bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ambient Ozone Primes Pulmonary Innate Immunity in Mice
Authors: Hollingsworth John W. , Maruoka Shuichiro , Li Zhuowei , Potts Erin N. , Brass David M. , Garantziotis Stavros , Fong Alan , Foster W. Michael , Schwartz David A. 
Published: April 2014

AbstractExposure to ozone in air pollution in urban environments is associated with increases in pulmonary-related hospitalizations and mortality. Because ozone also alters clearance of pulmonary bacterial pathogens, we hypothesized that inhalation of ozone modifies innate immunity in the lung. To address our hypothesis, we exposed C57BL/6J mice to either free air or ozone, and then subsequently challenged with an aerosol of Escherichia coli LPS. Pre-exposure to ozone resulted in enhanced airway hyperreactivity, higher concentrations of both total protein and proinflammatory cytokines in lung lavage fluid, enhanced LPS-mediated signaling in lung tissue, and higher concentrations of serum IL-6 following inhalation of LPS. However, pre-exposure to ozone dramatically reduced inflammatory cell accumulation to the lower airways in response to inhaled LPS. The reduced concentration of cells in the lower airways was associated with enhanced apoptosis of both lung macrophages and systemic circulating monocytes. Moreover, both flow cytometry and confocal microscopy indicate that inhaled ozone causes altered distribution of TLR4 on alveolar macrophages and enhanced functional response to endotoxin by macrophages. These observations indicate that ozone exposure increases both the pulmonary and the systemic biologic response to inhaled LPS by priming the innate immune system.
Serine Protease Inhibitor 6-Deficient Mice Have Increased Neutrophil Immunity to Pseudomonas aeruginosa
Authors: Zhang Manling , Liu Ni , Park Sun-Mi , Wang Yue , Byrne Susan , Murmann Andrea E. , Bahr Scott , Peter Marcus E. , Olson Steven T. , Belaaouaj Abderrazzaq , Ashton-Rickardt Philip G. 
Published: April 2014

Abstract
Inflammation is a localized, protective response to trauma or microbial invasion that destroys the injurious agent and the injured tissue. Neutrophil elastase (NE), a serine protease stored in the azurophil granules of polymorphonuclear neutrophils, digests microbes after phagocytosis. NE can also digest microbes extracellularly but is associated with tissue damage and inflammatory disease. In this study, we show that polymorphonuclear neutrophils from mice deficient in serine protease inhibitor 6, a weak intracellular NE inhibitor, had increased susceptibility to self-inflicted lysis because of increased NE activity. The resulting transient increase in local extracellular NE activity was within a narrow range that resulted in the clearance of Pseudomonas aeruginosa but did not damage the lung. Therefore, deficiency in a weak intracellular inhibitor of NE results in an acute inflammatory response that protects from P. aeruginosa but does not cause lung disease.
TLR4 on Follicular Dendritic Cells: An Activation Pathway That Promotes Accessory Activity
Authors: El Shikh Mohey Eldin M. , El Sayed Rania M. , Wu Yongzhong , Szakal Andras K. , Tew John G. 
Published: April 2014

AbstractMicrobial molecular patterns engage TLRs and activate dendritic cells and other accessory cells. Follicular dendritic cells (FDCs) exist in resting and activated states, but are activated in germinal centers, where they provide accessory function. We reasoned that FDCs might express TLRs and that engagement might activate FDCs by up-regulating molecules important for accessory activity. To test this hypothesis, TLR4 expression on FDCs was studied in situ with immunohistochemistry, followed by flow cytometry and RT-PCR analysis. TLR4 was expressed on FDC reticula in situ, and flow cytometry indicated that TLR4 was expressed on surface membranes and TLR4 message was readily apparent in FDCs by RT-PCR. Injecting mice or treating purified FDCs with LPS up-regulated molecules important for accessory activity including, FDC-FcγRIIB, FDC-ICAM-1, and FDC-VCAM-1. Treatment of purified FDCs with LPS also induced intracellular phospho-IκB-α, indicating NF-κB activation, and that correlated with increased FcγRIIB, ICAM-1, and VCAM-1. FDCs in C3H/HeJ mice were not activated with LPS even when mice were reconstituted with C3H/HeN leukocytes, suggesting that engagement of FDC-TLR4 is necessary for activation. Moreover, activated FDCs exhibited increased accessory activity in anti-OVA recall responses in vitro, and the FDC number could be reduced 4-fold if they were activated. In short, we report expression of TLR4 on FDCs for the first time and that engagement of FDC-TLR4 activated NF-κB, up-regulated expression of molecules important in FDC accessory function, including FcγRIIB, ICAM-1, and VCAM-1, as well as FDC accessory activity in promoting recall IgG responses.
B Cell Antigen Receptor-Induced Rac1 Activation and Rac1-Dependent Spreading Are Impaired in Transitional Immature B Cells Due to Levels of Membrane Cholesterol
Authors: Brezski Randall J. , Monroe John G. 
Published: April 2014

AbstractThe BCR-triggered responses of mature and transitional immature B cells differ at both the biochemical and functional level. In this study, we show that in mature B cells, BCR signaling triggers Vav phosphorylation and Rac1 activation. Furthermore, we demonstrate that although downstream actin-dependent BCR capping is independent of Rac1 activation, actin-dependent membrane ruffling and cell spreading are Rac1-dependent processes. In contrast, BCR-induced Vav phosphorylation and Rac1 activation is impaired in transitional immature B cells, resulting in defects in actin polymerization-dependent spreading and membrane ruffling while Rac1-independent BCR capping remains intact. Because transitional immature murine B cells maintain lower steady-state levels of plasma membrane cholesterol, we augmented their levels to that of mature B cells and found that BCR-induced Rac1 activation and Rac1-dependent membrane ruffling and cell spreading were restored. These studies provide a direct link between B cell cholesterol levels and downstream cellular signaling processes.
Negative Regulation of CD40-Mediated B Cell Responses by E3 Ubiquitin Ligase Casitas-B-Lineage Lymphoma Protein-B
Authors: Qiao Guilin , Lei Minxiang , Li Zhenping , Sun Yonglian , Minto Andrew , Fu Yang-Xin , Ying Haiyan , Quigg Richard J. , Zhang Jian 
Published: April 2014

Abstract
It has been documented that CD40 is essential for B cell function. Casitas-B-lineage lymphoma protein-b (Cbl-b), an adapter protein and ubiquitin ligase, has been shown to regulate the activation of T and B cells through their Ag receptors. In this study, we report that CD40-induced B cell proliferation is significantly augmented in mice lacking Cbl-b. Furthermore, Cbl-b−/− mice display enhanced thymus-dependent Ab responses and germinal center formation, whereas introduction of CD40 deficiency abolishes these effects. Hyper thymus-dependent humoral response in Cbl-b−/− mice is in part due to an intrinsic defect in B cells. Mechanistically, Cbl-b selectively down-modulates CD40-induced activation of NF-κB and JNK. Cbl-b associates with TNF receptor-associated factor 2 upon CD40 ligation, and inhibits the recruitment of TNF receptor-associated factor 2 to the CD40. Together, our data suggest that Cbl-b attenuates CD40-mediated NF-κB and JNK activation, thereby suppressing B cell responses.
The CD16−CD56bright NK Cell Subset Is Resistant to Reactive Oxygen Species Produced by Activated Granulocytes and Has Higher Antioxidative Capacity Than the CD16+CD56dim Subset
Authors: Harlin Helena , Hanson Mikael , Johansson C. Christian , Sakurai Daiju , Poschke Isabel , Norell Håkan , Malmberg Karl-Johan , Kiessling Rolf 
Published: April 2014

AbstractHuman NK cells can be divided into CD56dim and CD56bright subsets. These two types of NK cells respond to different types of stimuli, with CD56dim NK cells having direct cytotoxic ability and CD56bright NK cells having mainly an immunoregulatory function. We show that the CD16+CD56dim NK subset is characterized by sensitivity to cell death induced by activated granulocytes. We identified hydrogen peroxide (H2O2) as the major effector molecule responsible for the cytotoxic effect of granulocytes on CD56dim NK cells, because the ability of granulocytes to kill CD56dim NK cells was completely abrogated in the presence of the hydrogen peroxide scavenger catalase. When exposing NK cells to H2O2, CD56dim cells showed rapid mitochondrial depolarization and down-regulation of activating NKRs, eventually resulting in cell death, whereas CD56bright cells remained unaffected. The difference in sensitivity to H2O2 was mirrored by a difference in intracellular oxidation levels between CD56dim and CD56bright NK cells, and cell lysates from the latter subset possessed a greater ability to block H2O2-mediated oxidation. Our data may explain the preferential accumulation of CD56bright NK cells often seen in environments rich in reactive oxygen species, such as at sites of chronic inflammation and in tumors.
A Novel Mechanism for TNFR-Associated Factor 6-Dependent CD40 Signaling
Authors: Rowland Sarah L. , Tremblay Mikaela M. , Ellison Jason M. , Stunz Laura L. , Bishop Gail A. , Hostager Bruce S. 
Published: April 2014

AbstractMembers of the TNFR family play critical roles in the regulation of the immune system. One member of the family critical for efficient activation of T-dependent humoral immune responses is CD40, a cell surface protein expressed by B cells and other APC. The cytoplasmic domain of CD40 interacts with several members of the TNFR-associated factor (TRAF) family, which link CD40 to intracellular signaling pathways. TRAF2 and 6 appear to play particularly important roles in CD40 signaling. Previous studies suggest that the two molecules have certain overlapping roles in signaling, but that unique roles for each molecule also exist. To better define the roles of TRAF2 and TRAF6 in CD40 signaling, we used somatic cell gene targeting to generate TRAF-deficient mouse B cell lines. A20.2J cells deficient in TRAF6 exhibit marked defects in CD40-mediated JNK activation and the up-regulation of CD80. Our previous experiments with TRAF2-deficient B cell lines suggest that TRAF6 and TRAF2 may have redundant roles in CD40-mediated NF-κB activation. Consistent with this hypothesis, we found CD40-mediated activation of NF-κB intact in TRAF6-deficient cells and defective in cells lacking both TRAF2 and TRAF6. Interestingly, we found that TRAF6 mutants defective in CD40 binding were able to restore CD40-mediated JNK activation and CD80 up-regulation in TRAF6-deficient cells, indicating that TRAF6 may be able to contribute to certain CD40 signals without directly binding CD40.
TLR9 Activation Induces Normal Neutrophil Responses in a Child with IRAK-4 Deficiency: Involvement of the Direct PI3K Pathway
Authors: Hoarau Cyrille , Gérard Bénédicte , Lescanne Emmanuel , Henry Dominique , François Stéphanie , Lacapère Jean-Jacques , El Benna Jamel , Dang Pham My-Chan , Grandchamp Bernard , Lebranchu Yvon , Gougerot-Pocidalo Marie-Anne , Elbim Carole 
Published: April 2014

AbstractPolymorphonuclear neutrophils (PMN) play a key role in innate immunity. Their activation and survival are tightly regulated by microbial products via pattern recognition receptors such as TLRs, which mediate recruitment of the IL-1R-associated kinase (IRAK) complex. We describe a new inherited IRAK-4 deficiency in a child with recurrent pyogenic bacterial infections. Analysis of the IRAK4 gene showed compound heterozygosity with two mutations: a missense mutation in the death domain of the protein (pArg12Cys) associated in cis-with a predicted benign variant (pArg391His); and a splice site mutation in intron 7 that led to the skipping of exon 7. A nontruncated IRAK-4 protein was detected by Western blotting. The patient’s functional deficiency of IRAK-4 protein was confirmed by the absence of IRAK-1 phosphorylation after stimulation with all TLR agonists tested. The patient’s PMNs showed strongly impaired responses (L-selectin and CD11b expression, oxidative burst, cytokine production, cell survival) to TLR agonists which engage TLR1/2, TLR2/6, TLR4, and TLR7/8; in contrast, the patient’s PMN responses to CpG-DNA (TLR9) were normal, except for cytokine production. The surprisingly normal effect of CpG-DNA on PMN functions and apoptosis disappeared after pretreatment with PI3K inhibitors. Together, these results suggest the existence of an IRAK-4-independent TLR9-induced transduction pathway leading to PI3K activation. This alternative pathway may play a key role in PMN control of infections by microorganisms other than pyogenic bacteria in inherited IRAK-4 deficiency.
Aging Up-Regulates Expression of Inflammatory Mediators in Mouse Adipose Tissue
Authors: Wu Dayong , Ren Zhihong , Pae Munkyong , Guo Weimin , Cui Xuelin , Merrill Alfred H. , Meydani Simin Nikbin 
Published: April 2014

Abstract
Obesity is a leading risk factor for type 2 diabetes (T2D). Aging is associated with an increase in T2D incidence, which is not totally explained by the much lower prevalence of obesity in the elderly. Low-grade inflammation in adipose tissue (AT) contributes to insulin resistance and T2D. Thus, we determined whether inflammatory responses are up-regulated with age in AT. The results showed that visceral AT from old C57BL mice had significantly higher mRNA expression of the proinflammatory cytokines IL-1β, IL-6, TNF-α, and COX-2 and lower expression of anti-inflammatory PPAR-γ than those of young mice. We further showed that adipocytes (AD) and not stromal vascular cells including macrophages (Mφ) were the cells responsible for this higher inflammatory state of the aged AT, suggesting that the age-associated increase in AT inflammation is distinguished from that seen in obesity, in which Mφ are the main contributors. However, peritoneal Mφ of either age (young or old) produced more TNF-α and IL-6 after incubation in old AD-conditioned medium compared with young AD-conditioned medium. This suggests that in addition to producing more inflammatory cytokines, AD from old mice induce a higher inflammatory response in other cells. Sphingolipid ceramide was higher in old compared with young AD. Reducing ceramide levels or inhibiting NF-κB activation decreased cytokine production, whereas the addition of ceramide increased cytokine production in young AD to a level comparable to that seen in old AD, suggesting that ceramide-induced activation of NF-κB plays a key role in AT inflammation.
Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells
Authors: Koido Shigeo , Hara Eiichi , Homma Sadamu , Mitsunaga Makoto , Takahara Akitaka , Nagasaki Eijiro , Kawahara Hidejiro , Watanabe Michiaki , Toyama Yoichi , Yanagisawa Satoru , Kobayashi Susumu , Yanaga Katsuhiko , Fujise Kiyotaka , Gong Jianlin , Tajiri Hisao 
Published: April 2014

Abstract
Dendritic cell (DC)/tumor cell fusion cells (FCs) can induce potent CTL responses. The therapeutic efficacy of a vaccine requires the improved immunogenicity of both DCs and tumor cells. The DCs stimulated with the TLR agonist penicillin-killed Streptococcus pyogenes (OK-432; OK-DCs) showed higher expression levels of MHC class I and II, CD80, CD86, CD83, IL-12, and heat shock proteins (HSPs) than did immature DCs. Moreover, heat-treated autologous tumor cells displayed a characteristic phenotype with increased expression of HSPs, carcinoembryonic Ag (CEA), MUC1, and MHC class I (HLA-A2 and/or A24). In this study, we have created four types of FC preparation by alternating fusion cell partners: 1) immature DCs fused with unheated tumor cells; 2) immature DCs fused with heat-treated tumor cells; 3) OK-DCs fused with unheated tumor cells; and 4) OK-DCs fused with heat-treated tumor cells. Although OK-DCs fused with unheated tumor cells efficiently enhanced CTL induction, OK-DCs fused with heat-treated tumor cells were most active, as demonstrated by: 1) up-regulation of multiple HSPs, MHC class I and II, CEA, CD80, CD86, CD83, and IL-12; 2) activation of CD4+ and CD8+ T cells able to produce IFN- γ at higher levels; 3) efficient induction of CTL activity specific for CEA or MUC1 or both against autologous tumor; and 4) superior abilities to induce CD107+IFN-γ+CD8+ T cells and CD154+ IFN-γ+CD4+ T cells. These results strongly suggest that synergism between OK-DCs and heat-treated tumor cells enhances the immunogenicity of FCs and provides a promising means of inducing therapeutic antitumor immunity.
The Surprising Kinetics of the T Cell Response to Live Antigenic Cells
Authors: Tyznik Aaron J. , Bevan Michael J. 
Published: April 2014

Abstract
Cooperation between CD4+ and CD8+ T cells is required for the proper development of primary effector and memory CD8+ T cells following immunization with noninflammatory immunogens. In this study, we characterized murine CD4+ and CD8+ T cell responses to male-specific minor histocompatibility (HY) Ags following injection of live male cells into females of the same strain. Male cells are rejected 10–12 days after transfer, coinciding with the expansion and effector function of CD8+ CTLs to two H-2Db-restricted epitopes. Although anti-HY CD4+ T cell responses are readily detectable day 5 posttransfer, CD8+ responses are undetectable until day 10. The early CD4+ response is not dependent on direct presentation of Ag by donor male cells, but depends on presentation of the male cells by recipient APC. The CD4+ T cell response is required for the priming of CD8+ T cell effector responses and rejection of HY-incompatible cells. Unexpectedly, HY-specific CD4+ T cells are also capable of efficiently lysing target cells in vivo. The delay in the CD8+ T cell response can be largely abrogated by depleting T cells from the male inoculum, and donor male CD8+ T cells in particular suppress host anti-HY CD8+ responses. These data demonstrate dramatic differences in host T cell responses to noninflammatory Ags compared with responses to pathogens. We explain the delayed CD8+ response by proposing that there is a balance between cross-presentation of Ag by helper cell-licensed dendritic cells, on the one hand, and veto suppression by live male lymphocytes on the other.
The Countervailing Actions of Myeloid and Plasmacytoid Dendritic Cells Control Autoimmune Diabetes in the Nonobese Diabetic Mouse
Authors: Saxena Vijay , Ondr Jennifer K. , Magnusen Albert F. , Munn David H. , Katz Jonathan D. 
Published: April 2014

Abstract
Islet Ag-specific CD4+ T cells receive antigenic stimulation from MHC class II-expressing APCs. Herein, we delineate the direct in vivo necessity for distinct subsets of macrophages and dendritic cells (DC) in type 1 diabetes mellitus of the NOD mouse by using diphtheria toxin-mediated cell ablation. The ablation of macrophages had no impact on islet Ag presentation or on the induction of insulitis or diabetes in either transfer or spontaneous models. However, the ablation of CD11b+CD11c+ DC led to the loss of T cell activation, insulitis, and diabetes mediated by CD4+ T cells. When the specific myeloid DC subset was “added-back” to mice lacking total DC, insulitis and diabetes were restored. Interestingly, when NOD mice were allowed to progress to the insulitis phase, the ablation of DC led to accelerated insulitis. This accelerated insulitis was mediated by the loss of plasmacytoid DC (pDC). When pDC were returned to depleted mice, the localized regulation of insulitis was restored. The loss of pDC in the pancreas itself was accompanied by the localized loss of IDO and the acceleration of insulitis. Thus, CD11c+CD11b+ DC and pDC have countervailing actions in NOD diabetes, with myeloid DC providing critical antigenic stimulation to naive CD4+ T cells and pDC providing regulatory control of CD4+ T cell function in the target tissue.
The α1β1 Integrin and TNF Receptor II Protect Airway CD8+ Effector T Cells from Apoptosis during Influenza Infection
Authors: Richter Martin V. , Topham David J. 
Published: April 2014

Abstract
Primary viral infections of the lung induce potent effector CD8 T cell responses. To function in the influenza-infected airways, CD8 T cells must be able to resist cell death. The majority of the CD8 T cells in the airways and lung parenchyma expressed CD49a, the α-chain of the type IV collagen receptor VLA-1, and these cells were highly activated, producing both IFN-γ and TNF-α. In the airways, where type IV collagen is abundant, but not the spleen, the CD49a+ CD8 cells had reduced proportions of annexin V and caspase 8, and &gt;80% expressed the TNF-α receptor II, while Fas, TNFR-I, and CD27 expression were similar to CD49a− cells. Furthermore, the CD49a+, but not CD49a−, CD8 T cells from the airways were resistant to active induction of apoptosis in the presence of type IV collagen and TNF-α in vitro. We propose that TNFR-II and the VLA-1 synergize to protect effector CD8 T cells in the infected airways from apoptosis during the acute infection.
Expression of CD80/86 on B Cells Is Essential for Autoreactive T Cell Activation and the Development of Arthritis
Authors: O’Neill Shannon K. , Cao Yanxia , Hamel Keith M. , Doodes Paul D. , Hutas Gabor , Finnegan Alison 
Published: April 2014

Abstract
Depletion of B cells in rheumatoid arthritis is therapeutically efficacious. Yet, the mechanism by which B cells participate in the inflammatory process is unclear. We previously demonstrated that Ag-specific B cells have two important functions in the development of arthritis in a murine model of rheumatoid arthritis, proteoglycan (PG)-induced arthritis (PGIA). PG-specific B cells function as autoantibody-producing cells and as APCs that activate PG-specific T cells. Moreover, the costimulatory molecule CD86 is up-regulated on PG-specific B cells in response to stimulation with PG. To address the requirement for CD80/CD86 expression on B cells in the development of PGIA, we generated mixed bone marrow chimeras in which CD80/CD86 is specifically deleted on B cells and not on other APC populations. Chimeras with a specific deficiency in CD80/CD86 expression on B cells are resistant to the induction of PGIA. The concentration of PG-specific autoantibody is similar in mice sufficient or deficient for CD80/86-expressing B cells, which indicates that resistance to PGIA is not due to the suppression of PG-specific autoantibody production. CD80/86-deficient B cells failed to effectively activate PG-specific autoreactive T cells as indicated by the failure of T cells from PG-immunized CD80/86-deficient B cell chimeras to transfer arthritis into SCID mice. In vitro secondary recall responses to PG are also dependent on CD80/86-expressing B cells. These results demonstrate that a CD80/86:CD28 costimulatory interaction between B cells and T cells is required for autoreactive T cell activation and the induction of arthritis but not for B cell autoantibody production.