bluuebunny/crossref_metadata_2025_split huggingface dataset:
NK Cell Activity During Human Cytomegalovirus Infection Is Dominated by US2–11-Mediated HLA Class I Down-Regulation
Authors: Falk Christine S. , Mach Michael , Schendel Dolores J. , Weiss Elisabeth H. , Hilgert Ivan , Hahn Gabriele 
Published: April 2014

Abstract
A highly attractive approach to investigate the influence and hierarchical organization of viral proteins on cellular immune responses is to employ mutant viruses carrying deletions of various virus-encoded, immune-modulating genes. Here, we introduce a novel set of deletion mutants of the human CMV (HCMV) lacking the UL40 region either alone or on the background of a deletion mutant devoid of the entire US2–11 region. Deletion of UL40 had no significant effect on lysis of infected cells by NK cells, indicating that the expected enhancement of HLA-E expression by specific peptides derived from HCMV-encoded gpUL40 leader sequences was insufficient to confer target cell protection. Moreover, the kinetics of MHC class I down-regulation by US2–11 genes observed at early and late phases postinfection with wild-type virus correlated with increased susceptibility to NK lysis. Thus, the influence of HCMV genes on NK reactivity follows a hierarchy dominated by the US2–11 region, which encodes all viral genes capable of down-modulating expression of classical and non-classical MHC class I molecules. The insights gained from studies of such virus mutants may impact on future therapeutic strategies and vaccine development and incorporate NK cells in the line of defense mechanisms against HCMV infection.
Surfactant Protein D Binds Selectively toKlebsiella pneumoniaeLipopolysaccharides Containing Mannose-Rich O-Antigens
Authors: Sahly Hany , Ofek Itzhak , Podschun Rainer , Brade Helmut , He Yanchun , Ullmann Uwe , Crouch Erika 
Published: April 2014

AbstractSurfactant protein D (SP-D) plays important roles in the regulation of innate immune responses in the lung. We have previously shown that SP-D can agglutinate and enhance the macrophage-dependent killing of specific unencapsulated phase variants of Klebsiella pneumoniae. In the present studies, we used 16 clinical isolates of Klebsiella representing four O-serotypes and examined the interaction of SP-D with their isolated LPSs. Although SP-D bound to the core oligosaccharide of rough LPS from all isolates, it selectively bound to smooth forms of LPS expressed by O-serotypes with mannose-rich repeating units in their O-polysaccharides. SP-D was more potent in agglutinating unencapsulated phase variants of O-serotypes expressing these SP-D “reactive” O-polysaccharides, and more effectively inhibited the adhesion of these serotypes to lung epithelial cells. This novel anti-adhesion activity required the multimerization of trimeric SP-D subunits (dodecamers). Klebsiella serotypes expressing “nonreactive” LPS O-Ags were isolated at a significantly higher frequency from patients with K. pneumoniae. Our findings suggest that SP-D plays important roles in the clearance of opportunistic Gram-negative bacteria and contributes to known serotypic differences in the pathogenicity of Klebsiella through specific interactions with O-polysaccharides.
An Enteric Helminth Infection Protects Against an Allergic Response to Dietary Antigen
Authors: Bashir Mohamed Elfatih H. , Andersen Peter , Fuss Ivan J. , Shi Hai Ning , Nagler-Anderson Cathryn 
Published: April 2014

AbstractAlthough helminths induce a polarized Th2 response they have been shown, in clinical studies, to confer protection against allergies. To elucidate the basis for this paradox, we have examined the influence of an enteric helminth infection on a model of food allergy. Upon Ag challenge, mice fed peanut (PN) extract plus the mucosal adjuvant cholera toxin (CT) produced PN-specific IgE that correlated with systemic anaphylactic symptoms and elevated plasma histamine. PN-specific IgE was not induced in helminth-infected mice fed PN without CT. Moreover, when PN plus CT was fed to helminth-infected mice, both PN-specific IgE and anaphylactic symptoms were greatly diminished. The down-regulation of PN-specific IgE was associated with a marked reduction in the secretion of IL-13 by PN-specific T cells. When helminth-infected PN plus CT-sensitized mice were treated with neutralizing Abs to IL-10, the PN-specific IgE response and anaphylactic symptoms were similar to, or greater than, those seen in mice that receive PN and CT alone. Taken together, these results suggest that helminth-dependent protection against allergic disease involves immunoregulatory mechanisms that block production of allergen-specific IgE.
IL-6, Leukemia Inhibitory Factor, and Oncostatin M Stimulate Bone Resorption and Regulate the Expression of Receptor Activator of NF-κB Ligand, Osteoprotegerin, and Receptor Activator of NF-κB in Mouse Calvariae
Authors: Palmqvist Py , Persson Emma , Conaway H. Herschel , Lerner Ulf H. 
Published: April 2014

AbstractIL-6, leukemia inhibitory factor (LIF), and oncostatin M (OSM) are IL-6-type cytokines that stimulate osteoclast formation and function. In the present study, the resorptive effects of these agents and their regulation of receptor activator of NF-κB ligand (RANKL), RANK, and osteoprotegerin (OPG) were studied in neonatal mouse calvaria. When tested separately, neither human (h) IL-6 nor the human soluble IL-6R (shIL-6R) stimulated bone resorption, but when hIL-6 and the shIL-6R were combined, significant stimulation of both mineral and matrix release from bone explants was noted. Semiquantitative RT-PCR showed that hIL-6 plus shIL-6R enhanced the expression of RANKL and OPG in calvarial bones, but decreased RANK expression. Human LIF, hOSM, and mouse OSM (mOSM) also stimulated 45Ca release and enhanced the mRNA expression of RANKL and OPG in mouse calvaria, but had no effect on the expression of RANK. In agreement with the RT-PCR analyses, ELISA measurements showed that both hIL-6 plus shIL-6R and mOSM increased RANKL and OPG proteins. 1,25-Dihydroxyvitamin D3 (D3) also increased the RANKL protein level, but decreased the protein level of OPG. OPG inhibited 45Ca release stimulated by RANKL, hIL-6 plus shIL-6R, hLIF, hOSM, mOSM, and D3. An Ab neutralizing mouse gp130 inhibited 45Ca release induced by hIL-6 plus shIL-6R. These experiments demonstrated stimulation of calvarial bone resorption and regulation of mRNA and protein expression of RANKL and OPG by D3 and IL-6 family cytokines as well as regulation of RANK expression in preosteoclasts/osteoclasts of mouse calvaria by D3 and hIL-6 plus shIL-6R.
Identification, Cloning, and Functional Characterization of a Murine Lipoxin A4 Receptor Homologue Gene
Authors: Vaughn Michael W. , Proske Rita J. , Haviland David L. 
Published: April 2014

AbstractTo identify additional members of the murine N-formyl-Met-Leu-Phe peptide receptor family (fMLF-R), a mouse macrophage cDNA library was screened using the open reading frame of murine N-formyl peptide receptor. Four individual hybridizing cDNA clones were maintained through tertiary screening. One cDNA clone was a truncated, polyadenylated version of the previously described murine-fMLF-R. The other three cDNA clones varied in length, but contained identical open reading frame sequences. One clone, 8C10, was selected for further study and shared 70% sequence identity with murine-fMLF-R and 89% sequence identity with murine lipoxin A4 receptor cDNA. When placed into the pcDNA-3 expression vector and cotransfected with Gα16 cDNA into COS-1 cells, 8C10 cDNA induced the production of inositol-1,4,5-triphosphate when concentrations of 1–1600 nM lipoxin A4 (LXA4) were tested as ligands. Northern blot analysis of murine organs indicated that the 8C10 message is present in lung, spleen, and adipose tissue. Moreover, mice treated with LPS demonstrated increased expression of 8C10 message in spleen and adipose tissue, while showing a slight reduction in lung. We have also characterized the 8C10 structural gene from a 129Sv/J genomic library and have determined its size to be &gt;6.1 kb in length and comprised of two exons separated by a 4.8-kb intron. Collectively, these data indicate that this homologue receptor is closely related to the murine LXA4 receptor and functionally responds to LXA4 as a ligand.
Endotoxemia Prevents the Cerebral Inflammatory Wave Induced by Intraparenchymal Lipopolysaccharide Injection: Role of Glucocorticoids and CD14
Authors: Nadeau Sylvain , Rivest Serge 
Published: April 2014

Abstract
There is a robust and transient innate immune response in the brain during endotoxemia, which is associated with a cascade of NF-κB signaling events and transcriptional activation of genes that encode TNF-α and the LPS receptor CD14. The present study investigated whether circulating LPS has the ability to modulate the cerebral innate immune response caused by an intrastriatal (IS) injection of the endotoxin. We also tested the possibility that CD14 plays a role in these effects and male rats received an intracerebroventricular injection with an anti-CD14 before the IS LPS administration. The single LPS bolus into the striatum caused a strong and time-dependent transcriptional activation of TNF-α, IκBα, CD14, and monocyte chemoattractant protein-1 mRNA in microglial cells ipsilateral to the site of injection. Surprisingly, this wave of induced transcripts was essentially abolished by the systemic endotoxin pretreatment. Such anti-inflammatory properties of circulating LPS are mediated via plasma corticosterone, because exogenous corticoids mimicked while glucocorticoid receptor antagonist RU486 prevented the effects of systemic endotoxin challenge. Of interest is the partial involvement of CD14 in LPS-induced neuroinflammation; the anti-CD14 significantly abolished the microglial activity at day 3, but not at times earlier. The inflammatory response provoked by an acute intraparenchymal LPS bolus was not associated with convincing neurodegenerative processes. These data provide compelling evidence that systemic inflammation, through the increase in circulating glucocorticoids, has the ability to prevent the cerebral innate immune reaction triggered by an IS endotoxin injection. This study also further consolidates the existence of such system in the brain, which is finely regulated and its transient activation is not harmful for the neuronal elements.
Reconstitution of Lethally Irradiated Adult Mice with Dominant Negative TGF-β Type II Receptor-Transduced Bone Marrow Leads to Myeloid Expansion and Inflammatory Disease
Authors: Shah Ali H. , Tabayoyong William B. , Kimm Simon Y. , Kim Seong-Jin , van Parijs Luk , Lee Chung 
Published: April 2014

Abstract
TGF-β regulation of immune homeostasis has been investigated in the context of cytokine knockout (TGF-β null) mice, in which particular TGF-β isoforms are disrupted throughout the entire organism, as well as in B and T cell-specific transgenic models, but to date the immunoregulatory effects of TGF-β have not been addressed in the context of an in vivo mouse model in which multi-isoform TGF-β signaling is abrogated in multiple leukocyte lineages while leaving nonhemopoietic tissue unaffected. Here we report the development of a murine model of TGF-β insensitivity limited to the hemopoietic tissue of adult wild-type C57BL/6 mice based on retroviral-mediated gene transfer of a dominant negative TGF-β type II receptor targeting murine bone marrow. Unlike the lymphoproliferative syndrome observed in TGF-β1-deficient mice, the disruption of TGF-β signaling in bone marrow-derived cells leads to dramatic expansion of myeloid cells, primarily monocytes/macrophages, and is associated with cachexia and mortality in lethally irradiated mice reconstituted with dominant negative receptor-transduced bone marrow. Surprisingly, there was a notable absence of T cell expansion in affected animals despite the observed differentiation of most cells in the T cell compartment to a memory phenotype. These results indicate not only that TGF-β acts as a negative regulator of immune function, but that lack of functional TGF-β signaling in the myeloid compartment of adult mice may trigger suppression of lymphocytes, which would otherwise proliferate when rendered insensitive to TGF-β.
Evidence That Glycoprotein 96 (B2), a Stress Protein, Functions as a Th2-Specific Costimulatory Molecule
Authors: Banerjee Pinaki P. , Vinay Dass S. , Mathew Ajith , Raje Manoj , Parekh Vrajesh , Prasad Durbaka V. R. , Kumar Anil , Mitra Debashis , Mishra Gyan C. 
Published: April 2014

AbstractAfter the engagement of Ag receptor, most of the Th cells for their optimal activation require a second (costimulatory) signal provided by the APCs. We demonstrate the isolation and characterization of a 99- to 105-kDa protein (B2), from LPS-activated B cell surface, and its function as a Th2-specific costimulatory molecule. Appearance of B2 as a single entity on two-dimensional gel electrophoresis and as a distinct peak in reverse-phase HPLC ascertains the fact that B2 is homogeneous in preparation. Electron microscopy as well as competitive binding studies reveal that 125I-labeled B2 specifically binds anti-CD3-activated T cell surface and also competes with its unlabeled form. Internal amino acid sequences of B2 are found to be identical with stress protein gp96. The identity of B2 as gp96 is also revealed by immunological characterization and by confocal microscopic colocalization studies of B2 and gp96 on LPS-activated B cells. Confocal imaging studies also demonstrate that gp96 can be induced on B cell surface without association of MHC molecules. Furthermore, the novel role of gp96 in Th cell proliferation skewing its differentiation toward Th2 phenotype has also been established. Ab-mediated blocking of gp96-induced signaling not only abrogates in vitro proliferation of CD4+ T cells, but also diminishes the secretion of Th2-specific cytokines. Notably, the expression of CD91 (receptor of gp96/B2) is up-regulated on anti-CD3-activated Th cells and also found to be present on Th1 and Th2 subsets.
Contrasting Impacts of Immunosuppressive Agents (Rapamycin, FK506, Cyclosporin A, and Dexamethasone) on Bidirectional Dendritic Cell-T Cell Interaction During Antigen Presentation
Authors: Matsue Hiroyuki , Yang Chendong , Matsue Keiko , Edelbaum Dale , Mummert Mark , Takashima Akira 
Published: April 2014

AbstractRapamycin (RAP), tacrolimus (FK506), cyclosporin A, and glucocorticoids represent modern and classic immunosuppressive agents being used clinically. Although these agents have distinct molecular mechanisms of action and exhibit different immunoregulatory profiles, their direct influences on Ag presentation processes remain relatively unknown. Here we report quantitative and qualitative differences among the above four immunosuppressants in their impact on Ag-specific, bidirectional interaction between dendritic cells (DC) and CD4+ T cells. In the presence of relevant Ag, bone marrow-derived DC delivered activation signals to CD4+ T cells isolated from the DO11.10 TCR transgenic mice, leading to clonal expansion; secretion of IFN-γ, IL-2, and IL-4; and surface expression of CD69. Conversely, DO11.10 T cells delivered maturation signals to DC, leading to IL-6 and IL-12 production and CD40 up-regulation. FK506 (10−10–10−8 M) and cyclosporin A (10−9–10−7 M) each blocked efficiently and uniformly all the changes resulting from intercellular signaling in both DC→T cell and T cell→DC directions. Dexamethasone (10−9–10−6 M) suppressed all changes, except for CD69 up-regulation, rather incompletely. Remarkably, RAP (10−10–10−8 M) efficiently inhibited DC-induced T cell proliferation and T cell-mediated CD40 up-regulation by DC without abrogating other changes. Interestingly, T cell-independent DC maturation triggered by LPS stimulation was inhibited by dexamethasone, but not by other agents. Our results demonstrate contrasting pharmacological effects of RAP vs calcineurin inhibitors on Ag presentation, thus forming a conceptual framework for rationale-based selection (and combination) of immunosuppressive agents for clinical application.
Pulmonary Surfactant Protein A Up-Regulates Activity of the Mannose Receptor, a Pattern Recognition Receptor Expressed on Human Macrophages
Authors: Beharka Alison A. , Gaynor Cecilia D. , Kang Byoung K. , Voelker Dennis R. , McCormack Francis X. , Schlesinger Larry S. 
Published: April 2014

Abstract
Inhaled particulates and microbes are continually cleared by a complex array of lung innate immune determinants, including alveolar macrophages (AMs). AMs are unique cells with an enhanced capacity for phagocytosis that is due, in part, to increased activity of the macrophage mannose receptor (MR), a pattern recognition receptor for various microorganisms. The local factors that “shape” AM function are not well understood. Surfactant protein A (SP-A), a major component of lung surfactant, participates in the innate immune response and can enhance phagocytosis. Here we show that SP-A selectively enhances MR expression on human monocyte-derived macrophages, a process involving both the attached sugars and collagen-like domain of SP-A. The newly expressed MR is functional. Monocyte-derived macrophages on an SP-A substrate demonstrated enhanced pinocytosis of mannose BSA and phagocytosis of Mycobacterium tuberculosis lipoarabinomannan-coated microspheres. The newly expressed MR likely came from intracellular pools because: 1) up-regulation of the MR by SP-A occurred by 1 h, 2) new protein synthesis was not necessary for MR up-regulation, and 3) pinocytosis of mannose BSA via MR recycling was increased. AMs from SP-A−/− mice have reduced MR expression relative to SP-A+/+. SP-A up-regulation of MR activity provides a mechanism for enhanced phagocytosis of microbes by AMs, thereby enhancing lung host defense against extracellular pathogens or, paradoxically, enhancing the potential for intracellular pathogens to enter their intracellular niche. SP-A contributes to the alternative activation state of the AM in the lung.
Regulation of Mucosal Dendritic Cell Function by Receptor Activator of NF-κB (RANK)/RANK Ligand Interactions: Impact on Tolerance Induction
Authors: Williamson Eilidh , Bilsborough Janine M. , Viney Joanne L. 
Published: April 2014

AbstractThe mucosal immune system is uniquely equipped to discriminate between potentially invasive pathogens and innocuous food proteins. While the mechanisms responsible for induction of mucosal immunity vs tolerance are not yet fully delineated, recent studies have highlighted mucosal dendritic cells (DC) as being important in determining the fate of orally administered Ag. To further investigate the DC:T cell signals involved in regulating the homeostatic balance between mucosal immunity and tolerance, we have examined the expression and function of the TNFR family member receptor activator of NF-κB (RANK) and its cognate ligand, RANKL, in vitro and in vivo. Our data show that although DC isolated from mucosal lymphoid tissues expressed similar levels of surface RANK compared with DC isolated from peripheral lymphoid tissues, DC from the distinct anatomical sites displayed differential responsiveness to RANK engagement with soluble RANKL. Whereas splenic DC responded to RANKL stimulation with elevated IL-12 p40 mRNA expression, Peyer’s patch DC instead preferentially displayed increased IL-10 mRNA expression. Our data also show that the in vivo functional capacity of mucosal DC can be modulated by RANKL. Treatment with RANKL in vivo at the time of oral administration of soluble OVA enhanced the induction of tolerance in two different mouse models. These studies underscore the functional differences between mucosal and peripheral DC and highlight a novel role for RANK/RANKL interactions during the induction of mucosal immune responses.
Effector CD4 Cells Are Tolerized Upon Exposure to Parenchymal Self-Antigen
Authors: Higgins Amy D. , Mihalyo Marianne A. , Adler Adam J. 
Published: April 2014

AbstractIt has long been established that exposure of naive T cells to specific Ag in the absence of adjuvant leads to tolerization. Nonetheless, the potential of effector CD4 cells to be tolerized has been less well characterized. To address this issue, we have used an adoptive transfer system in which naive TCR transgenic hemagglutinin (HA)-specific CD4+ T cells are initially primed to express effector function upon exposure to an immunogenic recombinant vaccinia virus expressing HA, and then exposed to forms of HA that are tolerogenic for naive CD4 cells. HA-specific effector CD4 cells residing in both the spleen as well as in two separate nonlymphoid tissues were tolerized upon exposure to high doses of exogenous soluble HA peptide. Additionally, tolerance could also be induced by bone marrow-derived APCs that cross-present parenchymally derived self-HA. Thus, effector CD4 cells are susceptible to similar tolerogenic stimuli as are naive CD4 cells.
Lymphoadenopathy in IL-2-Deficient Mice: Further Characterization and Overexpression of the Antiapoptotic Molecule Cellular FLIP
Authors: Chastagner Patricia , Reddy Jay , Thèze Jacques 
Published: April 2014

AbstractIL-2 was originally identified as a potent T cell growth factor. It was subsequently demonstrated that IL-2 also exerts proapoptotic effects under certain conditions. Inactivation of IL-2 by gene targeting in mice showed that whereas IL-2 is not essential for the generation, clonal expansion, or differentiation of lymphocytes to effector cells, it has a unique role in preventing the accumulation of activated lymphocytes. IL-2−/− mice show lymphoadenopathy and autoimmune reactions, suggesting that the proapoptotic effects of IL-2 may predominate in vivo. In this study, we confirm that lymph nodes (LNs) are enlarged in IL-2−/− animals, but surprisingly, we found that their spleens are almost normal in size. Subsequent to this observation, we compare lymphocytes from LNs and spleens of IL-2−/− and IL-2+/− animals to analyze molecular and cellular correlates of the immunopathological disorders found in IL-2-deficient mice. LN lymphocytes from IL-2−/− are selectively activated and show an enhanced survival capacity and an increased ability to proliferate in vitro when compared with LN cells from IL-2+/− mice and splenocytes from IL-2−/− and IL-2+/− mice. Because the apoptosis inhibitor FLIP has been shown in vitro to participate in the IL-2 control of activation-induced cell death, we analyze its expression in IL-2−/− mice. FLIP was found to be selectively overexpressed in the LNs of IL-2−/− mice, but no overexpression was found in spleen cells or thymocytes. These results suggest that FLIP, in conjunction with other IL-2-regulated genes previously characterized in our laboratory, is involved in controlling lymphoadenopathy in IL-2−/− mice.