bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coinfection with Nonlethal Murine Malaria Parasites Suppresses Pathogenesis Caused by Plasmodium berghei NK65
Authors: Niikura Mamoru , Kamiya Shigeru , Kita Kiyoshi , Kobayashi Fumie 
Published: April 2014

Abstract
Mixed infection with different Plasmodium species is often observed in endemic areas, and the infection with benign malaria parasites such as Plasmodium vivax or P. malariae has been considered to reduce the risk of developing severe pathogenesis caused by P. falciparum. However, it is still unknown how disease severity is reduced in hosts during coinfection. In the present study, we investigated the influence of coinfection with nonlethal parasites, P. berghei XAT (Pb XAT) or P. yoelii 17X (Py 17X), on the outcome of P. berghei NK65 (Pb NK65) lethal infection, which caused high levels of parasitemia and severe pathogenesis in mice. We found that the simultaneous infection with nonlethal Pb XAT or Py 17X suppressed high levels of parasitemia, liver injury, and body weight loss caused by Pb NK65 infection, induced high levels of reticulocytemia, and subsequently prolonged survival of mice. In coinfected mice, the immune response, including the expansion of B220intCD11c+ cells and CD4+ T cells and expression of IL-10 mRNA, was comparable to that in nonlethal infection. Moreover, the suppression of liver injury and body weight loss by coinfection was reduced in IL-10−/− mice, suggesting that IL-10 plays a role for a reduction of severity by coinfection with nonlethal malaria parasites.
Macrophage Proinflammatory Response to Francisella tularensis Live Vaccine Strain Requires Coordination of Multiple Signaling Pathways
Authors: Cole Leah E. , Santiago Araceli , Barry Eileen , Kang Tae Jin , Shirey Kari Ann , Roberts Zachary J. , Elkins Karen L. , Cross Alan S. , Vogel Stefanie N. 
Published: April 2014

Abstract
The macrophage proinflammatory response to Francisella tularensis (Ft) live vaccine strain (LVS) was shown previously to be TLR2 dependent. The observation that intracellular Ft LVS colocalizes with TLR2 and MyD88 inside macrophages suggested that Ft LVS might signal from within the phagosome. Macrophages infected with LVSΔiglC, a Ft LVS mutant that fails to escape from the phagosome, displayed greatly increased expression of a subset of TLR2-dependent, proinflammatory genes (e.g., Tnf) but decreased expression of others (e.g., Ifnb1). This latter subset was similarly mitigated in IFN-β−/− macrophages indicating that while Ft LVS-induced TLR2 signaling is necessary, cytosolic sensing of Ft to induce IFN-β is required for full induction of the macrophage proinflammatory response. Although LVSΔiglC greatly increased IL-1β mRNA in wild-type macrophages, protein secretion was not observed. IL-1β secretion was also diminished in Ft LVS-infected IFN-β−/− macrophages. rIFN-β failed to restore IL-1β secretion in LVSΔiglC-infected macrophages, suggesting that signals in addition to IFN-β are required for assembly of the inflammasome and activation of caspase-1. IFN-β plays a central role in controlling the macrophage bacterial burden: bacterial recovery was greater in IFN-β−/− than in wild-type macrophages and treatment of Ft LVS-infected macrophages with rIFN-β or 5,6-dimethylxanthenone-4-acetic acid, a potent IFN-β inducer, greatly decreased the intracellular Ft LVS burden. In toto, these observations support the hypothesis that the host inflammatory response to Ft LVS is complex and requires engagement of multiple signaling pathways downstream of TLR2 including production of IFN-β via an unknown cytosolic sensor and activation of the inflammasome.
Dual Role of NOX2 in Respiratory Syncytial Virus- and Sendai Virus-Induced Activation of NF-κB in Airway Epithelial Cells
Authors: Fink Karin , Duval Annick , Martel Alexis , Soucy-Faulkner Anton , Grandvaux Nathalie 
Published: April 2014

Abstract
Human respiratory syncytial virus (RSV), a member of the Paramyxoviridae family, is the most important viral agent of pediatric respiratory tract disease worldwide. Human airway epithelial cells (AEC) are the primary targets of RSV. AEC are responsible for the secretion of a wide spectrum of cytokines and chemokines that are important mediators of the exacerbated airway inflammation triggered by the host in response to RSV infection. NF-κB is a key transcription factor responsible for the regulation of cytokine and chemokine gene expression and thus represents a potential therapeutic target. In the present study, we sought to delineate the role of RSV-induced reactive oxygen species in the regulation of the signaling pathways leading to NF-κB activation. First, we demonstrate that besides the well-characterized IκBα-dependent pathway, phosphorylation of p65 at Ser536 is an essential event regulating NF-κB activation in response to RSV in A549. Using antioxidant and RNA-interference strategies, we show that a NADPH oxidase 2 (NOX2)-containing NADPH oxidase is an essential regulator of RSV-induced NF-κB activation. Molecular analyses revealed that NOX2 acts upstream of both the phosphorylation of IκBα at Ser32 and of p65 at Ser536 in A549 and normal human bronchial epithelial cells. Similar results were obtained in the context of infection by Sendai virus, thus demonstrating that the newly identified NOX2-dependent NF-κB activation pathway is not restricted to RSV among the Paramyxoviridae. These results illustrate a previously unrecognized dual role of NOX2 in the regulation of NF-κB in response to RSV and Sendai virus in human AEC.
Toll-Like Receptor-4 Modulates Survival by Induction of Left Ventricular Remodeling after Myocardial Infarction in Mice
Authors: Riad Alexander , Jäger Sebastian , Sobirey Meike , Escher Felicitas , Yaulema-Riss Aymaru , Westermann Dirk , Karatas Aysun , Heimesaat Markus M. , Bereswill Stefan , Dragun Duska , Pauschinger Matthias , Schultheiss Heinz P. , Tschöpe Carsten 
Published: April 2014

Abstract
Left ventricular (LV) remodeling is known to contribute to morbidity and mortality after myocardial infarction (MI). Because LV remodeling is strongly associated with an inflammatory response, we investigated whether or not TLR-4 influences LV remodeling and survival in a mice model of MI. Six days after MI induction, TLR4 knockout (KO)-MI mice showed improved LV function 32 and reduced LV remodeling as indexed by reduced levels of atrial natriuretic factor and total collagen as well as by a reduced heart weight to body weight ratio when compared with WT-MI mice. This was associated with a reduction of protein levels of the intracellular TLR4 adapter protein MyD88 and enhanced protein expression of the anti-hypertrophic JNK in KO-MI mice when compared with wild-type (WT)-MI mice. In contrast, protein activation of the pro-hypertrophic kinases protein kinase Cδ and p42/44 were not regulated in KO-MI mice when compared with WT-MI mice. Improved LV function, reduced cardiac remodeling, and suppressed intracellular TLR4 signaling in KO-MI mice were associated with significantly improved survival compared with WT-MI mice (62 vs 23%; p &lt; 0.0001). TLR4 deficiency led to improved survival after MI mediated by attenuated left ventricular remodeling.
Properdin Deficiency in Murine Models of Nonseptic Shock
Authors: Ivanovska Nina D. , Dimitrova Petya A. , Luckett Jeni C. , El-Rachkidy Lonnen Rana , Schwaeble Wilhelm J. , Stover Cordula M. 
Published: April 2014

AbstractHereditary properdin deficiency is linked to susceptibility to meningococcal disease (Neisseria meningitidis serotypes Y and W-135) with high mortality. Its relative contribution toward the outcome of nonseptic shock has not been investigated. Using properdin-deficient C57BL/6 mice and their littermates, this study examines their survival of zymosan-induced and LPS-induced shock. Properdin-deficient mice were more resistant to zymosan shock compared with wild-type mice, which showed greater impairment of end-organ function 24 h after zymosan injection, higher TNF-α production by alveolar and peritoneal macrophages, higher TNF-α, and, inversely, lower IL-10 levels in peritoneal lavage and circulation and higher plasma C5a levels. Properdin-deficient mice showed significantly higher mortality in LPS shock, elevated TNF-α, and, inversely, reduced IL-10 production by peritoneal macrophages as well as lower plasma C5a levels compared with wild-type littermates. NO production by peritoneal macrophages and plasma α1-antitrypsin levels at 24 h after the injection of LPS or zymosan were decreased in properdin-deficient mice in both models, and fewer histopathologic changes in liver were observed in properdin-deficient animals. This study provides evidence that properdin deficiency attenuates zymosan-induced shock and exacerbates LPS-induced shock.
Development of Inflammatory Bowel Disease in Long-Evans Cinnamon Rats Based on CD4+CD25+Foxp3+ Regulatory T Cell Dysfunction
Authors: Ishimaru Naozumi , Yamada Akiko , Kohashi Masayuki , Arakaki Rieko , Takahashi Tetsuyuki , Izumi Keisuke , Hayashi Yoshio 
Published: April 2014

Abstract
A mutant strain with defective thymic selection of the Long-Evans Cinnamon (LEC) rat was found to spontaneously develop inflammatory bowel disease (IBD)-like colitis. The secretion of Th1-type cytokines including IFN-γ and IL-2 from T cells of mesenteric lymph node cells (MLNs) and lamina propria mononuclear cells, but not spleen cells, in LEC rats was significantly increased more than that of the control Long-Evans Agouti rats through up-regulated expression of T-bet and phosphorylation of STAT-1 leading to NF-κB activation. In addition, the number of CD4+CD25+Foxp3+ regulatory T (Treg) cells of the thymus, MLNs, and lamina propria mononuclear cells from LEC rats was significantly reduced, comparing with that of the control rats. Moreover, bone marrow cell transfer from LEC rats into irradiated control rats revealed significantly reduced CD25+Foxp3+ Treg cells in thymus, spleen, and MLNs compared with those from control rats. Indeed, adoptive transfer with T cells of MLNs, not spleen cells, from LEC rats into SCID mice resulted in the development of inflammatory lesions resembling the IBD-like lesions observed in LEC rats. These results indicate that the dysfunction of the regulatory system controlled by Treg cells may play a crucial role in the development of IBD-like lesions through up-regulated T-bet, STAT-1, and NF-κB activation of peripheral T cells in LEC rats.
Cutting Edge: K63-Linked Polyubiquitination of NEMO Modulates TLR Signaling and Inflammation In Vivo
Authors: Ni Chang-Yuan , Wu Zhao-Hui , Florence William C. , Parekh Vrajesh V. , Arrate Maria Pia , Pierce Steven , Schweitzer Brock , Van Kaer Luc , Joyce Sebastian , Miyamoto Shigeki , Ballard Dean W. , Oltz Eugene M. 
Published: April 2014

Abstract
Transcription factor NF-κB controls the expression of multiple genes involved in immunity and inflammation. The initial activation and duration of NF-κB signaling is regulated by posttranslational modifications to IκB kinase, which earmarks inhibitors of NF-κB for degradation. Prior studies suggest that K63-linked ubiquitination of NEMO (NF-κB essential modulator), an IκB kinase regulatory subunit, is critical for NF-κB and MAPK signaling following engagement of Ag receptors. We now demonstrate that NF-κB and MAPK pathways are largely unaffected in primary cells from mice harboring a ubiquitination-defective form of NEMO, NEMO-KR. TLR- but not Ag receptor-induced cellular responses are impaired in NEMO-KR mice, which are more resistant to LPS-induced endotoxic shock than wild-type animals. Thus, one function of NEMO ubiquitination is to fine tune innate immune responses under TLR control.
Differential Regulation of Antigen-Specific CD8+ T Cell Responses by IL-12p40 in a Dose-Dependent Manner
Authors: Kim Doo-Jin , Youn Je-In , Seo Sang-Hwan , Jin Hyun-Tak , Sung Young-Chul 
Published: April 2014

Abstract
IL-12p40 is a natural antagonist which inhibits IL-12- and IL-23-mediated biological activity by blocking the binding of IL-12/23 to their receptors. Recently, IL-12p40 was also shown to have immune-enhancing activity through the activation of macrophages or dendritic cells. In this study, we investigated the effects of IL-12p40 as a genetic adjuvant on immune modulation using recombinant adenoviruses expressing IL-12p40 (rAd/IL-12p40) and OVA (rAd/OVA). Coimmunization of rAd/IL-12p40 at a low dose (1 × 104 PFU) with rAd/OVA resulted in OVA-specific immune enhancement, while a high dose of rAd/IL-12p40 (1 × 108 PFU) caused significant suppression of CD8+ T cell responses. In addition, the enhancement and suppression of OVA-specific CD8+ T cell responses correlated with antitumor activity against E.G7-OVA tumor challenge, which subsequently affected the survival rate. Moreover, the differential CD8+ T cell response by IL-12p40 was still observed in IL-12Rβ2 knockout (IL-12Rβ2KO), but not in IL-12Rβ1 knockout (IL-12Rβ1KO) mice, indicating that IL-12p40 is a cytokine which can modulate Ag-specific T cell responses depending on IL-12Rβ1. Our findings provide a novel insight on the physiological role of IL-12p40, which can be informative in the design of vaccine strategies and therapeutic regimens.
A Critical Precursor Frequency of Donor-Reactive CD4+ T Cell Help Is Required for CD8+ T Cell-Mediated CD28/CD154-Independent Rejection
Authors: Ford Mandy L. , Wagener Maylene E. , Hanna Samantha S. , Pearson Thomas C. , Kirk Allan D. , Larsen Christian P. 
Published: April 2014

Abstract
Ag-specific precursor frequency is increasingly being appreciated as an important factor in determining the kinetics, magnitude, and degree of differentiation of T cell responses, and recently was found to play a critical role in determining the relative requirement of CD8+ T cells for CD28- and CD154-mediated costimulatory signals during transplantation. We addressed the possibility that variations in CD4+ T cell precursor frequency following transplantation might affect CD4+ T cell proliferation, effector function, and provision of help for donor-reactive B cell and CD8+ T cell responses. Using a transgenic model system wherein increasing frequencies of donor-reactive CD4+ T cells were transferred into skin graft recipients, we observed that a critical CD4+ T cell threshold precursor frequency was necessary to provide help following blockade of the CD28 and CD154 costimulatory pathways, as measured by increased B cell and CD8+ T cell responses and precipitation of graft rejection. In contrast to high-frequency CD8+ T cell responses, this effect was observed even though the proliferative and cytokine responses of Ag-specific CD4+ T cells were inhibited. Thus, we conclude that an initial high frequency of donor-reactive CD4+ T cells uncouples T cell proliferative and effector cytokine production from the provision of T cell help.
Kinetics of In Vivo Proliferation and Death of Memory and Naive CD8 T Cells: Parameter Estimation Based on 5-Bromo-2′-Deoxyuridine Incorporation in Spleen, Lymph Nodes, and Bone Marrow
Authors: Parretta Elisabetta , Cassese Giuliana , Santoni Angela , Guardiola John , Vecchio Antonia , Di Rosa Francesca 
Published: April 2014

Abstract
To study naive and memory CD8 T cell turnover, we performed BrdU incorporation experiments in adult thymectomized C57BL/6 mice and analyzed data in a mathematical framework. The following aspects were novel: 1) we examined the bone marrow, in addition to spleen and lymph nodes, and took into account the sum of cells contained in the three organs; 2) to describe both BrdU-labeling and -delabeling phase, we designed a general mathematical model, in which cell populations were distinguished based on the number of divisions; 3) to find parameters, we used the experimentally determined numbers of total and BrdU+ cells and the BrdU-labeling coefficient. We treated mice with BrdU continuously via drinking water for up to 42 days, measured by flow cytometry BrdU incorporation at different times, and calculated the numbers of BrdU+ naive (CD44int/low) and memory (CD44high) CD8 T cells. By fitting the model to data, we determined proliferation and death rates of both subsets. Rates were confirmed using independent sets of data, including the numbers of BrdU+ cells at different times after BrdU withdrawal. We found that both doubling time and half-life of the memory population were ∼9 wk, whereas for the naive subset the doubling time was almost 1 year and the half-life was roughly 7 wk. Our findings suggest that the higher turnover of memory CD8 T cells as compared with naive CD8 T cells is mostly attributable to a higher proliferation rate. Our results have implications for interpreting physiological and abnormal T cell kinetics in humans.
Induction of Anergy by Antibody Blockade of TCR in Myelin Oligodendrocyte Glycoprotein-Specific Cells
Authors: Wasserman Heather A. , Evavold Brian D. 
Published: April 2014

Abstract
Previous studies have found that a 95% reduction in TCR expression does not adversely affect response to foreign Ags, indicating that T cells have an excess of TCR for Ag recognition. Because self-reactive T cells may have low affinity for peptide:MHC, we investigated whether myelin-reactive T cells require these excess TCR for optimal response. To test this concept, mAb were used to effectively reduce the TCR of Vα3.2 and Vβ11 TCR transgenic mice (referred to as 2D2). After masking the TCR with either continuous or prepulsed anti-Vα3.2 Ab, 2D2 cells were immediately stimulated with myelin oligodendrocyte glycoprotein (MOG)35–55. These cells have a dramatic Ab dose-dependent reduction in proliferation, with a small reduction in TCR expression leading to a 50% reduction in proliferation in vitro. Additionally, 2D2 cells, treated with anti-Vα3.2 Ab and peptide for 7 days, were re-stimulated with MOG and continue to have a dose-dependent reduction in proliferation. TCR quantitation identified the same amount of TCR on the Ab/peptide treatment compared with the peptide-only control. These results point out that the combination of reduced TCR and peptide challenge leads to a phenotypic change resulting in T cell anergy. Importantly, adoptive transfer of these anergic T cells upon autoimmune disease induction had a marked reduction in disease severity compared with untreated MOG-specific CD4+ T cells, which had significant autoimmune disease manifested by optic neuritis and death. Thus, reduction of TCR expression may provide a potential therapy for self-reactive T cells involved in autoimmune diseases through the induction of anergy.
CD43 Regulates Th2 Differentiation and Inflammation
Authors: Cannon Judy L. , Collins Amélie , Mody Purvi D. , Balachandran Diwaker , Henriksen Kammi J. , Smith Cassandra E. , Tong Jiankun , Clay Bryan S. , Miller Stephen D. , Sperling Anne I. 
Published: April 2014

Abstract
CD43 is a highly glycosylated transmembrane protein that regulates T cell activation. CD43−/− T cells are hyperproliferative and the cytoplasmic tail of CD43 has been found to be sufficient to reconstitute wild-type proliferation levels, suggesting an intracellular mechanism. In this study, we report that upon TCR ligation CD43−/− T cells demonstrated no increase in tyrosine phosphorylation but a decreased calcium flux. Interestingly, CD43−/− T cells preferentially differentiated into Th2 cells in vitro, and CD43−/− T cells show increased GATA-3 translocation into the nucleus. In vivo, CD43−/− mice exhibited increased inflammation in two separate models of Th2-mediated allergic airway disease. In contrast, in Th1-mediated diabetes, nonobese diabetic CD43−/− mice did not significantly differ from wild-type mice in disease onset or progression. Th1-induced experimental autoimmune encephalomyelitis to MOG35–55 was also normal in the CD43−/− mice. Nonetheless, the CD43−/− mice produced more IL-5 when restimulated with MOG35–55 in vitro and demonstrated decreased delayed-type hypersensitivity responses. Together, these data demonstrate that although CD43−/− T cells preferentially differentiate into Th2 cells, this response is not sufficient to protect against Th1-mediated autoimmune responses.
B Lymphocyte Stimulator Regulates Adaptive Immune Responses by Directly Promoting Dendritic Cell Maturation
Authors: Chang Sook Kyung , Mihalcik Stephen A. , Jelinek Diane F. 
Published: April 2014

Abstract
B lymphocyte stimulator (BLyS) is a well-known direct costimulator of adaptive immune cells, particularly B lineage cells. However, we have reported recently that BLyS is also able to activate monocytes. Other innate immune cells, such as dendritic cells (DCs), play a key role in the initiation of adaptive immune responses and the purpose of the current study was to assess whether there is a direct role for BLyS in modulating human DC functions. In this study, we show that BLyS induces DC activation and maturation. Thus, BLyS strongly induced up-regulation of surface costimulatory molecule expression and secretion of specific cytokines and chemokines in DCs. BLyS-stimulated DCs (BLyS-DCs) were also able to augment allogeneic CD4 T cell proliferation to a greater extent than control DCs. BLyS-DCs secreted elevated levels of the major Th1-polarizing cytokine, IL-12p70, and they promoted naive CD4 T cell differentiation into Th1 T cells. Regarding BLyS receptor expression, DCs primarily express cytoplasmic transmembrane activator and CAML interactor; however, low levels of cell surface transmembrane activator and CAML interactor are expressed as well. Collectively, our data suggest that BLyS may modulate adaptive immune cells indirectly by inducing DC maturation.
Both Th1 and Th17 Are Immunopathogenic but Differ in Other Key Biological Activities
Authors: Cox Catherine A. , Shi Guangpu , Yin Hongen , Vistica Barbara P. , Wawrousek Eric F. , Chan Chi-Chao , Gery Igal 
Published: April 2014

Abstract
The role of Th17 lymphocytes in immunopathogenic processes has been well established, but little is known about their basic cell features. In this study, we compared polarized Th1 and Th17 for key biological activities related to pathogenicity and trafficking. Th1 and Th17 lineages were derived from TCR-transgenic CD4 murine cells specific against hen egg lysozyme. When adoptively transferred into mice expressing hen egg lysozyme in their eyes, both Th1 and Th17 induced ocular inflammation but with slight differences in histological pathology. PCR analysis revealed selective expression of IFN-γ or IL-17 in eyes of Th1 or Th17 recipients, respectively. Additionally, Th1 and Th17 were found to differ in three other key activities: 1) Th17 cells were inferior to Th1 cells in their capacity to trigger massive lymphoid expansion and splenomegaly; 2) the proportion of Th1 cells among infiltrating cells in inflamed recipient eyes declined rapidly, becoming a minority by day 7, whereas Th17 cells remained in the majority throughout this period; and 3) remarkable differences were noted between Th1 and Th17 cells in their expression of certain surface markers. In particular, reactivated Th1 expressed higher levels of CD49d and α4β7 (mucosal homing) in vitro and higher levels of CXCR3 (Th1 trafficking) in vivo. Reactivated Th17, however, expressed higher levels of αEβ7 (epithelial tissue homing) and CD38 (activation, maturation and trafficking) in vitro, but in vivo Th17 expressed higher levels of α4β7 and CCR6 (lymphocyte trafficking). These data reveal that Th1 and Th17 cells differ in several key biological activities influencing migration and pathogenic behavior during inflammatory disease.