bluuebunny/crossref_metadata_2025_split huggingface dataset:
T-bet Deficiency Facilitates Airway Colonization byMycoplasma pulmonisin a Murine Model of Asthma
Authors: Bakshi Chandra Shekhar , Malik Meenakshi , Carrico Pauline M. , Sellati Timothy J. 
Published: April 2014

AbstractEpidemiological and clinical evidence suggest a correlation between asthma and infection with atypical bacterial respiratory pathogens. However, the cellular and molecular underpinnings of this correlation remain unclear. Using the T-bet-deficient (T-bet−/−) murine model of asthma and the natural murine pathogen Mycoplasma pulmonis, we provide a mechanistic explanation for this correlation. In this study, we demonstrate the capacity of asthmatic airways to facilitate colonization by M. pulmonis and the capacity of M. pulmonis to exacerbate symptoms associated with acute and chronic asthma. This mutual synergism results from an inability of T-bet−/− mice to mount an effective immune defense against respiratory infection through release of IFN-γ and the ability of M. pulmonis to trigger the production of Th2-type cytokines (e.g., IL-4 and IL-5), and Abs (e.g., IgG1, IgE, and IgA), eosinophilia, airway remodeling, and hyperresponsiveness; all pathophysiological hallmarks of asthma. The capacity of respiratory pathogens such as Mycoplasma spp. to dramatically augment the pathological changes associated with asthma likely explains their association with acute asthmatic episodes in juvenile patients and with adult chronic asthmatics, &gt;50% of whom are found to be PCR positive for M. pneumoniae. In conclusion, our study demonstrates that in mice genetically predisposed to asthma, M. pulmonis infection elicits an inflammatory milieu in the lungs that skews the immune response toward the Th2-type, thus exacerbating the pathophysiological changes associated with asthma. For its part, airways exhibiting an asthmatic phenotype provide a fertile environment that promotes colonization by Mycoplasma spp. and one which is ill-equipped to kill and clear respiratory pathogens.
Alveolar Epithelial Cells Direct Monocyte Transepithelial Migration upon Influenza Virus Infection: Impact of Chemokines and Adhesion Molecules
Authors: Herold Susanne , von Wulffen Werner , Steinmueller Mirko , Pleschka Stephan , Kuziel William A. , Mack Matthias , Srivastava Mrigank , Seeger Werner , Maus Ulrich A. , Lohmeyer Juergen 
Published: April 2014

AbstractInfluenza A virus pneumonia is characterized by severe lung injury and high mortality. Early infection elicits a strong recruitment of monocytes from the peripheral blood across the endo-/epithelial barrier into the alveolar air space. However, it is currently unclear which of the infected resident lung cell populations, alveolar epithelial cells or alveolar macrophages, elicit monocyte recruitment during influenza A virus infection. In the current study, we investigated whether influenza A virus infection of primary alveolar epithelial cells and resident alveolar macrophages would elicit a basal-to-apical monocyte transepithelial migration in vitro. We found that infection of alveolar epithelial cells with the mouse-adapted influenza A virus strain PR/8 strongly induced the release of monocyte chemoattractants CCL2 and CCL5 followed by a strong monocyte transepithelial migration, and this monocytic response was strictly dependent on monocyte CCR2 but not CCR5 chemokine receptor expression. Analysis of the adhesion molecule pathways demonstrated a role of ICAM-1, VCAM-1, integrin-associated protein (CD47), and junctional adhesion molecule-c on the epithelial cell surface interacting with monocyte β1 and β2 integrins and integrin-associated protein in the monocyte transmigration process. Importantly, addition of influenza A virus-infected alveolar macrophages further enhanced monocyte transmigration across virus-infected epithelium in a TNF-α-dependent manner. Collectively, the data show an active role for virus-infected alveolar epithelium in the regulation of CCL2/CCR2-dependent monocyte transepithelial migration during influenza infection that is essentially dependent on both classical β1 and β2 integrins but also junctional adhesion molecule pathways.
γδ T Cells Facilitate Adaptive Immunity against West Nile Virus Infection in Mice
Authors: Wang Tian , Gao Yunfei , Scully Eileen , Davis C. Todd , Anderson John F. , Welte Thomas , Ledizet Michel , Koski Raymond , Madri Joseph A. , Barrett Alan , Yin Zhinan , Craft Joseph , Fikrig Erol 
Published: April 2014

Abstract
West Nile (WN) virus causes fatal meningoencephalitis in laboratory mice, and γδ T cells are involved in the protective immune response against viral challenge. We have now examined whether γδ T cells contribute to the development of adaptive immune responses that help control WN virus infection. Approximately 15% of TCRδ−/− mice survived primary infection with WN virus compared with 80–85% of the wild-type mice. These mice were more susceptible to secondary challenge with WN virus than the wild-type mice that survived primary challenge with the virus. Depletion of γδ T cells in wild-type mice that survived the primary infection, however, does not affect host susceptibility during secondary challenge with WN virus. Furthermore, γδ T cells do not influence the development of Ab responses during primary and at the early stages of secondary infection with WN virus. Adoptive transfer of CD8+ T cells from wild-type mice that survived primary infection with WN virus to naive mice afforded partial protection from lethal infection. In contrast, transfer of CD8+ T cells from TCRδ−/− mice that survived primary challenge with WN virus failed to alter infection in naive mice. This difference in survival correlated with the numeric and functional reduction of CD8 memory T cells in these mice. These data demonstrate that γδ T cells directly link innate and adaptive immunity during WN virus infection.
Complement Activation via Alternative Pathway Is Critical in the Development of Laser-Induced Choroidal Neovascularization: Role of Factor B and Factor H
Authors: Bora Nalini S. , Kaliappan Sankaranarayanan , Jha Purushottam , Xu Qin , Sohn Jeong-Hyeon , Dhaulakhandi Dhara B. , Kaplan Henry J. , Bora Puran S. 
Published: April 2014

Abstract
The objective of this study was to explore the role of classical, lectin, and alternative pathways of complement activation in laser-induced choroidal neovascularization (CNV). The classical and alternative pathways were blocked in C57BL/6 mice by small interfering RNAs (siRNA) directed against C1q and factor B, respectively. C4−/− mice developed CNV similar to their wild-type controls and inhibition of C1q by siRNA had no effect on the development of CNV. In contrast, CNV was significantly inhibited (p &lt; 0.001) in C5−/− mice and C57BL/6 mice treated with factor B siRNA. Inhibition of the alternative pathway by factor B siRNA resulted in decreased levels of membrane attack complex and angiogenic factors–vascular endothelial growth factor and TGF-β2. Furthermore, factor B was up-regulated in complement sufficient C57BL/6 mice at day 1 postlaser and remained elevated at day 7. Significantly reduced levels of factor H were observed at day 3 in these animals. In conclusion, our results demonstrate that activation of the factor B-dependent alternative pathway, but not the classical or lectin pathways, was essential for the development of CNV in mouse model of laser-induced CNV. Thus, specific blockade of the alternative pathway may represent a therapeutically relevant strategy for the inhibition of CNV.
Membrane-Bound Prostaglandin E Synthase-1-Mediated Prostaglandin E2 Production by Osteoblast Plays a Critical Role in Lipopolysaccharide-Induced Bone Loss Associated with Inflammation
Authors: Inada Masaki , Matsumoto Chiho , Uematsu Satoshi , Akira Shizuo , Miyaura Chisato 
Published: April 2014

AbstractPGE2 acts as a potent stimulator of bone resorption in several disorders including osteoarthritis and periodontitis. Three PGE synthases (PGES) were isolated for PGE2 production, but which PGES has the major role in inflammatory bone resorption is still unclear. In this study, we examined the role of PGE2 in LPS-induced bone resorption using membrane-bound PGES (mPGES)-1-deficient mice (mPges1−/−). In osteoblasts from wild-type mice, PGE2 production was greatly stimulated by LPS following the expression of cyclooxygenase 2 and mPGES-1 mRNA, whereas no PGE2 production was found in osteoblasts from mPges1−/−. LPS administration reduced the bone volume in wild-type femur that was associated with an increased number of osteoclasts. In mPges1−/−, however, LPS-induced bone loss was reduced. We next examined whether mPGES-1 deficiency could alter the alveolar bone loss in LPS-induced experimental periodontitis. LPS was injected into the lower gingiva and bone mineral density of alveolar bone was measured. LPS induced the loss of alveolar bone in wild-type, but not in mPges1−/− mice, suggesting an mPGES-1 deficiency resistant to LPS-induced periodontal bone resorption. To understand the pathway of LPS-induced PGE2 production in osteoblast, we used C3H/HeJ mice with mutated tlr4. Osteoblasts from C3H/HeJ mice did not respond to LPS, and PGE2 production was not altered at all. LPS-induced bone loss in the femur was also impaired in C3H/HeJ mice. Thus, LPS binds to TLR4 on osteoblasts that directly induce mPGES-1 expression for PGE2 synthesis, leading to subsequent bone resorption. Therefore, mPGES-1 may provide a new target for the treatment of inflammatory bone disease.
Role of 5-Lipoxygenase in IL-13-Induced Pulmonary Inflammation and Remodeling
Authors: Shim Yun M. , Zhu Zhou , Zheng Tao , Lee Chun G. , Homer Robert J. , Ma Bing , Elias Jack A. 
Published: April 2014

AbstractExaggerated levels of IL-13 and leukotriene (LT) pathway activation frequently coexist at sites of Th2 inflammation and in tissue fibrotic responses. However, the relationship(s) between the IL-13 and LTs in these responses have not been defined. We hypothesized that the 5-lipoxygenase (5-LO) pathway of LT metabolism plays an important role in the pathogenesis of IL-13-induced chronic inflammation and remodeling. To test this hypothesis, we evaluated the effects of IL-13 on components of the 5-LO metabolic and activation pathways. We also compared the effects of transgenic IL-13 in C57BL/6 mice with wild-type and null 5-LO genetic loci. These studies demonstrate that IL-13 increases the levels of mRNA encoding cytosolic phospholipase A2, LTA4 hydrolase, and 5-LO-activating protein without altering the expression of 5-LO, LTC4 synthase, LTB4 receptors 1 and 2, and cysteinyl-LT receptors 1 and 2. They also demonstrate that this activation is associated with the enhanced accumulation of LTB4 but not of cysteinyl-LTs. Furthermore, they demonstrate that this stimulation plays a critical role in the pathogenesis of IL-13-induced inflammation, tissue fibrosis, and respiratory failure-induced death while inhibiting alveolar remodeling. Lastly, mechanistic insights are provided by demonstrating that IL-13-induced 5-LO activation is required for optimal stimulation and activation of TGF-β1 and the inhibition of matrix metalloproteinase-12. When viewed in combination, these studies demonstrate that 5-LO plays an important role in IL-13-induced inflammation and remodeling.
Hypoxia Modifies the Transcriptome of Primary Human Monocytes: Modulation of Novel Immune-Related Genes and Identification Of CC-Chemokine Ligand 20 as a New Hypoxia-Inducible Gene
Authors: Bosco Maria Carla , Puppo Maura , Santangelo Clara , Anfosso Luca , Pfeffer Ulrich , Fardin Paolo , Battaglia Florinda , Varesio Luigi 
Published: April 2014

AbstractPeripheral blood monocytes migrate to and accumulate in hypoxic areas of inflammatory and tumor lesions. To characterize the molecular bases underlying monocyte functions within a hypoxic microenvironment, we investigated the transcriptional profile induced by hypoxia in primary human monocytes using high-density oligonucleotide microarrays. Profound changes in the gene expression pattern were detected following 16 h exposure to 1% O2, with 536 and 677 sequences showing at least a 1.5-fold increase and decrease, respectively. Validation of this analysis was provided by quantitative RT-PCR confirmation of expression differences of selected genes. Among modulated genes, 74 were known hypoxia-responsive genes, whereas the majority were new genes whose responsiveness to hypoxia had not been previously described. The hypoxic transcriptome was characterized by the modulation of a significant cluster of genes with immunological relevance. These included scavenger receptors (CD163, STAB1, C1qR1, MSR1, MARCO, TLR7), immunoregulatory, costimulatory, and adhesion molecules (CD32, CD64, CD69, CD89, CMRF-35H, ITGB5, LAIR1, LIR9), chemokines/cytokines and receptors (CCL23, CCL15, CCL8, CCR1, CCR2, RDC1, IL-23A, IL-6ST). Furthermore, we provided conclusive evidence of hypoxic induction of CCL20, a chemoattractant for immature dendritic cells, activated/memory T lymphocytes, and naive B cells. CCL20 mRNA up-regulation was paralleled by increased protein expression and secretion. This study represents the first transcriptome analysis of hypoxic primary human monocytes, which provides novel insights into monocyte functional behavior within ischemic/hypoxic tissues. CCL20 up-regulation by hypoxia may constitute an important mechanism to promote recruitment of specific leukocyte subsets at pathological sites and may have implications for the pathogenesis of chronic inflammatory diseases.
Monocyte/Macrophage-Derived Microparticles Up-Regulate Inflammatory Mediator Synthesis by Human Airway Epithelial Cells
Authors: Cerri Chiara , Chimenti Daniele , Conti Ilaria , Neri Tommaso , Paggiaro Pierluigi , Celi Alessandro 
Published: April 2014

AbstractCell-derived microparticles (MP) are membrane fragments shed by virtually all eukaryotic cells upon activation or during apoptosis that play a significant role in physiologically relevant processes, including coagulation and inflammation. We investigated whether MP derived from monocytes/macrophages have the potential to modulate human airway epithelial cell activation. Monocytes/macrophages were isolated from the buffy coats of blood donors by Ficoll gradient centrifugation, followed by overnight culture of the mononuclear cell fraction. Adherent cells were washed and incubated with the calcium ionophore, A23187, or with histamine. The MP-containing supernatant was incubated with cells of the human bronchial epithelial line BEAS-2B and of the human alveolar line A549. IL-8, MCP-1, and ICAM-1 production was assessed by ELISA and by RT-PCR. In some experiments, monocytes/macrophages were stained with the fluorescent lipid intercalating dye PKH67, and the supernatant was analyzed by FACS. Stimulation of monocytes/macrophages with A23187 caused the release of particles that retain their fluorescent lipid intercalating label, indicating that they are derived from cell membranes. Incubation with A549 and BEAS-2B cells up-regulate IL-8 synthesis. Ultrafiltration and ultracentrifugation of the material abolished the effect, indicating that particulate matter, rather than soluble molecules, is responsible for it. Up-regulation of MCP-1 and ICAM-1 was also demonstrated in A549 cells. Similar results were obtained with histamine. Our data show that human monocytes/macrophages release MP that have the potential to sustain the innate immunity of the airway epithelium, as well as to contribute to the pathogenesis of inflammatory diseases of the lungs through up-regulation of proinflammatory mediators.
Induction of Cytotoxic Granules in Human Memory CD8+ T Cell Subsets Requires Cell Cycle Progression
Authors: Meng Yuru , Harlin Helena , O’Keefe James P. , Gajewski Thomas F. 
Published: April 2014

AbstractMemory CD8+ T cell responses are thought to be more effective as a result of both a higher frequency of Ag-specific clones and more rapid execution of effector functions such as granule-mediated lysis. Murine models have indicated that memory CD8+ T cells exhibit constitutive expression of perforin and can lyse targets directly ex vivo. However, the regulated expression of cytotoxic granules in human memory CD8+ T cell subsets has been underexplored. Using intracellular flow cytometry, we observed that only a minor fraction of CD45RA−CD8+ T cells, or of CD8+ T cells reactive to EBV-HLA2 tetramer, expressed intracellular granzyme B (GrB). Induction of GrB-containing cytotoxic granules in both CD45RA+ and CD45RA− cells was achieved by stimulation with anti-CD3/anti-CD28 mAb-coated beads, required at least 3 days, occurred after several rounds of cell division, and required cell cycle progression. The strongest GrB induction was seen in the CCR7+ subpopulations, with poorest proliferation being observed in the CD45RA−CCR7− effector-memory pool. Our results indicate that, as with naive T cells, induction of cytotoxic granules in human Ag-experienced CD8+ T cells requires time and cell division, arguing that the main numerical advantage of a memory T cell pool is a larger frequency of CTL precursors. The fact that granule induction can be achieved through TCR and CD28 ligation has implications for restoring lytic effector function in the context of antitumor immunity.
Translationally Controlled Tumor Protein from Madurella mycetomatis, a Marker for Tumorous Mycetoma Progression
Authors: van de Sande Wendy W. J. , Janse Dirk-Jan , Hira Vishal , Goedhart Heidy , van der Zee Ruurd , Ahmed Abdalla O. A. , Ott Alewijn , Verbrugh Henri , van Belkum Alex 
Published: April 2014

Abstract
About 40 years ago Abs against the fungus Madurella mycetomatis were first demonstrated to be present in eumycetoma patients, a disease characterized by tumorous swellings. To date nothing is known about the individual immunoreactive Ags present in this fungus. In the present study, we identify its first immunogenic Ag, a protein homologous to the translationally controlled tumor protein (TCTP), a well-conserved histamine release factor in a range of eukaryotes. The gene for this Ag was demonstrated to be present in two variants in M. mycetomatis, with 13% aa difference between the two proteins encoded. In vitro, TCTP was secreted into the culture medium. In vivo, it was found to be expressed on hyphae present in developing stages of the eumycetoma-characteristic black grain. Significant IgG and IgM immune responses, against the whole protein and selected M. mycetomatis-specific peptides, were determined. The Ab levels correlated with lesion size and disease duration. Overall, the patients with the largest lesions had the highest Ab level, which lowered with decreasing size of the lesion. After 6–15 years of disease duration the Ab levels were the highest. TCTP is the first well-characterized immunogenic Ag, simultaneously the first monomolecular vaccine candidate, identified for the fungus M. mycetomatis.
Complex T Cell Memory Repertoires Participate in Recall Responses at Extremes of Antigenic Load
Authors: Naumov Yuri N. , Naumova Elena N. , Clute Shalyn C. , Watkin Levi B. , Kota Kalyani , Gorski Jack , Selin Liisa K. 
Published: April 2014

AbstractThe CD8 T cell memory response to the HLA-A2-restricted influenza epitope M158–66 can be an instructive model of immune memory to a nonevolving epitope of a frequently encountered pathogen that undergoes clearance. This memory repertoire can be complex, composed of a large number of clonotypes represented at low copy numbers, while maintaining a focus on the use of VB17 T cell receptors with identified Ag recognition motifs. Such a repertoire structure might provide a panoply of clonotypes whose differential avidity for the epitope would allow responses under varying antigenic loads. This possibility was tested experimentally by characterizing the responding repertoire in vitro while varying influenza Ag concentration over five orders of magnitude. At higher and lower Ag concentrations there was increased cell death, yet a focused but diverse response could still be observed. Thus, one of the characteristics of complex memory repertoires is to provide effector function at extremes of Ag load, a characteristic that is not generally considered in vaccination development but may be important in measuring its efficacy.
Susceptibility to Eating Disorders Among Collegiate Female Student–Athletes
Authors: McLester Cherilyn N. , Hardin Robin , Hoppe Stephanie 
Published: April 2014

Context:
Research has suggested that the prevalence of young women with eating disorders (EDs) is increasing, but determining the exact prevalence of EDs within the female student–athlete (FS-A) population is difficult. Looking at certain traits may help us to identify their level of susceptibility to developing an ED.

Objective:
To determine the susceptibility of FS-As to EDs in relation to self-concept, including self-esteem and body image.

Design:
Cross-sectional study.

Setting:
Athletic training and health centers at National Collegiate Athletic Association Division I, II, and III institutions via e-mail questionnaire correspondence.

Patients or Other Participants:
A total of 439 FS-As from 17 participating institutions completed the questionnaires. The sample was primarily white (83.1%) and underclass (61.8%).

Main Outcome Measure(s):
The questionnaire consisted of 4 parts: 3 subscales of the Eating Disorder Inventory-2, the Rosenberg Self-Esteem Scale, the Body Cathexis Scale, and demographic items.

Results:
A total of 6.8% of FS-As were susceptible to anorexia and 1.8% were susceptible to bulimia. The majority of FS-As (61%) reported normal self-esteem levels, whereas 29.4% had high self-esteem. Overall, 64.5% were satisfied and 23% were very satisfied with their body image.

Conclusions:
These results are generally positive in that they suggest FS-As have high levels of self-concept and are at low risk to develop EDs. However, these findings do not mean that all concerns should be dismissed. Although more than 90% of the respondents were not susceptible to an ED, there are still FS-As who may be. Athletic departments should evaluate their FS-As' levels of self-concept so that their susceptibility to EDs can be addressed. The emotional aspect of health care should be included in providing holistic care for student–athletes. Athletic trainers often are the primary health care providers for FS-As, so they should be made aware of this concern.