bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vaccination-Induced Systemic Autoimmunity in Farmed Atlantic Salmon
Authors: Koppang Erling O. , Bjerkås Inge , Haugarvoll Erlend , Chan Edward K. L. , Szabo Nancy J. , Ono Nobutaka , Akikusa Bunshiro , Jirillo Emilio , Poppe Trygve T. , Sveier Harald , Tørud Brit , Satoh Minoru 
Published: April 2014

Abstract
Over half of the salmon consumed globally are farm-raised. The introduction of oil-adjuvanted vaccines into salmon aquaculture made large-scale production feasible by preventing infections. The vaccines that are given i.p. contain oil adjuvant such as mineral oil. However, in rodents, a single i.p. injection of adjuvant hydrocarbon oil induces lupus-like systemic autoimmune syndrome, characterized by autoantibodies, immune complex glomerulonephritis, and arthritis. In the present study, whether the farmed salmon that received oil-adjuvanted vaccine have autoimmune syndrome similar to adjuvant oil-injected rodents was examined. Sera and tissues were collected from vaccinated or unvaccinated Atlantic salmon (experimental, seven farms) and wild salmon. Autoantibodies (immunofluorescence, ELISA, and immunoprecipitation) and IgM levels (ELISA) in sera were measured. Kidneys and livers were examined for pathology. Autoantibodies were common in vaccinated fish vs unvaccinated controls and they reacted with salmon cells/Ags in addition to their reactivity with mammalian Ags. Diffuse nuclear/cytoplasmic staining was common in immunofluorescence but some had more specific patterns. Serum total IgM levels were also increased in vaccinated fish; however, the fold increase of autoantibodies was much more than that of total IgM. Sera from vaccinated fish immunoprecipitated ferritin and ∼50% also reacted with other unique proteins. Thrombosis and granulomatous inflammation in liver, and immune-complex glomerulonephritis were common in vaccinated fish. Autoimmunity similar to the mouse model of adjuvant oil-induced lupus is common in vaccinated farmed Atlantic salmon. This may have a significant impact on production loss, disease of previously unknown etiology, and future strategies of vaccines and salmon farming.
Protein Kinase Cθ Regulates Stability of the Peripheral Adhesion Ring Junction and Contributes to the Sensitivity of Target Cell Lysis by CTL
Authors: Beal Allison M. , Anikeeva Nadia , Varma Rajat , Cameron Thomas O. , Norris Philip J. , Dustin Michael L. , Sykulev Yuri 
Published: April 2014

Abstract
Destruction of virus-infected cells by CTL is an extremely sensitive and efficient process. Our previous data suggest that LFA-1-ICAM-1 interactions in the peripheral supramolecular activation cluster (pSMAC) of the immunological synapse mediate formation of a tight adhesion junction that might contribute to the sensitivity of target cell lysis by CTL. Herein, we compared more (CD8+) and less (CD4+) effective CTL to understand the molecular events that promote efficient target cell lysis. We found that abrogation of the pSMAC formation significantly impaired the ability of CD8+ but not CD4+ CTL to lyse target cells despite having no effect of the amount of released granules by both CD8+ and CD4+ CTL. Consistent with this, CD4+ CTL break their synapses more often than do CD8+ CTL, which leads to the escape of the cytolytic molecules from the interface. CD4+ CTL treatment with a protein kinase Cθ inhibitor increases synapse stability and sensitivity of specific target cell lysis. Thus, formation of a stable pSMAC, which is partially controlled by protein kinase Cθ, functions to confine the released lytic molecules at the synaptic interface and to enhance the effectiveness of target cell lysis.
Neutrophil Elastase Mediates Innate Host Protection against Pseudomonas aeruginosa
Authors: Hirche Tim O. , Benabid Rym , Deslee Gaetan , Gangloff Sophie , Achilefu Samuel , Guenounou Moncef , Lebargy François , Hancock Robert E. , Belaaouaj Azzaq 
Published: April 2014

Abstract
According to the widely accepted view, neutrophil elastase (NE), a neutrophil-specific serine protease, is a major contributor to Pseudomonas aeruginosa infection-associated host tissue inflammation and damage, which in severe cases can lead to death. Herein, we provide for the first time compelling evidence that the host rather employs NE to protect itself against P. aeruginosa infection. Using a clinically relevant model of pneumonia, targeted deficiency in NE increased the susceptibility of mice to P. aeruginosa. We found that NE was required for maximal intracellular killing of P. aeruginosa by neutrophils. In investigating the mechanism of NE-mediated killing of P. aeruginosa, we found that NE degraded the major outer membrane protein F, a protein with important functions, including porin activity, maintenance of structural integrity, and sensing of host immune system activation. Consistent with this, the use of an isogenic mutant deficient in outer membrane protein F negated the role of NE in host defense against P. aeruginosa infection.
Multifunctional, High-Level Cytokine-Producing Th1 Cells in the Lung, but Not Spleen, Correlate with Protection against Mycobacterium tuberculosis Aerosol Challenge in Mice
Authors: Forbes Emily K. , Sander Clare , Ronan Edward O. , McShane Helen , Hill Adrian V. S. , Beverley Peter C. L. , Tchilian Elma Z. 
Published: April 2014

Abstract
Boosting bacillus Calmette-Guérin (BCG)-primed mice with a recombinant adenovirus expressing Mycobacterium tuberculosis Ag 85A by different administration routes has very different effects on protection against aerosol challenge with M. tuberculosis. Mice boosted intradermally make very strong splenic CD4 and CD8 Th1 cytokine responses to Ag 85A, but show no change in lung mycobacterial burden over BCG primed animals. In contrast, intranasally boosted mice show greatly reduced mycobacterial burden and make a much weaker splenic response but a very strong lung CD4 and CD8 response to Ag 85A and an increased response to purified protein derivative. This effect is associated with the presence in the lung of multifunctional T cells, with high median fluorescence intensity and integrated median fluorescence intensity for IFN-γ, IL-2, and TNF. In contrast, mice immunized with BCG alone have few Ag-specific cells in the lung and a low proportion of multifunctional cells, although individual cells have high median fluorescence intensity. Successful immunization regimes appear to induce Ag-specific cells with abundant intracellular cytokine staining.
IL-17 Is a Critical Component of Vaccine-Induced Protection against Lung Infection by Lipopolysaccharide-Heterologous Strains of Pseudomonas aeruginosa
Authors: Priebe Gregory P. , Walsh Rebecca L. , Cederroth Terra A. , Kamei Akinobu , Coutinho-Sledge Yamara S. , Goldberg Joanna B. , Pier Gerald B. 
Published: April 2014

Abstract
In a murine model of acute fatal pneumonia, we previously showed that nasal immunization with a live-attenuated aroA deletant of Pseudomonas aeruginosa strain PAO1 elicited LPS serogroup-specific protection, indicating that opsonic Ab to the LPS O Ag was the most important immune effector. Because P. aeruginosa strain PA14 possesses additional virulence factors, we hypothesized that a live-attenuated vaccine based on PA14 might elicit a broader array of immune effectors. Thus, an aroA deletant of PA14, denoted PA14ΔaroA, was constructed. PA14ΔaroA-immunized mice were protected against lethal pneumonia caused not only by the parental strain but also by cytotoxic variants of the O Ag-heterologous P. aeruginosa strains PAO1 and PAO6a,d. Remarkably, serum from PA14ΔaroA-immunized mice had very low levels of opsonic activity against strain PAO1 and could not passively transfer protection, suggesting that an antibody-independent mechanism was needed for the observed cross-serogroup protection. Compared with control mice, PA14ΔaroA-immunized mice had more rapid recruitment of neutrophils to the airways early after challenge. T cells isolated from P. aeruginosa ΔaroA-immunized mice proliferated and produced IL-17 in high quantities after coculture with gentamicin-killed P. aeruginosa. Six hours following challenge, PA14ΔaroA-immunized mice had significantly higher levels of IL-17 in bronchoalveolar lavage fluid compared with unimmunized, Escherichia coli-immunized, or PAO1ΔaroA-immunized mice. Antibody-mediated depletion of IL-17 before challenge or absence of the IL-17 receptor abrogated the PA14ΔaroA vaccine’s protection against lethal pneumonia. These data show that IL-17 plays a critical role in antibody-independent vaccine-induced protection against LPS-heterologous strains of P. aeruginosa in the lung.
Mast Cells Promote Airway Smooth Muscle Cell Differentiation via Autocrine Up-Regulation of TGF-β1
Authors: Woodman Lucy , Siddiqui Salman , Cruse Glenn , Sutcliffe Amanda , Saunders Ruth , Kaur Davinder , Bradding Peter , Brightling Christopher 
Published: April 2014

Abstract
Asthma is a major cause of morbidity and mortality worldwide. It is characterized by airway dysfunction and inflammation. A key determinant of the asthma phenotype is infiltration of airway smooth muscle bundles by activated mast cells. We hypothesized that interactions between these cells promotes airway smooth muscle differentiation into a more contractile phenotype. In vitro coculture of human airway smooth muscle cells with β-tryptase, or mast cells with or without IgE/anti-IgE activation, increased airway smooth muscle-derived TGF-β1 secretion, α-smooth muscle actin expression and agonist-provoked contraction. This promotion to a more contractile phenotype was inhibited by both the serine protease inhibitor leupeptin and TGF-β1 neutralization, suggesting that the observed airway smooth muscle differentiation was driven by the autocrine release of TGF-β1 in response to activation by mast cell β-tryptase. Importantly, in vivo we found that in bronchial mucosal biopsies from asthmatics the intensity of α-smooth muscle actin expression was strongly related to the number of mast cells within or adjacent to an airway smooth muscle bundle. These findings suggest that mast cell localization in the airway smooth muscle bundle promotes airway smooth muscle cell differentiation into a more contractile phenotype, thus contributing to the disordered airway physiology that characterizes asthma.
Evolution of the Inflammatory Response in Vertebrates: Fish TNF-α Is a Powerful Activator of Endothelial Cells but Hardly Activates Phagocytes
Authors: Roca Francisco J. , Mulero Iván , López-Muñoz Azucena , Sepulcre Maria P. , Renshaw Stephen A. , Meseguer José , Mulero Victoriano 
Published: April 2014

Abstract
TNF-α is conserved in all vertebrate classes and has been identified in all taxonomic groups of teleost fish. However, its biological activities and its role in infection are largely unknown. Using two complementary fish models, gilthead seabream and zebrafish, we report here that the main proinflammatory effects of fish TNF-α are mediated through the activation of endothelial cells. Thus, TNF-α promotes the expression of E-selectin and different CC and CXC chemokines in endothelial cells, thus explaining the recruitment and activation of phagocytes observed in vivo in both species. We also found that TLR ligands, and to some extent TNF-α, were able to increase the expression of MHC class II and CD83 in endothelial cells, which might suggest a role for fish endothelial cells and TNF-α in Ag presentation. Lastly, we found that TNF-α increases the susceptibility of the zebrafish to viral (spring viremia of carp virus) and bacterial (Streptococcus iniae) infections. Although the powerful actions of fish TNF-α on endothelial cells suggest that it might facilitate pathogen dissemination, it was found that TNF-α increased antiviral genes and, more importantly, had little effect on the viral load in early infection. In addition, the stimulation of ZF4 cells with TNF-α resulted in increased viral replication. Together, these results indicate that fish TNF-α displays different sorts of bioactivity to their mammalian counterparts and point to the complexity of the evolution that has taken place in the regulation of innate immunity by cytokines.
Prostaglandin E2 Exerts Catabolic Effects in Osteoarthritis Cartilage: Evidence for Signaling via the EP4 Receptor
Authors: Attur Mukundan , Al-Mussawir Hayf E. , Patel Jyoti , Kitay Alison , Dave Mandar , Palmer Glyn , Pillinger Michael H. , Abramson Steven B. 
Published: April 2014

Abstract
Elevated levels of PGE2 have been reported in synovial fluid and cartilage from patients with osteoarthritis (OA). However, the functions of PGE2 in cartilage metabolism have not previously been studied in detail. To do so, we cultured cartilage explants, obtained from patients undergoing knee replacement surgery for advanced OA, with PGE2 (0.1–10 μM). PGE2 inhibited proteoglycan synthesis in a dose-dependent manner (maximum 25% inhibition (p &lt; 0.01)). PGE2 also induced collagen degradation, in a manner inhibitable by the matrix metalloproteinase (MMP) inhibitor ilomastat. PGE2 inhibited spontaneous MMP-1, but augmented MMP-13 secretion by OA cartilage explant cultures. PCR analysis of OA chondrocytes treated with PGE2 with or without IL-1 revealed that IL-1-induced MMP-13 expression was augmented by PGE2 and significantly inhibited by the cycolooygenase 2 selective inhibitor celecoxib. Conversely, MMP-1 expression was inhibited by PGE2, while celecoxib enhanced both spontaneous and IL-1-induced expression. IL-1 induction of aggrecanase 5 (ADAMTS-5), but not ADAMTS-4, was also enhanced by PGE2 (10 μM) and reversed by celecoxib (2 μM). Quantitative PCR screening of nondiseased and end-stage human knee OA articular cartilage specimens revealed that the PGE2 receptor EP4 was up-regulated in OA cartilage. Moreover, blocking the EP4 receptor (EP4 antagonist, AH23848) mimicked celecoxib by inhibiting MMP-13, ADAMST-5 expression, and proteoglycan degradation. These results suggest that PGE2 inhibits proteoglycan synthesis and stimulates matrix degradation in OA chondrocytes via the EP4 receptor. Targeting EP4, rather than cyclooxygenase 2, could represent a future strategy for OA disease modification.
YKL-40 Is Elevated in Patients with Chronic Obstructive Pulmonary Disease and Activates Alveolar Macrophages
Authors: Létuvé Séverine , Kozhich Alexander , Arouche Nassim , Grandsaigne Martine , Reed Jennifer , Dombret Marie-Christine , Kiener Peter A. , Aubier Michel , Coyle Anthony J. , Pretolani Marina 
Published: April 2014

Abstract
YKL-40 is a chitin-binding protein that is elevated in patients with various inflammatory conditions associated with ongoing remodeling. We investigated whether the levels of YKL-40 were up-regulated in the circulation and the airways of patients with chronic obstructive pulmonary disease (COPD), and whether it promoted the production of inflammatory mediators from macrophages. Serum, bronchoalveolar lavage (BAL), bronchial biopsies, lung tissue specimens, and alveolar macrophages from never-smokers (n = 15), smokers without COPD (n = 20), and smokers with COPD (n = 30) were assessed for YKL-40 levels and immunolocalization. In addition, YKL-40-induced mediator release from alveolar macrophages was examined. We found that smokers with COPD had elevated levels of YKL-40 in serum (p ≤ 0.027) and BAL (p ≤ 0.007), more YKL-40-positive cells in bronchial biopsies (p ≤ 0.03), and a greater proportion of alveolar macrophages expressing YKL-40 than smokers without COPD or never-smokers. YKL-40 levels in serum and BAL were associated with airflow obstruction (pre-β2 agonist forced expiratory volume in 1 s, rs = −0.3892, p = 0.0072 and rs = −0.5491, p &lt; 0.0001, respectively) and impaired diffusion lung capacity (transfer factor of the lung for carbon monoxide, rs = −0.4667, p = 0.002 and rs = −0.3854, p = 0.0045, respectively). TNF-α stimulated YKL-40 synthesis in alveolar macrophages from smokers with COPD, and exposure of these cells to YKL-40 promoted the release of IL-8, MCP-1, MIP-1α, and metalloproteinase-9. We conclude that YKL-40 is up-regulated in COPD, in which it may contribute to tissue inflammation and remodeling by sustaining the synthesis of proinflammatory and fibrogenic chemokines and of metalloproteinases by alveolar macrophages.
Thymus Exosomes-Like Particles Induce Regulatory T Cells
Authors: Wang Gui-Jun , Liu Yuelong , Qin Aijian , Shah Spandan V. , Deng Zhong-bin , Xiang Xiaoyu , Cheng Ziqiang , Liu Cunren , Wang Jianhua , Zhang Liming , Grizzle William E. , Zhang Huang-Ge 
Published: April 2014

Abstract
Exosomes released from different types of cells have been proposed to contribute to intercellular communication. We report that thymic exosome-like particles (ELPs) released from cells of the thymus can induce the development of Foxp3+ regulatory T (Treg) cells in the lung and liver. Thymic ELPs also induce the conversion of thymic CD4+CD25− T cells into Tregs. Tregs induced by thymic ELPs suppress the proliferation of CD4+CD25− T cells in vitro and in vivo. We further show that neutralization of TGF-β in ELPs partially reverses thymic ELP-mediated induction of CD4+Foxp3+ T cells in the lung and liver. This study demonstrates that thymic ELPs participate in the induction of Foxp3+ Tregs. Also, TGF-β of thymic ELPs might be required for the generation of Tregs in the peripheral tissues.
Splenic Phagocytes Promote Responses to Nucleosomes in (NZB × NZW) F1 Mice
Authors: Okamoto Akiko , Fujio Keishi , van Rooijen Nico , Tsuno Nelson H. , Takahashi Koki , Tsurui Hiromichi , Hirose Sachiko , Elkon Keith B. , Yamamoto Kazuhiko 
Published: April 2014

Abstract
Autoantigen presentation to T cells is crucial for the development of autoimmune disease. However, the mechanisms of autoantigen presentation are poorly understood. In this study, we show that splenic phagocytes play an important role in autoantigen presentation in murine lupus. Nucleosomes are major autoantigens in systemic lupus erythematosus. We found that nucleosome-specific T cells were stimulated dominantly in the spleen, compared with lymph nodes, lung, and thymus. Among splenic APCs, F4/80+ macrophages and CD11b+CD11c+ dendritic cells were strong stimulators for nucleosome-specific T cells. When splenic phagocytes were depleted in (NZB × NZW) F1 (NZB/W F1) mice, nucleosome presentation in the spleen was dramatically suppressed. Moreover, depletion of splenic phagocytes significantly suppressed anti-nucleosome Ab and anti-dsDNA Ab production. Proteinuria progression was delayed and survival was prolonged in phagocyte-depleted mice. The numbers of autoantibody- secreting cells were decreased in the spleen from phagocyte-depleted mice. Multiple injections of splenic F4/80+ macrophages, not those of splenic CD11c+ dendritic cells, induced autoantibody production and proteinuria progression in NZB/W F1 mice. These results indicate that autoantigen presentation by splenic phagocytes including macrophages significantly contributes to autoantibody production and disease progression in lupus-prone mice.
Functional Consequences of Neuromyelitis Optica-IgG Astrocyte Interactions on Blood-Brain Barrier Permeability and Granulocyte Recruitment
Authors: Vincent Thierry , Saikali Philippe , Cayrol Romain , Roth Alejandro D. , Bar-Or Amit , Prat Alexandre , Antel Jack P. 
Published: April 2014

Abstract
Autoantibody neuromyelitis optica-IgG (NMO-IgG) recognizing aquaporin-4 (AQP4) is implicated as playing a central role in the physiopathology of NMO. The aim of this in vitro-based study was to characterize functional consequences of interaction between NMO-IgG and cells of the neurovascular unit (astrocytes and brain endothelium) that would provide insight into recognized features of NMO, namely altered blood-brain barrier (BBB) permeability and granulocyte recruitment. We used sera from NMO and longitudinally extensive transverse myelitis cases shown to bind in a characteristic perivascular pattern to primate cerebellar slices. Using flow cytometry, we found that sera from NMO-IgG-positive patients reacted with CNS-derived human fetal astrocytes, whereas sera from multiple sclerosis patients did not. We demonstrated that NMO-IgG binding to astrocytes alters aquaporin-4 polarized expression and increases permeability of a human BBB endothelium/astrocyte barrier. We further demonstrated that NMO-IgG binding to human fetal astrocytes can result in NK cell degranulation, astrocyte killing by Ab-dependent cellular cytotoxicity and complement-dependent granulocyte attraction through the BBB model. Our study highlights important functional roles for NMO-IgG that could account for pathological lesions and BBB dysfunction observed in NMO.
Subsets of Myeloid-Derived Suppressor Cells in Tumor-Bearing Mice
Authors: Youn Je-In , Nagaraj Srinivas , Collazo Michelle , Gabrilovich Dmitry I. 
Published: April 2014

Abstract
Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of cells that play a critical role in tumor associated immune suppression. In an attempt to identify a specific subset of MDSC primarily responsible for immunosuppressive features of these cells, 10 different tumor models were investigated. All models showed variable but significant increase in the population of MDSC. Variability of MDSC expansion in vivo matched closely the effect of tumor cell condition medium in vitro. MDSC consists of two major subsets of Ly6G+Ly6Clow granulocytic and Ly6G−Ly6Chigh monocytic cells. Granulocytic MDSC have increased level of reactive oxygen species and undetectable level of NO whereas monocytic MDSC had increased level of NO but undetectable levels of reactive oxygen species. However, their suppressive activity per cell basis was comparable. Almost all tumor models demonstrated a preferential expansion of granulocytic subset of MDSC. We performed a phenotypical and functional analysis of several surface molecules previously suggested to be involved in MDSC-mediated suppression of T cells: CD115, CD124, CD80, PD-L1, and PD-L2. Although substantial proportion of MDSC expressed those molecules no differences in the level of their expression or the proportion, positive cells were found between MDSC and cells from tumor-free mice that lack immune suppressive activity. The level of MDSC-mediated T cell suppression did not depend on the expression of these molecules. These data indicate that suppressive features of MDSC is caused not by expansion of a specific subset but more likely represent a functional state of these cells.
Cutting Edge: IFN-γ Enables APC to Promote Memory Th17 and Abate Th1 Cell Development
Authors: Kryczek Ilona , Wei Shuang , Gong Wenrong , Shu Xiaogong , Szeliga Wojciech , Vatan Linhua , Chen Lieping , Wang Guobin , Zou Weiping 
Published: April 2014

Abstract
Th1-derived IFN-γ targets naive T cells and inhibits Th17 development. However, Th1, Th17, and memory but not naive T cells are colocalized in an inflammatory environment. To demonstrate the kinetic relationship between these T cell subsets, we investigated the role of IFN-γ in regulating the development and balance between Th17 and Th1 in humans. We show that IFN-γ stimulates B7-H1 expression on APC subsets and abates their Th1 polarization capacity in a B7-H1-dependent manner. Interestingly, IFN-γ triggers APCs to produce IL-1 and IL-23 and enables them to induce memory Th17 expansion via IL-1 and IL-23 in a B7-H1-independent manner. We propose a novel dynamic between Th1 and Th17 in the course of inflammation as follows: Th1-mediated inflammation is attenuated by IFN-γ-induced B7-H1 on APCs and is evolved toward Th17-mediated chronic inflammation by IFN-γ-induced, APC-derived IL-1 and IL-23. Our study challenges the dogma that IFN-γ suppresses Th17 and enhances Th1 development.