutting Edge: Inflammatory Signals Drive Organ-Specific Autoimmunity to Normally Cross-Tolerizing Endogenous Antigen
Authors: Vezys Vaiva , Lefrançois Leo 
Published: April 2014

AbstractLinks have been observed between infections and the development of autoimmunity. Proposed explanations include activation of self-Ag-bearing APC. Using a model system in which transgenic OVA is expressed in enterocytes, we showed that CD8 T cell recognition of cross-presented Ag in gut-associated lymph nodes was tolerogenic. However, concomitant infection with vesicular stomatitis virus encoding OVA abrogated tolerance and induced disease. We now show that following transfer of naive OT-I T cells, the addition of wild-type vesicular stomatitis virus, oral cholera toxin, or CD40 triggering can induce intestinal disease in transgenic mice. Tissue damage accompanied dramatic increases in cytokine release by activated OT-I cells in the intestine. The data indicated that products of antigenically unrelated infections can combine with cross-presented self-Ags on APC to prime autoaggressiveness, independent of additional Ag release. These results help explain how diverse pathogens, lacking any homology to self-proteins, could be causative agents in induction of organ-specific autoimmunity.
Cutting Edge: A New Tool to Evaluate Human Pre-Erythrocytic Malaria Vaccines: Rodent Parasites Bearing a HybridPlasmodium falciparumCircumsporozoite Protein
Authors: Persson Cathrine , Oliveira Giane A. , Sultan Ali A. , Bhanot Purnima , Nussenzweig Victor , Nardin Elizabeth 
Published: April 2014

AbstractMalaria vaccines containing the Plasmodium falciparum Circumsporozoite protein repeat domain are undergoing human trials. There is no simple method to evaluate the effect of vaccine-induced responses on P. falciparum sporozoite infectivity. Unlike the rodent malaria Plasmodium berghei, P. falciparum sporozoites do not infect common laboratory animals and only develop in vitro in human hepatocyte cultures. We generated a recombinant P. berghei parasite bearing P. falciparum Circumsporozoite protein repeats. These hybrid sporozoites are fully infective in vivo and in vitro. Monoclonal and polyclonal Abs to P. falciparum repeats neutralize hybrid parasite infectivity, and mice immunized with a P. falciparum vaccine are protected against challenge with hybrid sporozoites.
Macrophages and Dendritic Cells Use the Cytosolic Pathway to Rapidly Cross-Present Antigen from Live, Vaccinia-Infected Cells
Authors: Ramirez Maria Carmen , Sigal Luis J. 
Published: April 2014

Abstract
Professional APCs (pAPC) can process and present on their own MHC class I molecules Ags acquired from Ag donor cells (ADC). This phenomenon of cross-presentation is essential in the induction of CD8+ T cell responses to viruses that do not infect pAPC and possibly contributes to the induction of CD8+ responses to many other viruses. However, little is known about the mechanisms underlying this process. In this study, we show that dendritic cells and macrophages cross-present a model Ag supplied by vaccinia virus-infected ADC via the cytosolic route. Strikingly, we also found that cross-presentation of Ags provided by vaccinia-infected cells occurs within a couple of hours of pAPC/ADC interaction, that the duration of cross-presentation lasts for only 16 h, and that cross-presentation can occur at early times of infection when the ADC are still alive.
Phospholipase Cγ2 Is Essential for Specific Functions of FcεR and FcγR
Authors: Wen Renren , Jou Shiann-Tarng , Chen Yuhong , Hoffmeyer Angelica , Wang Demin 
Published: April 2014

AbstractPhospholipase Cγ2 (PLCγ2) plays a critical role in the functions of the B cell receptor in B cells and of the FcRγ chain-containing collagen receptor in platelets. Here we report that PLCγ2 is also expressed in mast cells and monocytes/macrophages and is activated by cross-linking of FcεR and FcγR. Although PLCγ2-deficient mice have normal development and numbers of mast cells and monocytes/macrophages, we demonstrate that PLCγ2 is essential for specific functions of FcεR and FcγR. While PLCγ2-deficient mast cells have normal mitogen-activated protein kinase activation and cytokine production at mRNA levels, the mutant cells have impaired FcεR-mediated Ca2+ flux and inositol 1,4,5-trisphosphate production, degranulation, and cytokine secretion. As a physiological consequence of the effect of PLCγ2 deficiency, the mutant mice are resistant to IgE-mediated cutaneous inflammatory skin reaction. Macrophages from PLCγ2-deficient mice have no detectable FcγR-mediated Ca2+ flux; however, the mutant cells have normal FcγR-mediated phagocytosis. Moreover, PLCγ2 plays a nonredundant role in FcγR-mediated inflammatory skin reaction.